Key Points
-
Multiple myeloma, which is located at multiple sites in the bone-marrow compartment, is a malignant plasma-cell tumour that is characterized by osteolytic bone lesions. It is a slowly proliferating tumour, typically with less than 1% of tumour cells synthesizing DNA, until late in the disease, when multiple myeloma cells are often found outside the bone marrow.
-
A pre-malignant lesion called monoclonal gammopathy of undetermined significance (MGUS), which is present in 1% of adults, progresses to malignant multiple myeloma at a rate of 1% per year.
-
The karyotypes of multiple myeloma are complex, and more similar to those found in epithelial tumours and the blast phase of chronic myelogenous leukaemia than to those in other haematopoietic tumours.
-
Primary translocations — mediated by errors in B-cell-specific DNA modification processes — juxtapose one or more oncogenes and immunoglobulin transcriptional regulatory regions in ∼50% of MGUS and multiple myelomas. In contrast to other B-cell malignancies, these translocations simultaneously dysregulate a variety of oncogenes, such as the genes for cyclin D1 or D3, fibroblast growth factor receptor 3 (FGFR3) combined with the nuclear protein MMSET, and the transcription factor c-MAF.
-
Secondary translocations that do not involve B-cell-specific processes contribute to progression by dysregulating other oncogenes. Although c-MYC is dysregulated by primary translocations in some B-cell malignancies, it is dysregulated by secondary translocations, often without involvement of an immunogloublin locus, as myeloma tumours become more proliferative at a late stage of progression.
-
Genetic changes are similar in pre-malignant MGUS and multiple myeloma, although the latter is distinguished by the presence of activating mutations of NRAS or KRAS2, and also a higher incidence of monosomy 13, indicating a possible tumour-suppressor gene on chromosome 13.
-
Normal plasma cells, as well as MGUS and multiple myeloma cells, are dependent on the bone-marrow microenvironment for survival, growth and differentiation. These processes are, in part, mediated by paracrine interleukin-6 and insulin-like growth factor 1. The evolving interaction of multiple myeloma cells with the bone-marrow microenvironment is also involved in the secondary effects of malignancy, including osteolysis, anaemia and immunodeficiency.
-
Multiple myeloma is an incurable malignancy for which the median survival has remained fixed at about 3 years for the past decade. Although MGUS can be efficiently diagnosed by a simple blood test, it is not possible to prevent progression or even predict when progression to myeloma will occur. Recent advances in understanding the molecular pathogenesis of these tumours indicate that improved approaches for prevention and treatment should be possible in the near future.
Abstract
Multiple myeloma is a neoplasm of terminally differentiated B cells (plasma cells) in which chromosome translocations frequently place oncogenes under the control of immunoglobulin enhancers. Unlike most haematopoietic cancers, multiple myeloma often has complex chromosomal abnormalities that are reminiscent of epithelial tumours. What causes full-blown myeloma? And can our molecular understanding of this common haematological malignancy be used to develop effective preventive and treatment strategies?
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Malpas, J. S., Bergsagel, D. E., Kyle, R. & Anderson, K. Multiple Myeloma: Biology and Management (Oxford Univ. Press, Oxford, 1998).
Cohen, H. J., Crawford, J., Rao, M. K., Pieper, C. F. & Currie, M. S. Racial differences in the prevalence of monoclonal gammopathy in a community-based sample of the elderly. Am. J. Med. 104, 439–444 (1998).
Lynch, H. T., Sanger, W. G., Pirruccello, S., Quinn-Laquer, B. & Weisenburger, D. D. Familial multiple myeloma: a family study and review of the literature. J. Natl Cancer Inst. 93, 1479–1483 (2001).
Kyle, R. A., Beard, C. M., O'Fallon, W. M. & Kurland, L. T. Incidence of multiple myeloma in Olmsted County, Minnesota: 1978 through 1990, with a review of the trend since 1945. J. Clin. Oncol. 12, 1577–1583 (1994).
Kyle, R. A. & Rajkumar, S. V. Monoclonal gammopathies of undetermined significance. Hematol. Oncol. Clin. N. Am. 13, 1181–1202 (1999).
Hayman, S. R. et al. Translocations involving the immunoglobulin heavy-chain locus are possible early genetic events in patients with primary systemic amyloidosis. Blood 98, 2266–2268 (2001).
Drexler, H. G. & Matsuo, Y. Malignant hematopoietic cell lines: in vitro models for the study of multiple myeloma and plasma cell leukaemia. Leuk. Res. 24, 681–703 (2000).
Jernberg-Wiklund, H. & Nilsson, K. in Human Cell Culture Vol. 3 (eds Masters, J. R. W. & Palsson, B. O.) 81–155 (Kluwer Academic, The Netherlands, 2000).
Rajkumar, S. V. et al. Cytogenetic abnormalities correlate with the plasma cell labeling index and extent of bone marrow involvement in myeloma. Cancer Genet. Cytogenet. 113, 73–77 (1999).
Mitelman, F., Johansson, B. & Mertens, F. (eds) Mitelman Database of Chromosome Aberrations in Cancer [online] (cited 14 Feb 2002), 〈http://cgap.nci.nih.gov/Chromosomes/Mitelman〉 (2002).
