Smoldering multiple myeloma: Present position and potential promises

European Journal of Haematology

Volumn 92, Issue 1, 2014, Pages 1-12

  Tageja, Nishant ^a   Manasanch, Elisabet E ^a   Korde, Neha ^a   Kwok, Mary ^a   Mailankody, Sham ^a   Bhutani, Manisha ^a   Roschewski, Mark ^a   Landgren, Ola ^a  

^a NATIONAL CANCER INSTITUTE   (United States)

Author keywords

Carfilzomib; Flow cytometry; Lenalidomide; Multiple myeloma; Plasma cell dyscrasia; Smoldering myeloma

Indexed keywords

BORTEZOMIB; CARFILZOMIB; CELECOXIB; CURCUMIN; CYCLIN D1; DEXAMETHASONE; GREEN TEA EXTRACT; INTERLEUKIN 6; IXAZOMIB CITRATE; LENALIDOMIDE; M PROTEIN; MELPHALAN; MICRORNA; OMEGA 3 FATTY ACID; PAMIDRONIC ACID; PREDNISONE; RECOMBINANT INTERLEUKIN 1 RECEPTOR BLOCKING AGENT; SILTUXIMAB; THALIDOMIDE; ZOLEDRONIC ACID;

BONE DESTRUCTION; CASE STUDY; CELL CLONE; CLINICAL STUDY; DISEASE COURSE; DIZZINESS; EPIGENETICS; FLOW CYTOMETRY; HUMAN; LOW DRUG DOSE; MINIMAL RESIDUAL DISEASE; MORPHOMETRICS; MULTIPLE CYCLE TREATMENT; MULTIPLE MYELOMA; OSTEOCLAST ACTIVITY; OSTEOLYSIS; PATHOGENESIS; PERIPHERAL NEUROPATHY; PLASMA CELL; PRIORITY JOURNAL; PROTEIN BLOOD LEVEL; RADIOLOGICAL PROCEDURES; REVIEW; SMOLDERING MULTIPLE MYELOMA; TREATMENT RESPONSE; TUMOR MICROENVIRONMENT;

CARFILZOMIB; FLOW CYTOMETRY; LENALIDOMIDE; MULTIPLE MYELOMA; PLASMA CELL DYSCRASIA; SMOLDERING MYELOMA;

BONE AND BONES; BONE MARROW; DIAGNOSTIC IMAGING; DISEASE PROGRESSION; FLOW CYTOMETRY; HUMANS; MONOCLONAL GAMMOPATHY OF UNDETERMINED SIGNIFICANCE; MULTIPLE MYELOMA; PRECANCEROUS CONDITIONS; RISK FACTORS;

EID: 84890145812     PISSN: 09024441     EISSN: 16000609     Source Type: Journal    
DOI: 10.1111/ejh.12205     Document Type: Review

References (95)

