BCMA-targeted therapies for multiple myeloma: strategies to maximize efficacy and minimize adverse events

References

• International Myeloma Foundation. What is multiple myeloma? Available from: https://www.myeloma.org/what-is-multiple-myeloma
   Google Scholar
• Anderson KC. Progress and paradigms in multiple myeloma. Clin Cancer Res. 2016;22(22):5419–5427.
   PubMed Web of Science ®Google Scholar
• Lokhorst HM, Plesner T, Laubach JP, et al. Targeting CD38 with daratumumab monotherapy in multiple myeloma. N Engl J Med. 2015;373(13):1207–1219.
   PubMed Web of Science ®Google Scholar
• Summary of Product Characteristics (SmPC) - (emc). DARZALEX 1,800 mg solution for injection. Available from: https://www.medicines.org.uk/emc/product/11488/smpc
   Google Scholar
• Summary of Product Characteristics (SmPC) - (emc). SARCLISA 20mg/mL concentrate for solution for infusion. Available from: https://www.medicines.org.uk/emc/product/11535
   Google Scholar
• Summary of Product Characteristics (SmPC) - (emc). Empliciti 300 mg powder for concentrate for solution for infusion. Available from: https://www.medicines.org.uk/emc/product/7222/smpc
   Google Scholar
• Gandhi UH, Cornell RF, Lakshman A, et al. Outcomes of patients with multiple myeloma refractory to CD38-targeted monoclonal antibody therapy. Leukemia. 2019;33(9):2266–2275.
   PubMed Web of Science ®Google Scholar
• Carpenter RO, Evbuomwan MO, Pittaluga S, 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.
   PubMed Web of Science ®Google Scholar
• O’Connor BP, Raman VS, Erickson LD, et al. BCMA is essential for the survival of long-lived bone marrow plasma cells. J Exp Med. 2004;199(1):91–98.
   PubMed Web of Science ®Google Scholar
• Xu S, Lam K-P. B-Cell maturation protein, which binds the tumor necrosis factor family members baff and April, is dispensable for humoral immune responses. Mol Cell Biol. 2001;21(12):4067–4074.
   PubMed Web of Science ®Google Scholar
• Laurent SA, Hoffmann FS, Kuhn P-H, et al. γ-secretase directly sheds the survival receptor BCMA from plasma cells. Nat Commun. 2015;6(1):1–12.
   Google Scholar
• Rennert P, Schneider P, Cachero TG, et al. A soluble form of b cell maturation antigen, a receptor for the tumor necrosis factor family member April, inhibits tumor cell growth. J Exp Med. 2000;192(11):1677–1684.
   PubMed Web of Science ®Google Scholar
• Belnoue E, Pihlgren M, McGaha TL, et al. April is critical for plasmablast survival in the bone marrow and poorly expressed by early-life bone marrow stromal cells. Blood. 2008;111(5):2755–2764.
   PubMed Web of Science ®Google Scholar
• Novak AJ, Darce JR, Arendt BK, et al. Expression of BCMA, TACI, and BAFF-R in multiple myeloma: a mechanism for growth and survival. Blood. 2004;103(2):689–694.
   PubMed Web of Science ®Google Scholar
• Moreaux J, Legouffe E, Jourdan E, et al. BAFF and April protect myeloma cells from apoptosis induced by interleukin 6 deprivation and dexamethasone. Blood. 2004;103(8):3148–3157.
   PubMed Web of Science ®Google Scholar
• Tai YT, Acharya C, An G, et al. April and BCMA promote human multiple myeloma growth and immunosuppression in the bone marrow microenvironment. Blood. 2016;127(25):3225–3236.
   PubMed Web of Science ®Google Scholar
• Sanchez E, Li M, Kitto A, et al. Serum B-cell maturation antigen is elevated in multiple myeloma and correlates with disease status and survival. Br J Haematol. 2012;158(6):727–738.
