Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Journal of Hematology & Oncology
Published in: Journal of Hematology & Oncology 1/2021

01-12-2021 | Multiple Myeloma | Review

Emerging therapies for relapsed/refractory multiple myeloma: CAR-T and beyond

Authors: Christopher T. Su, J. Christine Ye

Published in: Journal of Hematology & Oncology | Issue 1/2021

Login to get access

Abstract

The pace of innovation of multiple myeloma therapy in recent years is remarkable with the advent of monoclonal antibodies and the approval of novel agents with new mechanisms of action. Emerging therapies are on the horizon for clinical approval with significant implications in extending patient survival and advancing closer to the goal of a cure, especially in areas of immunotherapy such as chimeric antigen receptor T cells, bispecific T cell engager antibodies, antibody drug conjugates, newer generations of monoclonal antibodies, and small molecule inhibitor and modulators. This review provides an update of current myeloma therapeutics in active preclinical and early clinical development and discusses the mechanism of action of several classes of novel therapeutics.
Literature
1.
Mikhael J, Ismaila N, Cheung MC, Costello C, Dhodapkar MV, Kumar S, Lacy M, Lipe B, Little RF, Nikonova A, et al. Treatment of multiple myeloma: ASCO and CCO joint clinical practice guideline. J Clin Oncol. 2019;37(14):1228–63.PubMedCrossRef
2.
van Beurden-Tan CHY, Franken MG, Blommestein HM, Uyl-de Groot CA, Sonneveld P. Systematic literature review and network meta-analysis of treatment outcomes in relapsed and/or refractory multiple myeloma. J Clin Oncol. 2017;35(12):1312–9.PubMedCrossRef
3.
4.
5.
Lonial S, Lee HC, Badros A, Trudel S, Nooka AK, Chari A, Abdallah AO, Callander N, Lendvai N, Sborov D, 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):207–21.PubMedCrossRef
6.
Munshi NC, Anderson LD, Shah N, Madduri D, Berdeja J, Lonial S, Raje N, Lin Y, Siegel D, Oriol A, et al. Idecabtagene vicleucel in relapsed and refractory multiple myeloma. N Engl J Med. 2021;384(8):705–16.PubMedCrossRef
7.
Madduri D, Berdeja JG, Usmani SZ, Jakubowiak A, Agha M, Cohen AD, Stewart AK, Hari P, Htut M, O’Donnell E, 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. Blood. 2020;136(Supplement 1):22–5.CrossRef
8.
Alsina M, Shah N, Raje NS, Jagannath S, Madduri D, Kaufman JL, Siegel DS, Munshi NC, Rosenblatt J, Lin Y, 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):25–6.CrossRef
9.
Nishihori T, Kaufman JL, Hoffman JE, Blouch K, Pandit S, Butler E, Jain A, Wu Y, DeYoung MP, Hasan AN, et al. Open-label pilot study of genetically engineered NY-ESO-1 specific T cells (GSK3377794) alone or in combination with pembrolizumab in relapsed and refractory multiple myeloma. Blood. 2019;134(Supplement_1):3134–3134.CrossRef
10.
Jiang H, Dong B, Gao L, Liu L, Ge J, He A, Du J Jr, Li L, Lu J, Chen X, et al. Clinical results of a multicenter study of the first-in-human dual BCMA and CD19 targeted novel platform fast CAR-T cell therapy for patients with relapsed/refractory multiple myeloma. Blood. 2020;136(Supplement 1):25–6.
11.
Li C, Mei H, Hu Y, Guo T, Liu L, Jiang H, Tang L, Wu Y, Ai L, Deng J, et al. A bispecific CAR-T cell therapy targeting Bcma and CD38 for relapsed/refractory multiple myeloma: updated results from a phase 1 dose-climbing trial. Blood. 2019;134(Supplement_1):930–930.CrossRef
12.
Mailankody S, Matous JV, Liedtke M, Sidana S, Malik S, Nath R, Oluwole OO, Karski EE, Lovelace W, Zhou X, 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):24–5.CrossRef
13.
Garfall AL, Usmani SZ, Mateos M-V, Nahi H, van de Donk NWCJ, San-Miguel JF, Oriol Rocafiguera A, Rosinol L, Chari A, Bhutani M, et al. Updated phase 1 results of teclistamab, a B-cell maturation antigen (BCMA) x CD3 bispecific antibody, in relapsed and/or refractory multiple myeloma (RRMM). Blood. 2020;136(Supplement 1):27–27.CrossRef
14.
Costa LJ, Wong SW, Bermúdez A, de la Rubia J, Mateos M-V, Ocio EM, Rodríguez-Otero P, San-Miguel J, Li S, Sarmiento R, 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(Supplement_1):143–143.CrossRef
15.
Lesokhin AM, Levy MY, Dalovisio AP, Bahlis NJ, Solh M, Sebag M, Jakubowiak A, Jethava YS, Costello CL, Chu MP, et al. Preliminary safety, efficacy, pharmacokinetics, and pharmacodynamics of subcutaneously (SC) administered PF-06863135, a B-cell maturation antigen (BCMA)-CD3 bispecific antibody, in patients with relapsed/refractory multiple myeloma (RRMM). Blood. 2020;136(Supplement 1):8–9.CrossRef
16.
Rodriguez C, D’Souza A, Shah N, Voorhees PM, Buelow B, Vij R, Kumar SK. 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):43–4.CrossRef
17.
Madduri D, Rosko A, Brayer J, Zonder J, Bensinger WI, Li J, Xu L, Adriaens L, Chokshi D, Zhang W, 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):41–2.CrossRef
18.
Chari A, Berdeja JG, Oriol A, van de Donk NWCJ, Rodriguez P, Askari E, Mateos M-V, Minnema MC, Verona R, Girgis S, 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 relapsed and/or refractory multiple myeloma (RRMM). Blood. 2020;136(Supplement 1):40–1.CrossRef
19.
Cohen AD, Harrison SJ, Krishnan A, Fonseca R, Forsberg PA, Spencer A, Berdeja JG, Laubach JP, Li M, Choeurng V, et al. Initial clinical activity and safety of BFCR4350A, a FcRH5/CD3 T-cell-engaging bispecific antibody, in relapsed/refractory multiple myeloma. Blood. 2020;136(Supplement 1):42–3.CrossRef
20.
Kumar SK, Migkou M, Bhutani M, Spencer A, Ailawadhi S, Kalff A, Walcott F, Pore N, Gibson D, Wang F, 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):26–7.CrossRef
21.
Kumar SK, Cornell RF, Landgren O, Ailawadhi S, Higgins JP, Willert EK, Waltzman R, Lin J, Zhang Y, Lublinsky AR, et al. A phase 1 first-in-human study of the anti-CD38 dimeric fusion protein TAK-169 for the treatment of patients (pts) with relapsed or refractory multiple myeloma (RRMM) who are proteasome inhibitor (PI)- and immunomodulatory drug (IMiD)-refractory, including Pts relapsed/refractory (R/R) or naïve to daratumumab (dara). Blood. 2019;134(Supplement_1):1867–1867.CrossRef
22.
Krishnan AY, Patel KK, Hari P, Jagannath S, Niesvizky R, Silbermann RW, Berg DT, Li Q, Allikmets K, Stockerl-Goldstein K. A phase Ib study of TAK-079, an investigational anti-CD38 monoclonal antibody (mAb) in patients with relapsed/ refractory multiple myeloma (RRMM): Preliminary results. J Clin Oncol. 2020;38(15_suppl):8539–8539.CrossRef
23.
Vogl DT, Kaufman JL, Holstein SA, Nadeem O, O’Donnell E, Suryanarayan K, Collins S, Parot X, Chaudhry M. TAK-573, an anti-CD38/attenuated Ifnα fusion protein, has clinical activity and modulates the Ifnα receptor (IFNAR) pathway in patients with relapsed/refractory multiple myeloma. Blood. 2020;136(Supplement 1):37–8.CrossRef
24.
Virone-Oddos A, Kassem S, Diallo B, Tang A, Fournier A, El-Murr N, Carrie-Constantin N, Nicolazzi C, Arnould I, Avet-Loiseau H, et al. Abstract 2266: SAR442085, a next generation anti-CD38 antibody with enhanced antibody-dependent cellular cytotoxicity (ADCC) against multiple myeloma. Cancer Res. 2020;80(16 Supplement):2266–2266.
25.
Bahlis N, Baz R, Harrison S, Quach H, Ho S-J, Vangsted AJ, Moreau P, Gibbs S, Salem AH, Ross JA, et al. First analysis from a phase 1/2 study of venetoclax in combination with daratumumab and dexamethasone, +/- Bortezomib, in patients with relapsed/refractory multiple myeloma. Blood. 2019;134(Supplement_1):925–925.CrossRef
26.
Kaufman JL, Gasparetto C, Schjesvold FH, Moreau P, Touzeau C, Facon T, Boise LH, Alzate S, Macartney T, Pesko J, et al. Phase I/II study evaluating the safety and efficacy of venetoclax in combination with dexamethasone as targeted therapy for patients with t(11;14) relapsed/refractory multiple myeloma. Blood. 2019;134(Supplement 1):926–926.CrossRef
