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CHAPTER 106 PLASMA CELL MYELOMA

CHAPTER 106 PLASMA CELL MYELOMA
Williams Hematology

CHAPTER 106 PLASMA CELL MYELOMA

BART BARLOGIE
JOHN SHAUGHNESSY
NIKHIL MUNSHI
JOSHUA EPSTEIN

Definition
Etiology and Pathogenesis

Animal Models

Environmental Exposure

Pathogenesis and Genetic Alterations

Phenotype and Cytokines

Myeloma Biology
Clinical Features

Pain

Infections

Nephropathy

Extramedullary Disease

Neuropathies

Hyperviscosity

Bleeding and Thrombosis
Laboratory Features

Initial Evaluation

Hematologic Abnormalities

Detection of Monoclonal Immunoglobulin

Immunocytochemical and Flow Cytometric Analyses

Labeling Index

Cytogenetics
Differential Diagnosis
Therapy, Course, and Prognosis

Staging

Therapy for Solitary Plasmacytoma

Therapy for Indolent Myeloma

Therapy for Symptomatic Multiple Myeloma

Primary Treatment Strategy

Supportive Care and Special Treatments

Course and Prognosis
Chapter References

Multiple myeloma is a B-cell malignancy of neoplastic plasma cells that generally produce a monoclonal immunoglobulin protein. It remains controversial whether all cases of myeloma evolve from an essential monoclonal gammopathy or MGUS condition (monoclonal gammopathy of undetermined significance). Through intricate interactions with the marrow microenvironment, myeloma plasma cells receive critical survival signals, which may explain the relative resistance of this generally hypoproliferative tumor to chemotherapy. This disease causes clinical symptoms by way of tumor mass effects (pain), cytokine production (anemia), and protein deposition in organs (kidney, heart). Clinical manifestations of myeloma vary as a result of the heterogeneous biology and span the entire spectrum from indolent disease to highly aggressive myeloma presenting with extramedullary features. Magnetic resonance imaging (MRI) has become an important staging tool to distinguish truly solitary plasmacytoma of bone from multiple myeloma and, within the latter category, to document the extent and pattern of marrow involvement that can be diffuse or distinctly macrofocal. Prognosis is best correlated with serum levels of beta-2-microglobulin and C-reactive protein but also with the plasma cell labeling index. Recent studies indicate that cytogenetics may help delineate a subgroup of patients who have neoplastic cells with deletions in chromosome 13 and a more adverse prognosis. Standard therapy with melphalan-prednisone or similar agents has been palliative. High-dose melphalan requiring hemopoietic stem cell support has increased the incidence of true complete remission from 5 percent to approximately 50 percent. Additional therapeutic developments include thalidomide that is active in one-third of patients relapsing after high-dose therapy, consolidation chemotherapy following high-dose stem-cell-supported therapy, and immune therapy. Bisphosphonates and recombinant erythropoietin represent two important adjuncts alleviating myeloma-associated bone disease and anemia, respectively.

Acronyms and abbreviations that appear in this chapter include: AML, acute myeloid leukemia; B2M, beta-2-microglobulin; CAM, cell adhesion molecules; CR, complete remission; CRP, c-reactive protein; CT, computed axial tomography; DEXA, dual energy x-ray absorptiometry dual energy x-ray absorptiometry; FGF, fibroblast growth factor; FISH, fluorescence in situ hybridization; G-CSF, granulocyte colony stimulating factor; HGF, human gene factor; HHV-8, human herpes virus; IGF, insulin growth factor; INF-a, interferon alpha; KSHV, Kaposi-sarcoma herpes virus; LCDD, light-chain deposition disease; LIF, leukemia inhibitory factor; MDR, multidrug resistance gene; MDS, myelodysplasia; MGUS, monoclonal gammopathy of undetermined significance; MM, multiple myeloma; MP, melphalan-prednisone; MRI, magnetic resonance imaging; MVD, microvessel density; OAF, osteoclast activating factor; SCF, stem cell factor; SCID, severe combined immunodeficiency; TNF-a, tumor neurosis factor alpha; VEGF-1, vascular endothelial growth factor 1.

DEFINITION
Multiple myeloma (MM) accounts for approximately 1 percent of all malignancies and 10 percent of hematological tumors and represents the second most frequently occurring hematological malignancy in the United States. At any one time, 40,000 people suffer from MM, and approximately 13,000 are diagnosed each year. The median age is approximately 65 years, although occasionally MM occurs in the second decade of life. Myeloma is a disease of neoplastic plasma cells that synthesize abnormal amounts of immunoglobulin or immunoglobulin fragments. Clinical manifestations are heterogeneous but include the formation of tumor, monoclonal immunoglobulin production, decreased immunoglobulin secretion by normal plasma cells leading to hypogammaglobulinemia, impaired hematopoiesis, osteolytic bone disease, hypercalcemia, and renal dysfunction. Symptoms are caused by tumor mass effects, cytokines released directly by tumor cells or indirectly by host cells (marrow stroma and bone cells) in response to adhesion of tumor cells, and, finally, by the abnormal MM protein leading to deposition diseases (AL amyloidosis and light-chain deposition) or autoimmune disorders (e.g., coagulopathies).
This disease belongs to a spectrum of disorders referred to as plasma cell dyscrasias. These include clinically benign conditions, such as essential monoclonal gammopathy (see Chap. 105, “Essential Monoclonal Gammopathy”); rare and biologically intriguing disorders, such as Castleman disease and alpha-heavy-chain disease (see Chap. 109, “Heavy-chain disease”); macroglobulinemia (see Chap. 108, “Macroglobulinemia”); solitary plasmacytoma with a high potential for cure when arising in soft tissue; and the most common malignant entity, plasma cell myeloma, a disseminated B-cell malignancy, not curable with standard dose-chemotherapy. All disorders share plasma-cell morphologic features, and most are associated with the production of immunoglobulin molecules (see Chap. 107, “Functions of B lymphocytes and plasma cells”). While most plasma cell dyscrasias result from the expansion of a single clone of cells, with resultant monoclonal protein secretion, oligoclonal and polyclonal protein abnormalities accompany some conditions, such as Castleman disease or angioimmunoblastic lymphoproliferative disease, now recognized as a T-cell lymphoma (see Chap. 103, “Lymphomas”).
ETIOLOGY AND PATHOGENESIS
ANIMAL MODELS
Plasmacytoma or myeloma can be induced in BALB/c mice by pristane oil or can develop spontaneously in some mouse strains.1,2 In the former, pristane oil induces an oil granuloma characterized by lymphoplasmacytic reaction to the chemical. This progresses to an autonomously growing plasmacytoma with uncontrolled expression of c-MYC due to its gene rearrangement. Generally, these plasmacytomas secrete monoclonal immunoglobulin of the IgA isotype. Essential monoclonal gammopathies and a malignancy resembling human plasma cell myeloma may arise spontaneously in inbred mice.3,4
Human myeloma cell lines can survive and disseminate in mice with severe combined immunodeficiency (SCID).5,6 Fetal bone implants (SCID-hu) can sustain survival and expansion of primary human myeloma cells from untreated patients with a high success rate.7 Thus, at last, the SCID-hu model provides a suitable in vivo read out system to study human myeloma biology. Tumor self-renewal capacity can be examined in relation to maturation stage and the contributions of host accessory cells and cytokines to disease manifestation and progression elucidated. It is anticipated that new treatment principles aimed, for example, at inactivating the marrow microenvironment (e.g., bisphosphonates8,9) and targeting neoangiogenesis (e.g., Thalidomide10,11) can be evaluated.
ENVIRONMENTAL EXPOSURE
Environmental exposure to radiation and chemicals has been associated with an increased incidence of myeloma.12 Studies of atomic bomb survivors observed an increased incidence of plasma cell myeloma 15 to 20 years after radiation exposure.13 On the other hand, epidemiological studies attempting to establish associations between myeloma and certain infections or autoimmune diseases have remained inconclusive.14
Human herpes virus, (HHV-8) (also called Kaposi-sarcoma herpes virus [KSHV]), already shown to be involved in the pathogenesis of Castleman disease,15 pleural cavity lymphoma16 and Kaposi sarcoma,17 has recently been shown to be present in marrow dendritic cells of the majority of patients with myeloma.18,19 Although confirmed by some groups,20,21 others failed to identify HHV-8 in dendritic cells generated from mobilized peripheral blood stem cells.22,23 Additionally, serologic evidence of HHV-8 infection has not been demonstrated.24 Using nested PCR, 60 percent of 30 myeloma samples were positive, but ORF 26 sequence was also amplified in 44 percent of 25 normal controls; other viral genome regions (ORF 72 and 75) were uniformly negative in all myeloma and control samples.24 The proposed pathogenic mechanism for HHV-8 in myeloma is unique in that tumorigenesis would involve the infection of a normal cell lineage (dendritic cells) exerting tumor cell-survival- and growth-promoting signals.
PATHOGENESIS AND GENETIC ALTERATIONS
A multistep process is probably involved in the malignant transformation leading to myeloma25,26 and 27 (Table 106-1, Fig. 106-1 and Fig. 106-2). Early mutations may be cryptic and involve virgin and memory B cells that, in the process of recycling through lymphoid follicles and antigen-triggered replication, accumulate genetic damage. Such “migrant plasmablasts” may be involved in the pathogenesis of solitary plasmacytoma, essential monoclonal gammopathy, and the progression to plasma cell myeloma27,28 (see Fig. 106-1). Although the tissue site of malignant transformation and incipient tumor growth in human myeloma is unknown, myeloma cell expansion occurs in the marrow in close interaction with normal stromal cell compartments. The presence of clonotypic cells in the blood even at diagnosis underscores the importance of hematogenous spread for disease dissemination and homing to the marrow, which may be distinctly macrofocal as recognized clinically on magnetic resonance imaging.29,30,31,32,33,34,35,36,37,38 and 39

TABLE 106-1 PLASMA CELL MYELOMA: BIOLOGY AND THERAPY

FIGURE 106-1 The origin of multiple myeloma in terms of site of transformation has not yet been elucidated. A putative model assumes a mutation to occur at the level of memory B cells undergoing antigen or T-cell stimulation to centroblasts/centrocytes and secondary B blasts, resulting in monoclonal migrant plasmablasts that circulate in the blood and eventually home to the marrow, where differentiation to mature plasma cells occurs. Thus, the pathogenesis of myeloma may occur in lymphoid follicles with subsequent blood circulation and spread to marrow sites. The sustained life span of malignant B cells with lymphoplasmacytoid/plasmacytic characteristics may be related to an imbalance of cytokine expression, especially IL-6. (Reproduced from Potter,11 with permission.)

FIGURE 106-2 Biology of multiple myeloma. Tumor cell hierarchy: The predominant tumor cell population in the marrow consists of mature plasma cells, and the tumor stem cell compartment with unlimited self-renewal capacity remains elusive. It appears that tumor progenitor cells are relatively infrequent and maintain, through a variety of cytokines, a systemic malignancy with a predominantly terminal B-cell phenotype. Oncogenes: As in the mouse model, c-MYC is overexpressed at the RNA and protein level in more than 80 percent of patients; MYC rearrangement is infrequent, however, but abnormal MYC RNA transcripts are commonly observed. N-RAS is mutated in about one-third of cases, H-ras protein is overexpressed in approximately 80 percent, and high BCL-2 expression is noted in both myeloma and normal plasma cells. Suppressor genes: Mutations and deletions of both RB and p53 have been reported. Cytokines: The cytokine network in myelomatosis is exceedingly complex, involving many of the cytokines also important in regulation of normal hemopoiesis. IL-6 induces tumor cells to proliferate, to differentiate, or to resist undergoing apoptosis at various stages of tumor cell differentiation. Inhibitory molecules include IFN-a (at high concentrations) and IFN-g (also at lower concentrations). Glucocorticoids block IL-6 production by tumor and normal accessory cells and thus induce apoptosis, which can be counteracted by exogenous IL-6.

