Immunotherapeutic Approaches for Multiple Myeloma: Where Are We Now?
- 145 Downloads
Purpose of Review
The treatment landscape for multiple myeloma has evolved rapidly with the availability of multiple new drugs; however, although patient survival has improved, the disease remains incurable. Multiple myeloma is characterized by the unregulated growth of malignant plasma cells accompanied by immune dysfunction as well as disrupted immune surveillance mechanisms. Here, we analyze clinical modalities, with a focus on monoclonal antibodies and adoptive cellular therapy that enhance patients’ immune systems and overcome these defects.
Early clinical trials with PD-1 inhibitors were promising, but randomized phase III trials with immunomodulatory drugs showed increased toxicities. Monoclonal antibodies targeting surface antigens led to substantial clinical efficiency in relapsed myeloma. Chimeric antigen receptor (CAR) T cell therapy for multiple myeloma represents a significant advance, as exciting and dramatic responses in early clinical trials have been seen.
Immunotherapeutic approaches are promising and can augment or replace the current standard of care, with the potential to offer extended survival for myeloma patients.
KeywordsAdoptive cellular therapy CAR T cells Checkpoint inhibitors mAbs Multiple myeloma Vaccine
Compliance with Ethical Standards
Conflict of Interest
The author declares that there is no conflict of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 10.Auner HW, Szydlo R, van Biezen A, et al. Reduced intensity-conditioned allogeneic stem cell transplantation for multiple myeloma relapsing or progressing after autologous transplantation: a study by the European Group for Blood and Marrow Transplantation. Bone Marrow Transplant. 2013;48(11):1395–400.CrossRefGoogle Scholar
- 15.•• 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(13):1207–19 This study was one of the first to study daratumumab as single agent therapy and provided justification for the development of combinatorial therapies containing daratumumab. CrossRefGoogle Scholar
- 16.Lonial S, Weiss BM, Usmani SZ, Singhal S, Chari A, Bahlis NJ, et al. Phase II study of daratumumab (DARA) monotherapy in patients with >= 3 lines of prior therapy or double refractory multiple myeloma (MM): 54767414MMY2002 (Sirius). ASCO Meet Abstr. 2015;33(18_suppl):LBA 8512.Google Scholar
- 17.Plesner T, Arkenau H-T, Lokhorst HM, Gimsing P, Krejcik J, Lemech C, et al. Safety and efficacy of Daratumumab with Lenalidomide and dexamethasone in relapsed or relapsed, refractory multiple myeloma. Blood. 2014;124(21):84.Google Scholar
- 18.•• Dimopoulos MA, Oriol A, Nahi H, San-Miguel J, Bahlis NJ, for the POLLUX Investigators, et al. Daratumumab, Lenalidomide, and Dexamethasone for Multiple Myeloma. N Engl J Med. 2016;375:1319–31. https://doi.org/10.1056/NEJMoa1607751 Potentially practice-changing data in RRMM patients treated with daratumumab/lenalidomide-based backbone treatment. CrossRefPubMedGoogle Scholar
- 19.•• 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(8):754–66 Potentially practice-changing data in RRMM patients treated with daratumumab/bortezomib-based backbone treatment. CrossRefGoogle Scholar
- 22.Jakubowiak AJ, Chari A, Lonial S, Weiss BM, Comenzo RL, Wu K, et al. Daratumumab (DARA) in combination with carfilzomib, lenalidomide, and dexamethasone (KRd) in patients (pts) with newly diagnosed multiple myeloma (MMY1001): An open-label, phase 1b study. J Clin Oncol. 2017;35(15_suppl):8000. https://doi.org/10.1200/JCO.2017.35.15_suppl.8000.CrossRefGoogle Scholar
- 24.• Martin TG, Hsu K, Strickland SA, Glenn MJ, Mikhael J, Charpentier E. A phase I trial of SAR650984, a CD38 monoclonal antibody, in relapsed or refractory multiple myeloma. J Clin Oncol. 2014;32(15_suppl):8532. https://doi.org/10.1200/jco.2014.32.15_suppl.8532 This study highlighted that other CD38-targeting agents aside from daratumumab hold clinical potential. CrossRefGoogle Scholar
- 25.Mikhael J, Richardson PG, Usmani Z, Raje N, Bensinger W, Kanagavel D, et al. A phase Ib study of isatuximab in combination with pomalidomide (Pom) and dexamethasone (Dex) in relapsed/refractory multiple myeloma (RRMM). 2017 ASCO Annual Meeting Abstracts. JCO. 2017;(35 suppl):abstr 8007.Google Scholar
- 32.Richardson PG, Jagannath S, Moreau P, Jakubowiak AJ, Raab MS, Facon T, et al. Elotuzumab in combination with lenalidomide and dexamethasone in patients with relapsed multiple myeloma: final phase 2 results from the randomised, open-label, phase 1b-2 dose-escalation study. Lancet Haematol. 2015;2(12):e516–27.CrossRefGoogle Scholar
- 33.•• Lonial S, Dimopoulos M, Palumbo A, White D, Grosicki S, et al. Elotuzumab Therapy for Relapsed or Refractory Multiple Myeloma. N Engl J Med. 2015;373:621–31. https://doi.org/10.1056/NEJMoa1505654 Potentially practice-changing data in RRMM patients treated with elotuzumab-/lenalidomide-based backbone treatment. CrossRefPubMedGoogle Scholar
- 34.•• Dimopoulos MA, Dytfeld D, Grosicki S, Moreau P, Takezako N, et al. Elotuzumab plus pomalidomide and dexamethasone for multiple myeloma. N Engl J Med. 2018;379:1811–22 Potentially practice-changing data in RRMM patients treated with elotuzumab-/pomalidomide-based backbone treatment. CrossRefGoogle Scholar
- 35.Heffner LT, Jagannath S, Zimmerman TM, Lee KP, Rosenblatt J, Lonial S, et al. BT062, an antibody-drug conjugate directed against CD138, given weekly for 3 weeks in each 4 week cycle: safety and further evidence of clinical activity. Am Soc Hematol Annu Meet Proc. 2012;120(21):653.Google Scholar
- 36.Kelly KR, Chanan-Khan A, Heffner LT, Somlo G, Siegel DS, Zimmerman T, et al. Indatuximab Ravtansine (BT062) in combination with Lenalidomide and low-dose dexamethasone in patients with relapsed and/or refractory multiple myeloma: clinical activity in patients already exposed to Lenalidomide and Bortezomib. Blood. 2014;124(21):4736.Google Scholar
- 38.Topp MS, Duell J, Zugmaier G, Attal M, Moreau P, Langer C, et al. Treatment with AMG 420, an anti-B-cell maturation antigen (BCMA) bispecific T-cell engager (BiTEs) antibody construct, induces minimal residual disease (MRD) negative complete responses in relapsed and/or refractory (R/R) multiple myeloma (MM) patients: results of a first-in-human (fih) phase i dose escalation study. ASH Annual meeting. 2018:abstract 1010.Google Scholar
- 39.Tamura H, Ishibashi M, Yamashita T, Tanosaki S, Okuyama N, Kondo A, et al. Marrow stromal cells induce B7-H1 expression on myeloma cells, generating aggressive characteristics in multiple myeloma. Leukemia. Nature Publishing Group. 2012;27(2):464–72.Google Scholar
- 40.Liu J, Hamrouni A, Wolowiec D, Coiteux V, Kuliczkowski K, Hetuin D, et al. Plasma cells from multiple myeloma patients express B7-H1 (PD-L1) and increase expression after stimulation with IFN-γ and TLR ligands via a MyD88-, TRAF6-, and MEK-dependent pathway. Blood. 2007;110(1):296–304.CrossRefGoogle Scholar
- 49.FDA news release: August 31, 2017. https://www.fda.gov/Drugs/DrugSafety/ucm574305.htm
- 52.Rapoport AP, Aqui NA, Stadtmauer EA, Vogl DT, Xu YY, Kalos M, et al. Combination immunotherapy after ASCT for multiple myeloma using MAGEA3/Poly-ICLC immunizations followed by adoptive transfer of vaccine-primed and costimulated autologous T cells. Clin Cancer Res. 2014;20(5):1355–65.CrossRefGoogle Scholar