1. Palumbo A, Rajkumar SV. Treatment of newly diagnosed Myeloma. Leukemia 2009;23:449-56.
2. Waxman AJ, Kuehl M, Balakumaran A, Weiss B, Landgren O. Smoldering (asymptomatic) multiple myeloma: revisiting the clinical dilemma and looking into the future. Clin Lymphoma Myeloma Leuk 2010;10:248-57.
3. Landgren O, Waxman AJ. Multiple myeloma precursor disease. JAMA 2010;304:2397-404.
4. Kyle RA, Greipp PR. Smoldering multiple myeloma. N Engl J Med 1980;302:1347-9.
5. Alexanian R, Barlogie B, Dixon D. Prognosis of asymptomatic multiple myeloma. Arch Intern Med 1988;148:1963-5.
6. Dimopoulos MA, Moulopoulos A, Smith T, Delasalle KB, Alexanian R. Risk of disease progression in asymptomatic multiple myeloma. Am J Med 1993;94:57-61.
7. Witzig TE, Kyle RA, O'Fallon WM, Greipp PR. Detection of peripheral blood plasma cells as a predictor of disease course in patients with smouldering multiple myeloma. Br J Haematol 1994;87:266-72.
8. Rajkumar SV, Dispenzieri A, Fonseca R, Lacy MQ, Geyer S, Lust JA, Kyle RA, Greipp PR, Gertz MA, Witzig TE. Thalidomide for previously untreated indolent or smoldering multiple myeloma. Leukemia 2001;15:1274-6.
9. International Myeloma Working Group. Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group. Br J Haematol 2003;121:749-57.
10. Kyle RA, Durie BG, Rajkumar SV, et al. Monoclonal gammopathy of undetermined significance (MGUS) and smoldering (asymptomatic) multiple myeloma: IMWG consensus perspectives risk factors for progression and guidelines for monitoring and management. Leukemia 2010;24:1121-7.
11. Kyle RA, Therneau TM, Rajkumar SV, Offord JR, Larson DR, Plevak MF, Melton LJ 3rd. A long-term study of prognosis in mono- clonal gammopathy of undetermined significance. N Engl J Med 2002;346:564-9.
12. Kyle RA, Therneau TM, Rajkumar SV, Larson DR, Plevak MF, Offord JR, Dispenzieri A, Katzmann JA, Melton LJ 3rd. Prevalence of monoclonal gammopathy of undetermined significance. N Engl J Med 2006;354:1362-9.
13. Kyle RA, Remstein ED, Therneau TM, et al. Clinical course and prognosis of smoldering (asymptomatic) multiple myeloma. N Engl J Med 2007;356:2582-90.
14. Chng WJ, Glebov O, Bergsagel PL, Kuehl WM. Genetic events in the pathogenesis of mul- tiple myeloma. Best Pract Res Clin Haematol 2007;20:571-96.
15. Rajkumar SV. Prevention of progression in monoclonal gammopathy of undetermined significance. Clin Cancer Res 2009;15:5606-8.
16. Dispenzieri A, Katzmann JA, Kyle RA, et al. Prevalence and risk of progression of light-chain monoclonal gammopathy of undetermined significance: a retrospective population-based cohort study. Lancet 2010;375:1721-8.
17. Katzmann JA, Clark R, Kyle RA, et al. Suppression of uninvolved immunoglobulins defined by heavy/light chain pair suppression is a risk factor for progression of MGUS. Leukemia 2013;27:208-12.
18. Dispenzieri A, Kyle RA, Katzmann JA, et al. Immunoglobulin free light chain ratio is an independent risk factor for progression of smoldering (asymptomatic) multiple myeloma. Blood 2008;111:785-9.
19. Pérez-Persona E, Vidriales MB, Mateo G, et al. New criteria to identify risk of progression in monoclonal gammopathy of uncertain significance and smoldering multiple myeloma based on multiparameter flow cytometry analysis of bone marrow plasma cells. Blood 2007;110:2586-92.
20. Pérez-Persona E, Mateo G, García-Sanz R, et al. Risk of progression in smouldering myeloma and monoclonal gammopathies of unknown significance: comparative analysis of the evolution of monoclonal component and multiparameter flow cytometry of bone marrow plasma cells. Br J Haematol 2010;148:110-4.
21. Cherry BM, Korde N, Kwok M, et al. Modeling progression risk for smoldering multiple myeloma: results from a prospective clinical study. Leuk Lymphoma 2013;54:2215-8.
