Table Info

Table 1.

List of drugs used in MM with FDA approval and labeled indications

Novel agents	Year approved	Indication (lines of therapy failed)	Approved in combination*
Thalidomide	1998	NDMM	Dexamethasone
Bortezomib (IV and SC)	2003	NDMM RRMM	Melphalan/prednisone
Lendalidomide	2005	RRMM Maintenance	Dexamethasone
Carfilzomib	2012	RRMM (1–3)**	Lenalidomide/dexamethasone Daratumumab/dexamethasone Dexamethasone
Pomalidomide	2013	RRMM (2)	Dexamethasone
Panobinostat	2015	RRMM (2)	Bortezomib/dexamethasone
Daratumumab (IV and SC)	2015	NDMM	Lenalidomide/dexamethasone Bortezomib/melphalan/prednisone Bortezomib/melphalan/dexamethasone
		RRMM (1)	Lenalidomide/dexamethasone Bortezomib/dexamethasone
		RRMM (1–3)** RRMM (2)	Carfilzomib/dexamethasone Pomalidomide/dexamethasone
Elotuzumab	2015	RRMM	Lenalidomide/dexamethasone Pomalidomide/dexamethasone
Ixazomib	2015	RRMM	Lenalidomide/dexamethasone
Selinexor	2019	RRMM (1) RRMM (PR)	Bortezomib/dexamethasone Dexamethasone
Belantamabmafodotin	2020	RRMM (4)
Isatuximab	2020	RRMM	Pomalidomide/dexamethasone

Cytotoxic chemotherapy

Cyclophospha-mide (IV and PO)	1959	MM (unspecified)
Melphalan (IV and PO)	1964	Palliative ASCT
Carmustine	1977	Palliative	Prednisone
Liposomal doxorubicin	1995	RRMM (1)	Bortezomib

Adjunctive therapy

Zoledronic acid	1964
Pamidronate	1995
Plerixafor	2008

If no drugs listed in table under Approved in combination then approval was for use as single agent;

FDA approval includes use as single agent. PR: penta-refractory; IV: intravenous; SC: subcutaneous; PO: oral; NDMM: newly diagnosed multiple myeloma; RRMM: relapsed/refractory multiple myeloma. Check FDA website and company prescribing for up-to-date details

Declarations

Author contributions

JHS, FED, EMB, LW and GJM wrote the manuscript. All authors contributed to manuscript revisions and read and approved the submitted version.

Conflicts of interest

JHS, EMB and LW declare that they have no conflicts of interest. FED has participated in advisory boards for BMS, GSK, Janssen, Oncopeptides, Roche, Takeda, and has consulted for Adaptive, BMS, Janssen, and Sanofi. GJM has participated in advisory boards for BMS, GSK, Janssen, Oncopeptides, and Roche.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

Not applicable.

Copyright

References

Drugs approved for multiple myeloma and other plasma cell neoplasms [Internet].Bethesda: NIH; [updated 2021 Jan 14; cited 2021 Jan 15]. Available from: https://www.cancer.gov/about-cancer/treatment/drugs/multiple-myeloma

Radley DC, Finkelstein SN, Stafford RS. Off-label prescribing among office-based physicians. Arch Intern Med. 2006;166:1021–6. [DOI] [PubMed]

Alexander GC, Gallagher SA, Mascola A, Moloney RM, Stafford RS. Increasing off-label use of antipsychotic medications in the United States, 1995–2008. Pharmacoepidemiol Drug Saf. 2011;20:177–84. [DOI] [PubMed] [PMC]

Lat I, Micek S, Janzen J, Cohen H, Olsen K, Haas C. Off-label medication use in adult critical care patients. J Crit Care. 2011;26:89–94. [DOI] [PubMed]

Loder EW, Biondi DM. Off-label prescribing of drugs in specialty headache practice. Headache. 2004;44:636–41. [DOI] [PubMed]

McElwain TJ, Powles RL. High-dose intravenous melphalan for plasma-cell leukaemia and myeloma. Lancet. 1983;2:822–4. [DOI] [PubMed]

Barlogie B, Hall R, Zander A, Dicke K, Alexanian R. High-dose melphalan with autologous bone marrow transplantation for multiple myeloma. Blood. 1986;67:1298–301. [PubMed]

Barlogie B, Alexanian R, Dicke KA, Zagars G, Spitzer G, Jagannath S, et al. High-dose chemoradiotherapy and autologous bone marrow transplantation for resistant multiple myeloma. Blood. 1987;70:869–72. [PubMed]

Attal M, Harousseau JL, Stoppa AM, Sotto JJ, Fuzibet JG, Rossi JF, et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Francais du Myelome. N Engl J Med. 1996;335:91–7. [DOI] [PubMed]

10.

