Safety and efficacy of belantamab mafodotin with pembrolizumab in patients with relapsed or refractory multiple myeloma.
belantamab mafodotin
benefit‐risk profile
dose‐escalation
dose‐expansion
pembrolizumab
refractory multiple myeloma
safety
Journal
Cancer
ISSN: 1097-0142
Titre abrégé: Cancer
Pays: United States
ID NLM: 0374236
Informations de publication
Date de publication:
17 Apr 2024
17 Apr 2024
Historique:
revised:
27
02
2024
received:
25
10
2023
accepted:
01
03
2024
medline:
17
4
2024
pubmed:
17
4
2024
entrez:
17
4
2024
Statut:
aheadofprint
Résumé
Belantamab mafodotin (belamaf) has shown promising antimyeloma activity in relapsed or refractory multiple myeloma (RRMM) as a single agent. It was hypothesized that its multimodal activity may be enhanced by programmed cell death protein 1 pathway inhibition and activation of T cell-mediated antitumor responses. This study investigated the efficacy and safety of belamaf with pembrolizumab in patients with RRMM. DREAMM-4 (NCT03848845) was an open-label, single-arm, phase 1/2 study divided into dose-escalation (part 1) and dose-expansion (part 2) phases. Patients were ≥18 years old with ≥3 prior lines of therapy including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 agent. Patients received belamaf (2.5 or 3.4 mg/kg, part 1; 2.5 mg/kg, part 2) and 200 mg pembrolizumab for ≤35 cycles. Of 41 enrolled patients, 34 (n = 6 part 1, n = 28 part 2) who received 2.5 mg/kg belamaf plus pembrolizumab were included in this final analysis. Sixteen patients (47%) achieved an overall response. Minimal residual disease negativity was achieved in three of 10 patients who had very good partial response or better. Five of eight patients who had prior anti-B-cell maturation antigen therapy achieved partial response or better, including two who had B-cell maturation antigen-refractory disease. Common grade ≥3 adverse events were keratopathy (38%) and thrombocytopenia (29%). Despite belamaf-related ocular events, quality-of-life measures remained stable over time. No new safety signals were observed. The results of DREAMM-4 demonstrated clinical activity and a favorable safety profile of belamaf plus pembrolizumab in patients with RRMM. This trial is registered at www. gov as NCT03848845.
Sections du résumé
BACKGROUND
BACKGROUND
Belantamab mafodotin (belamaf) has shown promising antimyeloma activity in relapsed or refractory multiple myeloma (RRMM) as a single agent. It was hypothesized that its multimodal activity may be enhanced by programmed cell death protein 1 pathway inhibition and activation of T cell-mediated antitumor responses. This study investigated the efficacy and safety of belamaf with pembrolizumab in patients with RRMM.
METHODS
METHODS
DREAMM-4 (NCT03848845) was an open-label, single-arm, phase 1/2 study divided into dose-escalation (part 1) and dose-expansion (part 2) phases. Patients were ≥18 years old with ≥3 prior lines of therapy including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 agent. Patients received belamaf (2.5 or 3.4 mg/kg, part 1; 2.5 mg/kg, part 2) and 200 mg pembrolizumab for ≤35 cycles.
RESULTS
RESULTS
Of 41 enrolled patients, 34 (n = 6 part 1, n = 28 part 2) who received 2.5 mg/kg belamaf plus pembrolizumab were included in this final analysis. Sixteen patients (47%) achieved an overall response. Minimal residual disease negativity was achieved in three of 10 patients who had very good partial response or better. Five of eight patients who had prior anti-B-cell maturation antigen therapy achieved partial response or better, including two who had B-cell maturation antigen-refractory disease. Common grade ≥3 adverse events were keratopathy (38%) and thrombocytopenia (29%). Despite belamaf-related ocular events, quality-of-life measures remained stable over time. No new safety signals were observed.
CONCLUSIONS
CONCLUSIONS
The results of DREAMM-4 demonstrated clinical activity and a favorable safety profile of belamaf plus pembrolizumab in patients with RRMM. This trial is registered at www.
CLINICALTRIALS
RESULTS
gov as NCT03848845.
Banques de données
ClinicalTrials.gov
['NCT03848845']
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : GlaxoSmithKline
Organisme : Merck Sharp & Dohme
Informations de copyright
© 2024 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.