   PubMed Web of Science ®Google Scholar
• Jew S, Chang T, Bujarski S, et al. Normalization of serum B-cell maturation antigen levels predicts overall survival among multiple myeloma patients starting treatment. Br J Haematol. 2021;192(2):272–280.
   PubMed Web of Science ®Google Scholar
• Bellucci R, Wu CJ, Chiaretti S, et al. Complete response to donor lymphocyte infusion in multiple myeloma is associated with antibody responses to highly expressed antigens. Blood. 2004;103(2):656–663.
   PubMed Web of Science ®Google Scholar
• Bellucci R, Alyea EP, Chiaretti S, et al. Graft-versus-tumor response in patients with multiple myeloma is associated with antibody response to BCMA, a plasma-cell membrane receptor. Blood. 2005;105(10):3945–3950.
   PubMed Web of Science ®Google Scholar
• Bruins WSC, Zweegman S, Mutis T, et al. Targeted therapy with immunoconjugates for multiple myeloma. Front Immunol. 2020;11:1155.
   PubMed Web of Science ®Google Scholar
• FDA. FDA granted accelerated approval to belantamab mafodotin-blmf for multiple myeloma. Available from: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-granted-accelerated-approval-belantamab-mafodotin-blmf-multiple-myeloma
   Google Scholar
• European Medicines Agency. Blenrep. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/blenrep
   Google Scholar
• Tai YT, Mayes PA, Acharya C, et al. Novel anti–B-cell maturation antigen antibody-drug conjugate (GSK2857916) selectively induces killing of multiple myeloma. Blood. 2014;123(20):3128–3138.
   PubMed Web of Science ®Google Scholar
• Montes De Oca R, Bhattacharya S, Vitali N, et al. The anti-BCMA antibody-drug conjugate GSK2857916 drives immunogenic cell death and immune-mediated anti-tumor responses, and in combination with an OX40 agonist potentiates in vivo activity. HemaSphere. 2019;3(S1):231.
   Google Scholar
• Lonial S, Lee HC, Badros 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(2):207–221.
   PubMed Web of Science ®Google Scholar
• Lee HC, Raje NS, Landgren O, et al. Phase 1 study of the anti-BCMA antibody-drug conjugate AMG 224 in patients with relapsed/refractory multiple myeloma. Leukemia. 2020;35(1): 255–258
   PubMed Web of Science ®Google Scholar
• Kumar SK, Migkou M, Bhutani M, et al. Phase 1, First-in-human study of MEDI2228, a BCMA-targeted ADC in patients with relapsed/refractory multiple myeloma. Blood. 2020;136(Supplement 1):26–27.
   Google Scholar
• Strassl I, Schreder M, Steiner N, et al. The agony of choice—where to place the wave of BCMA-targeted therapies in the multiple myeloma treatment puzzle in 2022 and beyond. Cancers. 2021;13(18):4701.
   PubMed Web of Science ®Google Scholar
• Labrijn AF, Janmaat ML, Reichert JM, et al. Bispecific antibodies: a mechanistic review of the pipeline. Nat Rev Drug Discov. 2019;18(8):585–608.
   PubMed Web of Science ®Google Scholar
• Lancman G, Sastow DL, Cho HJ, et al. Bispecific antibodies in multiple myeloma: present and future. Blood Cancer Discov. 2021;2(5):423–433.
   PubMedGoogle Scholar
• Vafa O, Trinklein ND. Perspective: designing T-Cell engagers with better therapeutic windows. Front Oncol. 2020;10:446.
   PubMed Web of Science ®Google Scholar
• Swan D, Routledge D, Harrison S. The evolving status of immunotherapies in multiple myeloma: the future role of bispecific antibodies. Br J Haematol. 2021. 10.1111/BJH.17805
   Web of Science ®Google Scholar
• Topp MS, Duell J, Zugmaier G, et al. Evaluation of AMG 420, an anti-BCMA bispecific T-cell engager (BiTE) immunotherapy, in R/R multiple myeloma (MM) patients: updated results of a first-in-human (FIH) phase I dose escalation study. J clin oncol. 2019;37(15_suppl):8007.
