TY - JOUR
T1 - Pembrolizumab plus pomalidomide and dexamethasone for patients with relapsed or refractory multiple myeloma (KEYNOTE-183)
T2 - a randomised, open-label, phase 3 trial
AU - KEYNOTE-183 Investigators
AU - Mateos, Maria Victoria
AU - Blacklock, Hilary
AU - Schjesvold, Fredrik
AU - Oriol, Albert
AU - Simpson, David
AU - George, Anupkumar
AU - Goldschmidt, Hartmut
AU - Larocca, Alessandra
AU - Chanan-Khan, Asher
AU - Sherbenou, Daniel
AU - Avivi, Irit
AU - Benyamini, Noam
AU - Iida, Shinsuke
AU - Matsumoto, Morio
AU - Suzuki, Kenshi
AU - Ribrag, Vincent
AU - Usmani, Saad Z.
AU - Jagannath, Sundar
AU - Ocio, Enrique M.
AU - Rodriguez-Otero, Paula
AU - San Miguel, Jesus
AU - Kher, Uma
AU - Farooqui, Mohammed
AU - Liao, Jason
AU - Marinello, Patricia
AU - Lonial, Sagar
AU - Nicol, Andrew
AU - Grigoriadis, George
AU - Catalano, John
AU - LeBlanc, Richard
AU - Elemary, Mohamed
AU - Bahlis, Nizar
AU - Facon, Thierry
AU - Karlin, Lionel
AU - Attal, Michel
AU - Engelhardt, Monika
AU - Weisel, Katja
AU - Mackensen, Andreas
AU - Nagler, Arnon
AU - Ben Yehuda, Dina
AU - Magen-Nativ, Hila
AU - Palumbo, Antonio
AU - Cavo, Michele
AU - Tobinai, Kensei
AU - Chou, Takaai
AU - Kosugi, Hiroshi
AU - Taniwaki, Masafumi
AU - Sunami, Kazutaka
AU - Ando, Kiyoshi
AU - Shah, Jatin
N1 - Funding Information:
Funding for this research was provided by Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, (Kenilworth, NJ, USA). Medical writing and editorial assistance were provided by Luana Atherly-Henderson, of Merck Sharp & Dohme Corp, and Matthew Grzywacz, of the ApotheCom pembrolizumab team (Yardley, PA, USA). This assistance was funded by Merck Sharp & Dohme Corp. We thank the patients and their families and caregivers, all primary investigators and their site personnel, Bethanne Friedmann, Caryn Hampton, Yeliz Kiziltan, Deborah Wolfe, and Michelle Gallion (Merck & Co, Kenilworth, NJ, USA) for clinical study support and Jonathan Cheng (Merck & Co, Kenilworth, NJ, USA) for critical review.