The tremendous karyotypic complexity, with an average of 11 abnormalities per karyotype and lack of obvious recurrent chromosomal changes in myeloma has precluded a focused search for specific molecular lesions.40,41,42 and 43 Screening for abnormalities of oncogenes and tumor suppressor genes involved in B-cell lymphomas and leukemias has revealed infrequent rearrangements of BCL-1, BCL-2, and C-MYC genes.44 Abnormal size C-MYC transcripts as well as high-level expression of c-MYC RNA and protein have been reported in the majority of patients studied.45 Mutations of N-RAS occur in up to 50 percent of patients.46,47,48,49 and 50 BCL2 protein is abundant in both normal and malignant plasma cells.51,52 Using fluorescence in situ hybridization (FISH), investigators have found RB1 or P53 mutations and deletions in malignant plasma cells of up to 50 percent of the patients studied.49,53,54 and 55 P53 can be inactivated by MDM 2, which is overexpressed in myeloma cell lines but rarely in clinical specimens 56
Unlike CLL, considered a pregerminal center B-cell malignancy with limited Ig gene hypermutations (see Chap. 98, “Chronic Lymphocytic Leukemia”), myeloma has all the hallmarks of a germinal center-derived tumor with a post-switch B-cell phenotype (IgM myeloma is exceedingly rare) and is characterized by extensive Ig gene hypermutation, reflecting antigenic stimulation.57,58,59,60 and 61 Given the recent findings that somatic mutation of other loci besides the immunoglobulin genes occurs in B cells, e.g., BCL6,62 it is possible to envision that oncogenes and/or tumor suppressor genes could also be affected by a somatic hypermutation mechanisms in myeloma.
Translocations involving 14q32, the site of the immunoglobulin heavy-chain (IgH) locus, occur in 20 to 40 percent of cases with abnormal karyotypes.27,41,42 In approximately 30 percent of the cases, the translocation affects the BCL1 (cyclin D) locus on 11q13.27 In most cases the partner loci are not identified and the chromosome is designated as an add 14q32. G-banded and spectral karyotyping of patient samples has demonstrated that the add 14q32 chromosome is frequently a t(14;16)(q32;q22~23).63 Molecular analysis of this translocation has shown that it results in a fusion of IgH switch region with the sequences near the c-MAF oncogene.64 Additional recurrent 14q32 translocations cloned from myeloma cell lines involve 4p16 (FGFR3 and MMSET65,66 and 6p25 (MUM1/IRF4).67 The promiscuous array of exchange partners involved in the 14q32 translocations makes it unclear as to their importance in myelomagenesis as the clinical implications of these translocations have not been reported.
Recent studies have demonstrated that partial or complete deletion of chromosome 13 represents an important negative prognostic variable and represents the first chromosomal abnormality linked to clinical outcome. While initially observed in the context of high-dose therapy,68,69 the high-risk implications of chromosome 13 deletion have recently been confirmed in the context of standard therapy using either G-banding or FISH using the RB1 gene.70,71 Further scrutiny of the entire length of chromosome 13 by molecular cytogenetic analysis in interphase cells has revealed deletions in nearly 90 percent of patients.72 Critical regions of the chromosome appear to lie in the 13q12, 13q14, and 13q21-22 bands. It is anticipated that myeloma-specific tumor suppressor genes will soon be identified on 13q.
PHENOTYPE AND CYTOKINES
The expression of the multidrug resistance gene (MDR) is observed in myeloma cells, even prior to therapy.73 This may explain the resistance to chemotherapeutic agents whose cellular efflux is mediated by the MDR pump.74,75,76,77 and 78 De novo MDR expression, albeit by only a small fraction of tumor cells,74 suggests that MDR may facilitate the survival and resistance of myeloma cells to therapy79 along with high-level expression of the BCL-251,52 and LRP-1 by the majority of myeloma plasma cells. Indeed, with standard melphalan-prednisone (MP), inferior prognosis was noted with high LRP expression, which could be overcome by melphalan dose escalation.80,81
Interleukin-6 functions as a paracrine and autocrine growth/survival factor for plasma cell myeloma82,83,84 and 85 (see Fig. 106-2). In addition, transduction of the IL-6 gene into hemopoietic cells leads to a disorder resembling Castleman disease in mice.86 IL-6 transgenic mice have a high incidence of polyclonal plasmacytosis.87 Thus, at least in experimental systems, the IL-6 gene seems crucial to the manifestation of some plasma cell disorders.
However, the growth of freshly obtained myeloma cells from patients’ marrow is not stimulated with IL-6 alone, or with IL-6 in combination with other cytokines. Marrow stromal cells provide adequate signals for expansion and maturation into monoclonal plasma cells of circulating B cells (CD11b, CD19).89,90 Similarly, preplasmacytic myeloma cells with pre-B-cell or B-cell surface antigen expression (see Chap. 83, “Functions of B lymphocytes and plasma cells”) can be expanded in vitro with a combination of cytokines such as IL-6 and IL-3, but maturation to the plasma cell stage with cytoplasmic immunoglobulin expression and secretion requires contact with marrow stromal cells.90 Cell adhesion molecules (CAM) have been identified on the surface of myeloma cells that vary with the stage of tumor cell maturation.91,92,93,94 and 95 These molecules may play a role in tumor cell trafficking as well as in the transduction of signals for growth, differentiation, and cell survival (and hence drug resistance).96
The expression of IL-1b, tumor necrosis factor beta (TNF-b), IL-6, and hepatocyte growth factor (HGF) by myeloma cells (linked to osteolytic bone disease, see below) also may account for the relative resistance of plasma cell myeloma to therapy.97,98,99,100,101,102 and 103 These cytokines apparently can decrease the sensitivity of neoplastic plasma cells to chemotherapy and irradiation, possibly by activation of NF-kB, which is a central modulator of myeloma cell apoptosis.104,105
Syndecan-1, a heparin proteoglycan present in pre-B cells, is reexpressed at the plasma cell differentiation stage, including the neoplastic myeloma plasma cell.106,107 The molecule is shed so that, similar to beta-2-microglobulin, its serum concentration reflects tumor burden.108 In vitro and in vivo experimental studies have documented a role of syndecan-1 in cell-cell and cell-matrix adhesion, delaying cell cycle progression and inducing myeloma cell apoptosis suggestive of a potentially important autoregulatory loop.109 Syndecan-1 may also serve to trap growth-regulatory molecules such as insulin growth factor (IGF) and fibroblast growth factor (FGF).110 Moreover, syndecan-1 promotes osteoblast activation and inhibits osteoclast differentiation, thereby exerting a potentially beneficial effect on bone.109
The feasibility of in vivo propagation of human myeloma cell lines (SCID mice)5,6 and of primary human tumor cells also from previously untreated patients (SCID-hu system)7,110 has opened up entirely new research avenues to identify in vivo the critical growth-promoting and growth-inhibitory cytokines and their host cell sources and to elucidate the mechanisms involved. Furthermore, the recapitulation of human disease in the SCID-hu system with anemia, bone destruction, wasting, and renal failure should serve as a powerful tool to identify therapies directed not only at myeloma growth control but at palliation of symptoms. Administration of bisphosphonates not only halts bone destruction, it also inhibits myeloma growth in this system, presumably by interfering with the interactions between the human marrow microenvironment and the myeloma cells, thus opening a novel avenue of myeloma growth control aimed at inactivating the “soil” on which the “seed” of tumor cells survive and expand.
MYELOMA BIOLOGY
Consistent with results seen in other germinal center cell-derived B-cell malignancies, such as follicular and diffuse large-cell lymphomas, plasma cell myelomas express immunoglobulin genes that have undergone somatic mutation. In addition, the BCL-6 in myeloma also can harbor mutations in the 5′ autoregulatory site. Conceivably, other tumor suppressor genes may be affected by the natural, but potentially pathogenic, process of immunoglobulin somatic mutation.”
A key candidate site for such mutations is located on chromosome 13, which, when morphologically deleted, is associated with rapid disease progression and grave prognosis. Molecular genetic studies employing FISH of interphase cells have recently demonstrated that nearly 90 percent of both newly diagnosed and previously treated patients harbor chromosome 13 deletions. The presence of biallelic deletions at specific loci at 13q12, q14, and q21 and the seemingly progressive acquisition of additional deletions on chromosome 13 are consistent with tumor suppressor gene activity in this region conferring survival or proliferation advantage. The clinically more benign numeric aberrations, mainly involving gains in the number of chromosomes, may result from centrosome disorganization.111
Myeloma cells are endowed with receptors for a multiplicity of potentially growth-promoting cytokines IL-6, IL-11, oncostatin-M, leukemia inhibitory factor (LIF), granulocyte colony stimulating factor (G-CSF), stem cell factor (SCF), interferon alpha (INF-a and IL-10), tumor necrosis factor (TNF-a), insulin growth factor (IGF-I and IGF-II).26,27 Antibodies to IL-6, as well as high concentrations of IFN-a, INFg, and soluble syndecan-1 inhibit cell growth. Most of these results have been observed in established myeloma cell lines, so that their relevance for clinical disease sustenance and progression remains to be elucidated. This is now possible with the availability of the SCID-hu host system for myeloma. The expression of multiple cell adhesion molecules such as CD44, CD49d (VLA-4), CD54 (ICAM-1), CD56 (NCAM), and CD138 (syndecan-1) is important for mediating adherence of myeloma cells to the marrow stroma, triggering the secretion of IL-6 and other cytokines in stromal cells that, in the case of IL-6, involves NF-kB activation of the IL-6 promoter, which may be mediated by RANKL.112
A role for tumor angiogenesis also has been demonstrated for myeloma where high microvessel density was associated with markedly inferior prognosis.113 Angiogenic factors such as vascular endothelial growth factor 1 (VEGF-1) are expressed by myeloma cells, and VEGF receptors (Flt-1) are present on endothelial cells.114 The recently observed clinical antitumor activity of thalidomide in about one-third of patients with far advanced disease may involve an antiangiogenic mechanism, possibly involving the down-regulation of VEGF.115,11
The progression of myeloma is intimately linked to the marrow microenvironment. Circulating clonotypic B cells, present even in the earliest stages of the disease, including solitary plasmacytoma, adhere to marrow stoma through unique adhesion molecule combinations. The survival of these cells is enhanced by growth signals elaborated by the various components of the marrow microenvironment. The genomic complexity, unique among B-cell malignancies, confers an unusual degree of resistance of typically hypoproliferative myeloma cells to both endogenous and exogenous (i.e., therapeutic) apoptosis-inducing signals. In the terminal disease phase, hyperproliferative features are acquired either due to mutations of cell cycle repressor genes or by way of translocations involving cell cycle activators such as cyclin D1. Thus, the B-cell maturation stage-dependent susceptibility to Ig gene mutations probably extends to critical cell cycle repressor genes and master switch genes such as BCL-6 that collectively lead to expression of genes that facilitate marrow adhesion and clinical disease development. Marrow stromal cell activation may be conferred by additional exogenous stimuli, such as viruses or other carcinogens.
CLINICAL FEATURES
Patients may present with symptoms of anemia, bone pain, pathologic fractures, a bleeding tendency, and/or peripheral neuropathies. These signs and symptoms generally result from tumor mass effects or from the proteins or cytokines secreted by tumor cells or normal accessory cells under the influence of tumor cell products (see Table 106-1 and Fig. 106-2).
PAIN
Pain suffered by subjects with myeloma results most frequently from vertebral compression fractures at sites of osteopenia or, more typically, lytic bone lesions. These are due to excessive osteoclast activating factor (OAF) activity exerted by IL-1-b,97 TNF-b,98 and/or IL-6.116 These factors apparently also inhibit compensatory osteoblastic activity.117 Localized pain can also be induced by regional tumor growth toward the spinal cord and nerve roots. Painful mass effects also can be provoked by amyloid deposition (see Chap. 107, “Amyloidosis”) in various anatomic sites, e.g., the median nerve sheath, as in amyloid-associated carpal tunnel syndrome.118
INFECTIONS
Deficiencies in cellular immune function account for the recurrent infections commonly seen in myeloma.119,120 and 121 The mechanisms underlying this immunodeficiency remain obscure, although transforming growth factor beta (TGF-b)122 and FAS-ligand have been incriminated.123 In addition, patients are impaired in their ability to mount a humoral immune response to antigen and, except for the myeloma protein, have low levels of other serum immunoglobulins. As a result, myeloma patients are more susceptible to serious infections with bacteria that ordinarily may be opsonized by specific antibody, such as Streptococcus pneumoniae.
NEPHROPATHY
Abnormalities of renal function occur when the tubular absorptive capacity of light chains is exhausted, resulting in interstitial nephritis with light-chain casts.124,125 The second most common cause of nephropathy is hypercalcemia with hypercalciuria, leading to volume depletion and prerenal azotemia. In addition, hypercalcemia is conducive to calcium deposits in the renal tubules, also producing interstitial nephritis.126,127 AL amyloidosis associated with light-chain proteinuria usually presents as nephrotic syndrome but can lead, over time, to renal failure128,129 and 130 (see Chap. 107, “Amyloidosis”). AL amyloidosis is more common in patients with l light-chain myeloma proteins than in patients with k light-chain myeloma, especially those with l light-chain proteins that have immunoglobulin variable regions belonging to the VI l light-chain subgroup. Probably underestimated, however, is the frequency of immunoglobulin light-chain deposition disease, a disease more commonly associated with k light-chain myeloma proteins. This also leads to impaired glomerular filtration.130,131
Tumor cell involvement of the kidneys is uncommon but should be suspected in patients with renal enlargement, which, however, is more often due to AL amyloid129 (see Chap. 107, “Amyloidosis”). Complicating factors in the pathogenesis of renal failure in myeloma include the frequent use of nonsteroidal anti-inflammatory drugs for pain control.132 Recent studies using IL-6 transgenic mice that express an IL-6 transgene under the control of the metallothionin-1 promoter indicate that constitutive high-level expression of IL-6 in the liver can induce dysproteinemia and a protracted acute-phase response leading to renal pathology with features remarkably similar to those in human myeloma kidney.133
EXTRAMEDULLARY DISEASE
Although uncommon at diagnosis, extramedullary disease manifestations are observed with increasing frequency as the duration of disease control can be extended by high-dose therapy. Liver, lymph nodes, spleen, kidneys, various subcutaneous and cutaneous sites, as well as meninges and brain-parenchyma, can be involved, sometimes accompanying secondary plasma cell leukemia.134,135 and 136 Such visceral organ involvement is typically associated with immunoblastic morphology, high LDH serum levels, high tumor-cell-labeling index, and complex karyotypes.
NEUROPATHIES
Neurologic abnormalities generally are caused by regional tumor growth compressing the spinal cord or cranial nerves. Polyneuropathies are observed with perineuronal or perivascular (vasa nervorum) amyloid deposition118 but also can be seen with osteosclerotic myeloma, sometimes as part of the complete POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes).137,138 The humoral and cellular mechanisms mediating this peculiar syndrome are unknown.
HYPERVISCOSITY
Hyperviscosity occurs in fewer than 10 percent of patients with myeloma.139,140,141 and 142 Although noted in a higher proportion of patients with Waldenström macroglobulinemia (see Chap. 108, “Macroglobulinemia”),143 hyperviscosity actually may be seen more commonly in association with myeloma because of its 10-fold higher incidence.144 Symptoms of hyperviscosity result from circulatory problems, leading to cerebral, pulmonary, renal, and other organ dysfunction (see “Hyperviscosity Syndrome,” Chap. 108, “Macroglobulinemia”). Hyperviscosity often is associated with bleeding.
While there is a general correlation between clinical symptoms and relative serum viscosity, the relationship between serum immunoglobulin levels and symptoms is not consistent from one patient to the next. This may be related to the different physicochemical properties of each of the classes and subclasses of immunoglobulin molecules (see Chap. 83, “Function of B cells and plasma cells”). Because of a greater tendency for IgA to form polymers, patients with IgA myeloma more often have hyperviscosity than patients with IgG myeloma, and almost one-quarter of IgA myeloma patients may have features of the hyperviscosity syndrome.141 Among patients with IgG myeloma, those with tumors expressing immunoglobulins of the IgG3 subclass are the most susceptible to developing this syndrome.145
BLEEDING AND THROMBOSIS
Bleeding has been reported in 15 percent of patients with IgG myeloma and in over 30 percent of patients with IgA myeloma.146,147 This may be due to anoxia and thrombosis in capillary circulation, to perivascular amyloid, and/or to an acquired coagulopathy.144 Thrombocytopenia, however, even with extensive marrow involvement, is rare in early phases of myeloma.148
Some patients present with thromboembolic disease. These patients may have a hypercoagulable state secondary to acquired deficiencies in protein C or to a lupus anticoagulant (see Chap. 128, “Lupus anticoagulants and related disorders”).
LABORATORY FEATURES
The diagnosis even of symptomatic plasma cell myeloma is often delayed by months. Patients may have complaints of persistent back pain following minor trauma or of recurrent infections. Such complaints in the setting of unexplained hyperproteinemia or proteinuria, anemia, renal insufficiency, hypoalbuminemia, dysproteinemia, or marked elevation of the erythrocyte sedimentation rate should prompt laboratory evaluation for plasma cell myeloma.
INITIAL EVALUATION
Minimal requirements include evaluation of the hemogram, inspection of the blood film for the presence of rouleaux, radiographic examination of axial skeleton (skull, entire spine, and pelvis) (Fig. 106-3), serum protein electrophoresis (see Chap. 106, “Plasma Cell Neoplasms: General Considerations”), measurement of urinary protein excretion, and marrow aspiration and biopsy.

FIGURE 106-3 Typical skeletal changes on roentgenogram. (a) Example of “punched-out” lytic lesions in skull. (b) Diffuse osteopenia with compression fractures of spine. (c) Lytic lesions in the left humerus. (Courtesy of Edgardo J. Angtuaco.)

HEMATOLOGIC ABNORMALITIES
Neoplastic myeloma cells may replace the normal hemopoietic tissue in the marrow. These cells consist predominantly of plasma cells exhibiting varying degrees of maturity. A larger cell with prominent nucleoli and scant cytoplasm is usually present in small numbers. Such plasmablasts tend to increase with disease progression and may represent the dominant tumor cell population during the terminal disease phase.149,150 Tumor involvement of the marrow typically causes anemia, the degree of which appears related to tumor mass (see below).
Serum erythropoietin levels are relatively low for the degree of anemia present.151 This blunted erythropoietin response to anemia may be due to abundant production of cytokines such as IL-1 and TNF-b.152 This also has been attributed to increased serum viscosity levels.153 Overproduction of IL-6 by marrow stroma, normal accessory cells, and/or tumor cells may contribute to the anemia of myeloma. However, possibly because of the thrombopoietic activity of this cytokine, myeloma patients typically do not manifest significant thrombocytopenia, in the absence of other factors.
However, thrombocytopenia may develop subsequent to therapy or from autoimmune mechanisms, such as those accounting for anemia or factor VIII deficiency.154,155 and 156 The antibody portion (Fab) of the myeloma protein may bind to fibrin during clotting and prevent fibrin aggregation. This probably represents the most common coagulopathy in patients with myeloma.157 Factor X deficiency associated with systemic AL amyloidosis apparently cannot be traced to an inhibitor in vitro158 (see Chap. 107, “Amyloidosis”).
Some patients present with thrombocytosis secondary to hyposplenism because of AL amyloid. In addition, hypercoagulable states may result from protein C deficiency, perhaps as a consequence of monoclonal immunoglobulins exhibiting anti-protein-C activity. Lupus anticoagulants also have been reported in association with myeloma. However, these have not been traced to be a direct action of the monoclonal immunoglobulin.159
DETECTION OF MONOCLONAL IMMUNOGLOBULIN
Most patients with myeloma secrete a monoclonal immunoglobulin that may be detected by immunoelectrophoresis or, more sensitively, by immunofixation analysis (see Chap. 106, “Plasma Cell Neoplasms: General Considerations”). Of the patients with plasma cell myeloma, approximately 60 percent have detectable monoclonal IgG (usually greater than 3.5 g/dl), 20 percent have monoclonal IgA (typically greater than 2 g/dl), and 20 percent only have monoclonal immunoglobulin light chains. A small proportion of patients have “nonsecretory myeloma,” in which the neoplastic plasma cells do not produce significant amounts of monoclonal immunoglobulin. Myelomas producing monoclonal IgD, IgE, IgM, or more than one immunoglobulin class are rare.
Suppression of uninvolved immunoglobulin classes is typical for symptomatic myeloma. Even patients with light-chain myeloma, nonsecretory myeloma, or IgD or IgE myeloma, often have depressed levels of serum IgG, IgA, and IgM. Unlike other myeloma isotypes, IgD myelomas make immunoglobulins that more commonly have l, rather than k, light chains. Patients with plasma cell myeloma often have Bence Jones proteinuria due to the excretion of k or l immunoglobulin light chains, often in excess of 1g per 24-h period.
The monoclonal nature of tumor cells can be verified by analyses of immunoglobulin gene rearrangements in the DNA isolated from neoplastic plasma cells.160,161 In addition, the immunoglobulins produced by the tumor cells can be found to have unique immunoglobulin idiotypes32 (see Chap. 83, “Functions of B Lymphocytes and Plasma Cells”).
IMMUNOCYTOCHEMICAL AND FLOW CYTOMETRIC ANALYSES
Like normal plasma cells, myeloma plasma cells contain cytoplasmic immunoglobulin. Consistent with the clonal nature of this B-cell malignancy, mature tumor cells typically express a single heavy and light chain. Immunoglobulin k or l light-chain restriction can be determined readily by immunocytochemical or flow cytometric analyses of the neoplastic plasma cells.162 When coupled with nuclear DNA analysis, two-parameter flow cytometric analyses can detect typically hyperdiploid tumor cells with monoclonal k or l light chain in the cytoplasm. (Fig. 106-4). DNA aneuploidy in the neoplastic myeloma cells is present in approximately 80 percent of all patients.163,164 This offers a convenient objective marker of malignancy that has facilitated more detailed analysis of the myeloma phenotype.165 Using appropriate monoclonal antibodies, myeloma cells have been found to express a wide array of early and late differentiation markers pertaining to myeloid, monocytic, erythroid, megakaryocytic, B-cell, T-cell, and/or natural killer cell lineages.91,165,166,167,168 and 169 Some of these markers are coexpressed with cytoplasmic immunoglobulin, an infrequent phenotype in normal B-cell development.165 Other DNA aneuploid and diploid cells express B and pre-B features (CD10, CD11b, CD19, and CD20) without cytoplasmic immunoglobulin.33,165 Such cells, present in both marrow and blood, are capable, under suitable in vitro conditions, of differentiating into monoclonal plasma cells.88,170 The expression of maturation-dependent cell adhesion molecules (e.g., CD56, CD54, or CD138) probably plays an important role in tumor dissemination (or lack thereof) and in the transduction of signals important for tumor cell proliferation and/or differentiation.91,106,167 In contrast to most B-cell malignancies, the neoplastic plasma cells of patients with myeloma express the pan-B-cell antigen, CD20, in less than 20%.

