MULTIPLE MYELOMA (MM) / PLASMA CELL MYELOMA / MULTIPLE PLASMACYTOMA OF BONE / KAHLER DISEASE (Kahler O. Zur Symptomathologie des Multiplen Myeloms Beobachtung von Albumosurie. Prag. Med. Wochenschr. 14:33-45 (1889)) (indolent)

Table of contents :

  • Epidemiology
  • Aetiology
  • Pathogenesis
  • Localizations
  • solitary plasmocytoma of bone
  • extramedullary plasmocytoma / soft tissue myeloma
  • indolent myeloma
  • plasma cell leukemia
  • Symptoms & signs
  • Laboratory examinations
  • Therapy 
  • Prognosis
  • Web resources

  • Epidemiology (USA) : after age 50; peak at age 60; diagnosed annually in approximately 15,000 new patients in the USA, with a prevalence of approximately 50,000 patientsref; incidence and mortality rates (per 100,000) 1993-1997 :
    African American
    African American
    year of diagnosis/death 1976 1977 1978 1979 1980 1981 1982 1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997
    SEER incidence 4.2 4.1 3.9 3.9 4.0 4.0 4.3 4.3 4.4 4.2 4.3 4.8 4.4 4.3 4.6 4.9 4.8 4.5 4.5 4.4 4.5 4.4
    US mortality 2.5 2.5 2.5 2.6 2.6 2.6 2.7 2.7 2.8 2.8 2.8 2.9 2.9 2.9 3.0 3.0 3.0 3.1 3.1 3.2 3.1 3.1
    SEER mortality 2.8 2.6 2.5 2.8 2.5 2.7 2.6 2.8 2.7 3.0 2.6 2.6 2.9 3.1 2.9 3.1 3.2 3.2 3.1 3.1 3.1 3.0
    1-yr 65.4 70.2 70.0 69.8 69.8 69.5 73.2 72.6 69.6 72.3 72.0 75.6 73.9 71.8 72.8 75.9 69.1 72.5 72.9 73.4 69.3
    2-yr 49.3 52.0 54.8 54.1 54.8 55.6 56.2 56.1 55.6 58.9 57.1 59.4 60.1 58.3 57.1 60.6 56.3 58.2 58.4 56.3
    3-yr 36.7 38.7 42.4 43.4 44.4 43.0 44.8 44.1 44.0 46.8 44.7 48.5 47.1 44.8 44.7 48.6 45.2 45.8 47.1
    4-yr 31.5 30.7 33.0 33.3 34.2 35.0 37.2 36.4 34.8 36.4 35.5 38.1 39.0 36.1 38.7 38.7 34.3 36.6
    5-yr 24.6 25.0 27.3 26.1 27.0 27.8 29.7 28.7 27.6 27.7 29.8 28.8 29.8 27.0 30.7 31.2 26.4
    6-yr 19.0 21.1 21.6 20.1 21.2 23.1 21.6 23.2 21.1 22.7 23.9 23.6 24.5 21.8 24.5 24.7
    7-yr 15.9 17.7 17.8 18.0 18.8 16.8 17.8 17.6 18.3 19.3 19.2 19.6 18.4 17.0 19.2
    8-yr 12.4 15.4 15.1 15.4 15.3 14.4 14.6 14.2 13.8 17.0 17.8 16.5 15.5 13.6
    9-yr 10.6 12.7 13.1 12.3 13.8 12.2 12.1 12.2 11.7 13.2 13.1 14.1 12.5
    10-yr 9.5 11.4 12.1 10.2 11.5 9.9 11.4 10.5 9.9 11.5 12.5 13.2
    11-yr 8.7 9.3 10.9 9.1 10.4 8.8 9.7 9.9 9.7 10.2 10.8
    12-yr 8.1 8.7 10.3 8.0 9.4 7.4 8.6 9.0 8.6 9.7
    13-yr 6.1 8.2 8.2 6.5 7.8 6.9 8.3 8.0 7.4
    14-yr 5.2 7.9 7.9 5.8 6.0 6.6 7.2 7.3
    15-yr 5.0 7.6 6.3 4.5 5.8 6.2 7.2
    16-yr 5.0 6.6 6.3 3.9 5.3 3.4
    17-yr 5.0 5.7 5.5 3.9 4.7
    18-yr 4.4. 4.6 5.0 3.7
    19-yr 3.6 4.5 4.5
    20-yr 2.3 4.4
    21-yr 2.3