27.
Ailawadhi S, Alegria VR, Ahmed S, Laplant B, Manna A, Parrondo R, Roy V, Sher T, Edwards B, Lanier S, et al. Phase I study of a novel Bcl-2 inhibitor, at-101 in combination with lenalidomide and dexamethasone in patients with relapsed and/or refractory multiple myeloma (RRMM). Blood. 2019;134(Supplement_1):3137–3137.CrossRef
28.
Min CK, Kim K, Kim SJ, Yoon DH, Park S-S, Han S. A phase 1, open-label, multi-center study of alteminostat (CKD-581) in combination with lenalidomide and dexamethasone in patients with previously treated multiple myeloma (MM). Blood. 2019;134(Supplement_1):1847–1847.CrossRef
29.
Shang J, Yao W, Yan L, Shi X, Wang R, Yan S, Liu Y, Wu D, Cheng Cheng F. Initial safety and efficacy of dose-escalating HDACs inhibitor chidamide with VRD (Chi-VRD) treatment for newly-diagnosed high-risk transplant eligible multiple myeloma patients. Blood. 2019;134(Supplement_1):1855–1855.CrossRef
30.
van de Donk NWCJ, Popat R, Larsen J, Minnema MC, Jagannath S, Oriol A, Zonder J, Richardson PG, Rodriguez-Otero P, Badros AZ, et al. First results of iberdomide (IBER; CC-220) in combination with dexamethasone (DEX) and daratumumab (DARA) or bortezomib (BORT) in patients with relapsed/refractory multiple myeloma (RRMM). Blood. 2020;136(Supplement 1):16–7.CrossRef
31.
Wong L, Lamba M, Jiménez Nuñez MD, Bauer D, Richardson PG, Bahlis NJ, Vangsted AJ, Ramasamy K, Trudel S, Martínez-Lopez J, et al. Dose- and schedule-dependent immunomodulatory effects of the novel celmod agent CC-92480 in patients with relapsed/refractory multiple myeloma. Blood. 2020;136(Supplement 1):47–8.CrossRef
32.
Schjesvold F, Ribrag V, Rodriguez-Otero P, Robak PJ, Hansson M, Hajek R, Amor AA, Martinez-López J, Onishi M, Gallo JD, et al. Safety and preliminary efficacy results from a phase Ib/II study of cobimetinib as a single agent and in combination with venetoclax with or without atezolizumab in patients with relapsed/refractory multiple myeloma. Blood. 2020;136(Supplement 1):45–6.CrossRef
33.
Raab MS, Giesen N, Scheid C, Besemer B, Miah K, Benner A, Metzler I, Khandanpour C, Seidel-Glaetzer A, Trautmann-Grill K, et al. 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. Blood. 2020;136(Supplement 1):44–5.CrossRef
34.
Ocio EM, Efebera YA, Hájek R, Granell M, Maisnar V, Straub J, Eveillard J-R, Karlin L, Ribrag V, Mateos M-V, et al. ANCHOR (OP-104): melflufen plus dexamethasone (dex) and daratumumab (dara) or bortezomib (BTZ) in relapsed/refractory multiple myeloma (RRMM) refractory to an IMiD and/or a proteasome inhibitor (PI)—updated efficacy and safety. Blood. 2020;136(Supplement 1):9–10.CrossRef
35.
Mateos M-V, Oriol A, Larocca A, Blade J, Cavo M, Otero PR, Leleu X, Hiemenz JW, Hassoun H, Touzeau C, et al. HORIZON (OP-106): An exploratory analysis of time-to-next treatment (TTNT) in patients (pts) with relapsed/refractory multiple myeloma (RRMM) who received melflufen plus dexamethasone (dex). J Clin Oncol. 2020;38(15_suppl):e20570–e20570.CrossRef
36.
Gagelmann N, Riecken K, Wolschke C, Berger C, Ayuk FA, Fehse B, Kröger N. Development of CAR-T cell therapies for multiple myeloma. Leukemia. 2020;34(9):2317–32.PubMedCrossRef
37.
38.
39.
40.
Novak AJ, Darce JR, Arendt BK, Harder B, Henderson K, Kindsvogel W, Gross JA, Greipp PR, Jelinek DF. Expression of BCMA, TACI, and BAFF-R in multiple myeloma: a mechanism for growth and survival. Blood. 2004;103(2):689–94.PubMedCrossRef
41.
42.
Roex G, Timmers M, Wouters K, Campillo-Davo D, Flumens D, Schroyens W, Chu Y, Berneman ZN, Lion E, Luo F, et al. Safety and clinical efficacy of BCMA CAR-T-cell therapy in multiple myeloma. J Hematol Oncol. 2020;13(1):164.PubMedPubMedCentralCrossRef
43.