Références
van de Donk N, Pawlyn C, Yong KL. Multiple myeloma. Lancet. 2021;397(10272):410‐427. doi:10.1016/s0140‐6736(21)00135‐5
Martin T, Jackson CC, Pacaud L, Madduri D, Jagannath S. Recent advances in the use of chimeric antigen receptor‐expressing T‐cell therapies for treatment of multiple myeloma. Clin Lymphoma Myeloma Leuk. 2023;23(1):22‐27. doi:10.1016/j.clml.2022.09.001
Parikh RH, Lonial S. Chimeric antigen receptor T‐cell therapy in multiple myeloma: a comprehensive review of current data and implications for clinical practice. CA Cancer J Clin. 2023;73(3):275‐285. doi:10.3322/caac.21771
Tanenbaum B, Miett T, Patel SA. The emerging therapeutic landscape of relapsed/refractory multiple myeloma. Ann Hematol. 2023;102(1):1‐11. doi:10.1007/s00277‐022‐05058‐5
Stewart AG, Henden AS. Infectious complications of CAR T‐cell therapy: a clinical update. Ther Adv Infect Dis. 2021;8:20499361211036773. doi:10.1177/20499361211036773
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. doi:10.1016/s1470‐2045(19)30788‐0
Trudel S, Lendvai N, Popat R, 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):1641‐1653. doi:10.1016/s1470‐2045(18)30576‐x
Rathi C, Collins J, Struemper H, Opalinska J, Jewell RC, Ferron‐Brady G. Population pharmacokinetics of belantamab mafodotin, a BCMA‐targeting agent in patients with relapsed/refractory multiple myeloma. CPT Pharmacometrics Syst Pharmacol. 2021;10(8):851‐863. doi:10.1002/psp4.12660
Montes de Oca R, Alavi AS, Vitali N, et al. Belantamab mafodotin (GSK2857916) drives immunogenic cell death and immune‐mediated antitumor responses in vivo. Mol Cancer Therapeut. 2021;20(10):1941‐1955. doi:10.1158/1535‐7163.mct‐21‐0035
Lonial S, Lee HC, Badros A, et al. Longer term outcomes with single‐agent belantamab mafodotin in patients with relapsed or refractory multiple myeloma: 13‐month follow‐up from the pivotal DREAMM‐2 study. Cancer. 2021;127(22):4198‐4212. doi:10.1002/cncr.33809
Keytruda (pembrolizumab). Prescribing information. Merck & Co., Inc; 2022. Accessed April 28, 2023. https://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf
Buchbinder EI, Desai A. CTLA‐4 and PD‐1 pathways: similarities, differences, and implications of their inhibition. Am J Clin Oncol. 2016;39(1):98‐106. doi:10.1097/coc.0000000000000239
Lesokhin AM, Ansell SM, Armand P, et al. Preliminary results of a phase I study of nivolumab (BMS‐936558) in patients with relapsed or refractory lymphoid malignancies. Blood. 2014;124(21):291. doi:10.1182/blood.v124.21.291.291
Suen H, Brown R, Yang S, Ho PJ, Gibson J, Joshua D. The failure of immune checkpoint blockade in multiple myeloma with PD‐1 inhibitors in a phase 1 study. Leukemia. 2015;29(7):1621‐1622. doi:10.1038/leu.2015.104
Ribrag V, Avigan DE, Green DJ, et al. Phase 1b trial of pembrolizumab monotherapy for relapsed/refractory multiple myeloma: KEYNOTE‐013. Br J Haematol. 2019;186(3):e41‐e44. doi:10.1111/bjh.15888
Badros A, Hyjek E, Ma N, et al. Pembrolizumab, pomalidomide, and low‐dose dexamethasone for relapsed/refractory multiple myeloma. Blood. 2017;130(10):1189‐1197. doi:10.1182/blood‐2017‐03‐775122
