Biology and therapy of multiple myeloma

Joshua, Douglas E; Bryant, Christian; Dix, Caroline; Gibson, John; Ho, Joy

doi:10.5694/mja2.50129

ARTICLE
AUTHORS
REFERENCES

Topics

Hematologic diseases

Immune system diseases

Summary

Genetic sequencing of the myeloma genome has not revealed a specific disease‐determining genetic alteration.
Multiple disease subclones exist at diagnosis and vary in clinical importance with time and drug sensitivity.
New diagnostic criteria have identified indications for early introduction of therapy.
Autologous stem cell transplantation remains an essential component of therapy in young and fit patients.
The use of continual suppressive (maintenance) therapy has been established as an important component in therapy.
Immune therapies and the harnessing of the innate immune system offer great promise for future treatments.
Since 2005, quality of life, supportive therapies, and survival have dramatically improved over a decade of remarkable progress.
The common manifestations of multiple myeloma, such as bone pain, fatigue and weight loss, may be non‐specific and are often initially ignored or missed by patients and medical practitioners.

Royal Prince Alfred Hospital, Sydney, NSW

Correspondence: Christian.Bryant@health.nsw.gov.au

Competing interests:

No relevant disclosures.

1. Joshua DE. Multiple myeloma: the present and the future. Med J Aust 2005 Oct 3; 183: 344. https://www.mja.com.au/journal/2005/183/7/multiple-myeloma-present-and-future
2. Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol 2014; 15: e538–e548.
3. Rajkumar SV. Multiple myeloma: 2016 update on diagnosis, risk‐stratification, and management. Am J Hematol 2016; 91: 719–734.
4. Kyle R, Gertz M, Witzig T, et al. Review of 1027 patients with newly diagnosed multiple myeloma. Mayo Clin Proc 2003; 78: 21–33.
5. Landgren O, Gridley G, Turesson I, et al. Risk of monoclonal gammopathy of undetermined significance (MGUS) and subsequent multiple myeloma among African American and white veterans in the United States. Blood 2006; 107: 904–906.
6. Kyle R, Therneau T, Rajkumar S, et al. A long‐term study of prognosis in monoclonal gammopathy of undetermined significance. N Engl J Med 2002; 346: 564–569.
7. Kyle R, Therneau T, Rajkumar S, et al. Prevalence of monoclonal gammopathy of undetermined significance. N Engl J Med 2006; 354: 1362–1369.
8. Blimark CH, Turesson I, Genell A, et al. Outcome and survival of myeloma patients diagnosed 2008–2015. Real‐world data on 4904 patients from the Swedish Myeloma Registry. Haematologica 2018; 103: 506–513.
9. Libby E, Garcia D, Quintana D, et al. Disease‐specific survival for patients with multiple myeloma: significant improvements over time in all age groups. Leuk Lymphoma 2014; 55: 2850–2857.
10. Chapman MA, Lawrence MS, Keats JJ, et al. Initial genome sequencing and analysis of multiple myeloma. Nature 2011; 471: 467–472.
11. Treon SP, Xu L, Yang G, et al. MYD88 L265P somatic mutation in Waldenstrom's macroglobulinemia. N Engl J Med 2012; 367: 826–833.
12. Walker BA, Mavrommatis K, Wardell CP, et al. Identification of novel mutational drivers reveals oncogene dependencies in multiple myeloma. Blood 2018; 132: 587–597.
13. Lohr JG, Stojanov P, Carter SL, et al. Widespread genetic heterogeneity in multiple myeloma: implications for targeted therapy. Cancer Cell 2014; 25: 91–101.
14. Bolli N, Biancon G, Moarii M, et al. Analysis of the genomic landscape of multiple myeloma highlights novel prognostic markers and disease subgroups. Leukemia 2018; 32: 2604–2616.
