Remarkable advances have been achieved in the treatment of multiple myeloma (MM) in the last decade, which saw targeted immunotherapy, represented by anti-CD38 monoclonal antibodies, successfully incorporated across indications. However, myeloma is still considered curable in only a small subset of patients, and the majority of them eventually relapse. B-cell maturation antigen (BCMA) is expressed exclusively in mature B lymphocytes and plasma cells, and represents an ideal new target for immunotherapy, presented by bispecific antibody (bsAb) constructs, antibody-drug conjugates (ADCs) and chimeric antigen receptor T (CAR-T) cells. Each of them has proved its efficacy with the potential for deep and long-lasting responses as a single agent therapy in heavily pretreated patients. As a result, belantamab mafodotin was approved by the United States Food and Drug Administration for the treatment of relapsed/refractory MM, as the first anti-BCMA agent. In the present review, we focus on monoclonal antibodies targeting BCMA - bsAbs and ADCs. The data from preclinical studies as well as first-in-human clinical trials will be reviewed, together with the coverage of their constructs and mechanisms of action. The present results have laid the groundwork for the ongoing or upcoming clinical trials with combinatory regimens, which have always been a cornerstone in the treatment of MM.

Department of Haemato oncology University Hospital Ostrava Ostrava Czech Republic

Faculty of Medicine University of Ostrava Ostrava Czech Republic

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Kumar SK, Rajkumar V, Kyle RA, van Duin M, Sonneveld P, Mateos MV, et al. Multiple myeloma. Nat Revi Dis Primer. 2017;3:1-20.

Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69:7-34.

Joseph NS, Kaufman JL, Dhodapkar MV, Hofmeister CC, Almaula DK, Heffner LT, 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;38:1928-37.

Chim CS, Kumar SK, Orlowski RZ, Cook G, Richardson PG, Gertz MA, et al. Management of relapsed and refractory multiple myeloma: novel agents, antibodies, immunotherapies and beyond. Leukemia. 2018;32:252-62.

Munshi NC, Avet-Loiseau H, Rawstron AC, Owen RG, Child JA, Thakurta A, et al. Association of minimal residual disease with superior survival outcomes in patients with multiple myeloma: a meta-analysis. JAMA Oncol. 2017;3:28-35.

Walker BA, Mavrommatis K, Wardell CP, Ashby TC, Bauer M, Davies FE, et al. Identification of novel mutational drivers reveals oncogene dependencies in multiple myeloma. Blood. 2018;132:587-97.

Chakraborty R, Muchtar E, Kumar SK, Jevremovic D, Buadi FK, Dingli D, et al. Impact of post-transplant response and minimal residual disease on survival in myeloma with high-risk cytogenetics. Biol Blood Marrow Transplant. 2017;23:598-605.

Walker BA, Mavrommatis K, Wardell CP, Ashby TC, Bauer M, Davies F, et al. A high-risk, Double-Hit, group of newly diagnosed myeloma identified by genomic analysis. Leukemia. 2019;33:159-70.

Paiva B, Puig N, Cedena MT, Rosiñol L, Cordón L, Vidriales MB, et al. Measurable residual disease by next-generation flow cytometry in multiple myeloma. J Clin Oncol. 2020;38:784-92.

Dougan M, Dranoff G, Dougan SK. Cancer immunotherapy: beyond checkpoint blockade. Annu Rev Cancer Biol. 2019;3:55-75.

Jelinek T, Mihalyova J, Kascak M, Duras J, Hajek R. PD-1/PD-L1 inhibitors in haematological malignancies: update 2017. Immunology. 2017;152:357-71.

Jelinek T, Paiva B, Hajek R. Update on PD-1/PD-L1 inhibitors in multiple myeloma. Front Immunol. 2018;9:2431.

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.

Lonial S, Dimopoulos M, Palumbo A, White D, Grosicki S, Spicka I, et al. Elotuzumab therapy for relapsed or refractory multiple myeloma. N Engl J Med. 2015;373:621-31.

Sanchez L, Wang Y, Siegel DS, Wang ML. Daratumumab: a first-in-class CD38 monoclonal antibody for the treatment of multiple myeloma. J Hematol Oncol. 2016;9:51.