   Web of Science ®Google Scholar
• ClinicalTrials.gov. Home. Available from: https://clinicaltrials.gov/ct2/home
   Google Scholar
• Usmani SZ, Garfall AL, van de Donk NWCJ, et al. Teclistamab, a B-cell maturation antigen × CD3 bispecific antibody, in patients with relapsed or refractory multiple myeloma (MajesTEC-1): a multicentre, open-label, single-arm, phase 1 study. Lancet. 2021;398(10301):665–674.
   PubMed Web of Science ®Google Scholar
• Harrison SJ, Minnema MC, Lee HC, et al. A phase 1 First in Human (FIH) study of AMG 701, an Anti-B-Cell Maturation Antigen (BCMA) Half-Life Extended (HLE) BiTE® (bispecific T-cell engager) molecule, in Relapsed/Refractory (RR) Multiple Myeloma (MM). Blood. 2020;136(Supplement 1):28–29.
   Google Scholar
• Bahlis NJ, Raje NS, Costello C, et al. Efficacy and safety of elranatamab (PF-06863135), a B-cell maturation antigen (BCMA)-CD3 bispecific antibody, in patients with relapsed or refractory multiple myeloma (MM). J Clin Oncol. 2021;39(15_suppl):8006.
   Web of Science ®Google Scholar
• Costa LJ, Wong SW, Bermudez A, et al. Interim results from the first phase 1 clinical study of the B-cell maturation antigen (BCMA) 2+1 T cell engage (TCE) CC-93269 in patients (Pts) with relapsed/refractory multiple myeloma (RRMM). EHA Library. 2020;295025.
   Google Scholar
• Madduri D, Rosko A, Brayer J, et al. REGN5458, a BCMA x CD3 bispecific monoclonal antibody, induces deep and durable responses in patients with relapsed/refractory multiple myeloma (RRMM). Blood. 2020;136(Supplement 1):41–42.
   Google Scholar
• Rodriguez C, D’Souza A, Shah N, 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. Blood. 2020;136(Supplement 1):43–44.
   Google Scholar
• Durie BGM, Harousseau JL, Miguel JS, et al. International uniform response criteria for multiple myeloma. Leukemia. 2006;20(9): 1467–1473
   PubMed Web of Science ®Google Scholar
• Mikkilineni L, Kochenderfer JN. CAR T cell therapies for patients with multiple myeloma. Nat Rev Clin Oncol. 2020;18(2):71–84.
   PubMed Web of Science ®Google Scholar
• Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017;377(26):2531–2544.
   PubMed Web of Science ®Google Scholar
• Maude SL, Laetsch TW, Buechner J, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 2018;378(5):439–448.
   PubMed Web of Science ®Google Scholar
• Schuster SJ, Bishop MR, Tam CS, et al. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2019;380(1):45–56.
   PubMed Web of Science ®Google Scholar
• van de Donk NWCJ, Themeli M, Usmani SZ. Determinants of response and mechanisms of resistance of CAR T-cell therapy in multiple myeloma. Blood Cancer Discov. 2021;2(4):302
   PubMedGoogle Scholar
• Raje N, Berdeja J, Lin Y, et al. Anti-BCMA CAR T-cell therapy bb2121 in relapsed or refractory multiple myeloma. N Engl J Med. 2019;380(18):1726–1737.
   PubMed Web of Science ®Google Scholar
• Li C, Wang Q, Zhu H, et al. T cells expressing anti B-cell maturation antigen chimeric antigen receptors for plasma cell malignancies. Blood. 2018;132(Supplement 1):1013.
   PubMed Web of Science ®Google Scholar
• 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. Blood. 2018;132(Supplement 1):959.