Carpenter RO, Evbuomwan MO, Pittaluga S, Rose JJ, Raffeld M, Yang S, Gress RE, Hakim FT, Kochenderfer JN. B-cell maturation antigen is a promising target for adoptive T-cell therapy of multiple myeloma. Clin Cancer Res. 2013;19(8):2048–60.PubMedPubMedCentralCrossRef
44.
Wang B-Y, Zhao W-H, Liu J, Chen Y-X, Cao X-M, Yang Y, Zhang Y-L, Wang F-X, Zhang P-Y, Lei B, et al. Long-term follow-up of a phase 1, first-in-human open-label study of LCAR-B38M, a structurally differentiated chimeric antigen receptor T (CAR-T) cell therapy targeting B-cell maturation antigen (BCMA), in patients (pts) with relapsed/refractory multiple myeloma (RRMM). Blood. 2019;134(Supplement_1):579–579.CrossRef
45.
Friedman KM, Garrett TE, Evans JW, Horton HM, Latimer HJ, Seidel SL, Horvath CJ, Morgan RA. Effective targeting of multiple B-cell maturation antigen-expressing hematological malignances by anti-B-cell maturation antigen chimeric antigen receptor T cells. Hum Gene Ther. 2018;29(5):585–601.PubMedPubMedCentralCrossRef
46.
Lin Y, Raje NS, Berdeja JG, Siegel DS, Jagannath S, Madduri D, Liedtke M, Rosenblatt J, Maus MV, Massaro M, et al. Idecabtagene vicleucel (ide-cel, bb2121), a BCMA-directed CAR T cell therapy, in patients with relapsed and refractory multiple myeloma: updated results from phase 1 CRB-401 study. Blood. 2020;136(Supplement 1):26–7.
47.
Timmers M, Roex G, Wang Y, Campillo-Davo D, Van Tendeloo VFI, Chu Y, Berneman ZN, Luo F, Van Acker HH, Anguille S. Chimeric antigen receptor-modified T cell therapy in multiple myeloma: beyond B cell maturation antigen. Front Immunol. 2019;10:1613.PubMedPubMedCentralCrossRef
48.
Thomas R, Al-Khadairi G, Roelands J, Hendrickx W, Dermime S, Bedognetti D, Decock J. NY-ESO-1 based immunotherapy of cancer: current perspectives. Front Immunol. 2018;9:947.PubMedPubMedCentralCrossRef
49.
Rapoport A, Hoffman JE, Kaufman JL, Blouch K, Butler E, Deyoung MP, Farsaci B, Hasan AN, Holmes AP, Huff A, et al. Open-label pilot study of genetically engineered NY-ESO-1–specific t cells (GSK3377794) alone or in combination with pembrolizumab in relapsed/refractory multiple myeloma. J Clin Oncol. 2020;38(15_suppl):TPS8555–TPS8555.CrossRef
50.
Kang L, Zhang J, Li M, Xu N, Qi W, Tan J, Lou X, Yu Z, Sun J, Wang Z, et al. Characterization of novel dual tandem CD19/BCMA chimeric antigen receptor T cells to potentially treat multiple myeloma. Biomark Res. 2020;8:14.PubMedPubMedCentralCrossRef
51.
52.
53.
Metelo AM, Walker I, Jozwik A, Graham C, Attwood C, Sanchez K, Dunlop A, Cuthill K, Rice C, Streetly M, et al. Allogeneic anti-Bcma CAR-T cells show tumour specific killing against primary multiple myeloma cells from different genomic sub-groups. Blood. 2019;134(Supplement_1):1834–1834.CrossRef
54.
Xia AL, He QF, Wang JC, Zhu J, Sha YQ, Sun B, Lu XJ. Applications and advances of CRISPR-Cas9 in cancer immunotherapy. J Med Genet. 2019;56(1):4–9.PubMedCrossRef
55.
Bachanova V, Maakaron J, McKenna DH, Cao Q, DeFor TE, He F, Janakiram M, Wangen R, Cayci Z, Grzywacz B, et al. Results of a phase 1 trial of Gda-201, nicotinamide-expanded allogeneic natural killer (NK) Cells in patients with refractory non-hodgkin lymphoma (NHL) and multiple myeloma. Blood. 2020;136(Supplement 1):6–6.CrossRef
56.
Topp MS, Gökbuget N, Zugmaier G, Klappers P, Stelljes M, Neumann S, Viardot A, Marks R, Diedrich H, Faul C, et al. Phase II trial of the anti-CD19 bispecific T cell-engager blinatumomab shows hematologic and molecular remissions in patients with relapsed or refractory B-precursor acute lymphoblastic leukemia. J Clin Oncol. 2014;32(36):4134–40.PubMedCrossRef
57.
58.
Shah N, Chari A, Scott E, Mezzi K, Usmani SZ. B-cell maturation antigen (BCMA) in multiple myeloma: rationale for targeting and current therapeutic approaches. Leukemia. 2020;34(4):985–1005.PubMedPubMedCentralCrossRef
59.