Moreno L, Perez C, Zabaleta A, Manrique I, Alignani D, Ajona D, et al. The mechanism of action of the anti-CD38 monoclonal antibody isatuximab in multiple myeloma. Clin. Cancer Res. 2019;25:3176-87.

Jelinek T, Hajek R. Monoclonal antibodies - A new era in the treatment of multiple myeloma. Blood Rev. 2016;30:101-10.

Wang Y, Sanchez L, Siegel DS, Wang ML. Elotuzumab for the treatment of multiple myeloma. J Hematol Oncol. 2016;9:55.

Tai Y-T, Anderson KC. Antibody-based therapies in multiple myeloma. Bone Marrow Res. 2011;2011:924058.

Jakubowiak A, Offidani M, Pégourie B, De La Rubia J, Garderet L, Laribi K, et al. Randomized phase 2 study: elotuzumab plus bortezomib/dexamethasone vs bortezomib/dexamethasone for relapsed/refractory MM. Blood. 2016;127:2833-40.

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.

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.

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.

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.

Topp MS, Gökbuget N, Stein AS, Zugmaier G, O’Brien S, Bargou RC, et al. Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study. Lancet Oncol. 2015;16:57-66.

Kantarjian H, Stein A, Gökbuget N, Fielding AK, Schuh AC, Ribera JM, et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med. 2017;376:836-47.

Laâbi Y, Gras MP, Carbonnel F, Brouet JC, Berger R, Larsen CJ, et al. A new gene, BCM, on chromosome 16 is fused to the interleukin 2 gene by a t(4;16)(q26;p13) translocation in a malignant T cell lymphoma. EMBO J. 1992;11:3897-904.

Huang HW, Chen CH, Lin CH, Wong CH, Lin KI. B-cell maturation antigen is modified by a single N-glycan chain that modulates ligand binding and surface retention. Proc Natl Acad Sci USA. 2013;110:10928-33.

Madry C, Laabi Y, Callebaut I, Roussel J, Hatzoglou A, Le Coniat M, et al. The characterization of murine BCMA gene defines it as a new member of the tumor necrosis factor receptor superfamily. Int Immunol. 1998;10:1693-702.

Avery DT, Kalled SL, Ellyard JI, Ambrose C, Bixler SA, Thien M, et al. BAFF selectively enhances the survival of plasmablasts generated from human memory B cells. J Clin Investig. 2003;112:286-97.

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.

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.

O’Connor BP, Raman VS, Erickson LD, Cook WJ, Weaver LK, Ahonen C, et al. BCMA is essential for the survival of long-lived bone marrow plasma cells. J Exp Med. 2004;199:91-8.

Day ES, Cachero TG, Qian F, Sun Y, Wen D, Pelletier M, et al. Selectivity of BAFF/BLyS and APRIL for Binding to the TNF Family Receptors BAFFR/BR3 and BCMA. Biochemistry. 2005;44:1919-31.

Moore PA, Belvedere O, Orr A, Pieri K, LaFleur DW, Feng P, et al. BLyS: member of the tumor necrosis factor family and b lymphocyte stimulator. Science. 1999;285:260-3.

Xu S, Lam KP. 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;21:4067-74.

Bossen C, Schneider P. BAFF, APRIL and their receptors: Structure, function and signaling. Semin Immunol. 2006;18:263-75.

Tai Y-T, Anderson KC. Targeting B-cell maturation antigen in multiple myeloma. Immunotherapy. 2015;7:1187-99.

Tai YT, Li XF, Breitkreutz I, Song W, Neri P, Catley L, et al. Role of B-cell-activating factor in adhesion and growth of human multiple myeloma cells in the bone marrow microenvironment. Can Res. 2006;66:6675-82.

Matthes T, Dunand-Sauthier I, Santiago-Raber ML, Krause KH, Donze O, Passweg J, et al. Production of the plasma-cell survival factor a proliferation-inducing ligand (APRIL) peaks in myeloid precursor cells from human bone marrow. Blood. 2011;118:1838-44.

An G, Acharya C, Feng X, Wen K, Zhong M, Zhang L, et al. Osteoclasts promote immune suppressive microenvironment in multiple myeloma: therapeutic implication. Blood. 2016;128:1590-603.

Bolkun L, Lemancewicz D, Jablonska E, Kulczynska A, Bolkun-Skornicka U, Kloczko J, et al. BAFF and APRIL as TNF superfamily molecules and angiogenesis parallel progression of human multiple myeloma. Ann Hematol. 2014;93:635-44.

Moreaux J, Sprynski AC, Dillon SR, Mahtouk K, Jourdan M, Ythier A, et al. APRIL and TACI interact with syndecan-1 on the surface of multiple myeloma cells to form an essential survival loop. Eur J Haematol. 2009;83:119-29.

Tai YT, Acharya C, An G, Moschetta M, Zhong MY, Feng X, et al. APRIL and BCMA promote human multiple myeloma growth and immunosuppression in the bone marrow microenvironment. Blood. 2016;127:3225-36.

Tai YT, Cho SF, Anderson KC. Osteoclast immunosuppressive effects in multiple myeloma: role of programmed cell death ligand 1. Front Immunol. 2018;9:1822.

Zheng Y, Cai Z, Wang S, Zhang X, Qian J, Hong S, et al. Macrophages are an abundant component of myeloma microenvironment and protect myeloma cells from chemotherapy drug-induced apoptosis. Blood. 2009;114:3625-8.

Laurent SA, Hoffmann FS, Kuhn PH, Cheng Q, Chu Y, Schmidt-Supprian M, et al. γ-secretase directly sheds the survival receptor BCMA from plasma cells. Nat Commun. 2015;6:1-12.

Sanchez E, Gillespie A, Tang G, Ferros M, Harutyunyan NM, Vardanyan S, et al. Soluble B-cell maturation antigen mediates tumor-induced immune deficiency in multiple myeloma. Clin Cancer Res. 2016;22:3383-97.

Sanchez E, Li M, Kitto A, Li J, Wang CS, Kirk DT, et al. Serum B-cell maturation antigen is elevated in multiple myeloma and correlates with disease status and survival. Br J Haematol. 2012;158:727-38.

Jew S, Bujarski S, Soof C, Chen H, Safaie T, Li M, et al. Estimating a normal reference range for serum B-cell maturation antigen levels for multiple myeloma patients. Br J Haematol. 2020 [Online ahead of print]. https://doi.org/10.1111/bjh.16673

Jew SK, Chang T, Bujarski SE, Soof C, Chen H, Safaie T, et al. Normalization of Serum B-Cell Maturation antigen levels from treatment predicts progression free and overall survival in multiple myeloma patients. Blood. 2019;134:4393.

Schwartz RS. Paul Ehrlich’s Magic Bullets. N Engl J Med. 2004;350:1079-80.

Chari RV. Targeted delivery of chemotherapeutics: tumor-activated prodrug therapy. Adv Drug Deliv Rev. 1998;31:89-104.

Chari RV. Targeted cancer therapy: conferring specificity to cytotoxic drugs. Acc Chem Res. 2008;41:98-107.

Tsuchikama K, An Z. Antibody-drug conjugates: recent advances in conjugation and linker chemistries. Protein Cell. 2018;9:33-46.

McCombs JR, Owen SC. Antibody drug conjugates: design and selection of linker, payload and conjugation chemistry. AAPS J. 2015;17:339-51.

Birrer MJ, Moore KN, Betella I, Bates RC. Antibody-drug conjugate-based therapeutics: state of the science. J Natl Cancer Institute. 2019;111:538-49.

Tai YT, Mayes PA, Acharya C, Zhong MY, Cea M, Cagnetta A, et al. Novel anti-B-cell maturation antigen antibody-drug conjugate (GSK2857916) selectively induces killing of multiple myeloma. Blood. 2014;123:3128-38.

Doronina SO, Mendelsohn BA, Bovee TD, Cerveny CG, Alley SC, Meyer DL, et al. Enhanced activity of monomethylauristatin F through monoclonal antibody delivery: effects of linker technology on efficacy and toxicity. Bioconjug Chem. 2006;17:114-24.