Child JA, Morgan GJ, Davies FE, Owen RG, Bell SE, Hawkins K, et al. High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med. 2003;348:1875–83. [DOI] [PubMed]

11.

Fermand JP, Katsahian S, Divine M, Leblond V, Dreyfus F, Macro M, et al. High-dose therapy and autologous blood stem-cell transplantation compared with conventional treatment in myeloma patients aged 55 to 65 years: long-term results of a randomized control trial from the Group Myelome-Autogreffe. J Clin Oncol. 2005;23:9227–33. [DOI] [PubMed]

12.

Barlogie B, Kyle RA, Anderson KC, Greipp PR, Lazarus HM, Hurd DD, et al. Standard chemotherapy compared with high-dose chemoradiotherapy for multiple myeloma: final results of phase III US Intergroup Trial S9321. J Clin Oncol. 2006;24:929–36. [DOI] [PubMed]

13.

Blade J, Rosinol L, Sureda A, Ribera JM, Diaz-Mediavilla J, Garcia-Larana J, et al. High-dose therapy intensification compared with continued standard chemotherapy in multiple myeloma patients responding to the initial chemotherapy: long-term results from a prospective randomized trial from the Spanish cooperative group PETHEMA. Blood. 2005;106:3755–9. [DOI] [PubMed]

14.

Kumar S, Flinn I, Richardson PG, Hari P, Callander N, Noga SJ, et al. Randomized, multicenter, phase 2 study (EVOLUTION) of combinations of bortezomib, dexamethasone, cyclophosphamide, and lenalidomide in previously untreated multiple myeloma. Blood. 2012;119:4375–82. [DOI] [PubMed]

15.

Jackson GH, Davies FE, Pawlyn C, Cairns DA, Striha A, Collett C, et al. Response-adapted intensification with cyclophosphamide, bortezomib, and dexamethasone versus no intensification in patients with newly diagnosed multiple myeloma (Myeloma XI): a multicentre, open-label, randomised, phase 3 trial. Lancet Haematol. 2019;6:e616–29. [DOI] [PubMed] [PMC]

16.

Alexanian R, Dimopoulos MA, Delasalle K, Barlogie B. Primary dexamethasone treatment of multiple myeloma. Blood. 1992;80:887–90. [PubMed]

17.

FDA. Dexamethasoneprescribing information. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/211379s000lbl.pdf

18.

Kumar S, Lacy MQ, Dispenzieri A, Rajkumar SV, Fonseca R, Geyer S, et al. Single agent dexamethasone for pre-stem cell transplant induction therapy for multiple myeloma. Bone Marrow Transplant. 2004;34:485–90. [DOI] [PubMed]

19.

Burwick N, Sharma S. Glucocorticoids in multiple myeloma: past, present, and future. Ann Hematol. 2019;98:19–28. [DOI] [PubMed]

20.

Combination chemotherapy versus melphalan plus prednisone as treatment for multiple myeloma: an overview of 6,633 patients from 27 randomized trials. Myeloma Trialists’ Collaborative Group. J Clin Oncol. 1998;16:3832–42. [DOI] [PubMed]

21.

Barlogie B, Smith L, Alexanian R. Effective treatment of advanced multiple myeloma refractory to alkylating agents. N Engl J Med. 1984;310:1353–6. [DOI] [PubMed]

22.

Alexanian R, Barlogie B, Dixon D. High-dose glucocorticoid treatment of resistant myeloma. Ann Intern Med. 1986;105:8–11. [DOI] [PubMed]

23.

Rajkumar SV, Jacobus S, Callander NS, Fonseca R, Vesole DH, Williams ME, et al. Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial. Lancet Oncol. 2010;11:29–37. [DOI] [PubMed] [PMC]

24.

Orlowski RZ, Nagler A, Sonneveld P, Bladé J, Hajek R, Spencer A, et al. Randomized phase III study of pegylated liposomal doxorubicin plus bortezomib compared with bortezomib alone in relapsed or refractory multiple myeloma: combination therapy improves time to progression. J Clin Oncol. 2007;25:3892–901. [DOI] [PubMed]

25.

Lee CK, Barlogie B, Munshi N, Zangari M, Fassas A, Jacobson J, et al. DTPACE: an effective, novel combination chemotherapy with thalidomide for previously treated patients with myeloma. J Clin Oncol. 2003;21:2732–9. [DOI] [PubMed]

26.

Nishimura KK, Barlogie B, van Rhee F, Zangari M, Walker BA, Rosenthal A, et al. Long-term outcomes after autologous stem cell transplantation for multiple myeloma. Blood Adv. 2020;4:422–31. [DOI] [PubMed] [PMC]

27.