    Aetiology : Pathogenesis : all patients with MM are felt to evolve from a MGUS/SMM stage, although in many MM patients these premalignant stages are unrecognized clinically due to their asymptomatic nature. A prior history of MGUS or SMM has no impact on the prognosis of MM. MM plasma cells, which originate from postfollicular B cells, are characterised by complex chromosomal aberrations. Among the earliest genetic events are

    Bone-marrow stromal cells support growth and survival of MM cells via various cytokines. Osteoclast activity factors (OAF = IL-1b, TNF-a, TNF-b, ... in particular CCL-3 / MIP-1a) and imbalances between RANKL and osteoprotegerin are major factors for the development of MM bone disease. MM cells secrete dikkopf homolog 1 (DKK1) which inhibits the differentiation of osteoblastic precursors in vitroref.
    Frequent expressions of TLRs were detected in cell lines from MM patients (minimum 6 TLRs in each). In comparison, only few TLRs (mainly TLR1 and or RP105) were found expressed in PCs from BM of healthy donors. In addition, TLR-specific ligands induce increased proliferation and survival of the MM cell lines, partially due to an autocrine IL-6 production. Importantly, also PC from MM patients proliferates in response to TLR-specific ligandsref.
    In MM patients, a large fraction of peripheral blood CD8+ cells display the phenotype of chronically activated memory T cells(CD25-28-38+45RO+ HLA-DR+). Unlike normal CD8+ T cells, in which CD94 is assembled with glycoproteins of the NKG2 family to form functional receptors with activating or inhibitory properties, most CD8+94+ MM T cells are devoid of both the NKG2-A and NKG2-C glycoproteins detected in the inhibitory or activating form respectively and do not express a functional CD94 receptor. Thus, their ability to 'fine-tune' an appropriate immune response against tumour cells can be impairedref. The degree of TCR diversity is similar in age-matched normal donors and MGUS, but progressively decreases from MGUS to MM at diagnosis and then to MM in remission. After high-dose chemotherapy and autologous peripheral blood progenitor cell infusion, on average, 33% of the total repertoire in both the peripheral blood (PB) and bone marrow (BM) consist of naive or memory CD8+ T cells expressing oligoclonal TCRb transcripts. There is a significant decrease of PCK-a in MM T cells; however, neither this decrease nor the heterogenous levels of the other T-cell signalling molecules are clearly correlated with prognosis, duration of tumour exposure, and disease statusref. Fas+ T cells are significantly higher, whereas bcl-2+ T cells are significantly lower in MM patients than in the controls, leading to enhanced susceptibility to apoptosisref. In bone marrow the percentage of CD4+ is profoundly reducedref. Severe and long-lasting disruption of TcR diversity in human myeloma may affect the clinical outcome of vaccine-based strategies delivered at the stage of MRDref : the immune competence status of MM patients is still susceptible to specific immunization after high-dose chemotherapy and PBPC transplantation and generates Id-specific T-cell proliferative responsesref whose ability to reduce the relapse rate of patients with MRD has not been determined yet.
    Several studies have shown that bone marrow-derived endothelial cells (ECs) may contribute to tumor angiogenesisref1, ref2, ref3, and that in the peripheral blood of cancer patients there is an increased amount of circulating ECs (CECs)ref (very low number of CECs in peripheral bloodref1, ref2) that may participate to vessel formationref. Microvascular ECs in B-cell lymphomas are in part tumor-related, reflecting a novel aspect of tumor angiogenesisref. All together, these observations suggest that tumors can elicit the sprouting of new vessels from existing capillaries through the secretion of angiogenic factorsref and that, in some cases, cancer cells can also mimic the activities of ECs by participating in the formation of vascular-like networksref1, ref2. In MM, the proliferation and survival of neoplastic plasma cells is regulated by microenvironmental bone marrow factors and, to this extent, neoangiogenesis is thought to have a key role in the pathogenesis and progression of the diseaseref. It has been shown that in patients with MM, ECs differ markedly from umbilical vein ECs, their quiescent counterpart, with regard to the secretion of growth factors, growth properties, genetic profile, and structural featuresref. In patients with MM, the level of CECs, which comprise mature ECs and endothelial progenitor cells (EPC), were higher than in controls and correlated positively with serum M protein and b2-microglobulin, thereby representing a vascular marker that reflects tumor mass and prognosisref. In addition, a correlation was documented between the level of CECs/EPCs and response to thalidomide treatmentref, suggesting an antiangiogenetic mechanism of thalidomide action. In 5 MM patients with 13q14 deletion, CECs carried the same chromosome aberration as the neoplastic plasma cells (11%-32% of CECs with 13q14 deletion; CD38-138-144+146+ UEA-1 lectin+, VWF+, VEGFR-2+) and presented the same immunoglobulin gene rearrangement as MM plasma cells. Most of the CECs displayed immunophenotypic features of endothelial progenitor cells (CD133+, a marker gradually lost during endothelial differentiation and absent on mature endothelial cells). To the contrary, in 3 patients with MGUS and 13q14 deletion, CECs were cytogenetically normal and had a mature immunophenotype. These findings suggest a possible origin of CECs from a common hemangioblast precursor that can give rise to both plasma cells and endothelial cells, as suggested by evidence