22. Kristinsson SY, Tang M, Pfeiffer RM, Björkholm M, Blimark C, Mellqvist UH, Wahlin A, Turesson I, Landgren O. Monoclonal gammopathy of undetermined significance and risk of skeletal fractures: a population-based study. Blood 2010;116:2651-5.
23. Gregersen H, Jensen P, Gislum M, Jorgensen B, Sorensen HT, Norgaard M. Fracture risk in patients with monoclonal gammopathy of undetermined significance. Br J Haematol 2006;135:62-7.
24. Melton LJ 3rd, Rajkumar SV, Khosla S, Achenbach SJ, Oberg AL, Kyle RA. Fracture risk in monoclonal gammopathy of undetermined significance. J Bone Miner Res 2004;19:25-30.
25. Bida JP, Kyle RA, Therneau TM, Melton LJ 3rd, Plevak MF, Larson DR, Dispenzieri A, Katzmann JA, Rajkumar SV. Disease associations with monoclonal gammopathy of undetermined significance: a population-based study of 17, 398 patients. Mayo Clin Proc 2009;84:685-93.
26. Bataille R, Chappard D, Basle MF. Quantifiable excess of bone resorption in monoclonal gammopathy is an early symptom of malignancy: a prospective study of 87 bone biopsies. Blood 1996;87:4762-9.
27. Politou M, Terpos E, Anagnostopoulos A, Szydlo R, Laffan M, Layton M, Apperley JF, Dimopoulos MA, Rahemtulla A. Role of receptor activator of nuclear factor-kappa B ligand (RANKL), osteoprotegerin and macrophage protein 1-alpha (MIP-1a) in monoclonal gammopathy of undetermined significance (MGUS). Br J Haematol 2004;126:686-9.
28. Edwards CM, Zhuang J, Mundy GR. The pathogenesis of the bone disease of multiple myeloma. Bone 2008;42:1007-13.
29. Kaiser M, Mieth M, Liebisch P, et al. Serum concentrations of DKK-1 correlate with the extent of bone disease in patients with multiple myeloma. Eur J Haematol 2008;80:490-4.
30. Tian E, Zhan F, Walker R, Barlogie B, Shaughnessy JD Jr. The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma. N Engl J Med 2003;349:2483-94.
31. Saad F, Lipton A, Cook R, Chen YM, Smith M, Coleman R. Pathologic fractures correlate with reduced survival in patients with malignant bone disease. Cancer 2007;110:1860-7.
32. Durie BG, Salmon SE. A clinical staging system for multiple myeloma. Correlation of measured myeloma cell mass with presenting clinical features, response to treatment, and survival. Cancer 1975;36:842-54.
33. Dimopoulos M, Terpos E, Comenzo RL, et al. International myeloma working group consensus statement and guidelines regarding the current role of imaging techniques in the diagnosis and monitoring of multiple Myeloma. Leukemia 2009;23:1545-56.
34. Edelstyn GA, Gillespie PJ, Grebbell FS. The radiological demonstration of osseous metastases. Experimental observations. Clin Radiol 1967;18:158-62.
35. Baur-Melnyk A, Buhmann S, Becker C, Schoenberg SO, Lang N, Bartl R, Reiser MF. Whole-body MRI versus whole-body MDCT for staging of multiple myeloma. AJR Am J Roentgenol 2008;190:1097-104.
36. Ghanem N, Lohrmann C, Engelhardt M, Pache G, Uhl M, Saueressig U, Kotter E, Langer M. Whole-body MRI in the detection of bone marrow infiltration in patients with plasma cell neoplasms in comparison to the radiological skeletal survey. Eur Radiol 2006;16:1005-14.
37. Moulopoulos LA, Dimopoulos MA, Smith TL, Weber DM, Delasalle KB, Libshitz HI, Alexanian R. Prognostic significance of magnetic resonance imaging in patients with asymptomatic multiple myeloma. J Clin Oncol 1995;13:251-6.
38. Bellaiche L, Laredo JD, Liote F, Koeger AC, Hamze B, Ziza JM. Magnetic resonance appearance of monoclonal gammopathies of unknown significance and multiple myeloma. The GRI Study Group. Spine 1997;22:2551-7.
39. Wang M, Alexanian R, Delasalle K, Weber D. Abnormal MRI of spine is the dominant risk factor for early progression of asymptomatic multiple myeloma. Blood 2003;102:687a.