Trudel S, Lendvai N, Popat R, Voorhees PM, Reeves B, Libby EN, Richardson PG, Anderson LD, Sutherland HJ, Yong K, 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(12):1641–53.PubMedPubMedCentralCrossRef
60.
Sherbenou DW, Aftab BT, Su Y, Behrens CR, Wiita A, Logan AC, Acosta-Alvear D, Hann BC, Walter P, Shuman MA, et al. Antibody-drug conjugate targeting CD46 eliminates multiple myeloma cells. J Clin Investig. 2016;126(12):4640–53.PubMedPubMedCentralCrossRef
61.
Seckinger A, Delgado JA, Moser S, Moreno L, Neuber B, Grab A, Lipp S, Merino J, Prosper F, Emde M, 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.CrossRefPubMed
62.
Smith EL, Harrington K, Staehr M, Masakayan R, Jones J, Long TJ, Ng KY, Ghoddusi M, Purdon TJ, Wang X, et al. GPRC5D is a target for the immunotherapy of multiple myeloma with rationally designed CAR T cells. Sci Transl Med. 2019;11(485):eaau7746.PubMedPubMedCentralCrossRef
63.
Ovacik AM, Li J, Lemper M, Danilenko D, Stagg N, Mathieu M, Ellerman D, Gupta V, Kalia N, Nguy T, et al. Single cell-produced and in vitro-assembled anti-FcRH5/CD3 T-cell dependent bispecific antibodies have similar in vitro and in vivo properties. MAbs. 2019;11(2):422–33.PubMedCrossRef
64.
Beck A, Goetsch L, Dumontet C, Corvaïa N. Strategies and challenges for the next generation of antibody-drug conjugates. Nat Rev Drug Discov. 2017;16(5):315–37.PubMedCrossRef
65.
66.
Chauhan D, Singh AV, Brahmandam M, Carrasco R, Bandi M, Hideshima T, Bianchi G, Podar K, Tai YT, Mitsiades C, et al. Functional interaction of plasmacytoid dendritic cells with multiple myeloma cells: a therapeutic target. Cancer Cell. 2009;16(4):309–23.PubMedPubMedCentralCrossRef
67.
Iberg A, Cornelison GL, Howard C, Robinson GL, Zhao J, Ramos HJ, Willert EK. Abstract 539: novel engineered toxin bodies targeting SLAMF7 (CS1). Cancer Res. 2020;80(16 Supplement):539–539.
68.
Richardson PG, Htut M, Gasparetto C, Zonder JA, Martin TG III, Chen J, Brooks C, McDonald P, Rupprecht N, Wysowskyj H, et al. Results from phase 1/2 trial of tagraxofusp in combination with pomalidomide and dexamethasone in relapsed or refractory multiple myeloma. Blood. 2019;134(Supplement_1):3145–3145.CrossRef
69.
Pemmaraju N, Lane AA, Sweet KL, Stein AS, Vasu S, Blum W, Rizzieri DA, Wang ES, Duvic M, Sloan JM, et al. Tagraxofusp in blastic plasmacytoid dendritic-cell neoplasm. N Engl J Med. 2019;380(17):1628–37.PubMedCrossRef
70.
Strassz A, Raab MS, Orlowski RZ, Kulke M, Schiedner G, Pahl A. A first in human study planned to evaluate Hdp-101, an anti-BCMA amanitin antibody-drug conjugate with a new payload and a new mode of action, in multiple myeloma. Blood. 2020;136(Supplement 1):34–34.CrossRef
71.
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.PubMedCrossRef
72.
Figueroa-Vazquez V, Ko J, Breunig C, Baumann A, Giesen N, Pálfi A, Müller C, Lutz C, Hechler T, Kulke M, et al. HDP-101, anti-BCMA antibody-drug conjugate, safely delivers amanitin to induce cell death in proliferating and resting multiple myeloma cells. Mol Cancer Ther. 2020;20:367–78.PubMedCrossRef
73.
Mateos MV, Dimopoulos MA, Cavo M, Suzuki K, Jakubowiak A, Knop S, Doyen C, Lucio P, Nagy Z, Kaplan P, et al. Daratumumab plus bortezomib, melphalan, and prednisone for untreated myeloma. N Engl J Med. 2018;378(6):518–28.PubMedCrossRef
74.
Fedyk ER, Zhao L, Koch A, Smithson G, Estevam J, Chen G, Lahu G, Roepcke S, Lin J, Mclean L. Safety, tolerability, pharmacokinetics and pharmacodynamics of the anti-CD38 cytolytic antibody TAK-079 in healthy subjects. Br J Clin Pharmacol. 2020;86(7):1314–25.PubMedPubMedCentralCrossRef
75.
Matlung HL, Szilagyi K, Barclay NA, van den Berg TK. The CD47-SIRPα signaling axis as an innate immune checkpoint in cancer. Immunol Rev. 2017;276(1):145–64.PubMedCrossRef
76.
Richards J, Bouchlaka MN, Puro RJ, Capoccia BJ, Hiebsch RR, Donio MJ, Wilson WC, Chakraborty P, Sung V, Pereira DS. Highly differentiated anti-CD47 antibody, AO-176, potently inhibits hematologic malignancies alone and in combination. Blood. 2019;134(Supplement_1):1844–1844.CrossRef