FIGURE 106-4 Two parameter flow cytometry of DNA content (abscissa, propidium iodide) and cytoplasmic immunoglobulin (ordinate, anti-k FITC); (left panel) at diagnosis: approximately 30 percent hyperdiploid tumor cells with kappa light-chain restriction; (right panel) at time of maximal response: small hyperdiploid and kappa light-chain-restricted population (less than 1 percent).

LABELING INDEX
Since mature plasma cells represent the dominant tumor phenotype in most myeloma cases, the proportion of cycling cells is typically exceedingly small.163,171,172,173 and 174 Thus, the plasma cell labeling index, as determined by tritiated thymidine or bromodeoxyuridine techniques, averages 1 percent. Fewer than 5 percent of patients display values in excess of 5 percent.173,175 The BrdU labeling index of marrow and blood has become an important prognostic variable. As values exceed the median of 1 percent at diagnosis, the durations of event-free and overall survival are progressively shortened.176
CYTOGENETICS
It is the low proliferative activity of most morphologically recognizable tumor cells that accounts for the great difficulty in obtaining cytogenetic data, requiring dividing cells to be arrested in metaphase.40,41 and 42,177 Contrasting with DNA aneuploidy in the majority of patients, abnormal karyotypes are observed in only 30 percent of untreated myeloma patients, suggesting that the normal diploid karyotype in the remaining cases originates in normal hemopoietic cells.164
Myeloma karyotypes have some of the most complex chromosomal aberrations observed in human malignancies. Marked numeric and structural changes involve virtually all chromosomes (Fig. 106-5). Although these anomalies do not appear random, unique myeloma-specific alterations have not been identified. Translocations common in other B-cell tumors, such as t(8;14), t(11;14), and t(14;18),27 also are observed in about 5 to 30 percent of patients with myeloma, although with different molecular breakpoints (see below).44,178,179 and 180 Most translocations involving 14q32 are unbalanced and involve IgH switch regions with a multiplicity of translocation partners.181,182 Whereas historical studies in individual patients failed to demonstrate further genetic evolution during the course of the disease,183 recent longitudinal investigations have clearly demonstrated clonal evolution including the fascinating observation that myelodysplasia-type anomalies can be acquired not only by normal hemopoietic cells but by myeloma cells as well.184,185 The acquisition of such “leukemic signature” in addition to the original myeloma karyotypic abnormalities conferred poor prognosis.184

FIGURE 106-5 Cytogenetics in multiple myeloma. (a) Summary of numeric abnormalities ovbserved among 100 abnormal karyoptyes, portraying the incidence of trisomies (top) and monosomies (bottom). The most common trisomies include those of chromosomes 3, 5, 7, 9, 11, 15, 19, and 21; monosmoies most commonly involve chromsomes 13 and 16. (b) Summary of chromosomal breakpoints involving the short arm (p, top) or the long arm (q, bottom) of each chromosome that were observed among 100 abnormal karyotypes. Translocations, deletions, and breakpoints most commonly involve both short and long arms of chromosome 1 as well as the long arm of chromosomes 6, 11, 13, and 14 (see part c). (c) Ideogram of 100 abnormal karyotypes, with 459 chromosomal breakpoints delineated by dots. Breakpoints involve areas of known oncogenes such as L-MYC (1p32), N-MYC (2p24), c-MYC (8q24), BCL-1 (11q13), BCL-2 (18q22), N-RAS (1p22), and H-RAS (11p15). Deletions in breakpoints are also seen at sites of suppressor genes (Rb, 13q14; p53, 17q13.) (Courtesy of Jeffery R. Sawyer)

The application of FISH using appropriate marker probes has made possible the detection of mainly numeric chromosomal aberrations in interphase cells so that the incidence of genetic abnormalities has been raised beyond 90 percent in some studies.186 This represents an important advance since chromosome 13 deletion abnormalities have been recognized as the dominant adverse pretreatment laboratory feature with both standard71 and high-dose therapy,68 recognized however on standard Giemsa-banded metaphase spreads in only 15 to 20 percent of cases. Rb-1 deletion, on the other hand, can be detected by FISH in interphase cells in approximately 40 percent55 and seems to distinguish a prognostically unfavorable group of patients receiving standard therapy.70,187 The application of a chromosome 13 cocktail covering the entire length of 13q has yielded molecular deletions in up to 90 percent of cases, although implications for therapy have yet to be defined.72 Other chromosomal abnormalities have failed to impart similar prognostic implications when controlled for chromosome 13 deletions.69 Recent studies with FISH, however, have demonstrated favorable effects of chromosomal gains resulting in trisomy of certain chromosomes,70 suggesting clinically relevant suppressor gene activity. Translocation (11;14), frequently associated with primary plasma cell leukemia,183 does not per se confer inferior outcome. Hypodiploidy recognized by DNA flow cytometry was associated with primary drug resistance,188 and deletion 6q was associated with more extensive bone disease.189
DIFFERENTIAL DIAGNOSIS
In most patients, the diagnosis of plasma cell myeloma is readily established.210,211 Major criteria include the demonstration of marked marrow plasmacytosis, lytic bone lesions, and monoclonal protein in serum and/or urine (Table 106-2). In the absence of lytic bone lesions or diffuse osteopenia, other criteria should feature more prominently, especially anemia, levels of monoclonal protein, marrow plasmacytosis, and/or renal insufficiency. MRI abnormalities are especially useful in assessing for nonsecretory myeloma.

TABLE 106-2 CRITERIA FOR DIAGNOSIS OF PLASMA CELL MYELOMA*

It is important to distinguish plasma cell myeloma from essential monoclonal gammopathy212,213 (Table 106-3). This condition is associated with lower serum levels of monoclonal protein, less Bence Jones proteinuria, and less detectable monoclonal plasmacytosis in the marrow (see Chap. 108, “Plasma Cell Neoplasms: General Considerations”). Patients with essential monoclonal gammopathy do not have associated anemia, bone lesions, or MRI abnormalities. The monoclonal plasma cells of essential monoclonal gammopathy may be aneuploid.29 However, these plasma cells have a lower labeling index than that of plasma cell myeloma so that the presence of abnormal metaphases on cytogenetic examination is incompatible with benign gammopathy.214

TABLE 106-3 CRITERIA FOR DIAGNOSIS OF ESSENTIAL MONOCLONAL GAMMOPATHY

SOLITARY PLASMACYTOMA
Solitary plasmacytoma of bone204,215,216 or soft tissue217,218 requires the absence of indicators of systemic disease, such as marrow plasmacytosis, anemia, or other lytic or soft tissue lesions. Computed axial tomography (CT) is recommended for more-detailed evaluation of early bone disease not recognized on standard roentgenographic examination.219 MRI is a powerful tool for detecting plasma cell myeloma involving the marrow in a macrofocal fashion (see Fig. 106-6a) or solitary plasmacytoma (see Fig. 106-6b).204,205,206,207,208 and 209 The detection of a solitary MRI lesion (cytologically proven) in the setting of an otherwise benign gammopathy changes the diagnosis to solitary plasmacytoma. In contrast to most patients with plasma cell myeloma, patients with solitary plasmacytoma or essential monoclonal gammopathy have normal serum immunoglobulin levels.

FIGURE 106-6 Magnetic resonance imaging (MRI) pattern in multiple myeloma at diagnosis: (a) STIR (short inversion-time inversion recovery) imaging shows approximately one-third each presenting with diffuse homogeneous pattern (panel A), heterogeneous pattern (panel B), and focal plasmacytoma lesions (panel C). Few patients have a hypo-intense and homogenous pattern seen also in normal individuals (panel D). (b) Some patients present with macrofocal disease. Panel A: normal pelvis and isolated L-4 lesion, panel B: T(2) focal lesion; panel C: computered-tomography-guided fine needle aspiration of L-4 lesion. Examination in 72 patients with MRI-focal disease showed tumor in 92 percent, indicating that MR focal lesions in myeloma represent tumor.

AMYLOIDOSIS
Additional diagnostic procedures are indicated for patients with lymphadenopathy or hepatosplenomegaly to evaluate for extramedullary disease or protein deposition disease. The diagnosis of AL amyloid (see Chap. 107, “Amyloidosis”) often can be made by fine-needle aspiration of subcutaneous fat or by biopsy of the rectal mucosa.220 Staining the tissue with Congo red may reveal perivascular amyloid with its classical apple-green birefringence when viewed under polarized light.221 AL amyloid also may be detectable on marrow biopsy.130 Amyloidosis should be suspected in patients with macroglossia, “racoon’s eyes” (resulting from periorbital subcutaneous hemorrhages due to vascular fragility), carpal tunnel syndrome, nephrosis, or cardiomegaly associated with arrhythmias or low-voltage and conduction defects on electrocardiogram.222 Patients suspected of having isolated cardiac amyloid with myeloma should be evaluated via echocardiography.223 Endomyocardial biopsy may establish the diagnosis. Orthostatic hypotension also should alert to the possibility of systemic amyloidosis as a result of amyloid deposition in vasa nervorum of the autonomic nervous system or in adrenal glands resulting in hypo-adrenalism. It can be difficult to recognize amyloidosis as a major cause of morbidity and mortality in patients with myeloma. Since immunoglobulin and mainly light-chain deposition disease (LCDD) can mimic many manifestations of AL but requires immunofluorescence analysis of unfixed tissue, formalin fixation should be avoided whenever protein deposition disease is suspected.
THERAPY, COURSE, AND PROGNOSIS
STAGING
Once the diagnosis of plasma cell myeloma has been established (Table 106-2), tumor staging should be performed190 (Table 106-4). Studies measuring in vitro immunoglobulin production by patients’ myeloma cells have led to a clinically applicable method to estimate tumor mass.191 A tumor-staging system has been derived using standard laboratory measurements, including hemoglobin concentration, protein levels in serum and urine, presence of hypercalcemia, and extent of bone disease.190 The Durie-Salmon staging system has remained in use for more than 20 years and has permitted better interpretation of therapeutic trials according to comparably staged patients.

TABLE 106-4 ASSESSMENT OF TUMOR MASS (DURIE-SALMON)

However, due to the variable interpretation especially of lytic bone lesions, other variables have been used for tumor staging which are more quantitative and discriminatory as far as risk assessment is concerned. Among a long list of individually relevant measurements, the serum concentration of b2-microglobulin currently provides the most reliable and quantitative prognosticator for survival in plasma cell myeloma.192,193 and 194 Additional independent factors include the plasma cell labeling index163,176 and C-reactive protein levels, reflecting in vivo IL-6 activity.196 Increased IL-6 activity mediates many of the abnormalities encountered in myeloma, including hypoalbuminemia, anemia, and lytic bone disease.197,198 and 199 The degree of marrow plasmacytosis, as assessed by flow cytometry of DNA and cytoplasmic immunoglobulin, obviously reflects tumor burden and hence has prognostic utility.162,200 However, this evaluation is compromised by the patchy marrow involvement often observed in this malignancy. Hypodiploidy identifies marked resistance to standard drug regimens and, as a result, is associated with inferior survival.188
Cytologically plasmablastic myeloma, present in 8 percent of newly diagnosed patients, is an adverse parameter frequently associated with high labeling index149,150 (see Plate XVI-7), higher incidence of extramedullary disease, elevated serum LDH levels,135,201 and a high incidence of karyotypic anomalies, all recognized to confer poor prognosis independently. In the setting of high-dose therapy, histological evaluation of marrow biopsy sections identified short event-free and overall survival in the 20 percent of patients presenting with immature morphology (Bartl grade greater than 1) and increased mitotic activity (greater than or equal to 1 per high-power field), regardless of beta-2-microglobulin, CRP, or cytogenetics (Fig. 106-7).202,203 Recently, marrow microvessel density (MVD) has been associated with prognosis. High MVD, possibly reflecting VEGF expression by most myeloma cells,114 conferred short event-free and overall survival.113

FIGURE 106-7 Bone marrow histology and prognosis with high-dose therapy (total therapy262). In the presence of Bartl grade greater than 1 and more than one mitotic figure per high-power field (38 pts), event-free (left panel) and overall survival (right panel) were significantly shorter in patients lacking these features (153 pts).