   Web of Science ®Google Scholar
• Fu W, Du J, Jiang H, et al. Efficacy and safety of CAR-T Therapy with safety switch targeting Bcma for patients with relapsed/refractory multiple myeloma in a phase 1 clinical study. Blood. 2019;134(Supplement_1):3154.
   Web of Science ®Google Scholar
• Popat R, Zweegman S, Cavet J, et al. Phase 1 first-in-human study of AUTO2, the first chimeric antigen receptor (CAR) T cell targeting April for patients with relapsed/refractory multiple myeloma (RRMM). Blood. 2019;134(Supplement_1):3112.
   Google Scholar
• Green DJ, Pont M, Sather BD, et al. Fully human bcma targeted chimeric antigen receptor T cells administered in a defined composition demonstrate potency at low doses in advanced stage high risk multiple myeloma. Blood. 2018;132(Supplement 1):1011.
   Web of Science ®Google Scholar
• Mailankody S, Htut M, Lee KP, 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(Supplement 1):957.
   Web of Science ®Google Scholar
• Jie J, Hao S, Jiang S, et al. Phase 1 trial of the safety and efficacy of fully human anti-Bcma CAR T cells in relapsed/refractory multiple myeloma. Blood. 2019;134(Supplement_1):4435.
   Google Scholar
• Li C, Wang J, Wang D, et al. Efficacy and safety of fully human bcma targeting CAR T cell therapy in relapsed/refractory multiple myeloma. Blood. 2019;134(Supplement_1):929.
   Google Scholar
• Mikkilineni L, Manasanch EE, Lam N, et al. T cells expressing an anti-B-cell maturation antigen (BCMA) chimeric antigen receptor with a fully-human heavy-chain-only antigen recognition domain induce remissions in patients with relapsed multiple myeloma. Blood. 2019;134(Supplement_1):3230.
   Web of Science ®Google Scholar
• Fierce Pharma. GlaxoSmithKline jumps into myeloma with “homemade” anti-BCMA drug blenrep. Available from: https://www.fiercepharma.com/pharma/glaxosmithkline-jumps-into-myeloma-homemade-anti-bcma-drug-blenrep
   Google Scholar
• National Cancer Institute. CAR T-cell therapy approved for multiple myeloma. Available from: https://www.cancer.gov/news-events/cancer-currents-blog/2021/fda-ide-cel-car-t-multiple-myeloma
   Google Scholar
• Munshi NC, Anderson LD, Shah N, et al. Idecabtagene vicleucel in relapsed and refractory multiple myeloma. N Engl J Med. 2021;384(8):705–716.
   PubMed Web of Science ®Google Scholar
• Jagannath S, Lin Y, Goldschmidt H, et al. KarMMa-RW: comparison of idecabtagene vicleucel with real-world outcomes in relapsed and refractory multiple myeloma. Blood Cancer J. 2021;11(6):1–9.
   PubMed Web of Science ®Google Scholar
• Zhao WH, Liu J, Wang B-Y, et al. 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 or refractory multiple myeloma. J Hematol Oncol. 2018;11(1):1–8.
   PubMedGoogle Scholar
• Berdeja JG, Madduri D, Usmani SZ, et al. Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b/2 open-label study. Lancet. 2021;398(10297):314–324.
   PubMed Web of Science ®Google Scholar
• Mailankody S, Jakubowiak AJ, Htut M, et al. Orvacabtagene autoleucel (orva-cel), a B-cell maturation antigen (BCMA)-directed CAR T cell therapy for patients (pts) with relapsed/refractory multiple myeloma (RRMM): update of the phase 1/2 EVOLVE study (NCT03430011). J. Clin. Oncol. 2020;38:8504.
   Web of Science ®Google Scholar
• Costello CL, Cohen AD, Patel KK, et al. Phase 1/2 study of the safety and response of P-BCMA-101 CAR-T cells in patients with relapsed/refractory (r/r) multiple myeloma (MM) (PRIME) with novel therapeutic strategies. Blood. 2020;136(Supplement 1):29–30.