Avet-Loiseau, H. et al. 14q32 translocations and monosomy 13 observed in monoclonal gammopathy of undetermined significance delineate a multistep process for the oncogenesis of multiple myeloma. Intergroupe Francophone du Myelome. Cancer Res. 59, 4546–4550 (1999).Uses interphase FISH on purified MGUS and myeloma tumour cells to determine the relationships in different patients and in different tumour cells from the same patient of three specific karyotypic abnormalities: IgH translocations, chromosome 13 monosomy and trisomy.
Drach, J. et al. Multiple myeloma: high incidence of chromosomal aneuploidy as detected by interphase fluorescence in situ hybridization. Cancer Res. 55, 3854–3859 (1995).
Flactif, M. et al. Interphase fluorescence in situ hybridization (FISH) as a powerful tool for the detection of aneuploidy in multiple myeloma. Leukemia 9, 2109–2114 (1995).
Fonseca, R. et al. Chromosomal abnormalities in systemic amyloidosis. Br. J. Haematol. 103, 704–710 (1998).
Zandecki, M. et al. Several cytogenetic subclones may be identified within plasma cells from patients with monoclonal gammopathy of undetermined significance, both at diagnosis and during the indolent course of this condition. Blood 90, 3682–3690 (1997).
Gutierrez, N. C. et al. Differences in genetic changes between multiple myeloma and plasma cell leukaemia demonstrated by comparative genomic hybridization. Leukemia 15, 840–845 (2001).
Cigudosa, J. C. et al. Characterization of nonrandom chromosomal gains and losses in multiple myeloma by comparative genomic hybridization. Blood 91, 3007–3010 (1998).
Aalto, Y. et al. Among numerous DNA copy number changes, losses of chromosome 13 are highly recurrent in plasmacytoma. Genes Chromosom. Cancer 25, 104–107 (1999).
Avet-Loiseau, H. et al. Molecular cytogenetic abnormalities in multiple myeloma and plasma cell leukaemia measured using comparative genomic hybridization. Genes Chromosom. Cancer 19, 124–133 (1997).
Sawyer, J. R. et al. Identification of new nonrandom translocations in multiple myeloma with multicolor spectral karyotyping. Blood 92, 4269–4278 (1998).
Sawyer, J. R. et al. Multicolour spectral karyotyping identifies new translocations and a recurring pathway for chromosome loss in multiple myeloma. Br. J. Haematol. 112, 1–9 (2000).
Sawyer, J. R., Tricot, G., Mattox, S., Jagannath, S. & Barlogie, B. Jumping translocations of chromosome 1q in multiple myeloma: evidence for a mechanism involving decondensation of pericentromeric heterochromatin. Blood 91, 1732–1741 (1998).
Smadja, N. V., Bastard, C., Brigaudeau, C., Leroux, D. & Fruchart, C. Hypodiploidy is a major prognostic factor in multiple myeloma. Blood 98, 2229–2238 (2001).
Bergsagel, P. L. & Kuehl, W. M. Chromosomal translocations in multiple myeloma. Oncogene 20, 5611–5622 (2001).
Bergsagel, P. L. et al. Promiscuous translocations into immunoglobulin heavy chain switch regions in multiple myeloma. Proc. Natl Acad. Sci. USA 93, 13931–13936 (1996).Provides the first description of frequent translocations into the IgH switch regions in multiple myeloma and provides the details for a comprehensive Southern blot assay that detects these translocations.
Avet-Loiseau, H., Daviet, A., Sauner, S. & Bataille, R. Chromosome 13 abnormalities in multiple myeloma are mostly monosomy 13. Br. J. Haematol. 111, 1116–1117 (2000).
Avet-Loiseau, H. in VIIIth International Myeloma Workshop 10–11 (Banff, Alberta, Canada, 2001).
Chesi, M. et al. Dysregulation of cyclin D1 by translocation into an IgH γ switch region in two multiple myeloma cell lines. Blood 88, 674–681 (1996).
Shaughnessy, J. et al. Cyclin D3 at 6p21 is dysregulated by recurrent Ig translocations in multiple myeloma. Blood 98, 217–223 (2001).
Chesi, M. et al. Frequent translocation t(4;14)(p16.3;q32.3) in multiple myeloma is associated with increased expression and activating mutations of fibroblast growth factor receptor 3. Nature Genet. 16, 260–264 (1997).
Chesi, M. et al. The t(4;14) translocation in myeloma dysregulates both FGFR3 and a novel gene, MMSET, resulting in IgH/MMSET hybrid transcripts. Blood 92, 3025–3034 (1998).References 30 and 31 show how IgH switch-mediated translocations can be detected, and also provide the first example of an IgH translocation in which two putative oncogenes are simultaneously dysregulated by IgH enhancers that have segregated to each derivative chromosome.
Ayton, P. M. & Cleary, M. L. Molecular mechanisms of leukemogenesis mediated by MLL fusion proteins. Oncogene 20, 5695–5707 (2001).
Chesi, M. et al. Frequent dysregulation of the c-maf proto-oncogene at 16q23 by translocation to an Ig locus in multiple myeloma. Blood 91, 4457–4463 (1998).
Hanamura, I. et al. Ectopic expression of MAFB gene in human myeloma cells carrying (14;20)(q32;q11) chromosomal translocations. Jpn. J. Cancer Res. 92, 638–644 (2001).
