Novel Approaches to Treating Relapsed and Refractory Multiple Myeloma with a Focus on Recent Approvals of Belantamab Mafodotin and Selinexor

References

• KumarSK, DimopoulosMA, KastritisE, et al. Natural history of relapsed myeloma, refractory to immunomodulatory drugs and proteasome inhibitors: a multicenter IMWG study. Leukemia. 2017;31(11):2443–2448. doi:10.1038/leu.2017.13828620163
   PubMed Web of Science ®Google Scholar
• Surveillance, Epidemiology, and End Results (SEER) Program. SEER*Stat Database: Populations - Total U.S. (1969-2019), National Cancer Institute, DCCPS, Surveillance Research Program, 2020.
   Google Scholar
• JosephN, KaufmanJ, DhodapkarM, et al. Long-Term follow-up results of lenalidomide, bortezomib, and dexamethasone induction therapy and risk-adapted maintenance approach in newly diagnosed multiple myeloma. J Clin Oncol. 2020;38:JCO.19.02515. doi:10.1200/JCO.19.02515
   Web of Science ®Google Scholar
• GandhiUH, CornellRF, LakshmanA, et al. Outcomes of patients with multiple myeloma refractory to CD38-targeted monoclonal antibody therapy. Leukemia. 2019;33(9):2266–2275. doi:10.1038/s41375-019-0435-730858549
   PubMed Web of Science ®Google Scholar
• CarpenterRO, EvbuomwanMO, PittalugaS, et al. B-cell maturation antigen is a promising target for adoptive T-cell therapy of multiple myeloma. Clin Cancer Res. 2013;19(8):2048–2060. doi:10.1158/1078-0432.CCR-12-242223344265
   PubMed Web of Science ®Google Scholar
• TaiYT, AndersonKC. Targeting B-cell maturation antigen in multiple myeloma. Immunotherapy. 2015;7(11):1187–1199. doi:10.2217/imt.15.7726370838
   PubMed Web of Science ®Google Scholar
• TaiYT, MayesPA, AcharyaC, et al. Novel anti-B-cell maturation antigen antibody-drug conjugate (GSK2857916) selectively induces killing of multiple myeloma. Blood. 2014;123(20):3128–3138. doi:10.1182/blood-2013-10-53508824569262
   PubMed Web of Science ®Google Scholar
• LonialS, LeeHC, BadrosA, 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(2):207–221. doi:10.1016/S1470-2045(19)30788-031859245
   PubMed Web of Science ®Google Scholar
• TrudelS, LendvaiN, PopatR, et al. Antibody-drug conjugate, GSK2857916, in relapsed/refractory multiple myeloma: an update on safety and efficacy from dose expansion phase I study. Blood Cancer J. 2019;9(4):37. doi:10.1038/s41408-019-0196-630894515
   PubMed Web of Science ®Google Scholar
• LonialS, LeeC, BadrosA, et al. Pivotal DREAMM-2 study: single-agent belantamab mafodotin (GSK2857916) in patients with Relapsed/Refractory Multiple Myeloma (RRMM) refractory to Proteasome Inhibitors (PIs), immunomodulatory agents, and refractory and/or intolerant to anti-CD38 Monoclonal Antibodies (mAbs). Presented at the 25th European Hematology Association (EHA) Congress. Virtual Format: 611–14; 2020; Poster No EP970; 2020.
   Google Scholar
• LonialS, LeeH, BadrosA. DREAMM-2: single-agent belantamab mafodotin (Belamaf) in patients with relapsed/refractory multiple myeloma (RRMM) - 1-year outcomes by prior therapies. Presented at the 2020 ASH Annual Meeting; 124–8; 2020; Virtual Absract 1417.
   Google Scholar
• CohenAD, TrudelS, LonialS, et al. DREAMM-2: single-agent belantamab mafodotin (GSK2867916) in patients with Relapsed/Refractory Multiple Myeloma (RRMM) and High-Risk (HR) cytogenetics. Presented at ASCO 2020 Annual Meeting, 6 2020; Poster No 441; 2020.
   Google Scholar
• NookaA, LeeH, BadrosA, et al. Infusion-related reaction (IRRs) in the DREAMM-2 study of single-agent belantamab mafodotin (Belamaf) in patients with Relapsed/Refractory Multiple Myeloma (RRMM). Presented at the 2020 ASH Annual Meeting124–8, 2020; Virtual Abstract 3221.