MAGNETIC RESONANCE IMAGING (MRI)
MRI-STIR images of the axial skeleton (skull, spine, and pelvis) are very useful not only for the delineation of truly solitary plasmacytoma of bone204 but for the assessment of tumor burden and the recognition of macrofocal disease where random marrow sampling from the iliac crest may not yield diagnostic information.204,205,206,207 and 208 In such circumstances, CT-guided fine-needle aspiration can render a cytological diagnosis and provide important prognostic information in terms of labeling index and karyotypic analysis.209 Virtually all patients with myeloma have abnormal MR images at diagnosis, presenting either as hyperintense diffuse, heterogeneous or as focal patterns (Fig. 106-6). As high-dose therapy approaches aim at cure, residual MRI abnormalities remaining in otherwise stringently defined complete remission (CR, see below) need to be recognized.
RISK ASSESSMENT
Given the multiplicity of prognostically relevant staging parameters, it is recommended that all patients with myeloma should have analysis performed of beta-2-microglobulin (B2M), C-reactive protein (CRP), LDH, and cytogenetics, as well as marrow biopsy evaluation to evaluate for key features with dominant adverse implications.
On the basis of the above considerations, high-risk myeloma can be identified on the basis of one of the following: cytogenetics revealing chromosome 13 deletion, plasma cell labeling index greater than 2 percent, LDH greater than 2 times normal unexplained by liver function abnormalities or hemolytic anemia, hemoglobin less than 8 percent in association with extensive marrow plasmacytosis greater than 50 percent, B2M and CRP elevations greater than 4 mg/liter, hypercalcemia or excess paraprotein production with IgG greater than 7 g/dl, IgA greater than 5g/dl, Bence Jones protein excretion greater than 10 g/liter. Low-risk disease requires the absence of unfavorable cytogenetics, labeling index not exceeding 1 percent, LDH within institutional normal range, hemoglobin greater than 12 percent, B2M and CRP less than 2.5 mg/liter, marrow plasmacytosis not exceeding 20 percent, normocalcemia, normal albumin. All others have an intermediate risk.
THERAPY FOR SOLITARY PLASMACYTOMA
The recommended therapy for solitary plasmacytoma lesions of soft tissue or bone is radiotherapy at potentially curative doses of 40 to 50 Gy. Using this approach, approximately 70 percent of patients with soft-tissue plasmacytoma can be cured,218,224,225 and 226 contrasting with less than 30 percent of those with solitary bone lesions.227 This discrepancy is probably due to the relative insensitivity of standard staging procedures for marrow and bone disease. Higher cure rates are anticipated when solitary plasmacytoma lesions are defined with more-sensitive techniques, such as CT scans219 or MRI.206,228
THERAPY FOR INDOLENT MYELOMA
Patients who have systemic but asymptomatic myeloma may have a low tumor mass and slow disease progression229,230 (see Table 106-5). Such patients generally do not have a marrow plasmacytosis that exceeds 30 percent of the marrow cells. Also, the monoclonal serum immunoglobulin levels, while exceeding those found in patients with essential monoclonal gammopathy, typically range from 3.5 g/dl to 7 g/dl for indolent IgG myeloma, or 2 g/dl to 5 g/dl for indolent IgA myeloma. Also, Bence Jones proteinuria generally does not exceed 10 g per day in indolent myeloma. Bone lesions typically are small and few in number. Severe anemia (hemoglobin less than 10 g/dl), renal failure (creatinine greater than 2 mg/dl), recurrent infections, and hypercalcemia are typically absent. The plasma cell labeling index is usually less than 1 percent124 (hypoproliferative myeloma). Such patients can be recognized only retrospectively, although reports suggest earlier progression to symptomatic myeloma in the presence of lytic bone lesions or serum myeloma protein levels in excess of 3 g/dl and Bence Jones proteinuria.231 Focal MRI abnormalities and hyperintense background signal on STIR images by MRI have also been associated with earlier disease progression. Treatment, previously withheld until the onset of symptoms or until disease progression, has recently been performed with pamidronate to delay the onset of bone disease and possibly progression of the disease process.

TABLE 106-5 CRITERIA FOR DIAGNOSIS OF INDOLENT MYELOMA*

THERAPY FOR SYMPTOMATIC MULTIPLE MYELOMA
“STANDARD THERAPY”
Therapeutic progress has been slow in myeloma. Oral melphalan and prednisone, introduced over 30 years ago, have remained standard therapy (Table 106-6), providing control of symptoms and/or tumor mass reduction by no more than 50 percent in one-half of patients treated.232,233 Various combination drug regimens have been tested that include nitrosoureas, doxorubicin, vinca alkaloids, and cyclophosphamide, in addition to melphalan and prednisone.234,235 and 236 Most studies, however, have failed to show that such regimens improve patient survival (Fig. 106-8). This is not surprising, considering that the overall cytotoxic dose intensity was low to avoid marked myelosuppression. Given the low incidence of stringently defined complete remissions (5 percent), the degree of tumor cytoreduction from standard therapy has typically not affected prognosis.237 However, patients achieving “plateau phase” fared significantly better than those with disease progression238 Although previous randomized trials showed no benefit due to maintenance therapy with cytotoxic agents,239,240 including interferon immunotherapy,241,242 and 243 significant extension of event-free and overall survival has recently been observed with high-dose prednisone.244

TABLE 106-6 CHEMOTHERAPY REGIMENS IN MYELOMA

FIGURE 106-8 Survival with combination chemotherapy (CCT) versus standard melphalan and prednisone (MP). Results of a meta-analysis of randomized trials revealed no difference in almost 2000 patients enrolled in CCT versus MP trials.

As a consequence of prolonged administration of alkylating agents targeting hemopoietic progenitor cells, myelotoxicity accumulates, potentially leading to myelodysplasia (MDS) or acute myeloid leukemia (AML)245 (see Chap. 93, “Acute Myelogenous Leukemia”). Myeloma and MDS/AML may share MDS cytogenetic features (“leukemic signature,” see above) without indicating, however, a common ancestral origin.
INTENSIVE GLUCOCORTICOID THERAPY AND VAD
Therapeutic benefit from high doses of glucocorticoids had been reported in occasional myeloma patients.246 However, serious investigations into the role of high-dose glucocorticoid therapy were conducted first as part of the VAD regimen, combining continuous infusions of vincristine, Adriamycin (doxorubicin), and 4-day pulses of high-dose dexamethasone at 40 mg daily247 (Table 106-6). In myeloma refractory to myelosuppressive doses of standard alkylating agent regimens, VAD produced rapid and marked cytoreduction of over 75 percent in more than 50 percent of treated patients, especially in those with relapsing disease (i.e., with prior response). Subsequent studies with high-dose dexamethasone alone revealed response rates comparable to VAD among subjects who had primary drug resistance.248 Responders to VAD or dexamethasone had not only protein reduction but also marrow remission (fewer than 5 percent tumor cells). These results represented a major advance, since there previously had not been effective salvage therapy for plasma cell myeloma resistant to alkylating agents.
Therapy with VAD, or modifications thereof, produced responses in about 65 percent of previously untreated myeloma patients, with a short median tumor halving time of about 21 days compared to 6 to 8 weeks with standard melphalan-prednisone.249,250 Signs and symptoms of disease resolved more quickly than with standard therapy with alkylating agents and prednisone. The faster tumor cytoreduction with high-dose glucocorticoid-containing regimens may result from down-regulation of various cytokines possibly involved in the pathogenesis of myeloma. Down-regulation of IL-6 induced by glucocorticoids, for example, is accompanied by rapid apoptosis of cultured human myeloma cells, explaining the absence of a tumor lysis syndrome clinically despite often dramatically rapid responses. Apoptosis can be prevented by coincubation of myeloma cells with recombinant IL-6100 or by stromal cell exposure.103
Despite its more profound and rapid cytoreduction, the VAD regimen failed to markedly extend the survival of newly diagnosed patients in comparison with standard alkylating drug-containing regimens.249,250,251 and 252 This may be due to the primordial tumor cells preferentially producing IL-6,253 which confers resistance to dexamethasone,100 and expressing MDR,77,78,79 and 80 which confers resistance to vincristine and doxorubicin. However, with VAD or dexamethasone alone, hemopoietic function was preserved. The 4-day continuous infusion regimen of doxorubicin is virtually devoid of cardiomyopathy, even after extended application, probably because of the lower drug serum levels that are used. Myelosuppression is uncommon with VAD, and dexamethasone accounts for most of the toxicity observed.
Recent randomized trials comparing VAD with standard VMCP-VBAP or VMCPP-VBAPP (Table 106-6) with more extensive prednisone revealed superior outcome with the more dose intensive glucocorticoid regimens,251 in line with subsequent observations that higher doses of prednisone are also beneficial in the setting of maintenance.244
BISPHOSPHONATES
An important adjunct is the administration of pamidronate, a newer-generation bisphosphonate, which has been shown to delay the onset of myeloma-related skeletal events and to prolong survival.268,269 Pamidronate inhibits osteoclast activity and seems to mediate antitumor activity through down-regulation of myeloma-survival signals elaborated by the marrow microenvironment.8,9,270 Pamidronate has been shown, in randomized trials, not only to delay the onset of myeloma-related skeletal events268 but also to extend overall survival.269 The survival extension may be due to direct or indirect antitumor effects, possibly involving the inhibition of cytokines sustaining myeloma growth and survival. Bone mineral density measured by DEXA (dual energy x-ray absorptiometry) has also been shown to increase substantially after monthly administrations of pamidronate at 90 to 180 mg.289 Observations of antitumor activity with pamidronate in smoldering myeloma form the basis for its current investigation along with glucocorticoids for patients over age 70 who may not be candidates for high-dose therapy.270
INTERFERON ALPHA
The role of interferon alpha (IFN-a) in the setting of standard therapy remains controversial. Meta-analyses evaluating the role of during induction or maintenance have, on the whole, shown more positive than negative results.242 Growth-inhibiting effects of IFM-a may be either direct or mediated by modulation of the immune response or through antiangiogenesis mechanisms.
HIGH-DOSE THERAPY WITH AUTOLOGOUS HEMOPOIETIC STEM CELL SUPPORT
Recent results of randomized and historically controlled clinical trials have demonstrated that, as a result of mainly melphalan-based high-dose therapy, the incidence of complete remission can be raised from 5 percent up to 50 percent, and event-free and overall survival durations have been extended from 1.5 to well over 3 years and from 3 to 5 to 6 years respectively.256,257 The use of peripheral blood stem cells, mobilized with stem cell-sparing cyclophosphamide alone, in combination with hemopoietic growth factor, such as G-CSF or GM-CSF, as well as G-CSF alone, have accelerated both neutrophil and platelet recovery so that the duration of marrow aplasia typically does not exceed 5 days and critical levels of granulocytes greater than 500/µl and platelets greater than 50,000/µl are typically attained within 2 weeks from autograft administration.258 Such results are superior to earlier studies utilizing autologous marrow as a source of hemopoietic stem cells. Melphalan at 200 mg/m2 as preparative regimen is well tolerated even by patients up to age 70.259 This regimen can be given in the setting of renal failure although it is associated with a higher incidence and greater degree of extramedullary toxicities.260 There is no indication that the addition of total body irradiation to chemotherapy with melphalan is beneficial.261 If the promise holds, also in myelomatosis, that CR is a necessary but possibly not sufficient first step toward prolonged disease control and eventual cure, high-dose therapy should be conducted early during the disease when CR can be attained most readily.262 Indeed, in the case of 2 cycles of high-dose therapy with melphalan 200 mg/m2 (“total therapy”), CR can be obtained in almost 50 percent of patients. Median CR duration exceeds 4 years with 60 percent projected in continuous complete remission at 6 years in those lacking chromosome 13 deletion and presenting with low B2M. The median event-free and overall survival durations were 3.3 and 5.7 months with 25 percent remaining relapse-free and 45 percent alive at 8 years (Fig. 106-9). Treatment-related mortality within the first year of total therapy was 7 percent.262 Issues currently under investigation include the role of multiple cycles of high-dose therapy,263 tumor cell removal by selection of CD34 hemopoietic progenitor cells,263,264 and post-high-dose therapy maintenance strategies.

FIGURE 106-9 Event-free and overall survival (left panel) as well as CR duration (right panel) following total therapy262 for newly diagnosed patients. Total therapy consisted of remission induction with non-cross-resistant regimens followed by two cycles of high-dose therapy with melphalan 200 mg/m2 and interferon-a2 maintenance. In the absence of chromosome 13 deletion and with B2M levels £ 4 mg/L (present in 57 of 91 CR patients), CR duration was markedly extended with about 60 percent remaining in continuous complete remission at 6 years compared to less than 10 percent among the remaining subjects.

To date, CD34 selection has not resulted in superior event-free survival or overall survival when compared in randomized trials with nonselected autografts in support of BUCY263 or MEL 140 + TBI,262 indicating that residual disease remaining after high-dose therapy dominantly affects prognosis. Even when very early hemopoietic stem cells devoid of clonal B cells (CD34+, Thy-1+, Lin–) were employed, relapses especially of deletion 13 disease were common.264 Importantly, compared to nonselected cells, hemopoietic and immune reconstitution were significantly delayed resulting in considerable morbidity and mortality.
CONSOLIDATION CHEMOTHERAPY
Consolidation chemotherapy with DCEP (dexamethasone 40mg on days 1–4; continuous infusions of cyclophosphamide 400mg/m2, etoposide 40mg/m2, and cisplatin 10mg/m2; all daily for 4 days) after tandem transplant (Table 106-6), effective for posttransplant relapses,265 not only delayed relapses but also converted PR to CR in almost 30 percent of 50 patients treated.266 Maintenance immunotherapy with IFN-a is currently being tested in a U.S. Intergroup trial of early versus late myeloablative therapy for patients achieving at least partial remission. Idiotype vaccination strategies have been promising in low-grade lymphoma and currently are being evaluated for their ability to generate tumor-specific anti-idiotype T- and B-cell responses in patients with myeloma, as well.267
ALLOGENEIC STEM CELL TRANSPLANTATION
In the case of HLA-identical twins, syngeneic transplants should be offered in support of maximally cytoreductive therapy such as with melphalan 200 mg/m2 or TBI-containing regimens. Data from the European Bone Marrow Registry involving 16 subjects indicate a complete remission rate of 50 percent, and median durations of event-free and overall survival were 32 and 60 months, respectively.271
RELATED HLA-MATCHED ALLOGENEIC TRANSPLANTS
HLA-matched sibling donor transplant data in myeloma from EBMT and several individual institutions indicate a high transplant-related mortality of typically 50 percent within the first year, usually as a result of pneumonia, sepsis, or graft-vs-host disease. Event-free survival at 6 years for those achieving CR was 34 percent.272,273 At 7 years, 28 percent of all patients survived. Results were superior when prior therapy was limited to one regimen and when CR was attained. In comparing results of patients undergoing allogeneic transplantation with matched patients undergoing autograft-supported high-dose therapy, an obvious survival advantage was observed with autologous transplant due to high treatment-related mortality (41 percent versus 13 percent); however, in patients surviving more than 1 year after a transplant, there was a significantly better progression-free survival (p = 0.02) and a trend toward better long-term survival (p = 0.07) after allotransplants (Fig. 106-10).274 Additional advances can be expected from careful selection of patients early after diagnosis whose prognosis, due to disease-intrinsic features, has been poor with autograft-supported high dose therapy (e.g., chromosome 13 deletion myeloma) and from graft manipulation to take advantage of a graft-vs.-myeloma effect275 while reducing the grave toxicities of graft-vs.-host disease. Similar considerations apply to matched unrelated donor transplants. Current efforts focus, like in other hemopoietic malignancies, on reducing the conditioning regimen intensity (“mini-allotransplants”)276 and hastening hemopoietic reconstitution by administering high doses of donor peripheral blood stem cells mobilized with G-CSF. Results indicate that morbidity and mortality can be decreased markedly even in older patients.

FIGURE 106-10 Improved progression-free and overall survival following allogeneic transplantation compared to autologous transplantation in patients alive at 1 year.