Dalla-Favera, R. & Gaidano, G. in Cancer: Principles and Practice of Oncology (eds DeVita, V. T., Hellman, S. & Rosenberg, S. A.) 2215–2235 (Lippincott Williams & Wilkins, Philadelphia, 2001).
Kakkis, E., Riggs, K. J., Gillespie, W. & Calame, K. A transcriptional repressor of c-myc. Nature 339, 718–721 (1989).
Potter, M. Experimental plasmacytomagenesis in mice. Hematol. Oncol. Clin. N. Am. 11, 323–347 (1997).
Shou, Y. et al. Diverse karyotypic abnormalities of the c-myc locus associated with c-myc dysregulation and tumor progression in multiple myeloma. Proc. Natl Acad. Sci. USA 97, 228–233 (2000).Shows that secondary translocations can dysregulate c- MYC as a late progression event in myeloma, and includes FISH analyses that illustrate these complex chromosomal structural abnormalities.
Difilippantonio, M. J. et al. DNA repair protein Ku80 suppresses chromosomal aberrations and malignant transformation. Nature 404, 510–514 (2000).Shows an animal model that recapitulates similar kinds of complex structural abnormalities of c- MYC as in reference 38.
Avet-Loiseau, H. et al. Rearrangements of the c-myc oncogene are present in 15% of primary human multiple myeloma tumors. Blood 98, 3082–3086 (2001).
Skopelitou, A. et al. Expression of c-myc p62 oncoprotein in multiple myeloma: an immunohistochemical study of 180 cases. Anticancer Res. 13, 1091–1095 (1993).
Pope, B., Brown, R., Luo, X. F., Gibson, J. & Joshua, D. Disease progression in patients with multiple myeloma is associated with a concurrent alteration in the expression of both oncogenes and tumour suppressor genes and can be monitored by the oncoprotein phenotype. Leuk. Lymphoma 25, 545–554 (1997).
Dewald, G. W., Kyle, R. A., Hicks, G. A. & Greipp, P. R. The clinical significance of cytogenetic studies in 100 patients with multiple myeloma, plasma cell leukaemia, or amyloidosis. Blood 66, 380–390 (1985).
Avet-Loiseau, H. et al. Monosomy 13 is associated with the transition of monoclonal gammopathy of undetermined significance to multiple myeloma. Intergroupe Francophone du Myelome. Blood 94, 2583–2589 (1999).
Konigsberg, R. et al. Deletions of chromosome 13q in monoclonal gammopathy of undetermined significance. Leukemia 14, 1975–1979 (2000).
Shaughnessy, J. et al. High incidence of chromosome 13 deletion in multiple myeloma detected by multiprobe interphase FISH. Blood 96, 1505–1511 (2000).
Seong, C. et al. Prognostic value of cytogenetics in multiple myeloma. Br. J. Haematol. 101, 189–194 (1998).
Fonseca, R. et al. Deletions of chromosome 13 in multiple myeloma identified by interphase FISH usually denote large deletions of the q arm or monosomy. Leukemia 15, 981–986 (2001).
Zojer, N. et al. Deletion of 13q14 remains an independent adverse prognostic variable in multiple myeloma despite its frequent detection by interphase fluorescence in situ hybridization. Blood 95, 1925–1930 (2000).
Perez-Simon, J. A. et al. Prognostic value of numerical chromosome aberrations in multiple myeloma: a FISH analysis of 15 different chromosomes. Blood 91, 3366–3371 (1998).
Desikan, R. et al. Results of high-dose therapy for 1000 patients with multiple myeloma: durable complete remissions and superior survival in the absence of chromosome 13 abnormalities. Blood 95, 4008–4010 (2000).
Facon, T. et al. Chromosome 13 abnormalities identified by FISH analysis and serum β2-microglobulin produce a powerful myeloma staging system for patients receiving high-dose therapy. Blood 97, 1566–1571 (2001).
Worel, N. et al. Deletion of chromosome 13q14 detected by fluorescence in situ hybridization has prognostic impact on survival after high-dose therapy in patients with multiple myeloma. Ann. Hematol. 80, 345–348 (2001).
Fonseca, R., Oken, M. M. & Greipp, P. R. The t(4;14)(p16.3;q32) is strongly associated with chromosome 13 abnormalities in both multiple myeloma and monoclonal gammopathy of undetermined significance. Blood 98, 1271–1272 (2001).
Zandecki, M. et al. The retinoblastoma gene (RB-1) status in multiple myeloma: a report on 35 cases. Leuk. Lymphoma 18, 497–503 (1995).
Juge-Morineau, N., Harousseau, J. L., Amiot, M. & Bataille, R. The retinoblastoma susceptibility gene RB-1 in multiple myeloma. Leuk. Lymphoma 24, 229–237 (1997).
Dohner, H., Stilgenbauer, S., Dohner, K., Bentz, M. & Lichter, P. Chromosome aberrations in B-cell chronic lymphocytic leukaemia: reassessment based on molecular cytogenetic analysis. J. Mol. Med. 77, 266–281 (1999).
Kipps, T. J. Genetics of chronic lymphocytic leukaemia. Hematol. Cell Ther. 42, 5–14 (2000).