Trudel S, Lendvai N, Popat R, Voorhees PM, Reeves B, Libby EN, et al. Targeting B-cell maturation antigen with GSK2857916 antibody-drug conjugate in relapsed or refractory multiple myeloma (BMA117159): a dose escalation and expansion phase 1 trial. Lancet Oncol. 2018;19:1641-53.

Trudel S, Lendvai N, Popat R, Voorhees PM, Reeves B, Libby EN, 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;9:1-10.

Eaton JS, Miller PE, Mannis MJ, Murphy CJ. Ocular adverse events associated with antibody-drug conjugates in human clinical trials. J Ocul Pharmacol Ther. 2015;31:589-604.

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.

Lonial S, Lee HC, Badros A, Trudel S, Nooka AK, Chari A, 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). J Clin Oncol. 2020;38(15_suppl):8536. Presented at the 2020 ASCO Annual Meeting, 29 May 2020; online access.

United States Food and Drug Administration (FDA). FDA granted accelerated approval to belantamab mafodotin-blmf for multiple myeloma; 2020. FDA Available at: https://www.fda.gov/drugs/drug-approvals-and-databases/fda-granted-accelerated-approval-belantamab-mafodotin-blmf-multiple-myeloma

Lee HC, Cohen AD, Chari A, Hultcrantz M, Nooka AK, Callander NS, et al. DREAMM-2: Single-agent belantamab mafodotin (GSK2857916) in patients with relapsed/refractory multiple myeloma (RRMM) and renal impairment. J Clin Oncol. 2020;38(15_suppl):8519. Presented at the 2020 ASCO Annual Meeting, 29 May 2020; online access.

Cohen AD, Trudel S, Lonial S, Libby EN, Lee HC, Besemer B, et al. DREAMM-2: Single-agent belantamab mafodotin (GSK2857916) in patients with relapsed/refractory multiple myeloma (RRMM) and high-risk (HR) cytogenetics. J Clin Oncol. 2020;38(15_suppl):8541. Presented at the 2020 ASCO Annual Meeting, 29 May 2020; online access.

Lonial S, Lee HC, Badros A, Trudel S, Nooka AK, Chari A, et al. DREAMM-2: Sinlge-agent belantamab mafodotin in patients with relapsed/refractory multiple myeloma (RRMM) - outcomes by prior therapies. Abstract #EP937; 2020. Presented at the 2020 EHA Annual Meeting, 12 June 2020; online access.

Trudel S, McCurdy A, Louzada M, Sutherland H, White D, Venner C, et al. A phase 2 study of belantamab mafodotin (GSK2857916) in combination with pomalidomide and dexamethasone in relapsed/refractory multiple myeloma (RRMM): results for part 1 dose finding, Abstract #EP934; 2020. Presented at the 2020 EHA Annual Meeting, 12 June 2020; online access.

Nooka AK, Manteca MVM, Bahlis N, Weisel K, Oriol A, Alonso AA, et al. DREAMM-4: Evaluating safety and clinical activity of belantamab mafodotin in combination with pembrolizumab in patients with relapsed/refractory multiple myeloma (RRMM), Abstract #EP955; 2020. Presented at the 2020 EHA Annual Meeting, 12 June 2020; online access.

Popat R, Stockerl-Goldstein K, Quach H, Forbes A, Mateos MV, Khot A, et al. DREAMM-6: Safety and tolerability of belantamab mafodotin in combination with bortezomib/dexamethasone in relapsed/refractory multiple myeloma (RRMM). J Clin Oncol. 2020;38:8502.

Shragai T, Gatt M, Jarchowsky O, Lavi N, Hertzog-Tzarfaty K, Tadmor T, et al. Real-world outcomes of belantamab mafodotin treatment for patients with relapsed/refractory myeloma via GSK expanded access program, Abstract #EP1002; 2020. Presented at the 2020 EHA Annual Meeting, 12 June 2020; online access.

O’Donnell EK, Raje NS. New monoclonal antibodies on the horizon in multiple myeloma. Therap Adv Hematol. 2016;8:41-53.