40. Blade J, Rosinol L. Smoldering multiple myeloma and monoclonal gammopathy of undetermined significance. Curr Treat Options Oncol 2006;7:237-45.
41. Mena E, Choyke P, Tan E, Landgren O, Kurdziel K. Molecular imaging in myeloma precursor disease. Semin Hematol 2011;48:22-31.
42. Hillengass J, Zechmann C, Bäuerle T, et al. Dynamic contrast-enhanced magnetic resonance imaging identifies a subgroup of patients with asymptomatic monoclonal plasma cell disease and pathologic microcirculation. Clin Cancer Res 2009;15:3118-25.
43. Durie BG, Waxman AD, D'Agnolo A, Williams CM. Whole-body (18)F-FDG PET identifies high-risk myeloma. J Nucl Med 2002;43:1457-63.
44. Hillengass J, Landgren O. Challenges and opportunities of novel imaging techniques in monoclonal plasma cell disorders: imaging "early myeloma. Leuk Lymphoma 2013;54:1355-63.
45. Schirrmeister H, Glatting G, Hetzel J, Nüssle K, Arslandemir C, Buck AK, Dziuk K, Gabelmann A, Reske SN, Hetzel M. Prospective evaluation of the clinical value of planar bone scans, SPECT, and (18)F-labeled NaF PET in newly diagnosed lung cancer. J Nucl Med 2001;42:1800-4.
46. Yuan CM, Stetler-Stevenson M. Role of flow cytometry of peripheral blood and bone marrow aspirates in early myeloma. Semin Hematol 2011;48:32-8.
47. Bianchi G, Kyle RA, Larson DR, Witzig TE, Kumar S, Dispenzieri A, Morice WG, Rajkumar SV. High levels of peripheral blood circulating plasma cells as a specific risk factor for progression of smoldering multiple myeloma. Leukemia 2013;27:680-5.
48. Jerez A, Ortuño FJ, Osma Mdel M, Español I, González AD, Roldán V, de Arriba F, Vicente V. Bone-marrow immunophenotypic analysis allows the identification of high risk of progression and immune condition-related monoclonal gammopathy of undetermined significance. Ann Med 2009;41:547-58.
49. Jego G, Bataille R, Geffroy-Luseau A, Descamps G, Pellat-Deceunynck C. Pathogen-associated molecular patterns are growth and survival factors for human myeloma cells through Toll-like receptors. Leukemia 2006;20:1130-7.
50. Bohnhorst J, Rasmussen T, Moen SH, Fløttum M, Knudsen L, Børset M, Espevik T, Sundan A. Toll-like receptors mediate proliferation and survival of multiple myeloma cells. Leukemia 2006;20:1138-44.
51. Mantovani A, Garlanda C. Inflammation and multiple myeloma: the Toll connection. Leukemia 2006;20:937-8.
52. Xiong Y, Donovan KA, Kline MP, Gornet MK, Moon-Tasson LL, Lacy MQ, Dispenzieri A, Gertz MA, Greipp PR, Lust JA. Identification of two groups of smoldering multiple myeloma patients who are either high or low producers of interleukin-1. J Interferon Cytokine Res 2006;26:83-95.
53. Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 2004;116:281-97.
54. Pichiorri F, Suh SS, Ladetto M, et al. MicroRNAs regulate critical genes associated with multiple myeloma pathogenesis. Proc Natl Acad Sci U S A 2008;105:12885-90.
55. Avet-Loiseau H, Facon T, Grosbois B, Magrangeas F, Rapp MJ, Harousseau JL, Minvielle S, Bataille R, Intergroupe Francophone du Myélome. Oncogenesis of multiple myeloma: 14q32 and 13q chromosomal abnormalities are not randomly distributed, but correlate with natural history, immunological features, and clinical presentation. Blood 2002;99:2185-91.
56. Fonseca R, Bailey RJ, Ahmann GJ, Rajkumar SV, Hoyer JD, Lust JA, Kyle RA, Gertz MA, Greipp PR, Dewald GW. Genomic abnormalities in monoclonal gammopathy of undetermined significance. Blood 2002;100:1417-24.
57. Konigsberg R, Ackermann J, Kaufmann H, et al. Deletions of chromosome 13q in monoclonal gammopathy of undetermined significance. Leukemia 2000;14:1975-9.
58. Rajkumar SV, Gupta V, Fonseca R, Dispenzieri A, Gonsalves WI, Larson D, Ketterling RP, Lust JA, Kyle RA, Kumar SK. Impact of primary molecular cytogenetic abnormalities and risk of progression in smoldering multiple myeloma. Leukemia 2013;27:1738-44.