Liu, P. et al. Activating mutations of N- and KRAS2 in multiple myeloma show different clinical associations: analysis of the Eastern Cooperative Oncology Group Phase III Trial. Blood 88, 2699–2706 (1996).
Bezieau, S. et al. High incidence of N and KRAS2 activating mutations in multiple myeloma and primary plasma cell leukaemia at diagnosis. Hum. Mutat. 18, 212–224 (2001).
Chesi, M. et al. Activated fibroblast growth factor receptor 3 is an oncogene that contributes to tumor progression in multiple myeloma. Blood 97, 729–736 (2001).References 59 and 60 show that activating mutations of NRAS or KRAS2 are often present in multiple myeloma but not in premalignant MGUS, whereas reference 61 shows that tumours with t(4;14) can have an activating mutation of dysregulated FGFR3 or RAS mutations but not both.
Corradini, P. et al. Mutational activation of N- and KRAS2 oncogenes in plasma cell dyscrasias. Blood 81, 2708–2713 (1993).
Billadeau, D., Jelinek, D. F., Shah, N., LeBien, T. W. & Van Ness, B. Introduction of an activated NRAS oncogene alters the growth characteristics of the interleukin 6-dependent myeloma cell line ANBL6. Cancer Res. 55, 3640–3646 (1995).
Billadeau, D. et al. Activating mutations in the N- and KRAS2 oncogenes differentially affect the growth properties of the IL-6-dependent myeloma cell line ANBL6. Cancer Res. 57, 2268–2275 (1997).
Plowright, E. E. et al. Ectopic expression of fibroblast growth factor receptor 3 promotes myeloma cell proliferation and prevents apoptosis. Blood 95, 992–998 (2000).
Klein, B., Zhang, X. G., Lu, Z. Y. & Bataille, R. Interleukin-6 in human multiple myeloma. Blood 85, 863–872 (1995).
Klein, B. Update of gp130 cytokines in multiple myeloma. Curr. Opin. Hematol. 5, 186–191 (1998).
Jego, G., Bataille, R. & Pellat-Deceunynck, C. Interleukin-6 is a growth factor for nonmalignant human plasmablasts. Blood 97, 1817–1822 (2001).Provides insight regarding the crucial role of IL-6 in regulating the growth and differentiation of activated B cells to plasmablasts and terminally differentiated plasma cells.
Georgii-Hemming, P., Wiklund, H. J., Ljunggren, O. & Nilsson, K. Insulin-like growth factor 1 is a growth and survival factor in human multiple myeloma cell lines. Blood 88, 2250–2258 (1996).
Jelinek, D. F., Witzig, T. E. & Arendt, B. K. A role for insulin-like growth factor in the regulation of IL-6-responsive human myeloma cell line growth. J. Immunol. 159, 487–496 (1997).
Ferlin, M. et al. Insulin-like growth factor induces the survival and proliferation of myeloma cells through an interleukin-6-independent transduction pathway. Br. J. Haematol. 111, 626–634 (2000).
Ge, N. L. & Rudikoff, S. Insulin-like growth factor 1 is a dual effector of multiple myeloma cell growth. Blood 96, 2856–2861 (2000).
Catlett-Falcone, R. et al. Constitutive activation of Stat3 signaling confers resistance to apoptosis in human U266 myeloma cells. Immunity 10, 105–115 (1999).
Kiuchi, N. et al. STAT3 is required for the gp130-mediated full activation of the c-myc gene. J. Exp. Med. 189, 63–73 (1999).
Ogata, A. et al. IL-6 triggers cell growth via the Ras-dependent mitogen-activated protein kinase cascade. J. Immunol. 159, 2212–2221 (1997).
Puthier, D. et al. Mcl-1 and Bcl-xL are co-regulated by IL-6 in human myeloma cells. Br. J. Haematol. 107, 392–395 (1999).
Shirogane, T. et al. Synergistic roles for Pim-1 and c-Myc in STAT3-mediated cell cycle progression and antiapoptosis. Immunity 11, 709–719 (1999).
Hideshima, T., Nakamura, N., Chauhan, D. & Anderson, K. C. Biologic sequelae of interleukin-6 induced PI3-K/Akt signaling in multiple myeloma. Oncogene 20, 5991–6000 (2001).
Tu, Y., Gardner, A. & Lichtenstein, A. The phosphatidylinositol 3-kinase/AKT kinase pathway in multiple myeloma plasma cells: roles in cytokine-dependent survival and proliferative responses. Cancer Res. 60, 6763–6770 (2000).
Tlsty, T. D. Stromal cells can contribute oncogenic signals. Semin. Cancer Biol. 11, 97–104 (2001).
Liotta, L. A. & Kohn, E. C. The microenvironment of the tumour–host interface. Nature 411, 375–379 (2001).
Cook, G., Dumbar, M. & Franklin, I. M. The role of adhesion molecules in multiple myeloma. Acta Haematol. 97, 81–89 (1997).
Cook, G. & Campbell, J. D. Immune regulation in multiple myeloma: the host–tumour conflict. Blood Rev. 13, 151–162 (1999).
Duhrsen, U. & Hossfeld, D. K. Stromal abnormalities in neoplastic bone marrow diseases. Ann. Hematol. 73, 53–70 (1996).