coming from studies in patients with chronic myeloid leukemiaref, and point to a direct contribution of MM-derived CECs to tumor vasculogenesis and possibly to the spreading and progression of the diseaseref. It has been shown that VEGFR-2 is the only marker shared by CECs and plasma cells, and that MM plasma cells are negative at mRNA and protein levels for most of endothelial cell markers including factor VIII-related antigen, VE-cadherin, and UEA-1ref. Cell fusion, in our study, seems unlikely because the fusion of MM plasma cells and ECs should result in a tetraploid karyotype and, in our patients with MM, all CECs contained a normal diploid copy number of chromosome 10. It seems also unlikely that, as observed in solid tumors, our findings could reflect an inherent cytogenetic instability of tumor endothelial cells, because FISH results were not consistent with the heterogeneous cytogenetic profile of ECs observed in solid tumorsref.
    Disease progression :
    initial phase
    medullary relapse
    extramedullary relapse
    site of myeloma cell accumulation or proliferation bone marrow bone marrow blood, pleural effusion, skin, many other sites
    growth fraction (rate of atypical cells proliferating in the bone marrow) < 1% >= 1% (1-95%) >= 1% (1-95%)
    genetic or oncogenic events deregulation of c-myc. Illegitimate switch recombination N-ras and K-ras mutations p53 point mutations
    phenotypic changes CD19 loss, CD56 overexpression CD28 expression, LFA-1 and VLA-5 loss CD28 expression, CD56 loss
    cytologic changes detectable plasmablastic compartment in 15% of cases plasmablastic compartment growing major plasmablastic compartment
    circulating malignant plasma cells < 1% increasing increasing
    Functional FoxP3+ Tregcells of naive, central, and effector memory phenotype as determined by CCR7 and CD45RA expression are significantly expanded. Low frequencies of TRECs in naive Treg cells in both healthy controls and MM patients point to peripheral expansion as the prominent mechanism of increased frequencies of naive Treg cells in these cancer patients. These findings strongly suggest that the increase of functional Treg cells in cancer patients is a response to the process of malignant transformationref.
    Cytology : in contrast to normal plasma cells, myeloma cells are often immature and may have the appearance of plasmablastsref. They usually are CD19- CD56brightref, CD38+, and syndecan-1, and they produce very low amounts of immunoglobulins (a few picograms per cell per day)ref. In almost all patients, the myeloma cells are aneuploid (more often hyperdiploid than hypodiploid)ref, and their chromosomes have many numerical and structural abnormalities, mainly on chromosomes 13 (13q-) and 14 (14q+)ref. These genetic abnormalities may prevent the differentiation and normal death of the myeloma cells, which continue to proliferate and accumulate in the bone marrow. The morphologic immaturity (cells taking the form of plasmablasts)ref1, ref2, hypodiploidyref, and the 13q- and 14q+ abnormalitiesref correlate with the resistance to treatment and short survival characteristic of aggressive disease. The somatic mutations of the immunoglobulin genes of myeloma cellsref indicate that the putative myeloma-cell precursors are stimulated by antigens and are either memory B cells or migrating plasmablasts. The stability of the mutationsref and of the antigenic properties (the idiotype) of the myeloma protein during the course of the disease has clinical implications. The mutations, which are molecular signatures of the neoplastic clone, might be useful for detecting residual myeloma cells after chemotherapy. Vaccination with the myeloma idiotype of a monoclonal immunoglobulin is a potential means of immunotherapy. Myeloma cells proliferate slowly in the marrow. < 1% of them divide at any one timeref, and they do not differentiate completely. The cause of this failure to differentiate is unknown, but translocations between 14q32 and its chromosome partners (chromosomes 11, 6, 16, 9, 18, and 8)ref1, ref2 and deregulation of the c-myc oncogeneref may be important. The growth fraction of the tumor is high (> 20%) in relapses in bone marrow, but especially so in relapses outside the bone marrowref. Point mutations of the N-ras and K-ras oncogenes have been found in relapses in marrowref, and point mutations of p53 have been identified in extramedullary relapses of myelomaref. Cytologicref1, ref2 and phenotypicref changes have also been associated with both these types of relapses. Although p53 mutations are rarely seen at the time of diagnosis, N-ras and K-ras mutations are apparent in up to 15% of patients given a new diagnosis of MM. K-ras mutations are associated with shorter survivalref. MM is usually thought to be confined to the bone marrow, but recent studies have noted circulating myeloma cells in many patientsref. The absolute number of these cells correlates with disease activity and predicts the progression of disease in SMM. Circulating myeloma cells may disseminate the tumor within the bone marrow and elsewhere. IL-6 is essential for the survival and growth of myeloma cellsref1, ref2, which express specific receptors for this cytokine. The IL-6R has 2 polypeptide components: the a chain (composed of the glycoprotein subunit gp80, or IL-6Ra) and the  chain, a transducer element (gp130). IL-6 belongs to a family containing 5 other cytokines that use gp130 as a transducer: oncostatin M, leukemia inhibitory factor, IL-11, CNTF, and cardiotrophin 1. IL-6 was initially found to be a growth factor for myeloma cellsref1, ref2, but recently it was also shown to promote the survival of myeloma cells by preventing spontaneous or dexamethasone-induced apoptosisref. These data from in vitro studies suggest that IL-6 promotes both tumor growth and resistance to dexamethasone in vivo. The beneficial effects of therapy with murine anti–IL-6 monoclonal antibodies in some patients with advanced MM also support this suppositionref. There is increasing evidence that IL-6 is not an autocrine growth factorref, but the product of other cells in the microenvironment of the marrowref. Indeed, myeloma cells can stimulate stromal cells and bone cells to release large amounts of IL-6ref. Various membrane proteins on myeloma cells (and on their normal neighbors in the marrow), in addition to soluble factors produced by normal cells in the microenvironment, help induce the production of IL-6ref. The increased levels of IL-6 in the serum of patients with MM can be explained by the overproduction of IL-6 in the marrow. Myeloma cells shed the soluble form of IL-6R, which can amplify the response of myeloma cells to IL-6ref. IL-6Ra is present in high amounts in the serum of patients with myeloma, especially those with a poor prognosis. The IL-6 system also has a role in the pathogenesis of bone lesions in MMref. IL-6, sIL-6Ra, and IL-1 activate osteoclasts in the vicinity of myeloma cells and thus provoke bone resorption.
    Localizations :
    Durie-Salmon and Bataille stagingref1, ref2 : Subclassification : Symptoms & signs : Laboratory examinations :
  • Durie criteria, 1986 :
  • International Myeloma Working Group diagnostic criteria for MM requiring systemic therapy, 2006 : 1 major + 1 minor criteria OR 3 minor criteria
  • International Myeloma Working Group uniform response criteria (all response categories require two consecutive assessments made at anytime before the institution of any new therapy; complete and PR and SD categories also require no known evidence of progressive or new bone lesions if radiographic studies were performed. Radiographic studies are not required to satisfy these response requirements.)  1. Wei A, Juneja A. Bone marrow immunohistology of plasma cell neoplasms. J Clin Pathol 2003; 56: 406–411.
     2. San Miguel JF, Almeida J, Mateo G et al. Immunophenotypic evaluation of the plasma cell compartment in MM: a tool for comparing the efficacy of different treatment strategies and predicting outcome. Blood 2002; 99: 1853–1856.
      Practical details of response evaluation : Therapyref : IMiDsref and bortezomibref have been shown to inhibit human MM cell growth, decrease tumor-associated angiogenesis, and prolong host survival in models of human MM xenografts implanted subcutaneously in SCID mice. Subsequent Phase I, II and III clinical trials of IMiDsref and bortezomibref have already demonstrated marked clinical activity even in patients with refractory and relapsed MM. Corresponding in vitro gene array studies of MM tumor cells before and after treatment with novel anti-MM agentsref1, ref2, ref3, ref2 have helped to identify in vivo targets and mechanisms of novel drug action as well as mechanisms of drug resistance. This helps to determine whether in vivo targets of these novel therapies correlate with their in vitro anti-MM activities in relapsed and refractory disease. Extensive studies have focused on the mechanisms whereby MM cells home to the host BM and adhere to BM stromal cells (BMSCs) and ECM proteins, and the functional sequelae of these interactions. Such studies have identified a series of cell adhesion molecules mediating MM cell binding to fibronectin and BMSCs, thereby increasing MM cell proliferation and survivalref. This proliferative and anti-apoptotic advantage conferred by stromal adhesion is largely due to BMSC-derived cytokines, such as IL-6ref and IGF-1ref1, ref2. In addition, the MM cell-BMSC binding interaction modulates the expression of other cytokines, such as VEGF, which in turn stimulates increased local angiogenesisref, thereby further facilitating MM cell proliferation and viability. Importantly, these aforementioned cytokines/growth factors can cooperate, in additive and/or synergistic manners, to stimulate MM cell proliferation and survivalref1, ref2, ref3. Antitumor activity of novel agents in animal models : the SCID-hu model of human MM has been developed to allow studies of the dynamic interaction between MM cells and the BM stroma, and to examine the efficacy of novel therapies in that setting. Human bone grafts are implanted bilaterally in the flanks of SCID mice. Human MM cells implanted into these grafts proliferate, secrete MM idiotypic protein detectable in mouse serum, and can migrate predominantly to the contralateral human BM graftref. This in vivo model of human MM has provided a means to evaluate the mechanisms mediating the specific homing of human MM cells to the human BM microenvironment, as opposed to the murine BM microenvironment, as well as for studying the role of microenvironmental factors (host-MM cell interactions, cytokines, angiogenesis) in MM pathogenesis. In vivo assays of drug efficacy have also used a beige-nude-xid mouse model of subcutaneous human plasmacytoma xenografts. These models were critical for preclinical evaluation of Thal, IMiDs, bortezomib and other novel agents. Clinical Trials of Agents Targeting MM and the BM Microenvironment
    Response criteria in MMref1, ref2 : Summary of similarities and specific changes introduced in the New Uniform Response Criteria compared to the EBMT/IBMTR Criteria Prognosis : average life expectancy : 3.5 yearsref1,ref2. Trends in 5 year survival rates (%) of MM (USA) 5 year survival rates (%), by age at diagnosis :
    <45 47.4 44.5 41.7 44.6 46.8
    45-54 36.2 37.8 41.4 40.7 41.8
    55-64 33.8 33.7 32.8 34.2 33.2
    65-75 26.6 27.7 26.4 25.6 25.9
    > 75 19.5 19.7 20.4 23.6 18.8