59. Chng WJ, Gonzalez-Paz N, Price-Troska T, et al. Clinical and biological significance of RAS mutations in multiple myeloma. Leukemia 2008;22:2280-4.
60. Chiecchio L, Dagrada GP, Protheroe RK, Smith AG, Orchard KH, Cross NC, Harrison CJ, Ross FM; UK Myeloma Forum. Loss of 1p and rearrangement of MYC are associated with progression of smouldering myeloma to myeloma: sequential analysis of a single case. Haematologica 2009;94:1024-8.
61. Zhan F, Barlogie B, Arzoumanian V, et al. Gene-expression signature of benign monoclonal gammopathy evident in multiple myeloma is linked to good prognosis. Blood 2007;109:1692-700.
62. Lopez-Corral L, Mateos MV, Corchete LA, Sarasquete ME, de la Rubia J, de Arriba F, Lahuerta JJ, García-Sanz R, San Miguel JF, Gutiérrez NC. Genomic analysis of high-risk smoldering multiple myeloma. Haematologica 2012;97:1439-43.
63. Hjorth M, Hellquist L, Holmberg E, Magnusson B, Rödjer S, Westin J. Initial versus deferred melphalan- prednisone therapy for asymptomatic multiple myeloma stage I-a randomized study. Myeloma Group of Western Sweden. Eur J Haematol 1993;50:95-102.
64. Barlogie B, van Rhee F, Shaughnessy JD Jr, et al. Seven-year median time to progression with thalidomide for smoldering myeloma: partial response identifies subset requiring earlier salvage therapy for symptomatic disease. Blood 2008;112:3122-5.
65. Lust JA, Lacy MQ, Zeldenrust SR, et al. Induction of a chronic disease states in patients with smoldering or indolent multiple myeloma by targeting interleukin 1{beta}- induced interleukin 6 production and the myeloma proliferative component. Mayo Clin Proc 2009;84:114-22.
66. Golombick T, Diamond TH, Badmaev V, Manoharan A, Ramakrishna R. The potential role of curcumin in patients with monoclonal gammopathy of undefined significance-its effect on paraproteinemia and the urinary n-telopeptide of type I collagen bone turnover marker. Clin Cancer Res 2009;15:5917-22.
67. Musto P, Petrucci MT, Bringhen S, et al. A multicenter, randomized clinical trial comparing zoledronic acid versus observation in patients with asymptomatic myeloma. Cancer 2008;113:1588-95.
68. Clinicaltrials.gov [Web site]. Celecoxib in preventing multiple myeloma in patients with monoclonal gammopathy or smoldering myeloma. ClinicalTrialsgov. http://clinicaltrials.gov/ct2/show/NCT00099047.
69. Clinicaltrials.gov [Web site]. Omega 3 supplementation for the prevention of disease progression in early stage chronic lymphocytic leukemia (ES-CLL), monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). ClinicalTrialsgov. http://clinicaltrials.gov/ct2/show/ NCT00899353.
70. Clinicaltrials.gov [Web site]. Green tea extract in treating patients with monoclonal gammopathy of undetermined significance and/or smoldering multiple myeloma. ClinicalTrialsgov. http://clinicaltrials.gov/ct2/show/NCT00942422.
71. Kyle RA, Rajkumar SV. Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma. Leukemia 2009;23:3-9.
72. Mateos MV, Hernández MT, Giraldo P, et al. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med 2013;369:438-47.
73. Attal M, Lauwers-Cances V, Marit G, et al. Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. N Engl J Med 2012;366:1782-91.
74. McCarthy PL, Owzar K, Hofmeister CC, et al. Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med 2012;366:1770-81.
75. Palumbo A, Hajek R, Delforge M, et al. Continuous lenalidomide treatment for newly diagnosed multiple myeloma. N Engl J Med 2012;366:1759-69.
76. Palumbo AP, Delforge M, Catalano J, et al. Incidence of second primary malignancy (SPM) in melphalan-prednisone-lenalidomide combination followed by lenalidomide maintenance (MPR-R) in newly diagnosed multiple myeloma patients (pts) age 65 or older. ASCO Meeting Abstracts. 2011;29(15, supplement, 8007)
