CHAPTER 106 PLASMA CELL MYELOMA
CHAPTER 106 PLASMA CELL MYELOMA
Etiology and Pathogenesis
Pathogenesis and Genetic Alterations
Phenotype and Cytokines
Bleeding and Thrombosis
Detection of Monoclonal Immunoglobulin
Immunocytochemical and Flow Cytometric Analyses
Therapy, Course, and Prognosis
Therapy for Solitary Plasmacytoma
Therapy for Indolent Myeloma
Therapy for Symptomatic Multiple Myeloma
Primary Treatment Strategy
Supportive Care and Special Treatments
Course and Prognosis
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.
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
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 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.
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.
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 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
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.
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
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.
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 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”).
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.
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.)
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).
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
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
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 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.
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
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.
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
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
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
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 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.
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 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.
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 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).
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Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn