Pembrolizumab plus pomalidomide and dexamethasone for patients with relapsed or refractory multiple myeloma (KEYNOTE-183): a randomised, open-label, phase 3 trial

KEYNOTE-183 Investigators

Research output: Contribution to journalArticle

Abstract

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).

Original languageEnglish (US)
Pages (from-to)e459-e469
JournalThe Lancet Haematology
Volume6
Issue number9
DOIs
StatePublished - Sep 2019

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Multiple Myeloma
Dexamethasone
United States Food and Drug Administration
Disease-Free Survival
Stevens-Johnson Syndrome
Myocarditis
pomalidomide
pembrolizumab
Survival
Therapeutics
Israel
Norway
Standard of Care
Patient Safety
New Zealand
Spain
Italy
France
Canada
Germany

All Science Journal Classification (ASJC) codes

  • Hematology

Cite this

@article{4dbc7343a2904d9394001ed26ab86c5b,
title = "Pembrolizumab plus pomalidomide and dexamethasone for patients with relapsed or refractory multiple myeloma (KEYNOTE-183): a randomised, open-label, phase 3 trial",
abstract = "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).",
author = "{KEYNOTE-183 Investigators} and Mateos, {Maria Victoria} and Hilary Blacklock and Fredrik Schjesvold and Albert Oriol and David Simpson and Anupkumar George and Hartmut Goldschmidt and Alessandra Larocca and Asher Chanan-Khan and Daniel Sherbenou and Irit Avivi and Noam Benyamini and Shinsuke Iida and Morio Matsumoto and Kenshi Suzuki and Vincent Ribrag and Usmani, {Saad Z.} and Sundar Jagannath and Ocio, {Enrique M.} and Paula Rodriguez-Otero and {San Miguel}, Jesus and Uma Kher and Mohammed Farooqui and Jason Liao and Patricia Marinello and Sagar Lonial and Andrew Nicol and George Grigoriadis and John Catalano and Richard LeBlanc and Mohamed Elemary and Nizar Bahlis and Thierry Facon and Lionel Karlin and Michel Attal and Monika Engelhardt and Katja Weisel and Andreas Mackensen and Arnon Nagler and {Ben Yehuda}, Dina and Hila Magen-Nativ and Antonio Palumbo and Michele Cavo and Kensei Tobinai and Takaai Chou and Hiroshi Kosugi and Masafumi Taniwaki and Kazutaka Sunami and Kiyoshi Ando and Neil Morganstein",
year = "2019",
month = "9",
doi = "10.1016/S2352-3026(19)30110-3",
language = "English (US)",
volume = "6",
pages = "e459--e469",
journal = "The Lancet Haematology",
issn = "2352-3026",
publisher = "Lancet Publishing Group",
number = "9",

}

Pembrolizumab plus pomalidomide and dexamethasone for patients with relapsed or refractory multiple myeloma (KEYNOTE-183) : a randomised, open-label, phase 3 trial. / KEYNOTE-183 Investigators.

In: The Lancet Haematology, Vol. 6, No. 9, 09.2019, p. e459-e469.

Research output: Contribution to journalArticle

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 - Morganstein, Neil

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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