Lee HC, Raje NS, Landgren O, Upreti VV, Wang J, Avilion AA, et al. Phase 1 study of the anti-BCMA antibody-drug conjugate AMG 224 in patients with relapsed/refractory multiple myeloma. Leukemia. 2020 [Online ahead of print]. https://doi.org/10.1038/s41375-020-0834-9

Leimgruber W, Stefanović V, Schenker F, Karr A, Berger J. Isolation and characterization of anthramycin, a new antitumor antibiotic. J Am Chem Soc. 1965;87:5791-3.

Tendler MD, Korman S. ‘Refuin’: a Non-cytotoxic Carcinostatic Compound proliferated by a Thermophilic Actinomycete. Nature. 1963;199:501.

Cipolla L, Araujo AC, Bini CA. Pyrrolo[2,1-c][1,4]benzodiazepine as a scaffold for the design and synthesis of anti- tumour drugs. Anticancer Agents Med Chem. 2008;9:1-31.

Tiberghien AC, Levy JN, Masterson LA, Patel NV, Adams LR, Corbett S, et al. Design and synthesis of tesirine, a clinical antibody-drug conjugate pyrrolobenzodiazepine dimer payload. ACS Med Chem Lett. 2016;7:983-7.

Kinneer K, Flynn M, Thomas SB, Meekin J, Varkey R, Xiao X, et al. Preclinical assessment of an antibody-PBD conjugate that targets BCMA on multiple myeloma and myeloma progenitor cells. Leukemia. 2019;33:766-71.

Xing L, Lin L, Yu T, Li Y, Cho SF, Liu J, et al. A novel BCMA PBD-ADC with ATM/ATR/WEE1 inhibitors or bortezomib induce synergistic lethality in multiple myeloma. Leukemia. 2020;34:2150-62.

Morgensztern D, Besse B, Greillier L, Santana-Davila R, Ready N, Hann CL, et al. Efficacy and safety of rovalpituzumab tesirine in third-line and beyond patients with DLL3-expressing, relapsed/refractory small-cell lung cancer: results from the Phase II TRINITY Study. Clin Cancer Res. 2019;25:6958-66.

Kahl BS, Hamadani M, Radford J, Carlo-Stella C, Caimi P, Reid E, et al. A Phase I Study of ADCT-402 (Loncastuximab Tesirine), a Novel Pyrrolobenzodiazepine-Based Antibody-Drug Conjugate, in Relapsed/Refractory B-Cell Non-Hodgkin Lymphoma. Clin Cancer Res. 2019;25:6986-94.

Matinkhoo K, Pryyma A, Todorovic M, Patrick BO, Perrin DM. Synthesis of the Death-Cap Mushroom Toxin α-Amanitin. J Am Chem Soc. 2018;140:6513-7.

Pahl A, Lutz C, Hechler T. Amanitins and their development as a payload for antibody-drug conjugates. Drug Discov Today Technol. 2018;30:85-9.

Ko J, Breunig C, Figueroa V, Lehners N, Baumann A, Pálfi A, et al. Preclinical evaluation of Hdp-101, a novel anti-BCMA antibody-drug conjugate, in multiple myeloma. Blood. 2017;130:3070.

Singh RK, Jones RJ, Shirazi F, Hong S, Wang H, Wan J, et al. HDP-101, a novel BCMA-targeted antibody conjugated to α-amanitin, is active against myeloma with preferential efficacy against pre-clinical models of deletion 17p. Clin Lymphoma Myeloma Leuk. 2019;19:e152.

Liu Y, Zhang X, Han C, Wan G, Huang X, Ivan C, et al. TP53 loss creates therapeutic vulnerability in colorectal cancer. Nature. 2015;520:697-701.

Epps HV, Anderson M, Yu C, Klussman K, Westendorf L, Carosino C, et al. SEA-BCMA: a highly active enhanced antibody for multiple myeloma. Cancer Res. 2018;78:3833.

Labrijn AF, Janmaat ML, Reichert JM, Parren PW. Bispecific antibodies: a mechanistic review of the pipeline. Nat Rev Drug Discov. 2019;18:585-608.

Suurs FV, Lub-de Hooge MN, de Vries EGE, de Groot DJA. A review of bispecific antibodies and antibody constructs in oncology and clinical challenges. Pharmacol Ther. 2019;201:103-19.

Baeuerle PA, Reinhardt C. Bispecific T-cell engaging antibodies for cancer therapy. Cancer Res. 2009;69:4941-4.