   Web of Science ®Google Scholar
• Barnett BE, Hermanson DL, Smith JB, et al. piggyBacTM-produced CAR-T cells exhibit stem-cell memory phenotype. Blood. 2016;128(22):2167.
   Web of Science ®Google Scholar
• Sheth VS, Gauthier J. Taming the beast: CRS and ICANS after CAR T-cell therapy for ALL. Bone Marrow Transplant. 2020;56(3):552–566.
   PubMed Web of Science ®Google Scholar
• Zhou X, Rasche L, Kortüm KM, et al. Toxicities of chimeric antigen receptor T cell therapy in multiple myeloma: an overview of experience from clinical trials, pathophysiology, and management strategies. Front Immunol. 2020;11:3403.
   Web of Science ®Google Scholar
• Roex G, Timmers M, Wouters K, et al. Safety and clinical efficacy of BCMA CAR-T-cell therapy in multiple myeloma. J Hematol Oncol. 2020;13(1):1–14.
   PubMed Web of Science ®Google Scholar
• van Oekelen O, Aleman A, Upadhyaya B, et al. Neurocognitive and hypokinetic movement disorder with features of parkinsonism after BCMA-targeting CAR-T cell therapy. Nat Med. 2021;27(12):2099–2103.
   PubMed Web of Science ®Google Scholar
• Atieh T, Atrash S, Mohan M, et al. Belantamab in combination with dexamethasone in patients with triple-class relapsed/refractory multiple myeloma. Blood. 2021;138(Supplement 1):1642.
   PubMedGoogle Scholar
• Vaxman I, Abeykoon J, Dispenzieri A, et al. “Real-life” data of the efficacy and safety of belantamab mafodotin in relapsed multiple myeloma—the Mayo Clinic experience. Blood Cancer J. 2021;11(12):1–5.
   PubMed Web of Science ®Google Scholar
• Hultcrantz M, Orozco J, Peterson TJ, et al. Belantamab mafodotin in patients with relapsed/refractory multiple myeloma, a real-world experience. Blood. 2021;138(Supplement 1):1644.
   Google Scholar
• Alegre A, Benzo Callejo G, Alonso Fernández R, et al. Compassionate use of belantamab mafodotin for treatment of patients with relapsed/refractory multiple myeloma heavily treated. Spanish experience. Blood. 2021;138(Supplement 1):3775.
   Google Scholar
• Mohan M, Nagavally S, Dhakal B, et al. Risk of infections with B cell maturation antigen (BCMA) directed Immunotherapy in multiple myeloma. Blood Adv. 2021;138(Supplement 1):1626.
   Google Scholar
• Trudel S, Lendvai N, Popat R, 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):1–10.
   Google Scholar
• Farooq AV, Degli Esposti S, Popat R, et al. Corneal epithelial findings in patients with multiple myeloma treated with antibody–drug conjugate belantamab mafodotin in the pivotal, randomized, DREAMM-2 Study. Ophthalmol Ther. 2020;9(4):889–911.
   PubMed Web of Science ®Google Scholar
• Popat R, Warcel D, O’Nions J, et al. Characterization of response and corneal events with extended follow-up after belantamab mafodotin (GSK2857916) monotherapy for patients with relapsed multiple myeloma: a case series from the first-time-in-human clinical trial. Haematologica. 2020;105(5):e261–e263.
   PubMed Web of Science ®Google Scholar
• Lonial S, Nooka AK, Thulasi P, et al. Management of belantamab mafodotin-associated corneal events in patients with relapsed or refractory multiple myeloma (RRMM). Blood Cancer J. 2021;11(5). DOI:10.1038/s41408-021-00494-4.
   PubMed Web of Science ®Google Scholar
• Cohen AD, Lee HC, Trudel S, et al. Impact of prolonged dose delays on response with belantamab mafodotin (belamaf; GSK2857916) treatment in DREAMM-2 study: 13-month follow-up. Hematol Rep. 2020;12:S304–S305.