SALVAGE THERAPIES
Such strategies must take into consideration the type and duration of prior therapy, disease responsiveness, and patient tolerance. High-dose dexamethasone alone, at 40 mg/day PO on days 1 to 4 each week, or combined with vincristine and doxorubicin (VAD regimen) represents a key element of therapy for myeloma unresponsive to or relapsing from remission induced with standard alkylating agent therapy.247 Such remissions can be further consolidated with autograft-supported high-dose melphalan when adequate quantities of hemopoietic stem cells can be procured. This is more likely when the patient has a normal platelet count over 150,000/µ liter and expected when CD34 quantities exceed 2 × 106/kg with up to 24 months of therapy and greater than 5 × 106/kg with more extended duration of treatment.257
In the case of high-risk disease with high LDH, labeling index greater than 2 percent and especially cytogenetic abnormalities involving chromosome 13 or other translocations, DCEP combination chemotherapy (Table 106-6) has proved effective in reestablishing disease control (approximately 75 percent tumor mass reduction) in up to 40 percent of cases, including true CR in 15 percent.265
Exciting results have been reported with thalidomide. This drug presumably works through an antiangiogenesis mechanism. It can produce both paraprotein and marrow responses in about one-third of cases treated mainly for posttransplant relapse often with high-risk cytogenetic features.11 Current trials are evaluating D.T. PACE (dexamethasone 40 mg daily × 4, thalidomide 400 mg daily continuously and 4-day continuous infusions of daily doses of cisplatin 10 mg/m2, doxorubicin 10 mg/m2, cyclophosphamide 400 mg/m2 and etoposide 40 mg/m2) followed by G-CSF administered subcutaneously until hemopoietic recovery.277
PRIMARY TREATMENT STRATEGY
Upon confirmation of a diagnosis of multiple myeloma, either symptomatic or progressive, a long-term strategy should be developed that considers, in addition to host features, the key myeloma prognosticators including B2M, CRP, labeling index, and, most important, cytogenetics or FISH to detect deletion 13 myeloma. These prognostic variables pertain to both standard and high-dose therapies. Given the rapid progress in myeloma biology and therapy during the past decade, practicing physicians and hematologists/oncologists should be aware of the latest developments offered as part of clinical research trials aimed at increasing the chance of durable complete remissions. Remission induction should avoid stem-cell-toxic therapy so that all patients can benefit potentially from dose-intensive regimens with autograft support. Available data clearly indicate that, although high-dose therapy induces CR with similar frequencies in good and high-risk myeloma, patients in the latter category require additional treatment to prevent relapse.
Those patients not qualifying for transplants for medical reasons or because of advanced age (greater than 75 years) can be managed with standard alkylator chemotherapy and glucocorticoids. Older patients with more limited life expectancy should be offered high-dose glucocorticoid-based induction plus pamidronate or intermediate dose melphalan with or without growth factor and stem cell support in case the former therapy turns out to be ineffective. High doses of glucocorticoids may be more toxic in some patients because of subclinical diabetes mellitus and susceptibility to infections and depressive disorders.
As the toxicity of allogeneic transplants seems to be alleviated by reducing conditioning regimen intensity, younger patients (younger than 60 years) should be evaluated for donor transplantation either from sibling or unrelated donors, especially when presenting with high-risk disease. However, it remains to be proved whether the anticipated beneficial graft-vs.-myeloma effect, occurring in about 30 to 40 percent of patients, depends on some of the same disease features that have been an obstacle to disease control with autograft-supported high-dose therapy. Given the immensely beneficial role of bisphosphonates (e.g., pamidronate) in delaying myeloma bone disease and in prolonging survival by favorably intervening with microenvironmental tumor survival signals, most patients should receive this adjunctive therapy.268,269
SUPPORTIVE CARE AND SPECIAL TREATMENTS
HYPERCALCEMIA AND RENAL FAILURE
Hypercalcemia and renal failure are best managed with high doses of dexamethasone alone or with the full VAD regimen. Occasionally, especially in refractory myeloma, calcitonin or pamidronate may be required. Hemodialysis should be used as clinically indicated for the management of acute or chronic renal failure.
In refractory conditions of persistent disease with recent onset of renal failure, high-dose therapy with melphalan and peripheral blood stem cell support should be considered in order to achieve maximum antitumor effect that, not infrequently, is associated with improvement or even normalization of renal function.
SPINAL CORD COMPRESSION
Spinal cord compression has traditionally been treated with local radiotherapy and/or decompressive laminectomy. While local radiotherapy has curative potential for the management of truly solitary plasmacytoma as demonstrated on MR imaging of axial marrow, its role in palliation has to be assessed in the context of long-term management and in light of the underlying cause. In more recently treated patients suffering from systemic disease, chemotherapy that includes high-dose dexamethasone pulsing with VAD or DCEP has been shown to provide remarkable activity. In the absence of symptom relief with tumor volume reduction on MRI within 1 week, local radiation and/or decompressive laminectomy should be added.
In case of cord compression as a result of vertebral collapse without readily identifiable plasmacytoma on MRI, radiation may not be beneficial, and decompressive laminectomy should be the treatment of choice. The local doses of radiotherapy to the spinal cord should not exceed 30 Gy, and liberal use of local radiation for the management of rib fractures is discouraged.
SYMPTOMATIC ANEMIA
Symptomatic anemia usually improves with therapy, especially with high doses of dexamethasone. Responses can be hastened by subcutaneous administration of recombinant erythropoietin at doses of 10,000 units thrice weekly or 40,000 once weekly.285,286 Such treatment is especially useful for patients failing to respond whose anemia is often worsened by alkylating agent therapy or renal failure.
MYELOSUPPRESSION
Hemopoietic growth factors, such as GM-CSF or G-CSF, are mainly used in the context of blood stem cell procurement and after transplant. They are not likely to facilitate more frequent administration of higher doses of melphalan or other alkylators targeting early hemopoietic progenitor cells. However, they have been shown to alleviate neutropenia associated with more intensive regimens such as EDAP,287 DCEP,265,266 D.T. PACE, or single-agent high-dose cyclophosphamide or etoposide (Table 106-6).288
RECURRENT INFECTIONS
Recurrent infections may be prevented with prophylactic use of broad-spectrum antibiotics, such as ciprofloxacin or trimethoprim-sulfamethoxazole on an alternating daily or twice weekly schedule. Patients prone to recurrent herpes simplex or zoster infections benefit from oral acyclovir at doses of 800 mg twice weekly. Intravenous immunoglobulins may reduce the risk for recurrent infections, but comparative trials with antibiotic prophylaxis have not been reported.
COURSE AND PROGNOSIS
With standard therapy, the clinical disease phase lasts an average of only 3 years, as a result of only temporary growth control with alkylating agents and glucocorticoids. Patients then succumb either to the consequences of rapid tumor cell expansion, akin to blast crisis of chronic myelogenous leukemia or transformation from an indolent to an aggressive malignant lymphoma,135 or to the consequences of marrow failure from chronic alkylating agent therapy, sometimes associated with the development of a myelodysplastic syndrome or frank acute myelogenous leukemia.245
Successful remissions induced by initial standard chemotherapy usually do not exceed a median of 18 months, and median survival of all patients averages 30 to 36 months. Few patients obtain true complete responses (as defined by absence of monoclonal protein production on immunofixation analysis and normal marrow aspirate and biopsy), typically on the order of 5 percent. Similarly, about 5 percent survive 10 to 15 years, usually when presenting with low tumor mass and responding to standard-dose regimens.254,255 However, virtually all patients with plasma cell myeloma receiving standard therapy succumb to their malignancy.
SECONDARY HEMOPOIETIC MALIGNANCIES
Due to their often advanced age, patients also may have a co-existing myelodysplastic syndrome. This can be recognized prior to the development of morphologic changes and cytopenia using cytogenetic analysis and, more recently, FISH using suitable probes to detect deletions of chromocome 5, 7, and 20, as well as trisomy 8. As in Hodgkin disease and malignant lymphoma, where autograft-supported high-dose therapy has been used extensively for salvage or for consolidation of high-risk disease, an accentuated frequency of myelodysplasia has been observed beginning about 2 years after autotransplants for myeloma.184,290 At 5 to 7 years, the incidence of MDS cytogenetic lesions did not exceed 1 to 2 percent in patients whose age did not exceed 50 years and when standard alkylating agent therapy was limited to 12 months. Otherwise, the frequency of cytogenetically recognized MDS reached 7 to 10 percent, especially when CD34 mobilization was impaired (Fig. 106-11). Thus, with a background of alkylating agent-induced DNA damage, hemopoietic stem cell replication stress after high-dose therapy may be associated with telomere shortening causing genomic instability and increasing the chance for clonal myelodysplasia and secondary AML.291 It remains to be investigated whether telomere shortening can be minimized by high dose CD34 autografting. This may reduce the potential for development of secondary hemopoietic malignancies.292

FIGURE 106-11 Development of myelodysplasia using cytogenetic criteria (5 or del 5q, 7 or del 7q, trisomy 8, del 20q11) following autologous hematopoietic stem cell-supported high-dose therapy with melphalan 200 mg/m2 (one or two cycles). Panel A: cumulative incidence of cytogenetic MDS in relationship to months of prior therapy (less than 12 versus greater than 12 months) and age (less than 50 versus greater than 50 years). Patients with no more than 12 months of prior therapy and aged 50 years or younger had the lowest risk of MDS compared to the three other groups. Panel B: examination of CD34 stem cell mobilization (CD34 × 106/kg) on MDS development among the 622 patients with either more than 12 months of prior therapy or more than 50 years of age. Note: MDS was least common in the subgroup with high CD34 yield (>23 × 106/kg).

CHAPTER REFERENCES

1.
Potter M: Pathogenesis of plasmacytomas in mice, in Cancer: A Comprehensive Treatise, edited by FF Becker, p 139. Plenum, New York, 1982.

2.
Radl J: Animal model of human disease. Benign monoclonal gammopathy (idiopathic paraproteinemia). Am J Pathol 105:91, 1981.

3.
Radl J, Croese JW, Zurcher C, et al: Animal model of human disease. Multiple myeloma. Am J Pathol 132:593, 1988.

4.
Radl J: Four major mechanisms in the development of monoclonal gammapathies. Postulations and facts, p 5. Proceedings of the Third EURAGE Symposium on Monoclonal Gammopathies: Clinical Significance and Basic Mechanisms, Brussels, Belgium, Sept 18–20, 1991.

5.
Feo-Zuppardi FJ, Taylor CW, Iwato K, et al: Long-term engraftment of fresh human myeloma cells in SCID mice. Blood 80:2843, 1992.

6.
Huang Y-W, Richardson JA, Tong AW, et al: Disseminated growth of a human multiple myeloma cell line in mice with severe combined immunodeficiency disease. Cancer Res 53:1392, 1993.

7.
Yaccoby S, Barlogie B, Epstein J: Primary myeloma cells growing in SCID-hu mice: a model for studying the biology and treatment of myeloma and its manifestations. Blood 92:2908, 1998.

8.
Shipman CM, Rogers MJ, Apperly JF, Russell RG, Croucher PI: Bisphosphonates induce apoptosis in human myeloma cell lines: a novel anti-tumor activity. Br J Hem 98(3):665–72, 1997.

9.
Aparicio A, Gardner A, Tu Y, Savage A, Berenson J, Lichtenstein A: In vitro cytoreductive effects on multiple myeloma cells induced by bisphosphonates. Leukemia 12: 220, 1998.

10.
D’Amato RJ, Loughnan MS, Flynn E, Folkman J: Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci USA 91:4082, 1994.

11.
Singhal S, Mehta J, Eddelmon P, et al: Marked anti-tumor effect from anti-angiogenesis therapy with thalidomide in high risk refractory multiple myeloma. Blood 92(suppl 1):318a (1306), 1998.

12.
Riedel DA, Potter LM: The epidemiology of multiple myeloma. Hematol Oncol Clin North Am 6:225, 1992.

13.
Ichimaru M, Ishimaru T, Mikami M, Matsunga M: Multiple myeloma among atomic bomb survivors in Hiroshima and Nagasaki, 1950–76: relationship to radiation dose absorbed by marrow. J Natl Cancer Inst 69:323, 1982.

14.
Gramenzi A, Buttino I, D’Avanzo B, et al: Medical history and the risk of multiple myeloma. Br J Cancer 63:679, 1991.

15.
Soulier J, Grollet L, Oksenhendler E, et al: Kaposi’s sarcoma-associated herpesvirus-like DNA sequences in multicentric Castleman’s disease. Blood 86:1276, 1995.

16.
Said W, Chien K, Takeuchi S, et al: Kaposi’s sarcoma-associated herpesvirus (KSHV or HHV8) in primary effusion lymphoma: ultrastructural demonstration of herpesvirus in lymphoma cells. Blood 87:4937, 1996.

17.
Schalling M, Ekman M, Kaaya EE, Linde A, Biberfeld P: A role for a new herpes virus (KSHV) in different forms of Kaposi’s sarcoma. Nat Med 1:707, 1995.

18.
Rettig MB, Ma HJ, Vescio RA, et al: Kaposi’s sarcoma-associated herpesvirus infection of bone marrow dendritic cells from multiple myeloma patients. Science 276:1851, 1997.

19.
Said JW, Rettig MR, Heppner K, et al: Localization of Kaposi’s sarcoma-associated herpesvirus in bone marrow biopsy samples from patients with multiple myeloma. Blood 90:4278, 1997.

20.
Chauhan D, Bharti A, Raje N, et al: Detection of Kaposi’s sarcoma herpesvirus DNA sequences in multiple myeloma bone marrow stromal cells. Blood 93:1482, 1999.

21.
Raje N, Gong J, Chauhan D, et al: Bone marrow and peripheral blood dendritic cells from patients with multiple myeloma are phenotypically and functionally normal despite the detection of Kaposi’s sarcoma herpesvirus gene sequences. Blood. 93:1487, 1999.

22.
Tarte K, Olsen SJ, Yang LZ, et al: Clinical-grade functional dendritic cells from patients with multiple myeloma are not infected with Kaposi’s sarcoma-associated herpesvirus. Blood 91:1852, 1998.

23.
Yi Q, Ekman M, Anton D, et al: Blood dendritic cells from myeloma patients are not infected with Kaposi’s sarcoma-associated herpesvirus (KSHV/HHV-8). Blood 92:402, 1998.

24.
Tisdale JF, Stewart AK, Dickstein B, et al: Molecular and serological examination of the relationship of human herpesvirus 8 to multiple myeloma: ORF 26 sequences in bone marrow stroma are not restricted to myeloma patients and other regions of the genome are not detected. Blood 92:2681, 1998.

25.
Potter M: Perspectives on the origins of multiple myeloma and plasmacytomas in mice. Hematol Oncol Clin North Am 6:211, 1992.

26.
Barlogie B, Epstein J, Selvanayagam P, Alexanian R: Plasma cell myeloma–new biological insights and advances in therapy. [Review]. Blood 73:865, 1989.

27.
Hallek M, Leif Bergsagel P, Anderson KC: Multiple myeloma: increasing evidence for a multistep transformation process. Blood 91:3, 1998.

28.
MacLennan ICM, Chan EYT: The origin of bone marrow plasma cells, in Epidemiology and Biology of Multiple Myeloma, edited by GI Obrams, M Potter, p 129. Springer, Berlin, 1991.

29.
Barlogie B, Alexanian R: Cellular aspects of myeloma: biologic and clinical implications, in Multiple Myeloma and Other Paraproteinemias, edited by IW Delamore, pp 154–168. Churchill Livingstone, Edinburgh, 1986.

30.
Bast E, van Camp B, Reynaert P, et al: Idiotypic peripheral blood lymphocytes in monoclonal gammopathy. Clin Exp Immunol 47:682, 1982.

31.
Berenson J, Wong R, Kim K, et al: Evidence of peripheral blood B lymphocyte but not T lymphocyte involvement in multiple myeloma. Blood 70:1550, 1987.

32.
Mellstedt H, Holm G, Pettersson D, et al: Idiotype-bearing lymphoid cells in plasma cell neoplasia. Clin Haematol 11:65, 1982.

33.
Pilarski LM, Jensen GS: Monoclonal circulating B cells in multiple myeloma: a continuously differentiating possibly invasive population as defined by expression of CD45 isoforms and adhesion molecules. Hematol/Oncol Clin North Am 6:297, 1992.

34.
Pilarski LM, Mant MJ, Reuther BA: Pre-B cells in peripheral blood of multiple myeloma patients. Blood 66:416, 1985.

35.
Ruiz-Arguelles GJ, Katzmann JA, Greipp PR, et al: Multiple myeloma: circulating lymphocytes that express plasma cell antigens. Blood 64:352, 1984.

36.
Berenson J, Lichtenstein A: Clonal rearrangement of immunoglobulin genes in the peripheral blood of multiple myeloma patients. Br J Haematol 73;425, 1989.

37.
Corradini P, Boccadoro M, Voena C, Pileri A: Evidence for a bone marrow B cell transcribing malignant plasma cell VDJ joined to C mu sequence in immunoglobulin (IgG)- and IgA- secreting multiple myelomas. J Exp Med 178:1091, 1993.

38.
Billadeau D, Ahmann G, Greipp P, Van Ness B: The bone marrow of multiple myeloma patients contains B cell populations at different stages of differentiation that are clonally related to the malignant plasma cell. J Exp Med 178:1023, 1993.

39.
Chen BJ, Epstein J: Circulating clonal lymphocytes in myeloma constitute a minor subpopulation of B cells. Blood 87:1972, 1996.

40.
Gould J, Alexanian R, Goodacre A, et al: Plasma cell karyotype in multiple myeloma. Blood 71:453, 1988.

41.
Dewald GW, Kyle RA, Hicks GA, Greipp PR: The clinical significance of cytogenetic studies in 100 patients with multiple myeloma, plasma cell leukemia, or amyloidosis. Blood 66(2):380, 1985.

42.
Sawyer JR, Waldron JA, Jagannath S, Barlogie B: Cytogenetic findings in 200 patients with multiple myeloma. Cancer Genet Cytogenet 82(1):41, 1995.

43.
Feinman R, Sawyer, J, Hardin J, Tricot G: Cytogenetics and molecular genetics in multiple myeloma. Hematol/Oncol Clin North Am 11:1, 1997.

44.
Selvanayagam P, Blick M, Narni F, et al: Alteration and abnormal expression of the c-MYC oncogene in human multiple myeloma. Blood 71:30, 1988.