Stieglmaier J, Benjamin J, Nagorsen D. Utilizing the BiTE (bispecific T-cell engager) platform for immunotherapy of cancer. Exp Opin Biol Ther. 2015;15:1093-9.

Offner S, Hofmeister R, Romaniuk A, Kufer P, Baeuerle PA. Induction of regular cytolytic T cell synapses by bispecific single-chain antibody constructs on MHC class I-negative tumor cells. Mol Immunol. 2006;43:763-71.

Shimabukuro-Vornhagen A, Gödel P, Subklewe M, Stemmler HJ, Schlößer HA, Schlaak M, et al. Cytokine release syndrome. J ImmunoTher Cancer. 2018;6:56.

Hipp S, Tai YT, Blanset D, Deegen P, Wahl J, Thomas O, 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;31:1743-51.

Topp MS, Duell J, Zugmaier G, Attal M, Moreau P, Langer C, et al. Anti-B-Cell Maturation Antigen BiTE Molecule AMG 420 Induces Responses in Multiple Myeloma. J Clin Oncol. 2020;38:775-83.

Goyos A, Li CM, Deegen P, Bogner P, Thomas O, Wahl J, et al. Abstract LB-299: Cynomolgus monkey plasma cell gene signature to quantify the in vivo activity of a half-life extended anti-BCMA BiTE® for the treatment of multiple myeloma. Cancer Res. 2018;78:LB-299.

Cho SF, Lin L, Xing L, Wen K, Yu T, Hsieh PA, et al. AMG 701 Potently Induces Anti-Multiple Myeloma (MM) Functions of T Cells and IMiDs Further Enhance Its Efficacy to Prevent MM Relapse In Vivo. Blood. 2019;134(Suppl):135.

Seckinger A, Delgado JA, Moser S, Moreno L, Neuber B, Grab A, et al. Target Expression, Generation, Preclinical Activity, and Pharmacokinetics of the BCMA-T Cell Bispecific Antibody EM801 for Multiple Myeloma Treatment. Cancer Cell. 2017;31:396-410.

Costa LJ, Wong SW, Bermúdez A, de la Rubia J, Mateos M-V, Ocio EM, et al. First Clinical Study 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(Suppl 1):143. Presented at the 2019 ASH Annual Meeting, 7 December 2019; Orlando, FL.

Panowski SH, Kuo T, Chen A, Geng T, Van Blarcom TJ, Lindquist K, et al. Preclinical Evaluation of a Potent Anti-Bcma CD3 Bispecific Molecule for the Treatment of Multiple Myeloma. Blood. 2016;128:383.

Lesokhin AM, Raje N, Gasparetto CJ, Walker J, Krupka HI, Joh T, et al. A Phase I, Open-Label Study to Evaluate the Safety, Pharmacokinetic, Pharmacodynamic, and Clinical Activity of PF-06863135, a B-Cell Maturation Antigen/CD3 Bispecific Antibody, in Patients with Relapsed/Refractory Advanced Multiple Myeloma. Blood. 2018;132:3229.

Raje NS, Jakubowiak A, Gasparetto C, Cornell RF, Krupka HI, Navarro D, et al. Safety, Clinical Activity, Pharmacokinetics, and Pharmacodynamics from a Phase I Study of PF-06863135, a B-Cell Maturation Antigen (BCMA)-CD3 Bispecific Antibody, in Patients with Relapsed/Refractory Multiple Myeloma (RRMM). Blood. 2019;134(Suppl 1):1869.

Gramer MJ, van den Bremer ET, van Kampen MD, Kundu A, Kopfmann P, Etter E, et al. Production of stable bispecific IgG1 by controlled Fab-arm exchange. mAbs. 2013;5:962-73.

Labrijn AF, Meesters JI, Priem P, de Jong RN, van den Bremer ET, van Kampen MD, et al. Controlled Fab-arm exchange for the generation of stable bispecific IgG1. Nat Protoc. 2014;9:2450-63.

Labrijn AF, Meesters JI, de Goeij BE, van den Bremer ET, Neijssen J, van Kampen MD, et al. Efficient generation of stable bispecific IgG1 by controlled Fab-arm exchange. Proc Natl Acad Sci USA. 2013;110:5145-50.

Usmani SZ, Mateos MV, Nahi H, Krishnan AY, van de Donk NW, San Miguel J, et al. Phase I study of teclistamab, a humanized B-cell maturation antigen (BCMA) x CD3 bispecific antibody, in relapsed/refractory multiple myeloma (R/R MM). J Clin Oncol. 2020;38(Suppl):100.

Smith EL, Harrington K, Staehr M, Masakayan R, Jones J, Long TJ, et al. GPRC5D is a target for the immunotherapy of multiple myeloma with rationally designed CAR T cells. Sci Transl Med. 2019;11:eaau7746.

Dilillo DJ, Olson K, Mohrs K, Meagher TC, Bray K, Sineshchekova O, et al. REGN5458, a Bispecific BCMAxCD3 T Cell Engaging Antibody, Demonstrates Robust In Vitro and In Vivo Anti-Tumor Efficacy in Multiple Myeloma Models, Comparable to That of BCMA CAR T Cells. Blood. 2018;132 (Suppl 1):1944.

Cooper D, Madduri D, Lentzsch S, Jagannath S, Li J, Boyapati A, et al. Safety and Preliminary Clinical Activity of REGN5458, an Anti-Bcma x Anti-CD3 Bispecific Antibody, in Patients with Relapsed/Refractory Multiple Myeloma. Blood. 2019;134 (Suppl 1):3176.

Buelow B, Pham D, Clarke S, Force Aldred S, Dang K, Pratap P, et al. Development of a fully human T cell engaging bispecific antibody for the treatment of multiple myeloma. J Clin Oncol. 2017;35 (Suppl):8017.

Buelow B, Choudry P, Clarke S, Dang K, Davison L, Force Aldred S, et al. Pre-clinical development of TNB-383B, a fully human T-cell engaging bispecific antibody targeting BCMA for the treatment of multiple myeloma. J Clin Oncol. 2018;36 (Suppl):8034.

Popat R, Warcel D, O’Nions J, Cowley A, Smith S, Tucker WR, 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:e261-3.

Stein AS, Schiller G, Benjamin R, Jia C, Zhang A, Zhu M, et al. Neurologic adverse events in patients with relapsed/refractory acute lymphoblastic leukemia treated with blinatumomab: management and mitigating factors. Ann Hematol. 2019;98:159-67.

Benkova K, Mihalyova J, Hajek R, Jelinek T. Selinexor, selective inhibitor of nuclear export: Unselective bullet for blood cancers. Blood Rev. 2020;100758.

Jelinek T. Venetoclax: the first anti-myeloma agent with a reliable biomarker. Br J Haematol. 2020;189:1003-5.

Frerichs KA, Broekmans ME, Soto JA, van Kessel B, Heymans MW, Holthof LC, et al. Preclinical Activity of JNJ-7957, a Novel BCMA×CD3 Bispecific Antibody for the Treatment of Multiple Myeloma, Is Potentiated by Daratumumab. Clin Cancer Res. 2020;26:2203-15.

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;36:2267-80.

Cohen AD, Garfall AL, Stadtmauer EA, Melenhorst JJ, Lacey SF, Lancaster E, et al. B cell maturation antigen-specific CAR T cells are clinically active in multiple myeloma. J Clin Investig. 2019;129:2210-21.

Raje N, Berdeja J, Lin Y, Siegel D, Jagannath S, Madduri D, et al. Anti-BCMA CAR T-Cell Therapy bb2121 in Relapsed or Refractory Multiple Myeloma. N Engl J Med. 2019;380:1726-37.

Xu J, Chen LJ, Yang SS, Sun Y, Wu W, Liu YF, et al. Exploratory trial of a biepitopic CAR T-targeting B cell maturation antigen in relapsed/refractory multiple myeloma. Proc Natl Acad Sci USA. 2019;116:9543-51.

Zhao WH, Liu J, Wang BY, Chen YX, Cao XM, Yang 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;11:141.

Promising Immunotherapeutic Modalities for B-Cell Lymphoproliferative Disorders

Monoclonal Antibodies and Antibody Drug Conjugates in Multiple Myeloma