   Google Scholar
• Lee DW, Gardner R, Porter DL, et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood. 2014;124(2):188–195.
   PubMed Web of Science ®Google Scholar
• Jatiani SS, Aleman A, Madduri D, et al. Myeloma CAR-T CRS management with IL-1R antagonist anakinra. Clin Lymphoma Myeloma Leukemia. 2020;20(9):632–636.e1.
   PubMed Web of Science ®Google Scholar
• Brudno JN, Kochenderfer JN. Recent advances in CAR T-cell toxicity: mechanisms, manifestations and management. Blood Rev. 2019;34:45–55.
   PubMed Web of Science ®Google Scholar
• Neill L, Rees J, Roddie C. Neurotoxicity—CAR T-cell therapy: what the neurologist needs to know. Pract Neurol. 2020;20(4):285–293.
   PubMedGoogle Scholar
• Brudno JN, Maric I, Hartman SD, 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.
   PubMed Web of Science ®Google Scholar
• Trinklein ND, Pham D, Schellenberger U, et al. Efficient tumor killing and minimal cytokine release with novel T-cell agonist bispecific antibodies. mAbs. 2019;11:639–652.
   PubMed Web of Science ®Google Scholar
• Ghorashian S, Kramer AM, Onuoha S, et al. Enhanced CAR T cell expansion and prolonged persistence in pediatric patients with ALL treated with a low-affinity CD19 CAR. Nat Med. 2019;25(9):1408–1414.
   PubMed Web of Science ®Google Scholar
• Zhao W-H, Liu J, Wang B-Y, 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. Blood. 2018;132(Supplement 1):955.
   Google Scholar
• Alvi RM, Frigault MJ, Fradley MG, et al. Cardiovascular events among adults treated with chimeric antigen receptor T-Cells (CAR-T). J Am Coll Cardiol. 2019;74(25):3099–3108.
   PubMed Web of Science ®Google Scholar
• Yakoub-Agha I, Chabannon C, Bader P, et al. Management of adults and children undergoing chimeric antigen receptor T-cell therapy: best practice recommendations of the European Society for Blood and Marrow Transplantation (EBMT) and the Joint Accreditation Committee of ISCT and EBMT (JACIE). Haematologica. 2020;105(2):297–316.
   PubMed Web of Science ®Google Scholar
• Cohen AD, Garfall AL, Stadtmauer EA, et al. B cell maturation antigen–specific CAR T cells are clinically active in multiple myeloma. J Clin Invest. 2019;129(6):2210–2221.
   PubMed Web of Science ®Google Scholar
• Eyquem J, Mansilla-Soto J, Giavridis T, et al. Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection. Nature. 2017;543(7643):113–117.
   PubMed Web of Science ®Google Scholar
• Wu L,Seung E, Xu L, et al. Trispecific antibodies enhance the therapeutic efficacy of tumor-directed T cells through T cell receptor co-stimulation. Nature Cancer. 2019;1(1): 86–98
   PubMedGoogle Scholar
• Fraietta JA, Lacey SF, Orlando EJ, et al. Determinants of response and resistance to CD19 chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia. Nat Med. 2018;24(5):563–571.
   PubMed Web of Science ®Google Scholar
• Garfall AL, Dancy EK, Cohen AD, et al. T-cell phenotypes associated with effective CAR T-cell therapy in postinduction vs relapsed multiple myeloma. Blood Adv. 2019;3:2812–2815.
   PubMed Web of Science ®Google Scholar
• Alsina M, Shah N, Raje NS, et al. Updated results from the phase I 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. Blood. 2020;136(Supplement 1):25–26.
   Web of Science ®Google Scholar
• Dhodapkar MV, Krasovsky J, Osman K, et al. Vigorous premalignancy-specific effector T cell response in the bone marrow of patients with monoclonal gammopathy. J Exp Med. 2003;198:1753–1757.