45.
Greil R, Fasching B, Loidl P, Huber H: Expression of the c-MYC proto-oncogene in multiple myeloma and chronic lymphocytic leukemia: an in situ analysis. Blood 78:180, 1991.

46.
Neri A, Murphy JP, Cro L, et al: RAS oncogene mutation in multiple myeloma. J Exp Med 170:1715, 1989.

47.
Ernst TJ, Gazdar A, Ritz J, Shipp MA: Identification of a second transforming gene, RASN, in a human multiple myeloma line with a rearranged c-MYC allele. Blood 72:1163, 1989.

48.
Paquette RL, Berenson J, Lichtenstein A, et al: Oncogenes in multiple myeloma: point mutation of N-RAS. Oncogene 5:1659, 1990.

49.
Portier M, Moles J-P, Mazars G-R, et al: p53 and RAS gene mutations in multiple myeloma. Oncogene 7:2539, 1992.

50.
Liu P, Leong T, Quam L, et al: Activating mutations of N- and K-ras in multiple myeloma show different clinical associations: analysis of the Eastern Cooperative Oncology Group phase III trial. Blood 88:2699, 1996.

51.
Hamilton MS, Barker HF, Ball J, et al: Normal and neoplastic human plasma cells express BCL-2 antigen. Leukemia 5:768, 1991.

52.
Pettersson M, Jernberg-Wiklund H, Larson LG, et al: Expression of the BCL-2 gene in human multiple myeloma cell lines and normal plasma cells. Blood 79:495, 1992.

53.
Neri A, Baldini L, Trecca D, et al: p53 gene mutations in multiple myeloma are associated with advanced forms of malignancy. Blood 81:128, 1993.

54.
Drach J, Ackermann J, Fritz E, et al: Presence of a p53 gene deletion in patients with multiple myeloma predicts for short survival after conventional-dose chemotherapy. Blood 92:802, 1998.

55.
Dao DD, Sawyer JR, Epstein J, Hoover RG, Barlogie B, Tricot G: Deletion of the retinoblastoma gene in multiple myeloma. Leukemia 8:1280, 1994.

56.
Teoh G, Urashima M, Ogata A, et al: MDM2 protein overexpression promotes proliferation and survival of multiple myeloma cells. Blood 90:1982, 1997.

57.
Korganow AS, Martin T, Weber JC, et al: Molecular analysis of rearranged VH genes during B cell chronic lymphocytic leukemia: intraclonal stability is frequent but not constant. Leuk Lymphoma 14:55, 1994.

58.
Oscier DG, Thompsett A, Zhu D, Stevenson FK: Differential rates of somatic hypermutation in V(H) genes among subsets of chronic lymphocytic leukemia defined by chromosomal abnormalities. Blood 89:4153, 1997.

59.
Fais F, Ghiotto F, Hashimoto S, et al: Chronic lymphocytic leukemia B cells express restricted sets of mutated and unmutated antigen receptors. J. Clin. Invest. 102:1515, 1998.

60.
Bakkus MH, Heirman C, Van Riet I, Van Camp B, Thielemans K: Evidence that multiple myeloma Ig heavy chain VDJ genes contain somatic mutations but show no intraclonal variation. Blood 80:2326, 1992.

61.
Vescio RA, Cao J, Hong CH, et al: Myeloma Ig heavy chain V region sequences reveal prior antigenic selection and marked somatic mutation but no intraclonal diversity. J Immunol 155:2487, 1995.

62.
Shen HM, Peters A, Baron B, Zhu X, Storb U: Mutation of BCL-6 gene in normal B cells by the process of somatic hypermutation of Ig genes. Science. 280:1750, 1998.

63.
Sawyer JR, Lukacs J, Munshi N, et al: Identification of new nonrandom translocations in multiple myeloma with multicolor spectral karyotyping. Blood 92:4269, 1998.

64.
Chesi M, Bergsagel PL, Shonukan OO, et al: Frequent dysregulation of the c-maf proto-oncogene at 16q23 by translocation to an Ig locus in multiple myeloma. Blood 91:4457, 1998.

65.
Chesi M, Nardini E, Brents LA, et al: Frequent translocation t(4;14)(p16.3;q32.3) in multiple myeloma is associated with increased expression and activating mutations of fibroblast growth factor receptor 3. Nat Genet 16:260, 1997.

66.
Chesi M, Nardini E, Lim RS, Smith KD, Kuehl WM, Bergsagel PL: The t(4;14) translocation in myeloma dysregulates both FGFR3 and a novel gene, MMSET, resulting in IgH/MMSET hybrid transcripts. Blood 92:3025, 1998.

67.
Iida S, Rao PH, Butler M, et al: Deregulation of MUM1/IRF4 by chromosomal translocation in multiple myeloma. Nat Genet 17:226, 1997.

68.
Tricot G, Barlogie B, Jagannath S, et al: Poor prognosis in multiple myeloma is associated only with partial or complete deletions of chromosome 13 or abnormalities involving 11q and not with other karyotypes abnormalities. Blood 86:4250, 1995.

69.
Barlogie B, Sawyer J, Ayers D, et al: Chromosome 13 myeloma is a distinct entity with poor prognosis despite tandem autotransplants. Blood 92(suppl 1):258a(#1059).

70.
Perez-Simon JA, Garcia-Sanz R, Tabernero MD, et al: Prognostic value of numerical chromosome aberrations in multiple myeloma: a FISH analysis of 15 different chromosomes. Blood 91: 3366, 1998.

71.
Seong C, Delasalle K, Hayes K, et al: Prognostic value of cytogenetics in multiple myeloma. Br J Haematol 101:189, 1998.

72.
Shaughnessy J, Tian E, Bell T, et al: Molecular cytogenetic analysis of chromosome 13q14, site of a putative tumor suppressor gene in multiple myeloma. Blood 92(suppl 1):259a, 1998.

73.
Epstein J, Barlogie B: Tumor resistance to chemotherapy associated with expression of the multidrug resistance phenotype. Cancer Bull 41:41, 1989.

74.
Epstein J, Xiao H, Oba BK: P-glycoprotein expression in plasma cell myeloma is associated with resistance to VAD. Blood 74:913, 1989.

75.
Dalton WS, Durie BGM, Alberts DS, et al: Characterization of a new drug resistant human myeloma cell line which expresses P-glycoprotein. Cancer Res 46:5125, 1986.

76.
Dalton WS, Grogan TM, Durie BGM, et al: Drug-resistance in multiple myeloma and non-Hodgkin’s lymphoma: detection of P-glycoprotein and potential circumvention by addition of verapamil to chemotherapy. J Clin Oncol 7:415, 1989.

77.
Dalton WS, Grogan TM, Rybski JA, et al: Immunohistochemical detection and quantitation of P-glycoprotein in multiple drug-resistant human myeloma cells: association with level of drug resistance and drug accumulation. Blood 73;747, 1989.

78.
Dalton WS: Detection of multidrug resistance gene expression in multiple myeloma. [Review]. Leukemia 11:1166, 1997.

79.
Chaudhary PM, Roninson IB: Expression and activity of p-glycoprotein, a multidrug efflux pump, in human hematopoietic stem cells. Cell 66:85, 1991.

80.
Sonneveld P, Lokhorst HM, Vossebeld P: Drug resistance in multiple myeloma. [Review] Semin Hematol 34:34, 1997.

81.
Raaijmakers HG, Izquierdo MA, Lokhorst HM, et al: Lung-resistance-related protein expression is a negative predictive factor for response to conventional low but not to intensified dose alkylating chemotherapy in multiple myeloma. Blood 91:1029, 1998.

82.
Kawano M, Hirano T, Matsuda T, et al: Autocrine generation and requirement of BSF-2/IL-6 for human multiple myelomas. Nature 332:83, 1988.

83.
Klein B, Zhang XG, Jourdan M, et al: Paracrine rather than autocrine regulation of myeloma-cell growth and differentiation by interleukin-6. Blood 73:517, 1989.

84.
Caligaris-Cappio F, Bergui L, Gaidano GL, et al: In vitro studies provide evidence that multiple paracrine loops may be operating in multiple myeloma, in Epidemiology and Biology of Multiple Myeloma, edited by GI Obrams, M Potter, p 123. Springer, Berlin, 1991.

85.
Hata H, Xiao H, Petrucci MT, Woodliff J, Chang R, Epstein J: Interleukin-6 gene expression in multiple myeloma: a characteristic of immature tumor cells. Blood 81:3357, 1993.

86.
Brandt S, Bodine D, Dunbar C, Nienhuis A: Dysregulated interleukin-6 expression produces a syndrome resembling Castleman’s disease in mice. J Clin Invest 86:592, 1990.

87.
Suematsu S, Matsusaka T, Matsuda T, et al: Generation of plasmacytomas with the chromosomal translocation t(12;15) in interleukin 6 transgenic mice. Proc Natl Acad Sci USA 89(1):232, 1992.

88.
Caligaris-Cappio F, Bergui L, Gregoretti MG, et al: Role of bone marrow stromal cells in the growth of human multiple myeloma. Blood 77:2688, 1991.

89.
Thomas X, Xiao HQ, Chang R, Epstein J: Circulating B lymphocytes in multiple myeloma patients contain an autocrine IL-6 driven pre-myeloma cell population. Curr Top Microbiol Immunol 182:201, 1992.

90.
Epstein J: Myeloma phenotype: clues to disease origin and manifestation. Hematol Oncol Clin North Am 6:249, 1992.

91.
Van Camp B, Durie BGM, Spier C, et al: Plasma cells in multiple myeloma express a natural killer cell-associated antigen: CD56 (NKH-1; Leu-19). Blood 75:377, 1990.

92.
Kawano MM, Huang N, Harada H, et al: Identification of immature and mature myeloma cells in the bone marrow of human myelomas. Blood 82:564, 1993.

93.
Omede P, Boccadoro M, Fusaro A, Gallone G, Pileri A: Multiple myeloma: “early” plasma cell phenotype identifies patients with aggressive biological and clinical characteristics. Br J Haematol 85:504, 1993.

94.
Huang N, Kawano MM, Harada H, et al: Heterogeneous expression of a novel MPC-1 antigen on myeloma cells: possible involvement of MPC-1 antigen in the adhesion of mature myeloma cells to bone marrow stromal cells. Blood 82:3721, 1993.

95.
Stauder R, Van Driel M, Schwarzler C, et al: Different CD44 splicing patterns define prognostic subgroups in multiple myeloma. Blood 88:3101, 1996.

96.
Damiano JS, Cress AE, Hazlehurst LA, Shtil AA, Dalton WS: Cell adhesion mediated drug resistance (CAM-DR): role of integrins and resistance to apoptosis in human myeloma cell lines. Blood 93:1658, 1999.

97.
Cozzolino F, Torcia M, Adinucci D, et al: Production of interleukin-1 by bone marrow myeloma cells. Blood 74:380, 1989.

98.
Garrett IR, Durie BGM, Nedwin GE, et al: Production of lymphotoxin, a bone resorbing cytokine, by cultured human myeloma cells. N Engl J Med 317:526, 1989.

99.
Mundy GR, Raisz LG, Cooper RA, et al: Evidence for the secretion of an osteoclast-stimulating factor in myeloma. N Engl J Med 291:1041, 1974.

100.
Hardin J, MacLeod S, Grigorieva I, et al: Interleukin-6 prevents dexamethasone-induced myeloma cell death. Blood 84:3063, 1994.

101.
Xu F, Gardner A, Tu Y, Michl P, Prager D, Lichtenstein A: Multiple myeloma cells are protected against dexamethasone-induced apoptosis by insulin-like growth factors. Br J Haematol 97:429, 1997.

102.
Borset M, Hjorth-Hansen H, Seidel C, Sundan A, Waage A: Hepatocyte growth factor and its receptor c-met in multiple myeloma. Blood 88:3998, 1996.

103.
Grigorieva I, Thomas X, Epstein J: The bone marrow stromal environment is a major factor in myeloma cell resistance to dexamethasone. Exp Hematol 26:597, 1998.

104.
Eastgate J, Moreb J, Nick HS, et al: A role for manganese superoxide dismutase in radioprotection of hematopoietic stem cells by interleukin-1. Blood 81:639, 1993.

105.
Feinman R, Koury J, Thames M, Barlogie B, Epstein J, Siegel DS: Role of NF-kB in the rescue of multiple myeloma cells from glucocorticoid-induced apoptosis by bcl-2. Blood (in press) 1999.

106.
Ridley RC, Xiao H, Hata H, Woodliff J, Epstein J, Sanderson RD: Expression of syndecan regulates human myeloma plasma cell adhesion to type I collagen. Blood 81:767, 1993.

107.
Wijdenes J, Vooijs WC, Clement C, et al: A plasmocyte selective monoclonal antibody (BB4) recognizes syndecan-1. Br J Haematol 94:318, 1996.

108.
Dhodapkar MV, Kelly T, Theus A, Athota AB, Barlogie B, Sanderson RD: Elevated levels of shed syndecan-1 correlate with tumour mass and decreased matrix metalloproteinase-9 activity in the serum of patients with multiple myeloma. Br J Haematol 99:368, 1997.

109.
Dhodapkar M, Abe E, Theus A, et al: Syndecan-1 is a multifunctional regulator of myeloma pathobiology: control of tumor cell survival, growth and bone cell differentiation. Blood 91:2679, 1998.

110.
Kleeff J, Ishiwata T, Kumbasar A, et al: The cell-surface heparan sulfate proteoglycan glypican-1 regulates growth factor action in pancreatic carcinoma cells and is overexpressed in human pancreatic cancer. J Clin Invest 102:1662, 1998.

111.
Pihan GA, Purohit A, Wallace J, et al: Centrosome defects and genetic instability in malignant tumors. Cancer Res 58:3974, 1998.

112.
Hofbauer LC, Heufelder AE: Osteoprotegerin and its cognate ligand: a new paradigm of osteoclastogenesis. Eur J Endocrinol 139:152, 1998.

113.
Munshi N, Wilson CS, Penn J, et al: Angiogenesis in newly diagnosed multiple myeloma: poor prognosis with increased microvessel density (MVD) in bone marrow biopsies Blood 92(suppl 1):97a, 1998.

114.
Bellamy WT, Richter L, Frutiger Y, Grogan TM: Expression of vascular endothelial growth factor and its receptors in hematopoietic malignancies. Cancer Res 59:728, 1999.

115.
Kruse FE, Joussen AM, Rohrschneider K, Becker MD, Volcker HE: Thalidomide inhibits corneal angiogenesis induced by vascular endothelial growth factor. Graefes Arch Clin Exp Ophthalmol 236:461, 1998.

116.
Bataille R, Klein B: The bone resorbing activity of interleukin-6. J Bone Min Res 9:1144, 1991.

117.
Bataille R, Chappard D, Marcelli C, et al: Mechanism of bone destruction in multiple myeloma. The importance of an unbalanced process in determining the severity of lytic bone disease. J Clin Oncol 7:1909, 1989.

118.
Hind CRK, Baltz ML, Pepys MB: Amyloidosis, in Multiple Myeloma and Other Paraproteinaemias, edited by IW Delamore, p 234. Churchill Livingstone, Edinburgh, 1986.

119.
Ullrich S, Zolla-Pazner S: Immunoregulatory circuits in myeloma. Clin Hematol 11:87, 1982.

120.
Jacobson DR, Zolla-Pazner S: Immunosuppression and infection in multiple myeloma. Semin Oncol 2:282, 1986.

121.
Broder S, Humphrey R, Durm M, et al: Impaired synthesis of (non-paraprotein) immunoglobulins by circulating lymphocytes from patients with multiple myeloma. N Engl J Med 293:887, 1975.

122.
Lynch RG: A role for TGF-beta in the immunodeficiency of malignant plasma cell tumors, abstract. Proceedings of the Third EURAGE Symposium, Brussels, Belgium, Sept 18–20, 1991.

123.
Villunger A, Egle A, Marschitz I, et al: Constitutive expression of Fas (Apo-1/CD95) ligand on multiple myeloma cells: a potential mechanism of tumor-induced suppression of immune surveillance. Blood 90:12, 1997.

124.
Solomon A, Weiss DT: A perspective of plasma cell dyscrasias: clinical implications of monoclonal light chains in renal disease, in The Kidney in Plasma Cell Dyscrasias, edited by L Minetti, G D’Amico, C Ponticelli, p 3. Kluwer, Dordrecht, Netherlands, 1988.