Funding Information:
M-VM reports receiving consulting fees from Amgen, Celgene, Janssen, and Takeda. HB reports receiving consulting fees from Celgene and Janssen. FS reports receiving honoraria from Amgen, Celgene, Takeda, AbbVie, and Janssen; consulting fees from Adaptive, Pfizer, Bristol-Myers Squibb (BMS), Amgen, Celgene, Takeda, and Bayer; research funding from Amgen and Janssen; and reimbursements from Celgene and Amgen. AO reports receiving consulting fees from Amgen, Janssen, and Takeda. DSi reports receiving honoraria from Merck Sharp & Dohme (MSD); honoraria and consulting fees from AbbVie, Celgene, Janssen, and Roche; and research funding from Amgen. AG reports receiving consulting fees and reimbursements from Celgene and Roche. HG reports receiving honoraria from Celgene, Janssen, Novartis, Chugai, BMS, and ArtTempi; consulting fees from Adaptive Biotechnology, Amgen, BMS, Celgene, Janssen, Sanofi, and Takeda; research funding from Amgen, BMS, Celgene, Chugai, Janssen, Sanofi, Takeda, Mundipharma, and Novartis; and reimbursements from Amgen, BMS, Celgene, Janssen, Sanofi, and Takeda. AL reports receiving honoraria from Amgen, BMS, Celgene, and Janssen; and has served on advisory boards for BMS, Celgene, Janssen, and Takeda. SI reports receiving honoraria from Takeda, Ono, Janssen, Celgene, BMS, and Novartis; and consulting fees from Takeda, Ono, Janssen, Sanofi, and MSD. VR reports a consulting or advisory role for Infinity Pharmaceuticals, BMS, Gilead Sciences, NanoString Technologies, Incyte, MSD, Roche/Genentech, Epizyme, immune design; research funding from arGEN-X BVBA; patents, royalties, and other intellectual property regarding BAY1000394 studies; expert testimony for Servier; travel, accommodations, and expenses from Roche, BMS, and AstraZeneca; principal investigator or subinvestigator of clinical trials for Abbvie, Agios Pharmaceuticals, Amgen, Argen-X Bvba, Arno Therapeutics, Astex Pharmaceuticals, AstraZeneca, Aveo, Bayer Healthcare, Bbb Technologies, Blueprint Medicines, Boehringer Ingelheim, BMS, Celgene Corporation, Chugai Pharmaceutical, Clovis Oncology, Daiichi Sankyo, Debiopharm, Eisai, Eli Lilly, Exelixis, Forma, Gamamabs, Genentech, GlaxoSmithKline, H3 Biomedicine, Hoffmann La Roche, Innate Pharma, Iris Servier, Janssen Cilag, Kyowa Kirin Pharm Dev, Loxo Oncology, Lytix Biopharma, Medimmune, Menarini Ricerche, MSD Chibret, Merrimack Pharmaceuticals, Merus, Millennium Pharmaceuticals, Nanobiotix, Nektar Therapeutics, Novartis Pharma, Octimet Oncology, Oncoethix, Onyx Therapeutics, Orion Pharma, Oryzon Genomics, Pfizer, Pharma Mar, Pierre Fabre, Roche, Sanofi Aventis, Taiho Pharma, Tesaro, and Xencor; and honoraria from Infinity Pharmaceuticals, BMS, Eisai, PharmaMar, and Gilead. SZU reports receiving consulting fees from Celgene, Millennium Takeda, Onyx, and Sanofi; speaker's fees from Celgene, Millennium Takeda, and Onyx; and research funding from Array BioPharma, Celgene, Janssen Oncology, Onyx, Pharmacyclics, and Sanofi. SJ reports receiving honoraria from Celgene and Karyopharm; and consulting fees from Celgene, Janssen, Karyopharm, BMS, and Novartis. EMO reports receiving honoraria from Novartis, Takeda, AbbVie, PharmaMar, Seattle Genetics, Amgen, Celgene, BMS, and Janssen; and research funding from Array Pharmaceuticals, Mundipharma, Celgene, Amgen, and Sanofi. PR-O reports receiving consulting fees from Celgene, Janssen, and Takeda; speaker's fees from Celgene, BMS, and Janssen; and research funding from BMS and Celgene. JSM reports receiving consulting fees from Amgen, BMS, Celgene, Janssen, MSD, Novartis, Takeda, Sanofi, and Roche. UK, MF, JL, and PM are employees of and report stock ownership in Merck & Co, (Kenilworth, NJ, USA). SL reports receiving consulting and advisory board fees from Amgen, Celgene, Novartis, BMS, Takeda, MSD, and Janssen; and research support from BMS, Janssen, Takeda, and Celgene. All other authors declare no competing interests.