77. Clinicaltrials.gov [Web site]. Carfilzomib, Lenalidomide, and Dexamethasone for Smoldering Multiple Myeloma. ClinicalTrialsgov. http://www.clinicaltrials.gov/ct2/show/NCT01572480.
78. Jakubowiak AJ, Siegel DS, Martin T, et al. Treatment outcomes in patients with relapsed and refractory multiple myeloma and high-risk cytogenetics receiving single-agent carfilzomib in the PX-171-003-A1 study. Leukemia 2013. 10.1038/leu.2013.152 [Epub ahead of print].
79. FDA.gov [Web site]. http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202714lbl.pdf
80. Clinicaltrials.gov [Web site]. MLN9708 and Dexamethasone for High-Risk Smoldering Multiple Myeloma. ClinicalTrialsgov. http://www.clinicaltrials.gov/ct2/show/NCT01660997
81. Clinicaltrials.gov [Web site]. A Study Evaluating the Effects of Siltuximab on the Heart in Patients With Monoclonal Gammopathy of Undetermined Significance, Smoldering Multiple Myeloma, or Indolent Multiple Myeloma. ClinicalTrialsgov. http://www.clinicaltrials.gov/ct2/show/NCT01219010.
82. Clinicaltrials.gov [Web site]. A Trial of TBL-12 Sea Cucumber Extract in Patients With Untreated Asymptomatic Myeloma. ClinicalTrialsgov. http://www.clinicaltrials.gov/ct2/show/NCT01302366
83. Clinicaltrials.gov [Web site]. Lenalidomide or Observation in Treating Patients With Asymptomatic High-Risk Smoldering Multiple Myeloma. ClinicalTrialsgov. http://www.clinicaltrials.gov/ct2/show/NCT01169337
84. Clinicaltrials.gov [Web site]. Study on the Anti-tumor Activity, Safety and Pharmacology of IPH2101 in Patients With Smoldering Multiple Myeloma (KIRMONO). ClinicalTrialsgov. http://www.clinicaltrials.gov/ct2/show/NCT01222286
85. Clinicaltrials.gov [Web site]. Phase 1/2a Study of Cancer Vaccine to Treat Smoldering Multiple Myeloma. ClinicalTrialsgov. http://www.clinicaltrials.gov/ct2/show/NCT01718899
86. Clinicaltrials.gov [Web site]. A Study of Siltuximab (Anti- IL 6 Monoclonal Antibody) in Patients With High-risk Smoldering Multiple Myeloma ClinicalTrialsgov. http://www.clinicaltrials.gov/ct2/show/NCT01484275
87. Clinicaltrials.gov [Web site]. Biomarker Study of Elotuzumab in High Risk Smoldering Myeloma ClinicalTrialsgov. http://www.clinicaltrials.gov/ct2/show/NCT01441973
88. Clinicaltrials.gov [Web site]. Study of BHQ880 in Patients With High Risk Smoldering Multiple Myeloma ClinicalTrialsgov. http://www.clinicaltrials.gov/ct2/show/NCT01302886
89. Clinicaltrials.gov [Web site]. A Phase II Trial of Anti-KIR in Smoldering Multiple Myeloma ClinicalTrialsgov. http://www.clinicaltrials.gov/ct2/show/NCT01248455
90. Clinicaltrials.gov [Web site]. Effect of Low Dose Bortezomib on Bone Formation in Smoldering Myeloma Patients ClinicalTrialsgov. http://www.clinicaltrials.gov/ct2/show/NCT00983346
91. Boucher K, Parquet N, Widen R, Shain K, Baz R, Alsina M, Koomen J, Anasetti C, Dalton W, Perez LE. Stemness of B-cell progenitors in multiple myeloma bone marrow. Clin Cancer Res 2012;18:6155-68.
92. Witzig TE, Laumann KM, Lacy MQ, et al. A phase III randomized trial of thalidomide plus zoledronic acid versus zoledronic acid alone in patients with asymptomatic multiple myeloma. Leukemia 2013;27:220-5.
93. Weber D, Rankin K, Gavino M, Delasalle K, Alexanian R. Thalidomide alone or with dexamethasone for previously untreated multiple myeloma. J Clin Oncol 2003;21:16-9.
94. D'Arena G, Gobbi PG, Broglia C, et al. Pamidronate versus observation in asymptomatic myeloma: final results with long-term follow-up of a randomized study. Leuk Lymphoma 2011;52:771-5.
95. Riccardi A, Mora O, Tinelli C, et al. Long-term survival of stage I multiple myeloma given chemotherapy just after diagnosis or at progression of the disease: a multicentre randomized study. Cooperative Group of Study and Treatment of Multiple Myeloma. Br J Cancer 2000;82:1254-60.