Tricot, G. New insights into role of microenvironment in multiple myeloma. Lancet 355, 248–250 (2000).
Shain, K. H., Landowski, T. H. & Dalton, W. S. The tumor microenvironment as a determinant of cancer cell survival: a possible mechanism for de novo drug resistance. Curr. Opin. Oncol. 12, 557–563 (2000).
Van Riet, I. Homing mechanisms of myeloma cells. Pathol. Biol. (Paris) 47, 98–108 (1999).
Asosingh, K. et al. In vivo induction of insulin-like growth factor-1 receptor and CD44v6 confers homing and adhesion to murine multiple myeloma cells. Cancer Res. 60, 3096–3104 (2000).
Asosingh, K. et al. A unique pathway in the homing of murine multiple myeloma cells: CD44v10 mediates binding to bone marrow endothelium. Cancer Res. 61, 2862–2865 (2001).
Costes, V. et al. Interleukin-1 in multiple myeloma: producer cells and their role in the control of IL-6 production. Br. J. Haematol. 103, 1152–1160 (1998).
Dankbar, B. et al. Vascular endothelial growth factor and interleukin-6 in paracrine tumor–stromal cell interactions in multiple myeloma. Blood 95, 2630–2636 (2000).
Lokhorst, H. M. et al. Primary tumor cells of myeloma patients induce interleukin-6 secretion in long-term bone marrow cultures. Blood 84, 2269–2277 (1994).
Lacy, M. Q., Donovan, K. A., Heimbach, J. K., Ahmann, G. J. & Lust, J. A. Comparison of interleukin-1β expression by in situ hybridization in monoclonal gammopathy of undetermined significance and multiple myeloma. Blood 93, 300–305 (1999).
Uchiyama, H., Barut, B. A., Mohrbacher, A. F., Chauhan, D. & Anderson, K. C. Adhesion of human myeloma-derived cell lines to bone marrow stromal cells stimulates interleukin-6 secretion. Blood 82, 3712–3720 (1993).Provides one of the first descriptions of the important functional consequences of multiple-myeloma–stromal-cell interactions.
Bellamy, W. T., Richter, L., Frutiger, Y. & Grogan, T. M. Expression of vascular endothelial growth factor and its receptors in hematopoietic malignancies. Cancer Res. 59, 728–733 (1999).
Bertolini, F., Mancuso, P., Gobbi, A. & Pruneri, G. The thin red line: angiogenesis in normal and malignant hematopoiesis. Exp. Hematol. 28, 993–1000 (2000).
Rajkumar, S. V. et al. Prognostic value of bone marrow angiogenesis in multiple myeloma. Clin. Cancer Res. 6, 3111–3116 (2000).
Rajkumar, S. V. et al. Thalidomide for previously untreated indolent or smoldering multiple myeloma. Leukemia 15, 1274–1276 (2001).
Sezer, O. et al. Decrease of bone marrow angiogenesis in myeloma patients achieving a remission after chemotherapy. Eur. J. Haematol. 66, 238–244 (2001).
Sezer, O. et al. Serum levels of the angiogenic cytokines basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) in multiple myeloma. Eur. J. Haematol. 66, 83–88 (2001).
Vacca, A. et al. Bone marrow neovascularization, plasma cell angiogenic potential, and matrix metalloproteinase-2 secretion parallel progression of human multiple myeloma. Blood 93, 3064–3073 (1999).
Dallas, S. L. et al. Ibandronate reduces osteolytic lesions but not tumor burden in a murine model of myeloma bone disease. Blood 93, 1697–1706 (1999).
Callander, N. S. & Roodman, G. D. Myeloma bone disease. Semin. Hematol. 38, 276–285 (2001).
Roodman, G. D. Biology of osteoclast activation in cancer. J. Clin. Oncol. 19, 3562–3571 (2001).
Han, J. H. et al. Macrophage inflammatory protein-1α is an osteoclastogenic factor in myeloma that is independent of receptor activator of nuclear factor κB ligand. Blood 97, 3349–3353 (2001).
Michigami, T. et al. Cell–cell contact between marrow stromal cells and myeloma cells via VCAM-1 and α4β1-integrin enhances production of osteoclast-stimulating activity. Blood 96, 1953–1960 (2000).
Pearse, R. N. et al. Multiple myeloma disrupts the TRANCE/ osteoprotegerin cytokine axis to trigger bone destruction and promote tumor progression. Proc. Natl Acad. Sci. USA 98, 11581–11586 (2001).Provides an intricate description of the perturbation of the TRANCE/OPG network in multiple myeloma and shows the therapeutic potential of targeting this pathway in an animal model of multiple myeloma bone disease.
Artandi, S. E. & DePinho, R. A. A critical role for telomeres in suppressing and facilitating carcinogenesis. Curr. Opin. Genet. Dev. 10, 39–46 (2000).
Romanov, S. R. et al. Normal human mammary epithelial cells spontaneously escape senescence and acquire genomic changes. Nature 409, 633–637 (2001).
Gado, K., Silva, S., Paloczi, K., Domjan, G. & Falus, A. Mouse plasmacytoma: an experimental model of human multiple myeloma. Haematologica 86, 227–236 (2001).