   Google Scholar
• LonialS, NookaA, ThulasiP, et al. Recovery of ocular events with longer-term follow-up in the DREAMM-2 study of single-agent belantamab mafodotin (Belamaf) in patients with Relapsed or Refractory Multiple Myeloma (RRMM). Presented at the 2020 ASH Annual Meeting124–8; 2020; Virtual Abstract 3224; 2020.
   Google Scholar
• EliasonL, CorrellJ, MartinM, et al. Patient-reported experiences during and following treatment with belantamab mafodotin (Belamaf) with Relapsed/Refractory Multiple Myeloma (RRMM) in the DREAMM-2 study. Presented at the 2020 ASH Annual Meeting; 124–8; Virtual Abstract 3248; 2020.
   Google Scholar
• CohenAD, LeeC, TrudelS, et al. impact of prolonged dose delays on response with belantamab mafodotin (Belamaf; GSK2857916) treatment in DREAMM-2 study: 13 month follow-up. Presented at the Society of Hematologic Oncology (SOHO) Annual Meeting; 99–12; 2020; Virtual Format; Poster MM-250; 2020.
   Google Scholar
• WeiselK, HopkinsT, FecteauD, et al. Dreamm-3: a phase 3, open-label, randomized study to evaluate the efficacy and safety of belantamab mafodotin (GSK2857916) monotherapy compared with pomalidomide plus low-dose dexamethasone (pom/dex) in participants with Relapsed/Refractory Multiple Myeloma (RRMM). Blood. 2019;134(Supplement_1):1900.
   Web of Science ®Google Scholar
• TrudelS, McCurdyA, SutherlandH, et al. Part 1 results of a dose finding study of belantamab mafodotin (GSK2857916) in combination with pomalidomide (POM) and Dexamethasone (DEX) for the treatment of relapsed/refractory multple myeloma (RRMM). Presented at the 2020 ASH Annual Meeting; 124–8; Virtual Abstract 725; 2020.
   Google Scholar
• TrudelS, DavisRE, LewisCE, et al. A phase III study of the efficacy and safety of belantamab mafodotin with pomalidomide and dexamethasone (B-Pd) vs. pomalidomide plus bortezomib and dexamethasone (PVd) in patients with Relapsed/Refractory Multiple Myeloma (RRMM). Presented at the 2020 ASH Annual Meeting; 124–8; Virtual Abstract 2302; 2020.
   Google Scholar
• RichardsonPG, OriolA, BeksacM, et al. Pomalidomide, bortezomib, and dexamethasone for patients with relapsed or refractory multiple myeloma previously treated with lenalidomide (OPTIMISMM): a randomised, open-label, phase 3 trial. Lancet Oncol. 2019;20(6):781–794. doi:10.1016/S1470-2045(19)30152-431097405
   PubMed Web of Science ®Google Scholar
• NookaA, MantecaM, BahlisN, et al. DREAMM-4: evaluating safety and clinical activity of blantamab mafodotin (belamaf) in combination with pembrolizumab in patients with relapsed/refractory multiple myeloma. Presented at the 25th European Hematology Association (EHA) Congress; Virtual Format; 611–14, 2020; 2020.
   Google Scholar
• RichardsonP, NookaA, QuachH, et al. Dreamm-5 platform trial: belantamb mafodotin (Belamaf) in combination with four differentnovel agents in patients with Relapsed/Refractory Multiple Myeloma (RRMM). Presented at the 2020 ASH Annual Meeting; 124–8; Virtual Abstract 2299; 2020.
   Google Scholar
• NookaA, Stockerl-GoldsteinK, QuachH, et al. DREAMM-6: safety and tolerability of belantamab mafodotin in combination with bortezomib/dexamethasone in relapsed/refractory multiple myeloma (RRMM). 2020.
   Google Scholar
• PopatR, NookaA, Stockerl-GoldsteinK, et al. DREAMM-6: safety, tolerability and clinical activity of belantamab mafodotin (Belamaf) in combination with bortezomib/dexamethasone (BorDex) in Relapsed/Refractory Multiple Myeloma (RRMM). Presented at the 2020 ASH Annual Meeting; 124–8; Virtual Abstract 1419; 2020.
   Google Scholar
• RifkinR, BoydK, GrosickiS, et al. DREAMM-7: a phase III study of the efficacy and safety of belantamab mafodotin (Belamaf) with bortezomib, and dexamethasone (B-Vd) in patients with Relapsed/Refractory Multiple Myeloma (RRMM). Presented at the 2020 ASH Annual Meeting; 124–8; Virtual Abstract 3247; 2020.