Rajkumar SV. Thalidomide: tragic past and promising future. Mayo Clin Proc. 2004;79:899–903. [DOI] [PubMed]

28.

Grabstald H, Golbey R. Clinical experiences with thalidomide in patients with cancer. Clin Pharmacol Ther. 1965;6:298–302. [DOI] [PubMed]

29.

Olson KB, Hall TC, Horton J, Khung CL, Hosley HF. Thalidomide (N-phthaloylglutamimide) in the treatment of advanced cancer. Clin Pharmacol Ther. 1965;6:292–7. [DOI] [PubMed]

30.

D’Amato RJ, Loughnan MS, Flynn E, Folkman J. Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci U S A. 1994;91:4082–5. [DOI] [PubMed] [PMC]

31.

Lu G, Middleton RE, Sun H, Naniong M, Ott CJ, Mitsiades CS, et al. The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins. Science. 2014;343:305–9. [DOI] [PubMed] [PMC]

32.

Davies FE, Raje N, Hideshima T, Lentzsch S, Young G, Tai YT, et al. Thalidomide and immunomodulatory derivatives augment natural killer cell cytotoxicity in multiple myeloma. Blood. 2001;98:210–6. [DOI] [PubMed]

33.

Hideshima T, Chauhan D, Shima Y, Raje N, Davies FE, Tai YT, et al. Thalidomide and its analogs overcome drug resistance of human multiple myeloma cells to conventional therapy. Blood. 2000;96:2943–50. [PubMed]

34.

Lentzsch S, LeBlanc R, Podar K, Davies F, Lin B, Hideshima T, et al. Immunomodulatory analogs of thalidomide inhibit growth of Hs Sultan cells and angiogenesis in vivo. Leukemia. 2003;17:41–4. [DOI] [PubMed]

35.

Mitsiades N, Mitsiades CS, Poulaki V, Chauhan D, Richardson PG, Hideshima T, et al. Apoptotic signaling induced by immunomodulatory thalidomide analogs in human multiple myeloma cells: therapeutic implications. Blood. 2002;99:4525–30. [DOI] [PubMed]

36.

Ito T, Ando H, Handa H. Teratogenic effects of thalidomide: molecular mechanisms. Cell Mol Life Sci. 2011;68:1569–79. [DOI] [PubMed]

37.

Krönke J, Udeshi ND, Narla A, Grauman P, Hurst SN, McConkey M, et al. Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells. Science. 2014;343:301–5. [DOI] [PubMed] [PMC]

38.

Singhal S, Mehta J, Desikan R, Ayers D, Roberson P, Eddlemon P, et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med. 1999;341:1565–71. [DOI] [PubMed]

39.

Dimopoulos MA, Zervas K, Kouvatseas G, Galani E, Grigoraki V, Kiamouris C, et al. Thalidomide and dexamethasone combination for refractory multiple myeloma. Ann Oncol. 2001;12:991–5. [DOI] [PubMed]

40.

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. [DOI] [PubMed]

41.

Cavo M, Zamagni E, Tosi P, Tacchetti P, Cellini C, Cangini D, et al. Superiority of thalidomide and dexamethasone over vincristine-doxorubicindexamethasone (VAD) as primary therapy in preparation for autologous transplantation for multiple myeloma. Blood. 2005;106:35–9. [DOI] [PubMed]

42.

Risk evaluation and mitigation strategies [Internet]. FDA; [updated 2019 Aug 8; cited 2021 Jan 15]. Available from: https://www.fda.gov/drugs/drug-safety-and-availability/risk-evaluation-and-mitigation-strategies-rems

43.

Weber DM, Chen C, Niesvizky R, Wang M, Belch A, Stadtmauer EA, et al. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med. 2007;357:2133–42. [DOI] [PubMed]

44.

Dimopoulos M, Spencer A, Attal M, Prince HM, Harousseau JL, Dmoszynska A, et al. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med. 2007;357:2123–32. [DOI] [PubMed]

45.

Rajkumar SV, Hayman SR, Lacy MQ, Dispenzieri A, Geyer SM, Kabat B, et al. Combination therapy with lenalidomide plus dexamethasone (Rev/Dex) for newly diagnosed myeloma. Blood. 2005;106:4050–3. [DOI] [PubMed] [PMC]

46.

Morgan GJ, Gregory WM, Davies FE, Bell SE, Szubert AJ, Brown JM, et al. Theroleof maintenance thalidomide therapy in multiple myeloma: MRC Myeloma IX results and meta-analysis. Blood. 2012;119:7–15. [DOI] [PubMed]

47.