15. Bahlis NJ. Darwinian evolution and tiding clones in multiple myeloma. Blood 2012; 120: 927–928.
16. Egan JB, Shi CX, Tembe W, et al. Whole‐genome sequencing of multiple myeloma from diagnosis to plasma cell leukemia reveals genomic initiating events, evolution, and clonal tides. Blood 2012; 120: 1060–1066.
17. Keats JJ, Chesi M, Egan JB, et al. Clonal competition with alternating dominance in multiple myeloma. Blood 2012; 120: 1067–1076.
18. Miller A, Asmann Y, Cattaneo L, et al. High somatic mutation and neoantigen burden are correlated with decreased progression‐free survival in multiple myeloma. Blood Cancer J 2017; 7: e612.
19. Benson DM. Checkpoint inhibition in myeloma. Hematology Am Soc Hematol Educ Program 2016; 2016: 528–533.
20. Chng WJ, Dispenzieri A, Chim CS, et al. IMWG consensus on risk stratification in multiple myeloma. Leukemia 2014; 28: 269–277.
21. Palumbo A, Avet‐Loiseau H, Oliva S, et al. Revised International Staging System for multiple myeloma: a report from International Myeloma Working Group. J Clin Oncol 2015; 33: 2863–2869.
22. Palumbo A, Avet‐Loiseau H, Oliva S, et al. Revised international staging system for multiple myeloma: a report from International Myeloma Working Group. J Clin Oncol 2015; 33: 2863–2869.
23. Zhan F, Huang Y, Colla S, et al. The molecular classification of multiple myeloma. Blood 2006; 108: 2020–2028.
24. Mateos MV, San Miguel JF. Smoldering multiple myeloma: when to observe and when to treat? Am Soc Clin Oncol Educ Book 2015: e484–e492.
25. Rajkumar SV, Landgren O, Mateos MV. Smoldering multiple myeloma. Blood 2015; 125: 3069–3075.
26. Mateos MV, Hernandez MT, Giraldo P, et al. Lenalidomide plus dexamethasone for high‐risk smoldering multiple myeloma. N Engl J Med 2013; 369: 438–447.
27. Terpos E. Multiple myeloma: clinical updates from the American Society of Hematology Annual Meeting, 2017. Clin Lymphoma Myeloma Leuk 2018; 18: 321–334.
28. Joshua D, Suen H, Brown R, et al. The T cell in myeloma. Clin Lymphoma Myeloma Leuk 2016; 16: 537–542.
29. Kyle RA, Gertz MA, Witzig TE, et al. Review of 1027 patients with newly diagnosed multiple myeloma. Mayo Clin Proc 2003; 78: 21–33.
30. Martinez‐Lopez J, Lahuerta JJ, Pepin F, et al. Prognostic value of deep sequencing method for minimal residual disease detection in multiple myeloma. Blood 2014; 123: 3073–3079.
31. Paiva B, Puig N, Garcia‐Sanz R, San Miguel JF. Is this the time to introduce minimal residual disease in multiple myeloma clinical practice? Clin Cancer Res 2015; 21: 2001–2008.
32. Rawstron AC, Gregory WM, de Tute RM, et al. Minimal residual disease in myeloma by flow cytometry: independent prediction of survival benefit per log reduction. Blood 2015; 125: 1932–1935.
33. Moreau P, Zamagni E. MRD in multiple myeloma: more questions than answers? Blood Cancer J 2017; 7: 639.
34. Mateos MV, Dimopoulos MA, Cavo M, et al. Daratumumab plus bortezomib, melphalan, and prednisone for untreated myeloma. N Engl J Med 2018; 378: 518–528.
35. Dimopoulos MA, Lonial S, Betts KA, et al. Elotuzumab plus lenalidomide and dexamethasone in relapsed/refractory multiple myeloma: extended 4‐year follow‐up and analysis of relative progression‐free survival from the randomized ELOQUENT‐2 trial. Cancer 2018; 124: 4032–4043.
36. Richardson PG, Attal M, Campana F, et al. Isatuximab plus pomalidomide/dexamethasone versus pomalidomide/dexamethasone in relapsed/refractory multiple myeloma: ICARIA Phase III study design. Future Oncol 2018; 14: 1035–1047.