125.
Solomon A, Weiss DT, Kattine AA: Nephrotoxic potential of Bence Jones proteins. N Engl J Med 324:1845, 1991.

126.
Alexanian R, Barlogie B, Dixon D: Renal failure in multiple myeloma: pathogenesis and prognostic implications. Arch Intern Med 150:1693, 1990.

127.
Alexanian R, Barlogie B: Implications of renal failure in multiple myeloma, in The Kidney in Plasma Cell Dyscrasias, edited by L Minetti, G D’Amico, C Ponticelli, p 260. Kluwer, Dordrecht, Netherlands, 1988.

128.
Zucker-Franklin D: Renal amyloidosis: new perspectives, in The Kidney in Plasma Cell Dyscrasias, edited by L Minetti, G D’Amico, C Ponticelli, p 45. Kluwer, Dordrecht, Netherlands, 1988.

129.
Kyle RA, Greipp PR: Amyloidosis (AL): clinical and laboratory features in 229 cases. Mayo Clinic Proc 58:665, 1983.

130.
Buxbaum J: Mechanisms of disease: monoclonal immunoglobulin deposition. Hematol Oncol Clin North Am 6:323, 1992.

131.
Gallo G, Buxbaum J: Monoclonal immunoglobulin deposition disease: immunopathologic aspects of renal involvement, in The Kidney in Plasma Cell Dyscrasias, edited by L Minetti, G D’Amico, C Ponticelli, p 171. Kluwer, Dordrecht, Netherlands, 1988.

132.
Reeves WB, Foley RJ, Weinman EJ: Nephrotoxicity from nonsteroidal anti-inflammatory drugs. South Med J 78:318, 1985.

133.
Fattori E, Della Rocca C, Costa P, et al: Development of progressive kidney damage and myeloma kidney in interleukin-6 transgenic mice. Blood 83:2570, 1994.

134.
Spiers ASD, Halpern R, Ross SC, et al: Meningeal myelomatosis. Arch Intern Med 140:256, 1980.

135.
Barlogie B, Smallwood L, Smith T, Alexanian R: High serum levels of lactic dehydrogenase identify a high-grade lymphoma-like myeloma. Ann Intern Med 110:521, 1989.

136.
Bichel J, Efferse P, Gormsen H, Harboe N: Leukemic myelomatosis (plasma cell leukemia). A review with report of four cases. Acta Radiol 37:196, 1952.

137.
Waldenström JG, Adner A, Gydell K, Zettervall O: Osteosclerotic “plasmacytoma” with polyneuropathy, hypertrichosis and diabetes. Acta Med Scand 203:297, 1978.

138.
Miralles GD, O’Fallon JR, Talley NJ: Plasma-cell dyscrasia with polyneuropathy—the spectrum of POEMS syndrome. N Engl J Med 327:1919, 1992.

139.
Pruzanski W, Watt JG: Serum viscosity and hyperviscosity syndrome in IgG multiple myeloma. Ann Intern Med 77:853, 1972.

140.
Preston FE, Cooke KB, Foster ME, et al: Myelomatosis and the hyperviscosity syndrome. Br J Haematol 38:517, 1978.

141.
Chandy KG, Stockley RG, Leonard RCF, et al: Relationships between serum viscosity and intravascular IgA polymer concentration in IgA myeloma. Clin Exp Immunol 46:653, 1981.

142.
Somer T: Hyperviscosity syndrome in plasma cell dyscrasias. Adv Microcirculation 6:1, 1975.

143.
Waldenström JG: Incipient myelomatosis or “essential” hyperglobulinaemia with fibrinogenopenia—a new syndrome. Acta Med Scand 117:216, 1944.

144.
Kelsey PR, Delamore IW: Clinical features of multiple myeloma, in Multiple Myeloma and Other Paraproteinaemias, edited by IW Delamore, p 117. Churchill Livingstone, Edinburgh, 1986.

145.
Capra JD, Kunkel HG: Aggregation of IgG3 proteins. Relevance to the hyperviscosity syndrome. J Clin Invest 49:610, 1970.

146.
Perkins HA, MacKenzie MR, Fudenberg HH: Haemostatic defects in dysproteinaemias. Blood 35:695, 1970.

147.
Lackner H: Haemostatic abnormalities associated with dysproteinaemias. Semin Haematol 10:125, 1973.

148.
Barlogie B, Gale RP: Multiple myeloma and chronic lymphocytic leukemia: parallels and contrasts. Am J Med 93:443, 1992.

149.
Greipp R, Raymond NM, Kyle RA, O’Fallon WM: Multiple myeloma: significance of plasmablastic subtype in morphological classification. Blood 65:305, 1985.

150.
Greipp PR, Leong T, Bennett JM, et al: Plasmablastic morphology—an independent prognostic factor with clinical and laboratory correlates: Eastern Cooperative Oncology Group (ECOG) myeloma trial E9486 report by the ECOG Myeloma Laboratory Group. Blood 91:2501, 1998.

151.
Ludwig H, Pecherstorfer M, Leitgeb C, Fritz E: Recombinant human erythropoietin for the treatment of chronic anemia in multiple myeloma and squamous cell carcinoma Stem Cells (Dayt) 11:348, 1993.

152.
Faquin WC, Schneider TJ, Goldberg MA: Effect of inflammatory cytokines on hypoxia-induced erythropoietin production. Blood 79:1987, 1992.

153.
Singh A, Eckardt KU, Zimmermann A, et al: Increased plasma viscosity as a reason for inappropriate erythropoietin formation. J Clin Invest 91:251, 1993.

154.
Gleuck HI, Hong RA: Circulating anticoagulant in multiple myeloma: its modification by penicillin. J Clin Invest 44:1866, 1965.

155.
Wenz B, Freidman G: Acquired factor VIII inhibitor in a patient with malignant lymphoma. Am J Med Sci 268:295, 1974.

156.
Kelsey PR, Leyland MJ: Acquired inhibitor to human factor VIII associated with paraproteinaemia and subsequent development of chronic lymphatic leukaemia. Br Med J 285:174, 1982.

157.
Coleman M, Vigliano EM, Weksler ME, Nachman RL: Inhibition of fibrin monomer polymerization by lambda myeloma globulin. Blood 39:210, 1972.

158.
Furie B, Greene E, Furie BC: Syndrome of acquired factor X deficiency and systemic amyloidosis. In vivo studies of the metabolic fate of factor X. N Engl J Med 297:81, 1977.

159.
Kunkel LA: Acquired circulating anticoagulants in malignancy. Semin Thromb Hemost 18:416, 1992.

160.
Billadeau D, Quam L, Thomas W, et al: Detection and quantitation of malignant cells in the peripheral blood of multiple myeloma patients. Blood 80:1818, 1992.

161.
Aubin J, Davi F, Nguyen-Salomon F, et al: Description of a novel FR1 IgH PCR strategy and its comparison with three other strategies for the detection of clonality in B cell malignancies. Leukemia 9:471, 1995.

162.
Barlogie B, Alexanian R, Pershouse M, et al: Cytoplasmic immunoglobulin content in multiple myeloma. J Clin Invest 76:765, 1985.

163.
Latreille J, Barlogie B, Johnston D, Drewinko B, Alexanian R: Ploidy and proliferative characteristics in monoclonal gammopathies. Blood 59:43, 1982.

164.
Latreille J, Barlogie B, Dosik G, Johnston DA, Drewinko B, Alexanian R: Cellular DNA content as a marker of human multiple myeloma. Blood 55:403, 1980.

165.
Epstein J, Barlogie B, Alexanian R: Phenotypic heterogeneity in aneuploid multiple myeloma indicates pre-B cell involvement. Blood 71:861, 1988.

166.
Grogan TM, Durie BG, Lomen C, et al: Delineation of a novel pre-B cell compartment in plasma cell myeloma: immunochemical, immunophenotypic, genotypic, cytologic, cell culture and kinetic features. Blood 70:832, 1987.

167.
Grogan TM, Durie BGM, Spier CM, et al: Myelomonocytic antigen positive multiple myeloma. Blood 73:763, 1989.

168.
Epstein J, Xiao H-Q, He X-Y: Markers of multiple hematopoietic-cell lineages in multiple myeloma. N Engl J Med 322:664, 1990.

169.
Durie BGM, Grogan TM: cALLa-positive myeloma: an aggressive subtype with poor survival. Blood 66:229, 1985.

170.
Caligaris-Cappio F, Bergui L, Tesio L, et al: Identification of malignant plasma cell precursors in the bone marrow of multiple myeloma. J Clin Invest 76:1243, 1985.

171.
Drewinko B, Alexanian R, Boyer H, et al: The growth fraction of human myeloma cells. Blood 57:333, 1981.

172.
Durie BGM, Salmon SE, Moon TE: Pretreatment tumor mass, cell kinetics, and prognosis in multiple myeloma. Blood 55:364, 1980.

173.
Greipp PR, Witzig TE, Gonchoroff NJ, et al: Immunofluorescence labeling indices in myeloma and related monoclonal gammopathies. Mayo Clin Proc 62:969, 1987.

174.
Boccadoro M, Massaia M, Dianzani U, et al: Multiple myeloma: biological and clinical significance of bone marrow plasma cell labelling index. Haematologica 72:171, 1987.

175.
Witzig TE, Gonchoroff NJ, Katzmann JA, et al: Peripheral blood B cell labeling indices are a measure of disease activity in patients with monoclonal gammopathies. J Clin Oncol 6:1041, 1988.

176.
Greipp PR, Lust JA, O’Fallon WM, Katzmann JA, Witzig TE, Kyle RA: Plasma cell labeling index and beta 2-microglobulin predict survival independent of thymidine kinase and C-reactive protein in multiple myeloma. Blood 81:3382, 1993.

177.
Van Den Berghe H: Chromosomes in plasma-cell malignancies. Eur J Haematol 43(suppl 51):47, 1989.

178.
Meeus P, Stul MS, Mecucci C, Cassiman JJ, Van den Berghe H: Molecular breakpoints of t (11;14)(q13;q32) in multiple myeloma. Cancer Genet Cytogenet 83:25, 1995.

179.
Ladanyi M, Wang S, Niesvizky R, Feiner H, Michaeli J: Proto-oncogene analysis in multiple myeloma Am Pathol 141:949, 1992.

180.
Avet-Loiseau H, Li JY, Facon T, et al: High incidence of translocations t(11;14)(q13;q32) and t(4;14)(p16;q32) in patients with plasma cell malignancies. Cancer Res 58:5640, 1998.

181.
Nishida K, Tamura A, Nakazawa N, et al: The Ig heavy chain gene is frequently involved in chromosomal translocations in multiple myeloma and plasma cell leukemia as detected by in situ hybridization. Blood 90(2):526, 1997.

182.
Bergsagel PL, Chesi M, Nardini E, Brents LA, Kirby SL, Kuehl WM: Promiscuous translocations into immunoglobulin heavy chain switch regions in multiple myeloma. Proc Natl Acad Sci USA 93:13931, 1996.

183.
Durie BGM: Cellular and molecular genetic features of myeloma and related disorders. Hematol Oncol Clin North Am 6:463, 1992.

184.
Drach J, Ayers D, Govindarajan R, Sawyer J, et al: MDS-associated cytogenetic abnormalities (CG?) in both hematopoietic and neoplastic cells after autotransplants (AT) in 868 patients with multiple myeloma (MM). Blood 92(suppl 1):97a(#398).

185.
Pedersen-Bjergaard J, Timshel S, Andersen MK, Andersen AS, Philip P: Cytogenetically unrelated clones in therapy-related myelodysplasia and acute myeloid leukemia: experience from the Copenhagen series updated to 180 consecutive cases. Genes Chromosomes Cancer 23:337, 1998.

186.
Shaughnessy J, Barlogie B: Chromosome 13 deletion in myeloma. Curr Top Microbiol Immunol 246:199, 1999.

187.
Dallinger S, Kaufmann H, Ackermann J, et al: Interphase fluorescence in situ hybridization (FISH) confirms the poor prognosis of patients with multiple myeloma (mm) and deletion of 13q. Blood 92(suppl 1):97a, 1998.

188.
Smith L, Barlogie B, Alexanian R: Biclonal and hypodiploid multiple myeloma. Am J Med 80:841, 1986.

189.
Durie BGM, Baum VE, Vela EE, Mundy GR: Abnormalities of chromosome 6q and osteoclast activating factor (LAF: TNF-b) production in multiple myeloma. Blood 68:208a, 1986.

190.
Durie B, Salmon S: A clinical staging system for multiple myeloma. Cancer 36:842, 1975.

191.
Salmon SE, Smith BA: Immunoglobulin synthesis and total body tumor cell number in IgG multiple myeloma. J Clin Invest 49:114, 1970.

192.
Child JA, Norfolk DR, Cooper EH: Serum beta-2-microglobulin in myelomatosis: potential value in stratification and monitoring. Br J Haematol 63:406, 1986.

193.
Garewal H, Durie BGM, Kyle RA, et al: Serum beta-2-microglobulin in the initial staging and subsequent monitoring of monoclonal plasma cell disorders. J Clin Oncol 2:51, 1984.

194.
Alexanian R, Barlogie B, Fritsche H: Beta 2 microglobulin myeloma: optimal use for staging, prognosis and treatment—a prospective study of 160 patients. Blood 63:468, 1984.

195.
Durie BGM, Young LA, Salmon SE: Human myeloma in vitro colony growth: interrelationship between drug sensitivity, cell kinetics and patient survival duration. Blood 61:929, 1983.

196.
Bataille R, Boccadoro M, Klein B, et al: C-reactive protein and beta-2-microglobulin produce a simple and powerful myeloma staging system. Blood 80:733, 1992.

197.
Klein B, Bataille R: Cytokine network in human multiple myeloma. Hematol Oncol Clin North Am 6:273, 1992.

198.
Bataille R, Chappard D, Klein B: Mechanisms of bone lesions in multiple myeloma. Hematol Oncol Clin North Am 6:285, 1992.

199.
Bataille R, Harousseau JL: Multiple myeloma. N Engl J Med 336(23):1657, 1997.

200.
Cherng NC, Asal NR, Kuebler JP, Lee ET, Solanki D: Prognostic factors in multiple myeloma. Cancer 67:3150, 1991.

201.
Dimopoulos MA, Alexanian R, Barlogie B: High serum lactic dehydrogenase as a marker of drug resistance in multiple myeloma. Ann Intern Med 115:931, 1991.

202.
Bartl R, Frisch B, Fateh-Moghadam A, Kettner G, Jaeger K, Sommerfeld W: Histologic classification and staging of multiple myeloma. A retrospective and prospective study of 674 cases. Am J Clin Pathol 87:342, 1987.

203.
Waldron J, Jazieh R, Jagannath S, et al: Bone marrow morphology (BMM) adds critical prognostic information to other standard parameters (SP) including cytogenetics among newly diagnosed multiple myeloma (MM) patients (PTS) receiving total therapy (TT). Blood 90:90a, 1997.

204.
Dimopoulos MA, Moulopoulos A, Delasalle K, Alexanian R: Solitary plasmacytoma of bone and asymptomatic multiple myeloma. Hematol Oncol Clin North Am 6:359, 1992.

205.
Daffner RH, Lupetin AR, Dash N, et al: MRI in the detection of malignant infiltration of bone marrow. Am J Roentgenol 146:353, 1986.

206.
Moulopoulos L, Dimopoulos M, Weber D, et al: Magnetic resonance imaging in the staging of solitary plasmacytoma of bone. J Clin Oncol 11:1311, 1993.

207.
Dohner H, Guckel F, Knowf W, et al: Magnetic resonance imaging of bone marrow in lymphoproliferative disorders: correlation with bone marrow biopsy. Br J Haematol 73:12, 1989.

208.
Moulopoulos LA, Dimopoulos MA, Weber D, Fuller L, Libshitz HI, Alexanian R: Magnetic resonance imaging in the staging of solitary plasmacytoma of bone. J Clin Oncol 11:1311, 1993.

209.
Angtuaco E, Jazieh A, Ferris E, et al: Complete remission by MRI (MR-CR) after tandem autotransplants associated with superior survival blood. 92(Suppl1):97a(#4117).