Mateos MV, Orlowski RZ, Ocio EM, et al. Pembrolizumab combined with lenalidomide and low‐dose dexamethasone for relapsed or refractory multiple myeloma: phase I KEYNOTE‐023 study. Br J Haematol. 2019;186(5):e117‐e121. doi:10.1111/bjh.15946
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. doi:10.1016/s2352‐3026(19)30110‐3
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. doi:10.1016/s2352‐3026(19)30109‐7
Iftikhar A, Hassan H, Iftikhar N, et al. Investigational monoclonal antibodies in the treatment of multiple myeloma: a systematic review of agents under clinical development. Antibodies. 2019;8(2):34. doi:10.3390/antib8020034
Jelinek T, Hajek R. PD‐1/PD‐L1 inhibitors in multiple myeloma: the present and the future. OncoImmunology. 2016;5(12):e1254856. doi:10.1080/2162402x.2016.1254856
Kepp O, Kroemer G. A novel platinum‐based chemotherapeutic inducing immunogenic cell death. OncoImmunology. 2020;9(1):1729022. doi:10.1080/2162402x.2020.1729022
Pfirschke C, Engblom C, Rickelt S, et al. Immunogenic chemotherapy sensitizes tumors to checkpoint blockade therapy. Immunity. 2016;44(2):343‐354. doi:10.1016/j.immuni.2015.11.024
Voorwerk L, Slagter M, Horlings HM, et al. Immune induction strategies in metastatic triple‐negative breast cancer to enhance the sensitivity to PD‐1 blockade: the TONIC trial. Nat Med. 2019;25(6):920‐928. doi:10.1038/s41591‐019‐0432‐4
Torres ETR, Emens LA. Emerging combination immunotherapy strategies for breast cancer: dual immune checkpoint modulation, antibody‐drug conjugates and bispecific antibodies. Breast Cancer Res Treat. 2022;191(2):291‐302. doi:10.1007/s10549‐021‐06423‐0
Yi M, Jiao D, Qin S, Chu Q, Wu K, Li A. Synergistic effect of immune checkpoint blockade and anti‐angiogenesis in cancer treatment. Mol Cancer. 2019;18(1):60. doi:10.1186/s12943‐019‐0974‐6
Jelinek T, Paiva B, Hajek R. Update on PD‐1/PD‐L1 inhibitors in multiple myeloma. Front Immunol. 2018;9:2431. doi:10.3389/fimmu.2018.02431
Study evaluating safety, tolerability and clinical activity of GSK2857916 in combination with pembrolizumab in subjects with relapsed/refractory multiple myeloma (RRMM) (DREAMM 4). ClinicalTrials.gov identifier: NCT03848845. Accessed November 3, 2022. https://clinicaltrials.gov/ct2/show/NCT03848845
Kumar S, Paiva B, Anderson KC, et al. International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol. 2016;17(8):e328‐e346. doi:10.1016/s1470‐2045(16)30206‐6
Ji Y, Liu P, Li Y, Bekele BN. A modified toxicity probability interval method for dose‐finding trials. Clin Trials. 2010;7(6):653‐663. doi:10.1177/1740774510382799
Suvannasankha A, Bahlis NJ, Trudel S, et al. Safety and clinical activity of belantamab mafodotin with pembrolizumab in patients with relapsed/refractory multiple myeloma (RRMM): DREAMM‐4 Study. J Clin Oncol. 2022;40(16)(suppl):8018. doi:10.1200/jco.2022.40.16_suppl.8018
Leung NR. Chapter 8: clinical tests for monoclonal proteins. In: Onco‐Nephrology Curriculum. American Society of Nephrology; 2016.