Epstein, J., Yaccoby, S. & Fujii, R. in VIIIth International Myeloma Workshop 21–22 (Banff, Alberta, Canada, 2001).
Urashima, M. et al. The development of a model for the homing of multiple myeloma cells to human bone marrow. Blood 90, 754–765 (1997).
Yaccoby, S., Barlogie, B. & Epstein, J. Primary myeloma cells growing in SCID–hu mice: a model for studying the biology and treatment of myeloma and its manifestations. Blood 92, 2908–2913 (1998).
Yaccoby, S. & Epstein, J. The proliferative potential of myeloma plasma cells manifest in the SCID–hu host. Blood 94, 3576–3582 (1999).References 113 and 114 provide elegant descriptions of the most relevant animal model for multiple myeloma — the SCID–hu model.
Pilarski, L. M. et al. Myeloma progenitors in the blood of patients with aggressive or minimal disease: engraftment and self-renewal of primary human myeloma in the bone marrow of NOD SCID mice. Blood 95, 1056–1065 (2000).
Calame, K. L. Plasma cells: finding new light at the end of B cell development. Nature Immunol. 2, 1103–1108 (2001).
Sze, D. M., Toellner, K. M., Garcia de Vinuesa, C., Taylor, D. R. & MacLennan, I. C. Intrinsic constraint on plasmablast growth and extrinsic limits of plasma cell survival. J. Exp. Med. 192, 813–821 (2000).
Attal, M. et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Francais du Myelome. N. Engl. J. Med. 335, 91–97 (1996).The most convincing clinical trial supporting the use of high-dose therapy in patients under the age of 65 years.
Dalton, W. S., Bergsagel, P. L., Kuehl, W. M., Anderson, K. C. & Harousseau, J. L. Multiple myeloma. Hematology (Am. Soc. Hematol. Educ. Program), 157–177 (2001).
SEER. Surveillance, Epidemiology, and End Results (SEER) Program Public-Use Data (1973–1998) (National Cancer Institute, Bethesda, Maryland, 2001).
Fonseca, R. et al. A molecular classification of multiple myeloma (MM), based on cytogenetic abnormalities detected by interphase FISH, is powerful in identifying discrete groups of patients with dissimilar prognosis. Blood 98, A733 (2001).
Senderowicz, A. M. Small molecule modulators of cyclin-dependent kinases for cancer therapy. Oncogene 19, 6600–6606 (2000).
Finegold, A. A., Schafer, W. R., Rine, J., Whiteway, M. & Tamanoi, F. Common modifications of trimeric G proteins and ras protein: involvement of polyisoprenylation. Science 249, 165–169 (1990).
Karp, J. E. et al. Current status of clinical trials of farnesyltransferase inhibitors. Curr. Opin. Oncol. 13, 470–476 (2001).
Honemann, D. et al. The IL-6 receptor antagonist SANT-7 overcomes bone marrow stromal-cell-mediated drug resistance of multiple myeloma cells. Int. J. Cancer 93, 674–680 (2001).
Bataille, R. et al. Biologic effects of anti-interleukin-6 murine monoclonal antibody in advanced multiple myeloma. Blood 86, 685–691 (1995).
Moreau, P. et al. A combination of anti-interleukin 6 murine monoclonal antibody with dexamethasone and high-dose melphalan induces high complete response rates in advanced multiple myeloma. Br. J. Haematol. 109, 661–664 (2000).
Chauhan, D. et al. Multiple myeloma cell adhesion-induced interleukin-6 expression in bone marrow stromal cells involves activation of NF-κB. Blood 87, 1104–1112 (1996).
Fong, T. A. et al. SU5416 is a potent and selective inhibitor of the vascular endothelial growth factor receptor (Flk-1/KDR) that inhibits tyrosine kinase catalysis, tumor vascularization, and growth of multiple tumor types. Cancer Res. 59, 99–106 (1999).
Wood, J. M. et al. PTK787/ZK 222584, a novel and potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, impairs vascular endothelial growth factor-induced responses and tumor growth after oral administration. Cancer Res. 60, 2178–2189 (2000).
Huang, P., Feng, L., Oldham, E. A., Keating, M. J. & Plunkett, W. Superoxide dismutase as a target for the selective killing of cancer cells. Nature 407, 390–395 (2000).
Berenson, J. R. et al. Efficacy of pamidronate in reducing skeletal events in patients with advanced multiple myeloma. Myeloma Aredia Study Group. N. Engl. J. Med. 334, 488–493 (1996).
Singhal, S. et al. Antitumor activity of thalidomide in refractory multiple myeloma. N. Engl. J. Med. 341, 1565–1571 (1999).
Stinchcombe, T. E. et al. PS-341 is active in multiple myeloma: preliminary reports of a Phase I trial of the proteasome inhibitor PS-341 in patients with hematologic malignancies. Blood 98, A516 (2000).
Kuppers, R., Klein, U., Hansmann, M. L. & Rajewsky, K. Cellular origin of human B-cell lymphomas. N. Engl. J. Med. 341, 1520–1529 (1999).
MacLennan, I. C. M. in Myeloma: Biology and Management (eds Malpas, J. S., Bergsagel, D. E., Kyle, R. A. & Anderson, K. C.) 29–47 (Oxford Univ. Press, Oxford, 1998).