   Google Scholar
• CohenAD, GarfallAL, StadtmauerEA, et al. B cell maturation antigen-specific CAR T cells are clinically active in multiple myeloma. J Clin Invest. 2019;129(6):2210–2221. doi:10.1172/JCI12639730896447
   PubMed Web of Science ®Google Scholar
• CohenAD, GarfallAL, DoganA, et al. Serial treatment of relapsed/refractory multiple myeloma with different BCMA-targeting therapies. Blood Adv. 2019;3(16):2487–2490. doi:10.1182/bloodadvances.201900046631451444
   PubMed Web of Science ®Google Scholar
• MaplesKT, JosephNS, HarveyRD. Current developments in the combination therapy of relapsed/refractory multiple myeloma. Expert Rev Anticancer Ther. 2020;20(12):1021–1035. doi:10.1080/14737140.2020.182807132969752
   PubMed Web of Science ®Google Scholar
• SchmidtTM, BarwickBG, JosephN, et al. Gain of Chromosome 1q is associated with early progression in multiple myeloma patients treated with lenalidomide, bortezomib, and dexamethasone. Blood Cancer J. 2019;9(12):94. doi:10.1038/s41408-019-0254-031767829
   PubMed Web of Science ®Google Scholar
• TaiYT, LandesmanY, AcharyaC, et al. CRM1 inhibition induces tumor cell cytotoxicity and impairs osteoclastogenesis in multiple myeloma: molecular mechanisms and therapeutic implications. Leukemia. 2014;28(1):155–165. doi:10.1038/leu.2013.11523588715
   PubMed Web of Science ®Google Scholar
• TanDS, BedardPL, KuruvillaJ, SiuLL, RazakAR. Promising SINEs for embargoing nuclear-cytoplasmic export as an anticancer strategy. Cancer Discov. 2014;4(5):527–537. doi:10.1158/2159-8290.CD-13-100524743138
   PubMed Web of Science ®Google Scholar
• ChariA, VoglDT, GavriatopoulouM, et al. Oral selinexor-dexamethasone for triple-class refractory multiple myeloma. N Engl J Med. 2019;381(8):727–738. doi:10.1056/NEJMoa190345531433920
   PubMed Web of Science ®Google Scholar
• SuvannasankhaA, KapetanakisV, PrawitzT, et al. MM-209: assessing efficacy via indirect comparison of single-agent belantamab mafodotin (Belamaf; GSK2857916) in DREAMM-2 versus STORM or MAMMOTH studies in Relapsed/Refractory Multiple Myeloma (RRMM). Clin Lymphoma Myeloma Leuk. 2020;20:S300–S301. doi:10.1016/S2152-2650(20)30942-3
   Web of Science ®Google Scholar
• ChariA, VoglDT, JagannathS, et al. Selinexor-based regimens for the treatment of myeloma refractory to chimeric antigen receptor T cell therapy. Br J Haematol. 2020;189(4):e126–e30. doi:10.1111/bjh.1655032124443
   PubMed Web of Science ®Google Scholar
• KashyapT, ArguetaC, AboukameelA, et al. Selinexor, a Selective Inhibitor of Nuclear Export (SINE) compound, acts through NF-kappaB deactivation and combines with proteasome inhibitors to synergistically induce tumor cell death. Oncotarget. 2016;7(48):78883–78895. doi:10.18632/oncotarget.1242827713151
   PubMedGoogle Scholar
• ArguetaC, KashyapT, KlebanovB, et al. Selinexor synergizes with dexamethasone to repress mTORC1 signaling and induce multiple myeloma cell death. Oncotarget. 2018;9(39):25529–25544. doi:10.18632/oncotarget.2536829876006
   PubMedGoogle Scholar
• RosebeckS, AlongeMM, KandarpaM, et al. Synergistic myeloma cell death via novel intracellular activation of caspase-10-dependent apoptosis by carfilzomib and selinexor. Mol Cancer Ther. 2016;15(1):60–71. doi:10.1158/1535-7163.MCT-15-048826637366
   PubMed Web of Science ®Google Scholar
• GrosickiS, SimonovaM, SpickaI, et al. Once-per-week selinexor, bortezomib, and dexamethasone versus twice-per-week bortezomib and dexamethasone in patients with multiple myeloma (BOSTON): a randomised, open-label, phase 3 trial. Lancet. 2020;396(10262):1563–1573. doi:10.1016/S0140-6736(20)32292-333189178
   PubMed Web of Science ®Google Scholar
• JakubowiakAJ, JasielecJK, RosenbaumCA, et al. Phase 1 study of selinexor plus carfilzomib and dexamethasone for the treatment of relapsed/refractory multiple myeloma. Br J Haematol. 2019;186(4):549–560. doi:10.1111/bjh.1596931124580
   PubMed Web of Science ®Google Scholar
• GasparettoC, SchillerG, CallanderN, et al. A phase 1b/2 study of selinexor, carfilzomib, and dexamethasone (SKd) in Relapsed/Refractory Multiple Myeloma (RRMM). HemaSphere. 2019;134(Supplement_1):3157.