    A patient with MM was being maintained on IFN-a after VAD and autologous HSCT (pretreated with melphalan). An episode of immune thrombocytopenia and (Coombs positive) autoimmune hemolytic anemia (AIHA) was noted while on maintenance INF-a, which remitted when it was withdrawn. Following this event, he achieved a state of stable disease that persists (> 3 years) with no specific MM treatment. This sequence of events suggests a relationship between an immunological reaction induced by IFN-a and the prolonged phase of stable diseaseref

    The presence of somatic hypermutations of the immunoglobulin variable region genes in MM plasma cells suggests that malignant transformation occurs in a B cell that has traversed the germinal centers of lymph nodes. However, the hypoproliferative nature of myeloma has led to the hypothesis that the bulk of the tumor arises from a transformed B cell with the capacity for both self-renewal and production of terminally differentiated progenyref1, ref2, ref3. The clinical course of patients requiring therapy for myeloma varies markedly. Even with tandem autotransplants yielding complete remission (CR) rates in excess of 60%, survival ranges from a few months to > 15 years. The extended time (almost 2 years) for those patients to achieve CR, and the even longer time to achieve MRI-CR, strongly suggests enormous tumor cell population heterogeneity in terms of drug responsiveness/resistance.

    Co-diagnoses : Bibliography : Web resources :
  • International Myeloma Foundation (IMF)
  • Myeloma Institute for Research and Therapy in the Arkansas Cancer Research Center at University of Arkansas for Medical Sciences (UAMS)
  • Multiple Myeloma Research Center at the Cleveland Clinic
  • Multiple Myeloma Research Foundation (MMRF)
  • Multiple Myeloma Research Web Server by Prof. Leif Bergsagel, MD, FRCP(C), Division of Hematology-Oncology, Weill Medical College of Cornell University
  • Multiple Myeloma : how far have we come ? in Mayo Clinic Proceedings
  • Myeloma mailing list at ACOR
  • Amyloidosis mailing list at ACOR
  • Multiple Myeloma Association (MMA) : MyelomaExchange
  • Multiple Myeloma
  • Multiple Myeloma Treatment

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