   PubMed Web of Science ®Google Scholar
• Kawano Y, Moschetta M, Manier S, et al. Targeting the bone marrow microenvironment in multiple myeloma. Immunol Rev. 2015;263:160–172.
   PubMed Web of Science ®Google Scholar
• Leblay N, Maity R, Hasan F, et al. Deregulation of adaptive T cell immunity in multiple myeloma: insights into mechanisms and therapeutic opportunities. Front Oncol. 2020;10:636.
   PubMed Web of Science ®Google Scholar
• Suen H, Brown R, Yang S, et al. Multiple myeloma causes clonal T-cell immunosenescence: identification of potential novel targets for promoting tumour immunity and implications for checkpoint blockade. Leukemia. 2016;30(8): 1716–1724
   PubMed Web of Science ®Google Scholar
• Dhodapkar MV, Krasovsky J, Olson K. T cells from the tumor microenvironment of patients with progressive myeloma can generate strong, tumor-specific cytolytic responses to autologous, tumor-loaded dendritic cells. Proc Natl Acad Sci. 2002;99:13009–13013.
   PubMed Web of Science ®Google Scholar
• El-Sherbiny YM, Meade JL, Holmes TD, et al. The requirement for DNAM-1, NKG2D, and NKp46 in the natural killer cell-mediated killing of myeloma cells. Cancer Res. 2007;67(18):8444–8449.
   PubMed Web of Science ®Google Scholar
• Usmani SZ, Schjesvold F, Oriol A, et al. Pembrolizumab plus lenalidomide and dexamethasone for patients with treatment-naive multiple myeloma (KEYNOTE-185): a randomised, open-label, phase 3 trial. Lancet Haematol. 2019;6(9):e448–e458.
   PubMed Web of Science ®Google Scholar
• Mateos MV, Blacklock H, Schjesvold F, et al. Pembrolizumab plus pomalidomide and dexamethasone for patients with relapsed or refractory multiple myeloma (KEYNOTE-183): a randomised, open-label, phase 3 trial. Lancet Haematol. 2019;6(9):e459–e469.
   PubMed Web of Science ®Google Scholar
• Leblay N, Maity R, Barakat E, et al. Cite-Seq profiling of T cells in multiple myeloma patients undergoing BCMA targeting CAR-T or bites immunotherapy. Myeloma. 2020;651. doi:10.1182/blood-2020-137650
   Google Scholar
• Fujisaki J, Wu J, Carlson AL, et al. In vivo imaging of treg cells providing immune privilege to the haematopoietic stem-cell niche. Nature. 2011;474(7350):216–219.
   PubMed Web of Science ®Google Scholar
• Foglietta M, Castella B, Mariani S, et al. The bone marrow of myeloma patients is steadily inhabited by a normal-sized pool of functional regulatory T cells irrespective of the disease status. Haematologica. 2014;99(10):1605–1610.
   PubMed Web of Science ®Google Scholar
• Dahlhoff J, Manz H, Steinfatt T, et al. Transient regulatory T-cell targeting triggers immune control of multiple myeloma and prevents disease progression. Leukemia. 2021;1–11. doi:10.1038/s41375-021-01422-y
   Web of Science ®Google Scholar
• Krejcik J, Casneuf T, Nijhof IS, et al. Daratumumab depletes CD38+ immune regulatory cells, promotes T-cell expansion, and skews T-cell repertoire in multiple myeloma. Blood. 2016;128(3):384–394.
   PubMed Web of Science ®Google Scholar
• Long AH, Highfill SL, Cui Y, et al. Reduction of MDSCs with all-trans retinoic acid improves CAR therapy efficacy for sarcomas. Cancer Immunol Res. 2016;4(10):869–880.