Kuppers, R. & Dalla-Favera, R. Mechanisms of chromosomal translocations in B cell lymphomas. Oncogene 20, 5580–5594 (2001).
Pasqualucci, L. et al. Hypermutation of multiple proto-oncogenes in B-cell diffuse large-cell lymphomas. Nature 412, 341–346 (2001).Shows that many of the loci (both Ig and non-Ig) that are involved in translocations in B-cell malignancies are subject to somatic mutation in normal germinal-centre B cells. This presumably contributes to the development of translocations by introducing double-stranded DNA breaks.
Bergsagel, P. L. & Kuehl, W. M. in Myeloma: Biology and Management (eds Malpas, J. S., Bergsagel, D. E., Kyle, R. & Anderson, K. C.) (Oxford Univ. Press, Oxford, 1998).
Max, E. E. in Fundamental Immunology (ed. Paul, W. E.) 113–184 (Lippincott–Raven, Philadelphia, 1999).
Papavasiliou, F. N. & Schatz, D. G. Cell-cycle-regulated DNA double-stranded breaks in somatic hypermutation of immunoglobulin genes. Nature 408, 216–221 (2000).
Avet-Loiseau, H. et al. p53 deletion is not a frequent event in multiple myeloma. Br. J. Haematol. 106, 717–719 (1999).
Corradini, P. et al. Inactivation of tumor suppressor genes, p53 and Rb1, in plasma cell dyscrasias. Leukemia 8, 758–767 (1994).
Mazars, G. R. et al. Mutations of the p53 gene in human myeloma cell lines. Oncogene 7, 1015–1018 (1992).
Neri, A. et al. p53 gene mutations in multiple myeloma are associated with advanced forms of malignancy. Blood 81, 128–135 (1993).
Ollikainen, H., Syrjanen, S., Koskela, K., Pelliniemi, T. T. & Pulkki, K. p53 gene mutations are rare in patients but common in patient-originating cell lines in multiple myeloma. Scand. J. Clin. Lab. Invest. 57, 281–289 (1997).
Taniguchi, T. et al. Expression of p16INK4A and p14ARF in hematological malignancies. Leukemia 13, 1760–1769 (1999).
Urashima, M. et al. Role of CDK4 and p16INK4A in interleukin-6-mediated growth of multiple myeloma. Leukemia 11, 1957–1963 (1997).
Uchida, T. et al. Hypermethylation of p16INK4A gene promoter during the progression of plasma cell dyscrasia. Leukemia 15, 157–165 (2001).
Guillerm, G. et al. p16(INK4a) and p15(INK4b) gene methylations in plasma cells from monoclonal gammopathy of undetermined significance. Blood 98, 244–246 (2001).
Urashima, M. et al. Characterization of p16(INK4A) expression in multiple myeloma and plasma cell leukaemia. Clin. Cancer Res. 3, 2173–2179 (1997).
Hyun, T. et al. Loss of PTEN expression leading to high Akt activation in human multiple myelomas. Blood 96, 3560–3568 (2000).
Ge, N. L. & Rudikoff, S. Expression of PTEN in PTEN-deficient multiple myeloma cells abolishes tumor growth in vivo. Oncogene 19, 4091–4095 (2000).
Bednarek, A. K. et al. WWOX, the FRA16D gene, behaves as a suppressor of tumor growth. Cancer Res. 61, 8068–8073 (2001).
Zhang, S. L. et al. Efficiency alleles of the Pctr1 modifier locus for plasmacytoma susceptibility. Mol. Cell Biol. 21, 310–318 (2001).
Garrett, I. R., Dallas, S., Radl, J. & Mundy, G. R. A murine model of human myeloma bone disease. Bone 20, 515–520 (1997).
Radl, J. Multiple myeloma and related disorders. Lessons from an animal model. Pathol. Biol. (Paris) 47, 109–114 (1999).
Radl, J. et al. The 5T mouse multiple myeloma model: absence of c-myc oncogene rearrangement in early transplant generations. Br. J. Cancer 61, 276–278 (1990).
van den Akker, T. W., Radl, J., Franken-Postma, E. & Hagemeijer, A. Cytogenetic findings in mouse multiple myeloma and Waldenstrom's macroglobulinemia. Cancer Genet. Cytogenet. 86, 156–161 (1996).
Vanderkerken, K. et al. Organ involvement and phenotypic adhesion profile of 5T2 and 5T33 myeloma cells in the C57BL/KaLwRij mouse. Br. J. Cancer 76, 451–460 (1997).
Zhu, D. et al. Immunoglobulin VH gene sequence analysis of spontaneous murine immunoglobulin-secreting B-cell tumours with clinical features of human disease. Immunology 93, 162–170 (1998).
Alsina, M. et al. Development of an in vivo model of human multiple myeloma bone disease. Blood 87, 1495–1501 (1996).
Rebouissou, C. et al. A gp130 interleukin-6 transducer-dependent SCID model of human multiple myeloma. Blood 91, 4727–4737 (1998).
Tsunenari, T. et al. New xenograft model of multiple myeloma and efficacy of a humanized antibody against human interleukin–6 receptor. Blood 90, 2437–2444 (1997).