   Google Scholar
• GasparettoC, LentzschS, SchillerG, et al. Selinexor, daratumumab, and dexamethasone in patients with relapsed/refractory multiple myeloma(MM). J clin oncol. 2020;38(15_suppl):8510. doi:10.1200/JCO.2020.38.15_suppl.8510
   Web of Science ®Google Scholar
• ChenA, BahlisN, GasparettoC, et al. Selinexor, pomalidomide, and dexamethasone (SPd) in patients with relapsed or refractory multiple myeloma. HemaSphere. 2019;134(Supplement_1):141.
   Google Scholar
• GasparettoC, LentzschS, SchillerG, et al. Selinexor, daratumumab, and dexamethasone in patients with relapse/refractory multiple myeloma (MM). J Clin Oncol. 2020;38(15_suppl):8510.
   Web of Science ®Google Scholar
• WhiteD, LeblancR, BaljevicM, et al. Seliexor, lenalidomide, and dexamethasone (SRd) for patients with Relapsed/Refractory and Newly Diagnosed Multiple Myeloma. Presented at ASH 2020 Annual Meeting; 124–7; 2020; Virtual Abstract 1393; 2020.
   Google Scholar
• McMillanA, WarcelD, PopatR. Antibody-drug conjugates for multiple myeloma. Expert Opin Biol Ther. 2020;21:1–13. doi:10.1080/14712598.2020.1802422
   Web of Science ®Google Scholar
• KumarA, MagdaliniM, BhutaniM, et al. Phase 1, first-in-human study of MEDI2228, a BCMA-targeted ADC in patients with Relapsed/Refractory Multiple Myeloma. Presented at the 2020 ASH Annual Meeting; 124–8; 2020; Virtual Absract 179.
   Google Scholar
• GarfallA, UsmaniS, MateosA, et al. Updated phase 1 results of teclistimab, a B-cell Maturation Antigen (BCMA) x CD3 bispecific antibody, in relapsed and/or Refractory Multiple Myeloma (RRMM). Presented at the 2020 ASH Annual Meeting; 124–8; 2020; Virtual Absract 180.
   Google Scholar
• UsmaniS, MateosM, NahiH. Phase 1 study of teclistimab, a humanized B-cell maturation antigen (BCMA) x CD3 bispecific antibody, in relapsed/refractory multiple myeloma (R/R MM). Presented at the 2020 ASCO Virtual Scientific Program; 529–21; 2020; Abstract 100.
   Google Scholar
• MadduriD, RoskoA, BrayerJ, et al. REGN5458, a BCMA x CD3 bispecific monoclonal antibody, induces deep and durable responses in patients with Relapsed/Refractory Multiple Myeloma (RRMM). Presented at the 2020 ASH Annual Meeting; 124–8; Virtual Absract 291; 2020.
   Google Scholar
• SeckingerA, DelgadoJA, MoserS, et al. Target expression, generation, preclinical activity, and pharmacokinetics of the BCMA-T cell bispecific antibody EM801 for multiple myeloma treatment. Cancer Cell. 2017;31(3):396–410. doi:10.1016/j.ccell.2017.02.00228262554
   PubMed Web of Science ®Google Scholar
• CostaLJ, WongS, BermudezA, et al. First clinical sutdy of the B-cell maturation antigen (BCMA) 2+1 T cell engager (TCE) CC-93269 in patients (Pts) with Relapsed/Refractory Multiple Myeloma (RRMM): interim results of a phase 1 multicenter trial. Blood. 2019;134(Supp_1):143. doi:10.1182/blood-2019-122895
   Web of Science ®Google Scholar
• RodriguezC, D’SouzaA, ShahN, et al. Initial results of a phase I study of TNB-383B, a BCMA x CD3 bispecific T-cell redirecting antibody, in relapsed/refractory multiple myeloma. Presented at aSH 2020 Annual Meeting; 124–7; 2020; Virtual Abstract 293; 2020.
   Google Scholar
• ChariA, BerdejaJG, OriolA, et al. A phase 1, first-in human study of talquetamab, a G protein-coupled receptor family C group 5 member D (GPRC5D) x CD3 bispecific antibody, in patients with relaped and/or refractory multiple myeloma (RRMM). Presented at the 2020 ASH Annual Meeting; 124–8; 2020; Virtual Absract 290.
   Google Scholar
• NakamuraR, LearS, WilsonD, et al. Early pharmacodynamic changes in T-cell activation, proliferation, and cytokine productino confirm the mode of action of BFCR4350A, a FcRH5/CD3 T-cell-engaging bispecific antibody, in patients with relapsed/refractory multiple myeloma. Presented at ASH 2020 Annual Meeting; 124–7; 2020; Abstract 3213; 2020.
   Google Scholar
• CohenAD, HarrisonS, KrishnanA, et al. Initial clinical activity and safety of BFCR4350A, a FcRH5/CD3 T-cell-engaging bispecific antibody, in relapsed/refractory multiple myeloma. Presented at the 2020 ASH Annual Meeting; 124–8; 2020; Virtual Absract 292.
   Google Scholar
• BjorklundCC, KangJ, LuL, et al. CC-220 is a potent cereblon modulating agent that displays anti-proliferative, pro-apoptotic and immunomodulatory activity on sensitive and resistant multiple myeloma cell lines. Blood. 2016;128(22):1591. doi:10.1182/blood.V128.22.1591.1591
   Web of Science ®Google Scholar
• RichardsonP, VangstedA, RamasamyK, et al. First-in-human phase 1 study of the novel celmod agent CC-92480 combined with dexamethasone in patients with relapsed/refractory myeloma. Presented at EHA 2020, Oral Presentation; Abstract S208; 2020.
   Google Scholar
• RajeN, BerdejaJ, LinY, et al. Anti-BCMA CAR T-cell Therapy bb2121 in relapsed or refractory multiple myeloma. N Engl J Med. 2019;380(18):1726–1737. doi:10.1056/NEJMoa181722631042825
   PubMed Web of Science ®Google Scholar
• MunshiN, AndersonLD, ShahN, JagannathS, BerdejaJ, LonialS. Idecabtagene vicleucel (ide-cel;bb2121), a BCMA-targeted CAR T-cell therapy, in patients with relapsed and refractory multiple myeloma (RRMM): initial KarMMA results. J Clin Oncol. 2020;38(15_suppl):8503. doi:10.1200/JCO.2020.38.15_suppl.8503
   Web of Science ®Google Scholar
• AlsinaM, ShahA, RajeN, et al. Updated results from the phase 1 CRB-402 study of anti-BCMA CAR-T cell therapy bb21217 in patients with relapsed and refractory multiple myeloma: correlation of expansion and duration of response with T-cell phenotypes. Presented at ASH 2020 Annual Meeting; 124–7; 2020; Abstract 130; 2020.
   Google Scholar
• UsmaniS, BerdejaJ, Truppel-HartmannA, et al. KarMMa-4: idecabtagene vicleucel (ide-cel), a BCMA-directed CAR T-cell therapy, in high-risk newly diagnosed multiple myeloma. Presented at ASCO 2020 Annual Meeting; 6 2020; Abstract 1418; 2020.
   Google Scholar
• MadduriD, BerdejaJ, UsmaniS, et al. CARTITUDE-1: phase 1b/2 study of ciltacabtagene autoleucel, A B-cell maturation antigen-directed chimeric antigen receptor T cell therapy, in relapsed/refractory multiple myeloma. Presented at ASH 2020 Annual Meeting; 124–7; 2020; Abstract 177; 2020.
   Google Scholar
• MailankodyS, HtutM, LeeC, et al. JCARH125, anti-BCMA CAR T-cell therapy for relapsed/refractory multiple myeloma: initial proof of concept results from a phase 1/2 multicenter study (EVOLVE). Blood. 2018;132:957. doi:10.1182/blood-2018-99-113548
   Web of Science ®Google Scholar
• CowanA, PontM, SatherB, et al. Efficacy and safety of fully human BCMA Car-T cells in combination with a gamma secretase inhibitor to increase BCMA surface expression in patients with relapsed or refractory multiple myeloma. Blood. 2019;134(Supplement_1):204. doi:10.1182/blood-2019-129405
   Web of Science ®Google Scholar
• RafiqS, YekuOO, JacksonHJ, et al. Targeted delivery of a PD-1-blocking scFv by CAR-T cells enhances anti-tumor efficacy in vivo. Nat Biotechnol. 2018;36(9):847–856. doi:10.1038/nbt.419530102295
   PubMed Web of Science ®Google Scholar