   PubMed Web of Science ®Google Scholar
• Iclozan C, Antonia S, Chiappori A, et al. Therapeutic regulation of myeloid-derived suppressor cells and immune response to cancer vaccine in patients with extensive stage small cell lung cancer. Cancer Immunol Immunother. 2013;62(5):909–918.
   PubMed Web of Science ®Google Scholar
• Gandhi AK, Kang J, Havens CG, et al. Immunomodulatory agents lenalidomide and pomalidomide co-stimulate T cells by inducing degradation of T cell repressors I karos and A iolos via modulation of the E 3 ubiquitin ligase complex CRL 4 CRBN. Br J Haematol. 2014;164(6):811–821.
   PubMed Web of Science ®Google Scholar
• Mei H, Li C, Jiang H, et al. A bispecific CAR-T cell therapy targeting BCMA and CD38 in relapsed or refractory multiple myeloma. J Hematol Oncol. 2021;14(1):1–17.
   PubMed Web of Science ®Google Scholar
• Nalawade SA, Shafer P, Bajgain P, et al. Selectively targeting myeloid-derived suppressor cells through TRAIL receptor 2 to enhance the efficacy of CAR T cell therapy for treatment of breast cancer. J Immunother Cancer. 2021;9(11):e003237.
   PubMed Web of Science ®Google Scholar
• Yeku OO, Brentjens RJ. Armored CAR T-cells: utilizing cytokines and pro-inflammatory ligands to enhance CAR T-cell anti-tumour efficacy. Biochem Soc Trans. 2016;44(2):412–418.
   PubMedGoogle Scholar
• Xu J, Chen LJ, Yang SS, et al. Exploratory trial of a biepitopic CAR T-targeting B cell maturation antigen in relapsed/refractory multiple myeloma. PNAS USA. 2019;116. 9543–9551.
   PubMed Web of Science ®Google Scholar
• Samur MK, Fulciniti M, Aktas Samur A, et al. Biallelic loss of BCMA as a resistance mechanism to CAR T cell therapy in a patient with multiple myeloma. Nat Commun. 2021;12(1):1–7.
   PubMed Web of Science ®Google Scholar
• da Vià MC, Dietrich O, Truger M, et al. Homozygous BCMA gene deletion in response to anti-BCMA CAR T cells in a patient with multiple myeloma. Nat Med. 2021;27(4):616–619.
   PubMed Web of Science ®Google Scholar
• Martin N, Thompson E, Dell’Aringa J, et al. Correlation of tumor BCMA expression with response and acquired resistance to idecabtagene vicleucel in the KarMMa study in relapsed and refractory multiple myeloma. HemaSphere. 2020;4:985.
   Google Scholar
• Chen H, Li M, Xu N, et al. Serum B-cell maturation antigen (BCMA) reduces binding of anti-BCMA antibody to multiple myeloma cells. Leuk Res. 2019;81:62–66.
   PubMed Web of Science ®Google Scholar
• Visram A, Dasari S, Anderson E, et al. Relapsed multiple myeloma demonstrates distinct patterns of immune microenvironment and malignant cell-mediated immunosuppression. Blood Cancer J. 2021;11(3):1–10.
   PubMed Web of Science ®Google Scholar
• Vuckovic S, Minnie SA, Smith D, et al. Bone marrow transplantation generates T cell–dependent control of myeloma in mice. J Clin Invest. 2019;129(1):106–121.
   PubMed Web of Science ®Google Scholar
• Gazeau N, Beauvais D, Yakoub-Agha I, et al. Effective anti-BCMA retreatment in multiple myeloma. Blood Adv. 2021;5(15):3016–3020.
   PubMed Web of Science ®Google Scholar
• Mailankody S, Matous JV, Liedtke M, et al. Universal: an allogeneic first-in-human study of the anti-Bcma ALLO-715 and the anti-CD52 ALLO-647 in relapsed/refractory multiple myeloma. Blood. 2020;136(Supplement 1):24–25.
   PubMedGoogle Scholar