Acknowledgements
The authors would like to thank S. Ely for providing the histology pictures in Figure 1, members of their labs who contributed unpublished data, and numerous other colleagues with whom they have discussed many of the issues covered in this review.
Author information
Authors and Affiliations
Related links
Glossary
- MONOCLONAL GAMMOPATHY OF UNDETERMINED SIGNIFICANCE
-
The presence of a stable, low level of monoclonal immunoglobulin in the serum or urine of persons with less than 10% plasma cells in the bone marrow and no evidence of multiple myeloma, amyloidosis, Waldenstrom's macroglobulinaemia or related disorder.
- AMYLOIDOSIS
-
A heterogeneous group of disorders associated with extracellular deposition of protein in a characterisitic fibrillar form. Amyloid fibrils are derived from monoclonal immunoglobulin light chains and most affected individuals die of heart failure, renal failure or some other effect of amyloid within 6–18 months of diagnosis.
- INTRAMEDULLARY SITE
-
Site of disease that is confined to the bone marrow, which is by far the most common location.
- SMOULDERING MYELOMA
-
Has a stable intramedullary tumour content of greater than 10% with none of the malignant features of multiple myeloma.
- EXTRAMEDULLARY SITE
-
Site of disease outside the bone marrow, such as blood, pleural fluid and skin.
- PLASMA-CELL LEUKAEMIA
-
Diagnosed when greater than 20% of the white blood cells are malignant plasma cells.
- PLASMA-CELL LABELLING INDEX
-
The percentage of plasma cells in a tumour specimen that incorporate a DNA precursor during a 30-minute in vitro incubation, thereby providing some measure of the fraction of tumour cells that are involved in proliferation.
- BALANCED TRANSLOCATION
-
A simple reciprocal translocation that generates two derivative chromosomes with no apparent loss (or gain) of sequences from either chromosome.
- UNBALANCED TRANSLOCATION
-
A translocation that generates a derivative chromosome(s) that has lost sequences from the involved chromosomes (sometimes more than two).
- COMPARATIVE GENOMIC HYBRIDIZATION
-
(CGH). This uses two sources of genomic DNA (typically from tumour and normal cells) that are differentially labelled with unique fluors, mixed and then hybridized to normal chromosomes. The ratio of signals reflects the representation of DNA sequences at different chromosomal locations in the two samples.
- SPECTRAL KARYOTYPING
-
(SKY). Simultaneous visualization of an organism's chromosomes, each labelled with a different colour. This technique is useful for identifying chromosome abnormalities.
- HYPODIPLOIDY/HYPERDIPLOIDY
-
A loss or gain of chromosome number or DNA content compared with a normal diploid cell.
- PRIMARY TRANSLOCATION
-
Translocations that occur as the early, perhaps initiating, event in tumorigenesis.
- SECONDARY TRANSLOCATION
-
Translocations that occur during tumour progression.
- ENHANCER
-
A cis-acting sequence that increases the use of (some) promoters, and can function in either orientation and in any location relative to a promoter.
- GERMINAL CENTRE
-
Follicular cell structure in secondary lymphoid tissues in which antigen-driven B-cell maturation occurs.
- FLUORESCENCE IN SITU HYBRIDIZATION
-
(FISH). Uses one or more probes (chromosome, region, gene or sub-gene specific) that are differentially labelled with fluors and then hybridized to metaphase chromosomes or interphase nuclei so that the numbers and locations of different sequences can be assessed in individual cells.
- SET DOMAIN
-
A protein domain that was first described in the Drosophila proteins Su(var)3-9, Enhancer of Zeste and Trithorax. Proteins with SET domains are thought to be involved in chromatin remodelling. MMSET, and MLL1 on 11q23, are mammalian SET domain proteins that are dysregulated by chromosome translocations.
- B-ZIP TRANSCRIPTION FACTOR
-
Transcription factor that has a basic and a leucine zipper domain. The best characterized are the AP1 factors c-JUN and c-FOS.
- FRAGILE SITE
-
An area of chromosome breakage that can be induced by exposure to inhibitors of DNA replication, such as aphidicolin. FRA16D (WWOX) and FRA3B (FHIT) are the most frequently expressed among more than 80 commonly described sites.
- INTERSTITIAL DELETION
-
An internal deletion of a chromosome of varying size that might not be identified by traditional G-banding techniques.
Rights and permissions
About this article
Cite this article
Kuehl, W., Bergsagel, P. Multiple myeloma: evolving genetic events and host interactions. Nat Rev Cancer 2, 175–187 (2002). https://doi.org/10.1038/nrc746
Issue Date:
DOI: https://doi.org/10.1038/nrc746
This article is cited by
-
Epigenetic regulation of CD38/CD48 by KDM6A mediates NK cell response in multiple myeloma
Nature Communications (2024)
-
Exploring the genetic and molecular basis of differences in multiple myeloma of individuals of African and European descent
Cell Death & Differentiation (2024)
-
PSGL-1 decorated with sialyl Lewisa/x promotes high affinity binding of myeloma cells to P-selectin but is dispensable for E-selectin engagement
Scientific Reports (2024)
-
Redefining high risk multiple myeloma with an APOBEC/Inflammation-based classifier
Leukemia (2024)
-
The role and regulation of Maf proteins in cancer
Biomarker Research (2023)