McCarthy PL, Owzar K, Hofmeister CC, Hurd DD, Hassoun H, Richardson PG, et al. Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012;366:1770–81. [DOI] [PubMed] [PMC]

48.

Jackson GH, Davies FE, Pawlyn C, Cairns DA, Striha A, Collett C, et al. Lenalidomide maintenance versus observation for patients with newly diagnosed multiple myeloma (Myeloma XI): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2019;20:57–73. [DOI] [PubMed] [PMC]

49.

Attal M, Lauwers-Cances V, Marit G, Caillot D, Moreau P, Facon T, et al. Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012;366:1782–91. [DOI] [PubMed]

50.

FDA. Lenalidomide prescribing information. Available from: https://packageinserts.bms.com/pi/pi_revlimid.pdf

51.

Richardson PG, Barlogie B, Berenson J, Singhal S, Jagannath S, Irwin D, et al. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med. 2003;348:2609–17. [DOI] [PubMed]

52.

Richardson PG, Sonneveld P, Schuster MW, Irwin D, Stadtmauer EA, Facon T, et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med. 2005;352:2487–98. [DOI] [PubMed]

53.

FDA. Bortezomib prescribing information. Available from: https://www.velcade.com/files/pdfs/VELCADE_PRESCRIBING_INFORMATION.pdf

54.

San Miguel JF, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M, et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med. 2008;359:906–17. [DOI] [PubMed]

55.

Moreau P, Mateos MV, Berenson JR, Weisel K, Lazzaro A, Song K, et al. Once weekly versus twice weekly carfilzomib dosing in patients with relapsed and refractory multiple myeloma (A.R.R.O.W.): interim analysis results of a randomised, phase 3 study. Lancet Oncol. 2018;19:953–64. [DOI] [PubMed]

56.

O’Donnell EK, Laubach JP, Yee AJ, Chen T, Huff CA, Basile FG, et al. A phase 2 study of modified lenalidomide, bortezomib and dexamethasone in transplant-ineligible multiple myeloma. Br J Haematol. 2018;182:222–30. [DOI] [PubMed] [PMC]

57.

Mateos MV, Oriol A, Martínez-López J, Gutiérrez N, Teruel AI, de Paz R, et al. Bortezomib, melphalan, and prednisone versus bortezomib, thalidomide, and prednisone as induction therapy followed by maintenance treatment with bortezomib and thalidomide versus bortezomib and prednisone in elderly patients with untreated multiple myeloma: a randomised trial. Lancet Oncol. 2010;11:934–41. [DOI] [PubMed]

58.

Rajkumar SV, Harousseau JL, Durie B, Anderson KC, Dimopoulos M, Kyle R, et al. Consensus recommendations for the uniform reporting of clinical trials: report of the International Myeloma Workshop Consensus Panel 1. Blood. 2011;117:4691–5. [DOI] [PubMed] [PMC]

59.

Kumar S, Paiva B, Anderson KC, Durie B, Landgren O, Moreau P, et al. International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol. 2016;17:e328–46. [DOI] [PubMed]

60.

Durie BG, Harousseau JL, Miguel JS, Blade J, Barlogie B, Anderson K, et al. International uniform response criteria for multiple myeloma. Leukemia. 2006;20:1467–73. [DOI] [PubMed]

61.

Kumar SK, Dimopoulos MA, Kastritis E, Terpos E, Nahi H, Goldschmidt H, et al. Natural history of relapsed myeloma, refractory to immunomodulatory drugs and proteasome inhibitors: a multicenter IMWG study. Leukemia. 2017;31:2443–8. [DOI] [PubMed]

62.

Network NCC [Internet&rsqb. Multiple myeloma (version 4.2021). [updated 2020 Dec 10; cited 2021 Jan 18]. Available from: https://www.nccn.org/professionals/physician_gls/pdf/myeloma.pdf

63.

Lokhorst HM, Plesner T, Laubach JP, Nahi H, Gimsing P, Hansson M, et al. Targeting CD38 with daratumumab monotherapy in multiple myeloma. N Engl J Med. 2015;373:1207–19. [DOI] [PubMed]

64.

Lonial S, Weiss BM, Usmani SZ, Singhal S, Chari A, Bahlis NJ, et al. Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): an open-label, randomised, phase 2 trial. Lancet. 2016;387:1551–60. [DOI] [PubMed]

65.

Usmani SZ, Nahi H, Plesner T, Weiss BM, Bahlis NJ, Belch A, et al. Daratumumab monotherapy in patients with heavily pretreated relapsed or refractory multiple myeloma: final results from the phase 2 GEN501 and SIRIUS trials. Lancet Haematol. 2020;7:e447–55. [DOI] [PubMed]

66.