210.
Kyle RA: Diagnostic criteria of multiple myeloma. Hematol Oncol Clin North Am 6:347, 1992.

211.
Alexanian R: Diagnosis and management of multiple myeloma, in Neoplastic Diseases of the Blood, 2d ed, edited by PH Weirnile, GP Canellos, RA Kyle, CA Schiffer, pp 453–465. Churchill Livingstone, New York, 1991.

212.
Waldenström JG: Benign monoclonal gammopathy. Acta Med Scand 216:435, 1984.

213.
Kyle RA: Monoclonal gammopathy of determined significance: natural history in 241 cases. Am J Med 64:814, 1978.

214.
Greipp PR, Kyle RA: Clinical morphological and cell kinetic differences among multiple myeloma, monoclonal gammopathy of undetermined significance, and smoldering multiple myeloma. Blood 62:166, 1983.

215.
Bataille R, Sany J: Solitary myeloma: clinical and prognostic features of a review of 114 cases. Cancer 48:845, 1981.

216.
Corwin J, Lindberg RD: Solitary plasmacytoma of bones versus extramedullary plasmacytomas and their relationship to multiple myeloma. Cancer 43:1007, 1979.

217.
Knowling MA, Harwood AR, Bergsagel DF: Comparison of extramedullary plasmacytomas with solitary and multiple plasma cell tumors of bone. J Clin Oncol 1:255, 1983.

218.
Whittaker JA: Solitary plasmacytoma, in Multiple Myeloma and Other Paraproteinaemias, edited by IW Delamore, p 193. Churchill Livingstone, New York, 1986.

219.
Kyle R, Schreiman J, McLeod R, et al: Computed tomography in diagnosis of multiple myeloma and its variants. Arch Intern Med 145:1451, 1985.

220.
Libbey CA, Skinner M, Cohen AS: Use of abdominal fat tissue aspirate in the diagnosis of systemic amyloidosis. Arch Intern Med 143:1549, 1983.

221.
Cooper JH: A histochemical construct of the amyloid fibril, in Amyloidosis E.A.R.S., edited by CR Tribe, PA Bacon, pp 31–34. Wright, Bristol, 1983.

222.
Ridolfi RL, Bulkley BH, Hutchins GM: The conduction system in cardiac amyloidosis. Am J Med 62:677, 1977.

223.
Hind CRK, Gibson DG, Lavender JP, Pepys MB: Non-invasive demonstration of cardiac involvement in acquired forms of systemic amyloidosis. Lancet 1:1417, 1984.

224.
Woodruff RK, Whittle JM, Malpas JS: Solitary plasmacytoma. I: Extramedullary soft tissue plasmacytoma. Cancer 43:2340, 1979.

225.
Mill WB, Griffith R: The role of radiation therapy in the management of plasma cell tumors. Cancer 45:647, 1980.

226.
Liebross RH, Ha CS, Cox JD, Weber D, Delasalle K, Alexanian R: Solitary bone plasmacytoma: outcome and prognostic factors following radiotherapy. Int J Radiat Oncol Biol Phys 41:1063, 1998.

227.
Woodruff RK, Malpas JS, White FE: Solitary plasmacytoma. II: Solitary plasmacytoma of bone. Cancer 43:2344, 1979.

228.
Fruehwald FXJ, Tscholakoff D, Schwaighoffer B, et al: Magnetic resonance imaging of the lower vertebral column in patients with multiple myeloma. Radiology 23:193, 1988.

229.
Alexanian R: Localized and indolent myeloma. Blood 56:521, 1980.

230.
Kyle RA, Greipp R: Smoldering multiple myeloma. N Engl J Med 302:1347, 1980.

231.
Dimopoulos M, Moulopoulos A, Smith T, et al: Risk of disease progression in asymptomatic multiple myeloma. Am J Med 94:57, 1993.

232.
Bergsagel DE, Sprague CC, Austin C, Griffith KM: Evaluation of new chemotherapeutic agents in the treatment of multiple myeloma IV: l-phenylalanine mustard. Cancer Chemother Rep 21:87, 1962.

233.
Alexanian R, Haut A, Khan AU, et al: Treatment of multiple myeloma: combination chemotherapy with different melphalan dose regimens. JAMA 208:1680, 1969.

234.
Boccadoro M, Marmont F, Tribalto M, et al: Multiple myeloma: VMCP/VBAP alternating combination chemotherapy is not superior to melphalan and prednisone even in high-risk patients. J Clin Oncol 9:444, 1991.

235.
Gregory WM, Richards MA, Malpas JS: Combination chemotherapy versus melphalan and prednisolone in the treatment of multiple myeloma: an overview of published trials. J Clin Oncol 10:334, 1992.

236.
Combination chemotherapy versus melphalan plus prednisone as treatment for multiple myeloma: an overview of 6,633 patients from 27 randomized trials. Myeloma Trialists’ Collaborative Group. J Clin Oncol 16:3832, 1998.

237.
Palmer M, Belch A, Hanson J, et al: Reassessment of the relationship between M-protein decrement and survival in multiple myeloma. Br J Cancer 59:110, 1989.

238.
Durie BGM, Russel DH, Salmon SE: Reappraisal of plateau phase in myeloma. Lancet 1:65, 1980.

239.
Alexanian R, Gehan E, Haut A, et al: Unmaintained remission in multiple myeloma. Blood 51:1005, 1978.

240.
Belch A, Shelley W, Bergsagel D, et al: A randomized trial of maintenance versus no maintenance melphalan and prednisone in responding multiple myeloma patients. Br J Cancer 57:94, 1988.

241.
Mandelli F, Avvisati G, Amadori S, et al: Maintenance treatment with recombinant interferon alfa-2b in patients with multiple myeloma responding to conventional induction chemotherapy. N Engl J Med 20:1430, 1990.

242.
Ludwig H, Cohen AM, Polliack A, et al: Interferon-alpha for induction and maintenance in multiple myeloma: results of two multicenter randomized trials and summary of other studies. Ann Oncol 6:467, 1995.

243.
Salmon SE, Crowley JJ, Balcerzak SP, et al: Interferon versus interferon plus prednisone remission maintenance therapy for multiple myeloma: a Southwest Oncology Group Study. J Clin Oncol 16:890, 1998.

244.
Berenson J, Crowley J, Barlogie B, Salmon S: Alternate day oral prednisone maintenance therapy improves progression-free and overall survival in multiple myeloma patients Blood 92(suppl1):97a, 1998.

245.
Bergsagel DE, Bailey AJ, Langley GR, et al: The chemotherapy of plasma cell myeloma and the incidence of acute leukemia. N Engl J Med 301:743, 1979.

246.
Salmon SE, Shadduck RK, Schilling A: Intermittent high dose prednisone therapy for multiple myeloma. Cancer Chemother Rep 51:179, 1967.

247.
Barlogie B, Smith L, Alexanian R: Effective treatment of advanced multiple myeloma refractory to alkylating agents. N Engl J Med 310:1353, 1984.

248.
Alexanian R, Barlogie B, Dixon D: High dose glucocorticoid treatment for resistant multiple myeloma. Ann Intern Med 105:8, 1986.

249.
Alexanian R, Barlogie B, Tucker S: VAD-based regimens as primary treatment for multiple myeloma. Am J Hematol 33:86, 1990.

250.
Samson D, Gaminara E, Newland A, et al: Infusion of vincristine and doxorubicin with oral dexamethasone as first-line therapy for multiple myeloma. Lancet 2:882, 1989.

251.
Salmon SE, Crowley JJ, Grogan TM, Finley P, Pugh RP, Barlogie B: Combination chemotherapy glucocorticoids, and interferon alfa in the treatment of multiple myeloma: a Southwest Oncology Group study. J Clin Oncol 12:2405, 1994.

252.
Alexanian R, Dimopoulos MA, Delasalle K, Barlogie B: Primary dexamethasone treatment of multiple myeloma. Blood 80:887, 1992.

253.
Hata H, Xiao H, Petrucci MT, Woodliff J, Chang R, Epstein J: Interleukin-6 gene expression in multiple myeloma: a characteristic of immature tumor cells. Blood 81:3357, 1993.

254.
Kyle RA: Long-term survival in multiple myeloma. N Engl J Med 308:314, 1983.

255.
Alexanian R: Ten year survival in multiple myeloma. Arch Intern Med 145:2073, 1985.

256.
Attal M, Harousseau JL, Stoppa AM, et al: A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Francais du Myelome. N Engl J Med 335:91, 1996.

257.
Barlogie B, Jagannath S, Vesole D, et al: Superiority of tandem autologous transplantation over standard therapy for previously untreated multiple myeloma. Blood, 89:789, 1997.

258.
Tricot G, Jagannath S, Vesole DH, et al: Peripheral blood stem cell transplants for multiple myeloma identification of favorable variables for rapid engraftment in 225 patients. Blood 85:588, 1995.

259.
Siegel DS, Desikan KR, Mehta J, et al: Age is not a prognostic variable with autotransplants for multiple myeloma. Blood 93:51, 1999.

260.
Mehta J, Tricot G, Jagannath S, et al: High-dose chemotherapy with carboplatin, cyclophosphamide and etoposide and autologous transplantation for multiple myeloma relapsing after a previous transplant. Bone Marrow Transplant 20:113, 1997.

261.
Desikan KR, Fassas A, Siegel D, et al: Superior outcome with melphalan 200 mg/m2 (MEL 200) for scheduled second autotransplant compared MEL+TBI or CTX for myeloma (MM) in pre-Tx-2 PR. Blood 90:231a, 1997.

262.
Barlogie B, Jagannath S, Desikan KR, et al: Total therapy with tandem transplants for newly diagnosed multiple myeloma Blood 93:55, 1999.

263.
Vescio R, Schiller G, Stewart AK, et al: Multicenter phase III trial to evaluate CD34(+) selected versus unselected autologous peripheral blood progenitor cell transplantation in multiple myeloma. Blood 93:1858, 1999.

264.
Tricot G, Gazitt Y, Leemhuis T, et al: Collection, tumor contamination and engraftment kinetics of highly purified hematopoietic prognitor cells to support high dosetherapy in multiple myeloma. Blood 91:4489, 1998.

265.
Munshi NC, Desikan KR, Jagannath S, et al: Dexamethasone, cyclophosphamide, etoposide and cis-platinum (DCEP) an effective regimen for relapse after high-dose chemotherapy and autologous transplantation (AT). Blood 88:586a, 1996.

266.
Desikan R, Siegel D, Fassas A, et al: DCEP consolidation after tandem autotransplants (AT) in high risk multiple myeloma (MM)—improved prognosis compared to matched historical controls. Blood 92(suppl 1):97a, 1998.

267.
Kwak LW, Taub DD, Duffey PL, et al: Transfer of myeloma idiotype-specific immunity from an actively immunised marrow donor. Lancet 345:1016, 1995.

268.
Berenson JR, Lichtenstein A, Porter L, et al: Efficacy of pamidronate in reducing skeletal events in patients with advanced multiple myeloma. Myeloma Aredia Study Group. N Engl J Med 334:488, 1996.

269.
Berenson JR, Lichtenstein A, Porter L, et al: Long-term pamidronate treatment of advanced multiple myeloma patients reduces skeletal events. Myeloma Aredia Study Group. J Clin Oncol 16:593, 1998.

270.
Dhodapkar MV, Singh J, Mehta J, et al: Anti-myeloma activity of pamidronate in vivo. Br J Haematol 103:530, 1998.

271.
Gahrton G, Svensson H, Bjorkstrand B, et al: Syngeneic bone marrow transplantation in multiple myeloma. BMT 19:S88, 1997.

272.
Gahrton G, Tura S, Ljungman P: Allogeneic bone marrow transplantation in multiple myeloma. N Engl J Med 325:1267, 1991.

273.
Bensinger WI, Gahrthon G: Allogeneic hematopoietic cell transplantation for multiple myeloma, in Hematopoietic Cell Transplantation, 2nd ed, edited by S Forman, K Blume, E Thomas.: Blackwell Science, Oxford, UK 1999.

274.
Bjorkstrand BB, Ljungman P, Svensson H, et al: Allogeneic bone marrow transplantation versus autologous stem cell transplantation in multiple myeloma: a retrospective case-matched study from the European Group for Blood and Marrow Transplantation. Blood 88:4711, 1996.

275.
Tricot G, Vesole DH, Jagannath S, Hilton J, Munshi NC, Barlogie B: Graft vs myeloma effect: proof of principle. Blood 87:1196, 1996.

276.
Khouri IF, Keating M, Korbling M, et al: Transplant-lite: induction of graft-versus-malignancy using fludarabine-based nonablative chemotherapy and allogeneic blood progenitor-cell transplantation as treatment for lymphoid malignancies. J Clin Oncol 16:2817, 1998.

277.
Barlogie B, Desikan R, Munshi N, et al: Single course D.T. PACE anti-angiochemotherapy effects CR in plasma cell leukemia and fulminant multiple myeloma (MM). 92(suppl 1):97a, 1998.

278.
Cunningham D, Paz-Ares L, Gore ME, et al: High-dose melphalan for multiple myeloma: long-term follow-up data. J Clin Oncol 12:764, 1994.

279.
Cunningham D, Paz-Ares L, Milan S, et al: High-dose melphalan and autologous bone marrow transplantation as consolidation in previously untreated myeloma. J Clin Oncol 12:759, 1994.

280.
Anderson KC, Andersen J, Soiffer R, et al: Monoclonal antibody-purged bone marrow transplantation therapy for multiple myeloma. Blood 82:2568, 1993.

281.
Bensinger WI, Rowley SD, Demirer T, et al: High-dose therapy followed by autologous hematopoietic stem cellfusion for patients with multiple myeloma. J Clin Oncol 14:1447, 1996.

282.
Bjorkstrand B, Ljungman P, Bird JM, et al: Autologous stem cell transplantation in multiple myeloma: results of the European Group for Bone Marrow Transplantation. Stem Cells (Dayt) 13(suppl 2):140, 1995.

283.
Fermand JP, Chevret S, Ravaud P, Divine M, Leblond V, Dreyfus F, Mariette X, Brouet JC High-dose chemoradiotherapy and autologous blood stem cell transplantation in multiple myeloma: results of a phase II trial involving 63 patients. Blood 82:2005, 1993.

284.
Harousseau JL, Attal M, Divine M, Marit G, Leblond V, Stoppa AM, Bourhis JH, Caillot D, Boasson M, Abgrall JF, et al: Autologous stem cell transplantation after first remission induction treatment in multiple myeloma: a report of the French Registry on autologous transplantation in multiple myeloma. Blood 85:3077, 1995.

285.
Ludwig H, Fritz E, Kotzmann H, et al: Erythropoietin treatment of anemia associated with multiple myeloma. N Engl J Med 322:1693, 1990.

286.
Barlogie B, Beck T: Recombinant human erythropoietin and the anemia of multiple myeloma. Stem Cell 11:88, 1993.

287.
Barlogie B, Alexanian R, Cabanillas F: Etoposide, dexamethasone, cytarabine, and cisplatin in vincristine, doxorubicin, and dexamethasone-refractory myeloma. J Clin Oncol 7:1514, 1989.

288.
Dimopoulos MA, Delasalle KB, Champlin R, Alexanian R: Cyclophosphamide and etoposide therapy with GM-CSF for VAD-resistant multiple myeloma. Br J Haematol 83:240, 1993.

289.
Dhodapkar MV, Weinstein R, Tricot G, et al: Biologic and therapeutic determinants of bone mineral density in multiple myeloma. Leuk Lymphoma 32:121, 1998.

290.
Govindarajan R, Jagannath S, Flick J, et al: Preceeding standard therapy is the likely cause of MDS after autotransplants for multiple myeloma. Br J Haematol 95:349, 1996.

291.
Counter CM, Gupta J, Harley CB, Leber B, Bacchetti S: Telomerase activity in normal leukocytes and in hematologic malignancies. Blood 85:2315, 1995.

292.
Engelhardt M, Kumar R, Albanell J, Pettengell R, Han W, Moore MA: Telomerase regulation, cell cycle, and telomere stability in primitive hematopoietic cells. Blood 90:182, 1997.
Books@Ovid
Copyright © 2001 McGraw-Hill
Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn
Williams Hematology

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One comment on “CHAPTER 106 PLASMA CELL MYELOMA

  1. […] CHAPTER 106 PLASMA CELL MYELOMA | Free Medical Textbook […]

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