Funding Information:
Funding for this research was provided by Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, (Kenilworth, NJ, USA). Medical writing and editorial assistance were provided by Luana Atherly-Henderson, of Merck Sharp & Dohme Corp, and Matthew Grzywacz, of the ApotheCom pembrolizumab team (Yardley, PA, USA). This assistance was funded by Merck Sharp & Dohme Corp. We thank the patients and their families and caregivers, all primary investigators and their site personnel, Bethanne Friedmann, Caryn Hampton, Yeliz Kiziltan, Deborah Wolfe, and Michelle Gallion (Merck & Co, Kenilworth, NJ, USA) for clinical study support and Jonathan Cheng (Merck & Co, Kenilworth, NJ, USA) for critical review.
Publisher Copyright:
© 2019 Elsevier Ltd
PY - 2019/9
Y1 - 2019/9
N2 - Background: Pomalidomide and dexamethasone is a standard of care for patients with multiple myeloma in whom bortezomib and lenalidomide treatment has failed. KEYNOTE-183 assessed efficacy and safety of pomalidomide and dexamethasone with or without pembrolizumab in patients with relapsed or refractory multiple myeloma. Here, we present the findings of an unplanned, ad-hoc interim analysis at the request of the US Food and Drug Administration (FDA). Methods: KEYNOTE-183 was a randomised, open-label, phase 3 trial done at 97 medical centres across 11 countries (Australia, Canada, France, Germany, Israel, Italy, Japan, New Zealand, Norway, Spain, and USA). Patients aged at least 18 years with multiple myeloma, an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, previously treated with at least two lines of therapy (excluding pomalidomide) and refractory to the last line were randomly assigned 1:1 to the pembrolizumab plus pomalidomide and dexamethasone group or the pomalidomide and dexamethasone group via an interactive voice response or integrated web response system. Patients received oral pomalidomide 4 mg daily on days 1–21 and oral low-dose dexamethasone 40 mg on days 1, 8, 15, and 22 in 28-day cycles, with or without intravenous pembrolizumab 200 mg every 3 weeks. The dual primary endpoints were progression-free survival and overall survival. Efficacy was assessed in all randomly assigned patients and safety was assessed in patients who received at least one dose of study treatment. The trial is registered at ClinicalTrials.gov, number NCT02576977, and it is closed for accrual. Findings: Between Jan 18, 2016, and June 7, 2017, 249 patients were randomly assigned to either the pembrolizumab plus pomalidomide and dexamethasone group (n=125) or the pomalidomide and dexamethasone group (n=124). On July 3, 2017, the FDA established that risks associated with the triple combination outweighed benefits and halted the study. Median follow-up was 8·1 months (IQR 4·5–10·9). Median progression-free survival was 5·6 months (95% CI 3·7–7·5) in the pembrolizumab plus pomalidomide and dexamethasone group versus 8·4 months (5·9–not reached) in the pomalidomide and dexamethasone group; progression-free survival estimates at 6 months were 48% (95% CI 37–58) versus 60% (49–69) at 6 months (hazard ratio [HR] 1·53; 95% CI 1·05–2·22; p=0·98). Median overall survival was not reached (95% CI 12·9–not reached) versus 15·2 months (12·7–not reached; HR 1·61; 95% CI 0·91–2·85; p=0·95); overall survival estimates at 6 months were 82% (95% CI 74–88) versus 90% (82–95). Serious adverse events occurred in 75 (63%) of 120 patients in the pembrolizumab plus pomalidomide and dexamethasone group versus 56 (46%) of 121 patients in the pomalidomide and dexamethasone group. Four (3%) treatment-related deaths occurred in the pembrolizumab plus pomalidomide and dexamethasone group (one each of unknown cause, neutropenic sepsis, myocarditis, and Stevens–Johnson syndrome); myocarditis and Stevens-Johnson syndrome were considered related to pembrolizumab. No treatment-related deaths were reported in the pomalidomide and dexamethasone group. Interpretation: The results from this unplanned, FDA-requested, interim analysis showed that the benefit–risk profile of pembrolizumab plus pomalidomide and dexamethasone is unfavourable for patients with relapsed or refractory multiple myeloma. Funding: Merck Sharp & Dohme, a subsidiary of Merck & Co (Kenilworth, NJ, USA).