Lee JJ, Liu DD. A predictive probability design for phase II cancer clinical trials. Clin Trials. 2008;5(2):93‐106. doi:10.1177/1740774508089279
Eliason L, Loubert A, Gorsh B, et al. Methodology for evaluating meaningful change thresholds in patient‐reported outcome (PRO) measures for corneal events in patients with relapsed/refractory multiple myeloma (RRMM) receiving single‐agent belantamab mafodotin (belamaf). Value Health. 2020;23:S477. doi:10.1016/j.jval.2020.08.446
Popat R, Lonial S, Voorhees PM, et al. DREAMM‐2: single‐agent belantamab mafodotin (belamaf) effects on patient‐reported outcome (PRO) measures in patients with relapsed/refractory multiple myeloma (RRMM). Blood. 2020;136(Supplement 1):27‐28. doi:10.1182/blood‐2020‐140013
Rosenblatt J, Avigan D. Targeting the PD‐1/PD‐L1 axis in multiple myeloma: a dream or a reality? Blood. 2017;129(3):275‐279. doi:10.1182/blood‐2016‐08‐731885
Nooka AK, Cohen A, Lee HC, et al. Single‐agent belantamab mafodotin in patients with relapsed or refractory multiple myeloma: final analysis of the DREAMM‐2 trial. 64th ASH Annual Meeting and Exposition. Blood. 2022;140(Supplement 1):7301‐7303. Abstract 3246. doi:10.1182/blood‐2022‐164877
Dimopoulos MA, Hungria VTM, Radinoff A, et al. Efficacy and safety of single‐agent belantamab mafodotin versus pomalidomide plus low‐dose dexamethasone in patients with relapsed or refractory multiple myeloma (DREAMM‐3): a phase 3, open‐label, randomised study. Lancet Haematol. 2023;10(10):e801‐e812. doi:10.1016/s2352‐3026(23)00243‐0
Hungria V, Weisel K, Currie B, et al. Patient (pt)‐reported outcomes in pts with relapsed/refractory multiple myeloma (RRMM) treated with belantamab mafodotin (belamaf) vs pomalidomide/low dose dexamethasone (Pd) in the DREAMM‐3 study. Poster presented at EHA 2023. HemaSphere. 2023;7(S3):e35249ae. Abstract P964. doi:10.1097/01.hs9.0000970760.35249.ae
Becnel MR, Lee HC. The role of belantamab mafodotin for patients with relapsed and/or refractory multiple myeloma. Ther Adv Hematol. 2020;11:2040620720979813. doi:10.1177/2040620720979813
Rinaldi I, Muthalib A, Edina BC, Wiyono L, Winston K. Role of anti‐B‐cell maturation antigen (BCMA) in the management of multiple myeloma. Cancers (Basel). 2022;14(14):3507. doi:10.3390/cancers14143507
Sanchez E, Gillespie A, Tang G, et al. Soluble B‐cell maturation antigen mediates tumor‐induced immune deficiency in multiple myeloma. Clin Cancer Res. 2016;22(13):3383‐3397. doi:10.1158/1078‐0432.ccr‐15‐2224
Richardson PG, Lee HC, Abdallah AO, et al. Single‐agent belantamab mafodotin for relapsed/refractory multiple myeloma: analysis of the lyophilised presentation cohort from the pivotal DREAMM‐2 study. Blood Cancer J. 2020;10(10):106. doi:10.1038/s41408‐020‐00369‐0
Swan D, Murphy P, Glavey S, Quinn J. Bispecific antibodies in multiple myeloma: opportunities to enhance efficacy and improve safety. Cancers. 2023;15(6):1819. doi:10.3390/cancers15061819
Zhu C, Song Z, Wang A, et al. Isatuximab acts through Fc‐dependent, independent, and direct pathways to kill multiple myeloma cells. Front Immunol. 2020;11:1771. doi:10.3389/fimmu.2020.01771
Tremblay‐LeMay R, Rastgoo N, Chang H. Modulating PD‐L1 expression in multiple myeloma: an alternative strategy to target the PD‐1/PD‐L1 pathway. J Hematol Oncol. 2018;11(1):46. doi:10.1186/s13045‐018‐0589‐1
Suda K, Mitsudomi T. Inter‐tumor heterogeneity of PD‐L1 status: is it important in clinical decision making? J Thorac Dis. 2020;12(5):1770‐1775, doi:10.21037/jtd‐20‐1661
Mateos M‐V, Robak P, Hus M, et al. Results from the randomized phase III DREAMM‐7 study of belantamab mafodotin (belamaf) + bortezomib, and dexamethasone (BVd) vs daratumumab, bortezomib, and dexamethasone (DVd) in relapsed/refractory multiple myeloma (RRMM). J Clin Oncol. 2024;42(36)(suppl):439572. doi:10.1200/jco.2024.42.36_suppl.439572
Trudel S, McCurdy A, Louzada ML, et al. Belantamab mafodotin, pomalidomide and dexamethasone in refractory multiple myeloma: a phase 1/2 trial. Nat Med. 2024;30(2):543‐551. doi:10.1038/s41591‐023‐02703‐y