- 57.• Garfall AL, Maus MV, Hwang W-T, Lacey SF, Mahnke YD, Melenhorst JJ, et al. Chimeric antigen receptor T cells against CD19 for multiple myeloma. N Engl J Med. 2015;373(11):1040–7 This study was one of the first to investigate CAR T cells for MM and demonstrated efficacy in a subset of patients despite the lack of CD19 expression in most MM cells. CrossRefGoogle Scholar
- 61.• Brudno JN, Maric I, Hartman SD, Rose JJ, Wang M, Lam N, et al. T cells genetically modified to express an anti–B-cell maturation antigen chimeric antigen receptor cause remissions of poor-prognosis relapsed multiple myeloma. J Clin Oncol. 2018;36(22):2267–80. https://doi.org/10.1200/JCO.2018.77.8084 An early trial of BCMA-directed CAR T cells, demonstrating responses in the majority of patients. CrossRefPubMedGoogle Scholar
- 62.Berdeja JG, Lin Y, Raje N, Munshi N, Siegel D, Liedtke M, et al. Durable clinical responses in heavily pretreated patients with relapsed/refractory multiple myeloma: updated results from a multicenter study of bb2121 anti-BCMA CAR T cell therapy. Blood. 2017;130:740.Google Scholar
- 63.Zhao W-H, Liu J, Wang B-Y, Chen Y-X, et al. Updated analysis of a phase 1, open-label study of LCAR-B38M, a chimeric antigen receptor T cell therapy directed against B-cell maturation antigen, in patients with relapsed/refractory multiple myeloma. 2018 ASH annual meeting. Abstract – 955.Google Scholar
- 64.Cohen AD, Garfall AL, Stadtmauer EA, Lacey SF, Lancaster E, Vogl DT, et al. Safety and efficacy of B-cell maturation antigen (BCMA)-specific chimeric antigen receptor T cells (CART-BCMA) with cyclophosphamide conditioning for refractory multiple myeloma (MM). Blood. 2017;130:505.CrossRefGoogle Scholar
- 65.Mailankody S, Ghosh A, Staehr M, et al. Clinical responses and pharmacokinetics of MCARH171, a human-derived BCMA targeted CAR T cell therapy in relapsed/refractory multiple myeloma: final results of a phase I clinical trial. 2018 ASH Annual meeting. Abstract 959.Google Scholar
- 66.Mailankody S, Htut M, Lee K, Bensinger W, DeVries T, Piasecki J, et al. First-in human multicenter study of JCARH125, anti-BCMA CAR T-cell therapy for relapsed/refractory multiple myeloma. 2018 ASH annual meeting. Abstract: 957.Google Scholar
- 67.Gregory T, Cohen AD, Costello CL, Ali SA, Berdeja JG, Ostertag EM, et al. Efficacy and safety of P-BCMA-101 CAR-T cells in patients with relapsed/refractory (r/r) multiple myeloma (MM): ASH; 2018. abstract 1012Google Scholar
- 68.•• Noonan KA, Huff CA, Davis J, Lemas MV, Fiorino S, Bitzan J, et al. Adoptive transfer of activated marrow-infiltrating lymphocytes induces measurable antitumor immunity in the bone marrow in multiple myeloma. Sci Transl Med. 2015;7(288):288ra78 The first clinical trial using marrow infiltrating lymphocytes in MM, demonstrating feasibility and efficacy. CrossRefGoogle Scholar
- 69.•• Rapoport AP, Stadtmauer EA, Binder-Scholl GK, Goloubeva O, Vogl DT, Lacey SF, et al. NY-ESO-1-specific TCR-engineered T cells mediate sustained antigen-specific antitumor effects in myeloma. Nat Med. 2015;21(8):914–21 Supports that encouraging clinical responses can be associated with T cells engineered to express an affinity-enhanced T cell receptor. CrossRefGoogle Scholar
- 71.• Sommermeyer D, Hudecek M, Kosasih PL, Gogishvili T, Maloney DG, Turtle CJ, et al. Chimeric antigen receptor-modified T cells derived from defined CD8+ and CD4+ subsets confer superior antitumor reactivity in vivo. Leukemia. 2015;30(2):492–500 Suggests that CAR T cells derived from defined subsets may improve activity and provide uniform potency. CrossRefGoogle Scholar