AB - Background: Pomalidomide and dexamethasone is a standard of care for patients with multiple myeloma in whom bortezomib and lenalidomide treatment has failed. KEYNOTE-183 assessed efficacy and safety of pomalidomide and dexamethasone with or without pembrolizumab in patients with relapsed or refractory multiple myeloma. Here, we present the findings of an unplanned, ad-hoc interim analysis at the request of the US Food and Drug Administration (FDA). Methods: KEYNOTE-183 was a randomised, open-label, phase 3 trial done at 97 medical centres across 11 countries (Australia, Canada, France, Germany, Israel, Italy, Japan, New Zealand, Norway, Spain, and USA). Patients aged at least 18 years with multiple myeloma, an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, previously treated with at least two lines of therapy (excluding pomalidomide) and refractory to the last line were randomly assigned 1:1 to the pembrolizumab plus pomalidomide and dexamethasone group or the pomalidomide and dexamethasone group via an interactive voice response or integrated web response system. Patients received oral pomalidomide 4 mg daily on days 1–21 and oral low-dose dexamethasone 40 mg on days 1, 8, 15, and 22 in 28-day cycles, with or without intravenous pembrolizumab 200 mg every 3 weeks. The dual primary endpoints were progression-free survival and overall survival. Efficacy was assessed in all randomly assigned patients and safety was assessed in patients who received at least one dose of study treatment. The trial is registered at ClinicalTrials.gov, number NCT02576977, and it is closed for accrual. Findings: Between Jan 18, 2016, and June 7, 2017, 249 patients were randomly assigned to either the pembrolizumab plus pomalidomide and dexamethasone group (n=125) or the pomalidomide and dexamethasone group (n=124). On July 3, 2017, the FDA established that risks associated with the triple combination outweighed benefits and halted the study. Median follow-up was 8·1 months (IQR 4·5–10·9). Median progression-free survival was 5·6 months (95% CI 3·7–7·5) in the pembrolizumab plus pomalidomide and dexamethasone group versus 8·4 months (5·9–not reached) in the pomalidomide and dexamethasone group; progression-free survival estimates at 6 months were 48% (95% CI 37–58) versus 60% (49–69) at 6 months (hazard ratio [HR] 1·53; 95% CI 1·05–2·22; p=0·98). Median overall survival was not reached (95% CI 12·9–not reached) versus 15·2 months (12·7–not reached; HR 1·61; 95% CI 0·91–2·85; p=0·95); overall survival estimates at 6 months were 82% (95% CI 74–88) versus 90% (82–95). Serious adverse events occurred in 75 (63%) of 120 patients in the pembrolizumab plus pomalidomide and dexamethasone group versus 56 (46%) of 121 patients in the pomalidomide and dexamethasone group. Four (3%) treatment-related deaths occurred in the pembrolizumab plus pomalidomide and dexamethasone group (one each of unknown cause, neutropenic sepsis, myocarditis, and Stevens–Johnson syndrome); myocarditis and Stevens-Johnson syndrome were considered related to pembrolizumab. No treatment-related deaths were reported in the pomalidomide and dexamethasone group. Interpretation: The results from this unplanned, FDA-requested, interim analysis showed that the benefit–risk profile of pembrolizumab plus pomalidomide and dexamethasone is unfavourable for patients with relapsed or refractory multiple myeloma. Funding: Merck Sharp & Dohme, a subsidiary of Merck & Co (Kenilworth, NJ, USA).
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U2 - 10.1016/S2352-3026(19)30110-3
DO - 10.1016/S2352-3026(19)30110-3
M3 - Article
C2 - 31327687
AN - SCOPUS:85071223893
SN - 2352-3026
VL - 6
SP - e459-e469
JO - The Lancet Haematology
JF - The Lancet Haematology
IS - 9
ER -