77.
Wilson WC, Richards J, Puro RJ, Andrejeva G, Capoccia BJ, Donio MJ, Hiebsch RR, Chakraborty P, Sung V, Pereira DS. AO-176, a highly differentiated clinical stage anti-CD47 antibody, exerts potent anti-tumor activity in preclinical models of multiple myeloma as a single agent and in combination with approved therapeutics. Blood. 2020;136(Supplement 1):3–4.CrossRef
78.
Chari A, Vogl DT, Gavriatopoulou M, Nooka AK, Yee AJ, Huff CA, Moreau P, Dingli D, Cole C, Lonial S, et al. Oral selinexor-dexamethasone for triple-class refractory multiple myeloma. N Engl J Med. 2019;381(8):727–38.CrossRefPubMed
79.
Kumar S, Kaufman JL, Gasparetto C, Mikhael J, Vij R, Pegourie B, Benboubker L, Facon T, Amiot M, Moreau P, et al. Efficacy of venetoclax as targeted therapy for relapsed/refractory t(11;14) multiple myeloma. Blood. 2017;130(22):2401–9.PubMedCrossRef
80.
Moreau P, Chanan-Khan A, Roberts AW, Agarwal AB, Facon T, Kumar S, Touzeau C, Punnoose EA, Cordero J, Munasinghe W, et al. Promising efficacy and acceptable safety of venetoclax plus bortezomib and dexamethasone in relapsed/refractory MM. Blood. 2017;130(22):2392–400.CrossRefPubMed
81.
Kumar SK, Harrison SJ, Cavo M, de la Rubia J, Popat R, Gasparetto C, Hungria V, Salwender H, Suzuki K, Kim I, 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(12):1630–42.PubMedCrossRef
82.
Kaufman JL, Baz RC, Harrison SJ, Quach H, Ho S-J, Vangsted AJ, Moreau P, Gibbs SD, Salem AH, Coppola S, et al. Updated analysis of a phase I/II study of venetoclax in combination with daratumumab and dexamethasone, +/- bortezomib, in patients with relapsed/refractory multiple myeloma. J Clin Oncol. 2020;38(15_suppl):8511–8511.CrossRef
83.
84.
Caenepeel S, Karen R, Belmontes B, Verlinsky A, Tan H, Yang Y, Chen X, Li K, Allen J, Wahlstrom J, et al. Abstract 6218: Discovery and preclinical evaluation of AMG 397, a potent, selective and orally bioavailable MCL1 inhibitor. Cancer Res. 2020;80(16 Supplement):6218–6218.
85.
Chen J, Wu C, Jiao L, Zhao L, Zhou Y, Li D, Tang G, Gu S, Deng J, Wang G, et al. Abstract 73: development of APG-3526 as a novel and highly efficacious MCL-1 inhibitor. Cancer Res. 2020;80(16 Supplement):73–73.
86.
San-Miguel JF, Hungria VT, Yoon SS, Beksac M, Dimopoulos MA, Elghandour A, Jedrzejczak WW, Günther A, Nakorn TN, Siritanaratkul N, et al. Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double-blind phase 3 trial. Lancet Oncol. 2014;15(11):1195–206.PubMedCrossRef
87.
Cengiz Seval G, Beksac M. A comparative safety review of histone deacetylase inhibitors for the treatment of myeloma. Expert Opin Drug Saf. 2019;18(7):563–71.PubMedCrossRef
88.
Cho H, Yoon DH, Kim KP, Bae KS, Kim WS, Eom HS, Kim JS, Hong JY, Kim SJ, Lee H, et al. Phase I study of CKD-581, a pan-histone deacetylase inhibitor, in patients with lymphoma or multiple myeloma refractory to standard therapy. Investig New Drugs. 2018;36(5):877–85.CrossRef
89.
Shi Y, Jia B, Xu W, Li W, Liu T, Liu P, Zhao W, Zhang H, Sun X, Yang H, et al. Chidamide in relapsed or refractory peripheral T cell lymphoma: a multicenter real-world study in China. J Hematol Oncol. 2017;10(1):69.PubMedPubMedCentralCrossRef
90.
Yuan XG, Huang YR, Yu T, Jiang HW, Xu Y, Zhao XY. Chidamide, a histone deacetylase inhibitor, induces growth arrest and apoptosis in multiple myeloma cells in a caspase-dependent manner. Oncol Lett. 2019;18(1):411–9.PubMedPubMedCentral
91.
Sivanandhan D, Rajagopal S, Nair S, Basavaprabhu B, Dhkar R, Viswakarma S, Siddiqui A, Zainuddin M, Rudresh G, Daram P, et al. Abstract 1756: JBI-802 novel dual inhibitor of LSD1-HDAC6 for treatment of cancer. Cancer Res. 2020;80(16 Supplement):1756–1756.
92.