37. Hipp S, Tai YT, Blanset D, et al. A novel BCMA/CD3 bispecific T‐cell engager for the treatment of multiple myeloma induces selective lysis in vitro and in vivo. Leukemia 2017; 31: 1743–1751.
38. Suen H, Bryant C, Hart D, Joshua D. Novel T cell therapies in multiple myeloma. Ann Hematol Oncol 2016; 3: 1120.
39. Bu DX, Singh R, Choi EE, et al. Pre‐clinical validation of B cell maturation antigen (BCMA) as a target for T cell immunotherapy of multiple myeloma. Oncotarget 2018; 9: 25764–25780.
40. Rosenblatt J, Avivi I, Vasir B, et al. Vaccination with dendritic cell/tumor fusions following autologous stem cell transplant induces immunologic and clinical responses in multiple myeloma patients. Clin Cancer Res 2013; 19: 3640–3648.
41. Larocca A, Dold SM, Zweegman S, et al. Patient‐centered practice in elderly myeloma patients: an overview and consensus from the European Myeloma Network (EMN). Leukemia 2018; 32: 1697–1712.
42. Quach H, Joshua D, Ho J, et al. Treatment of patients with multiple myeloma who are eligible for stem cell transplantation: position statement of the Myeloma Foundation of Australia Medical and Scientific Advisory Group. Intern Med J 2015; 45: 94–105.
43. Quach H, Joshua D, Ho J, et al. Treatment of patients with multiple myeloma who are not eligible for stem cell transplantation: position statement of the myeloma foundation of Australia Medical and Scientific Advisory Group. Intern Med J 2015; 45: 335–343.
44. Quach H, Prince HM; Medical Scientific Advisory Group. Clinical practice guideline — multiple myeloma. Myeloma Australia, 2014. http://myeloma.org.au/wp-content/uploads/2017/10/MSAG-Clinical-Practice-Guideline-Myeloma-V4-March-2017.pdf (viewed Feb 2019).
45. Gibson J, Ho PJ, Joshua D. Evolving transplant options for multiple myeloma: autologous and nonmyeloablative allogenic. Transplant Proc 2004; 36: 2501–2503.
46. Mahajan S, Tandon N, Kumar S. The evolution of stem‐cell transplantation in multiple myeloma. Ther Adv Hematol 2018; 9: 123–133.
47. Krishnan A, Pasquini MC, Logan B, et al. Autologous haemopoietic stem‐cell transplantation followed by allogeneic or autologous haemopoietic stem‐cell transplantation in patients with multiple myeloma (BMT CTN 0102): a phase 3 biological assignment trial. Lancet Oncol 2011; 12: 1195–1203.
48. McCarthy PL, Holstein SA, Petrucci MT, et al. Lenalidomide maintenance after autologous stem‐cell transplantation in newly diagnosed multiple myeloma: a meta‐analysis. J Clin Oncol 2017; 35: 3279–3289.
49. Facon T, Dimopoulos MA, Dispenzieri A, et al. Final analysis of survival outcomes in the phase 3 FIRST trial of up‐front treatment for multiple myeloma. Blood 2018; 131: 301–310.
50. Moreau P, Masszi T, Grzasko N, et al. Oral ixazomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med 2016; 374: 1621–1634.
51. Varga C, Maglio M, Ghobrial IM, Richardson PG. Current use of monoclonal antibodies in the treatment of multiple myeloma. Br J Haematol 2018; 181: 447–459.
52. Zamagni E, Tacchetti P, Pantani L, Cavo M. Anti‐CD38 and anti‐SLAMF7: the future of myeloma immunotherapy. Expert Rev Hematol 2018; 11: 423–435.
53. Kumar SK, Berdeja JG, Niesvizky R, et al. Safety and tolerability of ixazomib, an oral proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients with previously untreated multiple myeloma: an open‐label phase 1/2 study. Lancet Oncol 2014; 15: 1503–1512.
54. Kumar SK, Lee JH, Lahuerta JJ, et al. Risk of progression and survival in multiple myeloma relapsing after therapy with IMiDs and bortezomib: a multicenter international myeloma working group study. Leukemia 2012; 26: 149–157.
55. Dimopoulos MA, Goldschmidt H, Niesvizky R, et al. Carfilzomib or bortezomib in relapsed or refractory multiple myeloma (ENDEAVOR): an interim overall survival analysis of an open‐label, randomised, phase 3 trial. Lancet Oncol 2017; 18: 1327–1337.
56. Mateos MV, Goldschmidt H, San‐Miguel J, et al. Carfilzomib in relapsed or refractory multiple myeloma patients with early or late relapse following prior therapy: a subgroup analysis of the randomized phase 3 ASPIRE and ENDEAVOR trials. Hematol Oncol 2018; 36: 463–470.
57. Stewart AK, Rajkumar SV, Dimopoulos MA, et al. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med 2015; 372: 142–152.
58. Bringhen S, Mina R, Cafro AM, et al. Once‐weekly carfilzomib, pomalidomide, and low‐dose dexamethasone for relapsed/refractory myeloma: a phase I/II study. Leukemia 2018; 32: 1803–1807.
59. Scott A, Weber N, Tiley C, et al. “Real‐world” Australian experience of pomalidomide for relapsed and refractory myeloma. Leuk Lymphoma 2018; 59: 1514–1516.
60. Ailawadhi S, Mikhael JR, LaPlant BR, et al. Pomalidomide‐dexamethasone in refractory multiple myeloma: long‐term follow‐up of a multi‐cohort phase II clinical trial. Leukemia 2018; 32: 719–728.
61. Henry DH, Costa L, Goldwasser F, et al. Randomized, double‐blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma. J Clin Oncol 2011; 29: 1125–1132.
62. Terpos E, Berenson J, Raje N, Roodman GD. Management of bone disease in multiple myeloma. Expert Rev Hematol 2014; 7: 113–125.
63. Dimopoulos MA, Roussou M, Gavriatopoulou M, et al. Bortezomib‐based triplets are associated with a high probability of dialysis independence and rapid renal recovery in newly diagnosed myeloma patients with severe renal failure or those requiring dialysis. Am J Hematol 2016; 91: 499–502.
64. Dimopoulos MA, Terpos E, Chanan‐Khan A, et al. Renal impairment in patients with multiple myeloma: a consensus statement on behalf of the International Myeloma Working Group. J Clin Oncol 2010; 28: 4976–4984.
65. Scheid C, Sonneveld P, Schmidt‐Wolf IG, et al. Bortezomib before and after autologous stem cell transplantation overcomes the negative prognostic impact of renal impairment in newly diagnosed multiple myeloma: a subgroup analysis from the HOVON‐65/GMMG‐HD4 trial. Haematologica 2014; 99: 148–154.
66. Bridoux F, Carron PL, Pegourie B, et al. Effect of high‐cutoff hemodialysis vs conventional hemodialysis on hemodialysis independence among patients with myeloma cast nephropathy: a randomized clinical trial. JAMA 2017; 318: 2099–2110.
67. Vacca A, Melaccio A, Sportelli A, et al. Subcutaneous immunoglobulins in patients with multiple myeloma and secondary hypogammaglobulinemia: a randomized trial. Clin Immunol 2018; 191: 110–115.
68. Australian Institute of Health and Welfare. Cancer in Australia 2017 (Cat. No. CAN 100; Cancer Series No. 101). Canberra: AIHW; 2017. https://www.aihw.gov.au/reports/cancer/cancer-in-australia-2017/contents/table-of-contents (viewed Feb 2019).
69. Bergin K, Moore E, McQuilten Z, et al. Design and development of the Australian and New Zealand (ANZ) myeloma and related diseases registry. BMC Med Res Methodol 2016; 16: 151.
70. Bergin K, Moore E, McQuilten Z, et al. Design and development of the Australian and New Zealand (ANZ) myeloma and related diseases registry. BMC Med Res Methodol 2016; 16: 151.

Online responses are no longer available. Please refer to our instructions for authors page for more information.

Biology and therapy of multiple myeloma

Topics

Summary

Author

Comment

Do you have any competing interests to declare? *