Dimopoulos MA, Oriol A, Nahi H, San-Miguel J, Bahlis NJ, Usmani SZ, et al. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375:1319–31. [DOI] [PubMed]

67.

Palumbo A, Chanan-Khan A, Weisel K, Nooka AK, Masszi T, Beksac M, et al. Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375:754–66. [DOI] [PubMed]

68.

Dimopoulos M, Quach H, Mateos MV, Landgren O, Leleu X, Siegel D, et al. Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for patients with relapsed or refractory multiple myeloma (CANDOR): results from a randomised, multicentre, open-label, phase 3 study. Lancet. 2020;396:186–97. [DOI] [PubMed]

69.

Siegel DS, Schiller GJ, Samaras C, Sebag M, Berdeja J, Ganguly S, et al. Pomalidomide, dexamethasone, and daratumumab in relapsed refractory multiple myeloma after lenalidomide treatment. Leukemia. 2020;34:3286–97. [DOI] [PubMed] [PMC]

70.

Chari A, Suvannasankha A, Fay JW, Arnulf B, Kaufman JL, Ifthikharuddin JJ, et al. Daratumumab plus pomalidomide and dexamethasone in relapsed and/or refractory multiple myeloma. Blood. 2017;130:974–81. [DOI] [PubMed] [PMC]

71.

Attal M, Richardson PG, Rajkumar SV, San-Miguel J, Beksac M, Spicka I, et al. Isatuximab plus pomalidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): a randomised, multicentre, open-label, phase 3 study. Lancet. 2019;394:2096–107. [DOI] [PubMed]

72.

Facon T, Kumar S, Plesner T, Orlowski RZ, Moreau P, Bahlis N, et al. Daratumumab plus lenalidomide and dexamethasone for untreated myeloma. N Engl J Med. 2019;380:2104–15. [DOI] [PubMed]

73.

Moreau P, Attal M, Hulin C, Arnulf B, Belhadj K, Benboubker L, et al. Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): a randomised, open-label, phase 3 study. Lancet. 2019;394:29–38. [DOI] [PubMed]

74.

Mateos MV, Cavo M, Blade J, Dimopoulos MA, Suzuki K, Jakubowiak A, et al. Overall survival with daratumumab, bortezomib, melphalan, and prednisone in newly diagnosed multiple myeloma (ALCYONE): a randomised, open-label, phase 3 trial. Lancet. 2020;395:132–41. [DOI] [PubMed]

75.

Voorhees PM, Kaufman JL, Laubach J, Sborov DW, Reeves B, Rodriguez C, et al. Daratumumab, lenalidomide, bortezomib, and dexamethasone for transplant-eligible newly diagnosed multiple myeloma: the GRIFFIN trial. Blood. 2020;136:936–45. [DOI] [PubMed] [PMC]

76.

FDA. DARZALEX prescribing information. Available from: https://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/DARZALEX-pi.pdf

77.

FDA. DARZALEX FASPRO prescribing information. Available from: https://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/DARZALEX+Faspro-pi.pdf

78.

Gandhi UH, Cornell RF, Lakshman A, Gahvari ZJ, McGehee E, Jagosky MH, et al. Outcomes of patients with multiple myeloma refractory to CD38-targeted monoclonal antibody therapy. Leukemia. 2019;33:2266–75. [DOI] [PubMed] [PMC]

79.

Lonial S, Lee HC, Badros A, Trudel S, Nooka AK, Chari A, et al. Belantamab mafodotin for relapsed or refractory multiple myeloma (DREAMM-2): a two-arm, randomised, open-label, phase 2 study. Lancet Oncol. 2020;21:207–21. [DOI] [PubMed]

80.

Carpenter RO, Evbuomwan MO, Pittaluga S, Rose JJ, Raffeld M, Yang S, et al. B-cell maturation antigen is a promising target for adoptive T-cell therapy of multiple myeloma. Clin Cancer Res. 2013;19:2048–60. [DOI] [PubMed] [PMC]

81.

Novak AJ, Darce JR, Arendt BK, Harder B, Henderson K, Kindsvogel W, et al. Expression of BCMA, TACI, and BAFF-R in multiple myeloma: a mechanism for growth and survival. Blood. 2004;103:689–94. [DOI] [PubMed]

82.

Chari A, Vogl DT, Gavriatopoulou M, Nooka AK, Yee AJ, Huff CA, et al. Oral selinexor-dexamethasone for triple-class refractory multiple myeloma. N Engl J Med. 2019;381:727–38. [DOI] [PubMed]

83.

Chauhan D, Ray A, Viktorsson K, Spira J, Paba-Prada C, Munshi N, et al. In vitro and in vivo antitumor activity of a novel alkylating agent, melphalan-flufenamide, against multiple myeloma cells. Clin Cancer Res. 2013;19:3019–31. [DOI] [PubMed] [PMC]

84.

Strese S, Wickstrom M, Fuchs PF, Fryknas M, Gerwins P, Dale T, et al. The novel alkylating prodrug melflufen (J1) inhibits angiogenesis in vitro and in vivo. Biochem Pharmacol. 2013;86:888–95. [DOI] [PubMed]

85.

Wickstrom M, Nygren P, Larsson R, Harmenberg J, Lindberg J, Sjoberg P, et al. Melflufen-a peptidase-potentiated alkylating agent in clinical trials. Oncotarget. 2017;8:66641–55. [DOI] [PubMed] [PMC]

86.

Ray A, Ravillah D, Das DS, Song Y, Nordstrom E, Gullbo J, et al. A novel alkylating agent Melflufen induces irreversible DNA damage and cytotoxicity in multiple myeloma cells. Br J Haematol. 2016;174:397–409. [DOI] [PubMed] [PMC]

87.

Richardson PG, Bringhen S, Voorhees P, Plesner T, Mellqvist UH, Reeves B, et al. Melflufen plus dexamethasone in relapsed and refractory multiple myeloma (O-12-M1): a multicentre, international, open-label, phase 1–2 study. Lancet Haematol. 2020;7:e395–407. [DOI] [PubMed]

88.

Zweegman S, van der Holt B, Mellqvist UH, Salomo M, Bos GM, Levin MD, et al. Melphalan, prednisone, and lenalidomide versus melphalan, prednisone, and thalidomide in untreated multiple myeloma. Blood. 2016;127:1109–16. [DOI] [PubMed]

89.

Facon T, Dimopoulos MA, Dispenzieri A, Catalano JV, Belch A, Cavo M, et al. Final analysis of survival outcomes in the phase 3 FIRST trial of up-front treatment for multiple myeloma. Blood. 2018;131:301–10. [DOI] [PubMed] [PMC]

90.

Chesi M, Bergsagel PL, Brents LA, Smith CM, Gerhard DS, Kuehl WM. Dysregulation of cyclin D1 by translocation into an IgH gamma switch region in two multiple myeloma cell lines. Blood. 1996; 88:674–81. [PubMed]

91.

Gabrea A, Bergsagel PL, Chesi M, Shou Y, Kuehl WM. Insertion of excised IgH switch sequences causes overexpression of cyclin D1 in a myeloma tumor cell. Mol Cell. 1999;3:119–23. [DOI] [PubMed]

92.

Chesi M, Nardini E, Brents LA, Schrock E, Ried T, Kuehl WM, 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. Nat Genet. 1997;16:260–4. [DOI] [PubMed] [PMC]

93.

Chesi M, Nardini E, Lim RS, Smith KD, Kuehl WM, Bergsagel PL. The t(4;14) translocation in myeloma dysregulates both FGFR3 and a novel gene, MMSET, resulting in IgH/MMSET hybrid transcripts. Blood. 1998;92:3025–34. [PubMed]

94.

Trudel S, Ely S, Farooqi Y, Affer M, Robbiani DF, Chesi M, et al. Inhibition of fibroblast growth factor receptor 3 induces differentiation and apoptosis in t(4;14) myeloma. Blood. 2004;103:3521–8. [DOI] [PubMed]

95.

Trudel S, Stewart AK, Rom E, Wei E, Li ZH, Kotzer S, et al. The inhibitory anti-FGFR3 antibody, PRO-001, is cytotoxic to t(4;14) multiple myeloma cells. Blood. 2006;107:4039–46. [DOI] [PubMed]

96.

Clinicaltrials.gov [Internet]. The MATCH Screening Trial. [updated 2021 Jan 15; cited Feburary 1, 2021]. Available from: https://www.clinicaltrials.gov/ct2/show/NCT02465060

97.

Bezieau S, Devilder MC, Avet-Loiseau H, Mellerin MP, Puthier D, Pennarun E, et al. High incidence of N and K-Ras activating mutations in multiple myeloma and primary plasma cell leukemia at diagnosis. Hum Mutat. 2001;18:212–24. [DOI] [PubMed]

98.

Walker BA, Boyle EM, Wardell CP, Murison A, Begum DB, Dahir NM, et al. Mutational spectrum, copy number changes, and outcome: results of a sequencing study of patients with newly diagnosed myeloma. J Clin Oncol. 2015;33:3911–20. [DOI] [PubMed] [PMC]

99.

Heuck CJ, Jethava Y, Khan R, van Rhee F, Zangari M, Chavan S, et al. Inhibiting MEK in MAPK pathway-activated myeloma. Leukemia. 2016;30:976–80. [DOI] [PubMed] [PMC]

100.

Andrulis M, Lehners N, Capper D, Penzel R, Heining C, Huellein J, et al. Targeting the BRAF V600E mutation in multiple myeloma. Cancer Discov. 2013;3:862–9. [DOI] [PubMed]

101.

Raab MSea, Giesen N, Scheid C, Besemer B, Miah K, Benner A, et al. 294 safety and preliminary efficacy results from a phase II study evaluating combined BRAF and MEK inhibition in relapsed/refractory multiple myeloma (rrMM) patients with activating BRAF V600E mutations: the GMMG-Birma Trial. Proceedings of the 62nd ASH Annual Meeting and Exposition; 2020 Dec 5–8; Washington. US: ASH; 2020.

102.

Auclair D, Anderson KC, Avigan D, Bianchi G, Biran N, Chaudhry M, et al. The myeloma-developing regimens using genomics (MyDRUG) master protocol. J Clin Oncolo. 2019;37:TPS8057. [DOI]

103.

Milestones in U. S. Food and Drug Law History [Internet]. FDA; [updated 2018 Jan 31; cited 2021 Jan 18]. Available from: https://www.fda.gov/about-fda/fdas-evolving-regulatory-powers/milestones-us-food-and-drug-law-history

104.

Tobinick EL. The value of drug repositioning in the current pharmaceutical market. Drug News Perspect. 2009;22:119–25. [DOI] [PubMed]

105.

Adams CP, Brantner VV. Estimating the cost of new drug development: is it really 802 million dollars? Health Aff (Millwood). 2006;25:420–8. [DOI] [PubMed]

106.

Hay M, Thomas DW, Craighead JL, Economides C, Rosenthal J. Clinical development success rates for investigational drugs. Nat Biotechnol. 2014;32:40–51. [DOI] [PubMed]

107.

Desai A, Gyawali B. Financial toxicity of cancer treatment: moving the discussion from acknowledgement of the problem to identifying solutions. EClinicalMedicine. 2020;20:100269. [DOI] [PubMed] [PMC]

108.

Ekwueme DU, Zhao J, Rim SH, de Moor JS, Zheng Z, Khushalani JS, et al. Annual out-of-pocket expenditures and financial hardship among cancer survivors aged 18–64 years-United States, 2011–2016. MMWR Morb Mortal Wkly Rep. 2019;68:494–9. [DOI] [PubMed] [PMC]

109.

Pantziarka P, Bouche G, Meheus L, Sukhatme V, Sukhatme VP, Vikas P. The repurposing drugs in oncology (ReDO) project. Ecancermedicalscience. 2014;8:442. [DOI] [PubMed] [PMC]

110.

Sasaki J, Ramesh R, Chada S, Gomyo Y, Roth JA, Mukhopadhyay T. The anthelmintic drug mebendazole induces mitotic arrest and apoptosis by depolymerizing tubulin in non-small cell lung cancer cells. Mol Cancer Ther. 2002;1:1201–9. [PubMed]

111.

Mukhopadhyay T, Sasaki J, Ramesh R, Roth JA. Mebendazole elicits a potent antitumor effect on human cancer cell lines both in vitro and in vivo. Clin Cancer Res. 2002;8:2963–9. [PubMed]

112.

Martarelli D, Pompei P, Baldi C, Mazzoni G. Mebendazole inhibits growth of human adrenocortical carcinoma cell lines implanted in nude mice. Cancer Chemother Pharmacol. 2008;61:809–17. [DOI] [PubMed]

113.

Doudican N, Rodriguez A, Osman I, Orlow SJ. Mebendazole induces apoptosis via Bcl-2 inactivation in chemoresistant melanoma cells. Mol Cancer Res. 2008;6:1308–15. [DOI] [PubMed]

114.

Bai RY, Staedtke V, Aprhys CM, Gallia GL, Riggins GJ. Antiparasitic mebendazole shows survival benefit in 2 preclinical models of glioblastoma multiforme. Neuro Oncol. 2011;13:974–82. [DOI] [PubMed] [PMC]

115.

Coyne CP, Jones T, Bear R. Gemcitabine-(C4-amide)-[anti-HER2/neu] anti-neoplastic cytotoxicity in dual combination with mebendazole against chemotherapeutic-resistant mammary adenocarcinoma. J Clin Exp Oncol. 2013;2:1000109. [PubMed] [PMC]

116.

Chen XH, Xu YJ, Wang XG, Lin P, Cao BY, Zeng YY, et al. Mebendazole elicits potent antimyeloma activity by inhibiting the USP5/c-Maf axis. Acta Pharmacol Sin. 2019;40:1568–77. [DOI] [PubMed] [PMC]

117.

Feng R, Li S, Lu C, Andreas C, Stolz DB, Mapara MY, et al. Targeting the microtubular network as a new antimyeloma strategy. Mol Cancer Ther. 2011;10:1886–96. [DOI] [PubMed]

118.

Niesvizky R, Jayabalan DS, Christos PJ, Furst JR, Naib T, Ely S, et al. BiRD (Biaxin [clarithromycin]/Revlimid [lenalidomide]/dexamethasone) combination therapy results in high complete- and overall-response rates in treatment-naive symptomatic multiple myeloma. Blood. 2008;111:1101–9. [DOI] [PubMed]

119.

Ghosh N, Tucker N, Zahurak M, Wozney J, Borrello I, Huff CA. Clarithromycin overcomes resistance to lenalidomide and dexamethasone in multiple myeloma. Am J Hematol. 2014;89:E116–20. [DOI] [PubMed] [PMC]

120.

Mark TM, Forsberg PA, Rossi AC, Pearse RN, Pekle KA, Perry A, et al. Phase 2 study of clarithromycin, pomalidomide, and dexamethasone in relapsed or refractory multiple myeloma. Blood Adv. 2019; 3:603–11. [DOI] [PubMed] [PMC]

121.

Demartini G, Esposti D, Marthyn P, Lapidari A, Fraschini F, Scaglione F. Effect of multiple doses of clarithromycin and amoxicillin on IL-6, IFNgamma and IL-10 plasma levels in patients with community acquired pneumonia. J Chemother. 2004;16:82–5. [DOI]

122.

Ding FM, Zhu SL, Shen C, Jiang YQ. Low-dose clarithromycin therapy modulates CD4+ T-cell responses in a mouse model of chronic Pseudomonas aeruginosa lung infection. Respirology. 2012;17:727–34. [DOI] [PubMed]

123.

Nakamura M, Kikukawa Y, Takeya M, Mitsuya H, Hata H. Clarithromycin attenuates autophagy in myeloma cells. Int J Oncol. 2010;37:815–20. [PubMed]

124.

Dalva-Aydemir S, Bajpai R, Martinez M, Adekola KU, Kandela I, Wei C, et al. Targeting the metabolic plasticity of multiple myeloma with FDA-approved ritonavir and metformin. Clin Cancer Res. 2015;21:1161–71. [DOI] [PubMed] [PMC]

125.

Shibata R, Bassermann F, Chandra P, Resemann H, Mazumder A, Pagano M, et al. Ritonavir sensitizes multiple myeloma cells to bortezomib-induced apoptosis. Blood. 2008;112:5159. [DOI]

126.

Driessen C, Müller R, Novak U, Cantoni N, Betticher D, Mach N, et al. Promising activity of nelfinavir-bortezomib-dexamethasone in proteasome inhibitor-refractory multiple myeloma. Blood. 2018;132:2097–100. [DOI] [PubMed] [PMC]

127.

Mendez-Lopez M, Sutter T, Driessen C, Besse L. HIV protease inhibitors for the treatment of multiple myeloma. Clin Adv Hematol Oncol. 2019;17:615–23. [PubMed]

128.

Kumar S, Kaufman JL, Gasparetto C, Mikhael J, Vij R, Pegourie B, et al. Efficacy of venetoclax as targeted therapy for relapsed/refractory t(11;14) multiple myeloma. Blood. 2017;130:2401–9. [DOI] [PubMed]

129.

Kaufman JL, Gasparetto C, Schjesvold FH, Moreau P, Touzeau C, Facon T, et al. Targeting BCL-2 with venetoclax and dexamethasone in patients with relapsed/refractory t(11;14) multiple myeloma. Am J Hematol. 2021;96:418–27. [DOI] [PubMed] [PMC]

130.

Premkumar VJ, Lentzsch S, Pan S, Bhutani D, Richter J, Jagannath S, et al. Venetoclax induces deep hematologic remissions in t(11;14) relapsed/refractory AL amyloidosis. Blood Cancer J. 2021;11:10. [DOI] [PubMed] [PMC]

131.

Kumar SK, Harrison SJ, Cavo M, de la Rubia J, Popat R, Gasparetto C, et al. Venetoclax or placebo in combination with bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma (BELLINI): a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol. 2020;21:1630–42. [DOI] [PubMed]