Li Z, Cheng Y, Shen X, Wang Y. Abstract 513: preclinical evaluation of novel HDAC6 selective inhibitors CVL608 with potent in vitro and in vivo profiles in tumors. Cancer Res. 2020;80(16 Supplement):513–513.
93.
Li Z, Ren Z, Ma J, Tang L, Lu L, Zhu Y, Wu Y, Liu T, Zhang J, Bao Y, et al. Abstract 4441: CS3003, an HDAC6-selective inhibitor, improves anti-PD-1 immune checkpoint blockade therapy efficacy. Cancer Res. 2020;80(16 Supplement):4441–4441.
94.
Chamberlain PP, Hamann LG. Development of targeted protein degradation therapeutics. Nat Chem Biol. 2019;15(10):937–44.PubMedCrossRef
95.
96.
Lonial S, Amatangelo M, Popat R, Minnema MC, Zonder JA, Larsen J, Oriol Rocafiguera A, Campagnaro EL, Rodriguez Otero P, Badros AZ, et al. Translational and clinical evidence of a differentiated profile for the novel CELMoD, iberdomide (CC-220). Blood. 2019;134(Supplement_1):3119–3119.CrossRef
97.
Ge C, Liao B, Zhang L. Abstract 6367: KPG-818, a novel cereblon modulator, inhibits hematological malignancies in preclinical models. Cancer Res. 2020;80(16 Supplement):6367–6367.
98.
Chourasia AH, Fung L, Pasis A, McElwee B, Schoolmeesters A, Richard N, Lam I, Torres E, Erdman P, Sullivan R, et al. Abstract 1963: Targeting hematological malignancies with two functionally and mechanistically distinct classes of cereblon mediated protein homeostatic modulators. Cancer Res. 2020;80(16 Supplement):1963–1963.
99.
Heuck CJ, Jethava Y, Khan R, van Rhee F, Zangari M, Chavan S, Robbins K, Miller SE, Matin A, Mohan M, et al. Inhibiting MEK in MAPK pathway-activated myeloma. Leukemia. 2016;30(4):976–80.CrossRefPubMed
100.
Robiou du Pont S, Cleynen A, Fontan C, Attal M, Munshi N, Corre J, Avet-Loiseau H. Genomics of multiple myeloma. J Clin Oncol. 2017;35(9):963–7.PubMedCrossRef
101.
Packiriswamy N, Upreti D, Zhou Y, Khan R, Miller A, Diaz RM, Rooney CM, Dispenzieri A, Peng KW, Russell SJ. Oncolytic measles virus therapy enhances tumor antigen-specific T-cell responses in patients with multiple myeloma. Leukemia. 2020;34:3310–22.PubMedPubMedCentralCrossRef
102.
Wang H, Huang W, Gao H, Liu TT. NY-ESO-1 Protein vaccine combining alum, CpG ODN, and HH2 complex adjuvant induces protective and therapeutic anti-tumor responses in murine multiple myeloma. Onco Targets Ther. 2020;13:8069–77.PubMedPubMedCentralCrossRef
103.
Bae J, Song W, Smith R, Daley J, Tai YT, Anderson KC, Munshi NC. A novel immunogenic CS1-specific peptide inducing antigen-specific cytotoxic T lymphocytes targeting multiple myeloma. Br J Haematol. 2012;157(6):687–701.PubMedCrossRef
104.
Cook J, Peng K-W, Ginos BF, Dueck AC, Giers M, Packiriswamy N, Brunton B, Patnaik MM, Witzig TE, Buadi FK, et al. Phase I trial of systemic administration of vesicular stomatitis virus genetically engineered to express NIS and human interferon beta, in patients with relapsed or refractory multiple myeloma (MM), acute myeloid leukemia (AML), and T-cell neoplasms (TCL). Blood. 2020;136(Supplement 1):7–8.CrossRef
105.
Perica K, De León MA, Durai M, Chiu YL, Bieler JG, Sibener L, Niemöller M, Assenmacher M, Richter A, Edidin M, et al. Nanoscale artificial antigen presenting cells for T cell immunotherapy. Nanomedicine. 2014;10(1):119–29.PubMedCrossRef
106.
Vallet S, Pecherstorfer M, Podar K. Adoptive cell therapy in multiple Myeloma. Expert Opin Biol Ther. 2017;17(12):1511–22.PubMedCrossRef
107.
Goodridge JP, Bjordahl R, Mahmood S, Reiser J, Gaidarova S, Blum R, Cichocki F, Chu H-Y, Bonello G, Lee T, et al. FT576: multi-specific off-the-shelf CAR-NK cell therapy engineered for enhanced persistence, avoidance of self-fratricide and optimized mab combination therapy to prevent antigenic escape and elicit a deep and durable response in multiple myeloma. Blood. 2020;136(Supplement 1):4–5.CrossRef
108.
Li X, Sun WJ. The clinical activity of arsenic trioxide, ascorbic acid, ifosfamide and prednisone combination therapy in patients with relapsed and refractory multiple myeloma. Onco Targets Ther. 2015;8:775–81.PubMedPubMedCentralCrossRef
109.
Sivaraj D, Green MM, Kang Y, Long GD, Rizzieri DA, Li Z, Garrett AH, McIntyre JL, Chao NJ, Gasparetto C. Bendamustine, pomalidomide, and dexamethasone for relapsed and/or refractory multiple myeloma. Blood Cancer J. 2018;8(8):71.PubMedPubMedCentralCrossRef
110.
Goldsmith SR, Fiala MA, Wang B, Schroeder MA, Wildes TM, Ghobadi A, Stockerl-Goldstein K, Vij R. DCEP and bendamustine/prednisone as salvage therapy for quad- and penta-refractory multiple myeloma. Ann Hematol. 2020;99(5):1041–8.PubMedCrossRef
111.
Leng S, Bhutani D, Raza S, Assal A, Pan S, Hu J, Wei A, Mapara M, Lentzsch S. Phase I/II study of carfilzomib, bendamustine, and dexamethasone (CBD) in patients with newly diagnosed multiple myeloma. Blood Cancer J. 2020;10(2):13.PubMedPubMedCentralCrossRef
112.
Zhou X, Steinhardt MJ, Grathwohl D, Meckel K, Nickel K, Leicht HB, Krummenast F, Einsele H, Rasche L, Kortüm KM. Multiagent therapy with pomalidomide, bortezomib, doxorubicin, dexamethasone, and daratumumab (“Pom-PAD-Dara”) in relapsed/refractory multiple myeloma. Cancer Med. 2020;9:5819–26.PubMedPubMedCentralCrossRef
113.
Wickström M, Nygren P, Larsson R, Harmenberg J, Lindberg J, Sjöberg P, Jerling M, Lehmann F, Richardson P, Anderson K, et al. Melflufen—a peptidase-potentiated alkylating agent in clinical trials. Oncotarget. 2017;8(39):66641–55.PubMedPubMedCentralCrossRef
114.
Slipicevic A, Munawar U, Stühmer T, Aschan J, Lehmann F, Nupponen NN, Miettinen J, Huppunen M-E, Heckman CA, Mateos M-V, et al. Abstract 1843: melflufen efficacy in multiple myeloma with TP53 aberrations. Cancer Res. 2020;80(16 Supplement):1843–1843.
115.
Richardson PG, Oriol A, Larocca A, Bladé J, Cavo M, Rodriguez-Otero P, Leleu X, Nadeem O, Hiemenz JW, Hassoun H, et al. Melflufen and dexamethasone in heavily pretreated relapsed and refractory multiple myeloma. J Clin Oncol. 2021;39(7):757–67.PubMedCrossRef
116.
Heng HH. Chapter 3—genome chaos and macrocellular evolution: how evolutionary cytogenetics unravels the mystery of cancer. In: Heng HH, editor. genome chaos. Cambridge: Academic Press; 2019. p. 95–168.CrossRef
117.
Ye CJ, Sharpe Z, Alemara S, Mackenzie S, Liu G, Abdallah B, Horne S, Regan S, Heng HH. Micronuclei and genome chaos: changing the system inheritance. Genes (Basel). 2019;10(5):366.CrossRef
118.
Lin JK, Muffly LS, Spinner MA, Barnes JI, Owens DK, Goldhaber-Fiebert JD. Cost effectiveness of chimeric antigen receptor T-cell therapy in multiply relapsed or refractory adult large B-cell lymphoma. J Clin Oncol. 2019;37(24):2105–19.PubMedCrossRef
119.
Ho LD, Oso SO, Levine AD. Medical crowdfunding to access CAR T-cell therapy. Lancet Oncol. 2019;20(8):1062–4.PubMedCrossRef
Metadata
Title
Emerging therapies for relapsed/refractory multiple myeloma: CAR-T and beyond
Authors
Christopher T. Su
J. Christine Ye
Publication date
01-12-2021
Publisher
BioMed Central
Published in
Journal of Hematology & Oncology / Issue 1/2021
Electronic ISSN: 1756-8722
DOI
https://doi.org/10.1186/s13045-021-01109-y

Other articles of this Issue 1/2021

Journal of Hematology & Oncology 1/2021 Go to the issue

Letter to the Editor

Multi-dimensional fragmentomic assay for ultrasensitive early detection of colorectal advanced adenoma and adenocarcinoma

Review

MEK inhibitors for the treatment of non-small cell lung cancer

Research

Phase 1 study of M2698, a p70S6K/AKT dual inhibitor, in patients with advanced cancer

Research

Cell-permeable transgelin-2 as a potent therapeutic for dendritic cell-based cancer immunotherapy

Review

Mesenchymal stem/stromal cells in cancer therapy

Letter to the Editor

Bispecific antibody-activated T cells enhance NK cell-mediated antibody-dependent cellular cytotoxicity
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits