Pomalidomide, bortezomib, and dexamethasone for patients with relapsed or refractory multiple myeloma previously treated with lenalidomide (OPTIMISMM): a randomised, open-label, phase 3 trial

OPTIMISMM trial investigators

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Background: As lenalidomide becomes increasingly established for upfront treatment of multiple myeloma, patients refractory to this drug represent a population with an unmet need. The combination of pomalidomide, bortezomib, and dexamethasone has shown promising results in phase 1/2 trials of patients with relapsed or refractory multiple myeloma. We aimed to assess the efficacy and safety of this triplet regimen in patients with relapsed or refractory multiple myeloma who previously received lenalidomide. Methods: We did a randomised, open-label, phase 3 trial at 133 hospitals and research centres in 21 countries. We enrolled patients (aged ≥18 years)with a diagnosis of multiple myeloma and measurable disease, an Eastern Cooperative Oncology Group performance status of 0–2, who received one to three previous regimens, including a lenalidomide-containing regimen for at least two consecutive cycles. We randomly assigned patients (1:1)to bortezomib and dexamethasone with or without pomalidomide using a permutated blocked design in blocks of four, stratified according to age, number of previous regimens, and concentration of β2 microglobulin at screening. Bortezomib (1·3 mg/m2)was administered intravenously until protocol amendment 1 then either intravenously or subcutaneously on days 1, 4, 8, and 11 for the first eight cycles and subsequently on days 1 and 8. Dexamethasone (20 mg [10 mg if age >75 years])was administered orally on the same days as bortezomib and the day after. Patients allocated pomalidomide received 4 mg orally on days 1–14. Treatment cycles were every 21 days. The primary endpoint was progression-free survival in the intention-to-treat population, as assessed by an independent review committee. Safety was assessed in all patients who received at least one dose of study medication. This trial is registered at ClinicalTrials.gov, number NCT01734928; patients are no longer being enrolled. Findings: Between Jan 7, 2013, and May 15, 2017, 559 patients were enrolled. 281 patients were assigned pomalidomide, bortezomib, and dexamethasone and 278 were allocated bortezomib and dexamethasone. Median follow-up was 15·9 months (IQR 9·9–21·7). Pomalidomide, bortezomib, and dexamethasone significantly improved progression-free survival compared with bortezomib and dexamethasone (median 11·20 months [95% CI 9·66–13·73]vs 7·10 months [5·88–8·48]; hazard ratio 0·61, 95% CI 0·49–0·77; p<0·0001). 278 patients received at least one dose of pomalidomide, bortezomib, and dexamethasone and 270 patients received at least one dose of bortezomib and dexamethasone, and these patients were included in safety assessments. The most common grade 3 or 4 treatment-emergent adverse events were neutropenia (116 [42%]of 278 patients vs 23 [9%]of 270 patients; nine [3%]vs no patients had febrile neutropenia), infections (86 [31%]vs 48 [18%]), and thrombocytopenia (76 [27%]vs 79 [29%]). Serious adverse events were reported in 159 (57%)of 278 patients versus 114 (42%)of 270 patients. Eight deaths were related to treatment; six (2%)were recorded in patients who received pomalidomide, bortezomib, and dexamethasone (pneumonia [n=2], unknown cause [n=2], cardiac arrest [n=1], cardiorespiratory arrest [n=1])and two (1%)were reported in patients who received bortezomib and dexamethasone (pneumonia [n=1], hepatic encephalopathy [n=1]). Interpretation: Patients with relapsed or refractory multiple myeloma who previously received lenalidomide had significantly improved progression-free survival when treated with pomalidomide, bortezomib, and dexamethasone compared with bortezomib and dexamethasone. Adverse events accorded with the individual profiles of pomalidomide, bortezomib, and dexamethasone. This study supports use of pomalidomide, bortezomib, and dexamethasone as a treatment option in patients with relapsed or refractory multiple myeloma who previously received lenalidomide. Funding: Celgene.

Original languageEnglish (US)
Pages (from-to)781-794
Number of pages14
JournalThe Lancet Oncology
Volume20
Issue number6
DOIs
StatePublished - Jun 1 2019

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Multiple Myeloma
Dexamethasone
Bortezomib
pomalidomide
lenalidomide
Disease-Free Survival
Safety
Pneumonia
Therapeutics
Febrile Neutropenia
Hepatic Encephalopathy

ASJC Scopus subject areas

  • Oncology

Cite this

@article{da890971efae43a78f5e4599f525f4f2,
title = "Pomalidomide, bortezomib, and dexamethasone for patients with relapsed or refractory multiple myeloma previously treated with lenalidomide (OPTIMISMM): a randomised, open-label, phase 3 trial",
abstract = "Background: As lenalidomide becomes increasingly established for upfront treatment of multiple myeloma, patients refractory to this drug represent a population with an unmet need. The combination of pomalidomide, bortezomib, and dexamethasone has shown promising results in phase 1/2 trials of patients with relapsed or refractory multiple myeloma. We aimed to assess the efficacy and safety of this triplet regimen in patients with relapsed or refractory multiple myeloma who previously received lenalidomide. Methods: We did a randomised, open-label, phase 3 trial at 133 hospitals and research centres in 21 countries. We enrolled patients (aged ≥18 years)with a diagnosis of multiple myeloma and measurable disease, an Eastern Cooperative Oncology Group performance status of 0–2, who received one to three previous regimens, including a lenalidomide-containing regimen for at least two consecutive cycles. We randomly assigned patients (1:1)to bortezomib and dexamethasone with or without pomalidomide using a permutated blocked design in blocks of four, stratified according to age, number of previous regimens, and concentration of β2 microglobulin at screening. Bortezomib (1·3 mg/m2)was administered intravenously until protocol amendment 1 then either intravenously or subcutaneously on days 1, 4, 8, and 11 for the first eight cycles and subsequently on days 1 and 8. Dexamethasone (20 mg [10 mg if age >75 years])was administered orally on the same days as bortezomib and the day after. Patients allocated pomalidomide received 4 mg orally on days 1–14. Treatment cycles were every 21 days. The primary endpoint was progression-free survival in the intention-to-treat population, as assessed by an independent review committee. Safety was assessed in all patients who received at least one dose of study medication. This trial is registered at ClinicalTrials.gov, number NCT01734928; patients are no longer being enrolled. Findings: Between Jan 7, 2013, and May 15, 2017, 559 patients were enrolled. 281 patients were assigned pomalidomide, bortezomib, and dexamethasone and 278 were allocated bortezomib and dexamethasone. Median follow-up was 15·9 months (IQR 9·9–21·7). Pomalidomide, bortezomib, and dexamethasone significantly improved progression-free survival compared with bortezomib and dexamethasone (median 11·20 months [95{\%} CI 9·66–13·73]vs 7·10 months [5·88–8·48]; hazard ratio 0·61, 95{\%} CI 0·49–0·77; p<0·0001). 278 patients received at least one dose of pomalidomide, bortezomib, and dexamethasone and 270 patients received at least one dose of bortezomib and dexamethasone, and these patients were included in safety assessments. The most common grade 3 or 4 treatment-emergent adverse events were neutropenia (116 [42{\%}]of 278 patients vs 23 [9{\%}]of 270 patients; nine [3{\%}]vs no patients had febrile neutropenia), infections (86 [31{\%}]vs 48 [18{\%}]), and thrombocytopenia (76 [27{\%}]vs 79 [29{\%}]). Serious adverse events were reported in 159 (57{\%})of 278 patients versus 114 (42{\%})of 270 patients. Eight deaths were related to treatment; six (2{\%})were recorded in patients who received pomalidomide, bortezomib, and dexamethasone (pneumonia [n=2], unknown cause [n=2], cardiac arrest [n=1], cardiorespiratory arrest [n=1])and two (1{\%})were reported in patients who received bortezomib and dexamethasone (pneumonia [n=1], hepatic encephalopathy [n=1]). Interpretation: Patients with relapsed or refractory multiple myeloma who previously received lenalidomide had significantly improved progression-free survival when treated with pomalidomide, bortezomib, and dexamethasone compared with bortezomib and dexamethasone. Adverse events accorded with the individual profiles of pomalidomide, bortezomib, and dexamethasone. This study supports use of pomalidomide, bortezomib, and dexamethasone as a treatment option in patients with relapsed or refractory multiple myeloma who previously received lenalidomide. Funding: Celgene.",
author = "{OPTIMISMM trial investigators} and Richardson, {Paul G.} and Albert Oriol and Meral Beksac and Liberati, {Anna Marina} and Monica Galli and Fredrik Schjesvold and Jindriska Lindsay and Katja Weisel and Darrell White and Thierry Facon and {San Miguel}, Jesus and Kazutaka Sunami and Peter O'Gorman and Pieter Sonneveld and Pawel Robak and Sergey Semochkin and Steve Schey and Xin Yu and Thomas Doerr and Amine Bensmaine and Tsvetan Biyukov and Teresa Peluso and Mohamed Zaki and Kenneth Anderson and Meletios Dimopoulos and Niels Abildgaard and Howard Adler and Fevzi Altuntas and Akay, {Olga Meltem} and Bipinkumar Amin and Achilleas Anagnostopoulos and Larry Anderson and Pekka Anttila and Carla Araujo and Carlos Arce-Lara and Yildiz Aydin and Supratik Basu and Ramakrishna Battini and Thaddeus Beeker and Lotfi Benboubker and Dina Ben-Yehuda and Joan Blad{\'e} and Blau, {Igor Wolfgang} and Ralph Boccia and Lillian Burke and Peter Byeff and Nicola Cascavilla and Michele Cavo and Murali Janakiram and Verma, {Amit K.}",
year = "2019",
month = "6",
day = "1",
doi = "10.1016/S1470-2045(19)30152-4",
language = "English (US)",
volume = "20",
pages = "781--794",
journal = "The Lancet Oncology",
issn = "1470-2045",
publisher = "Lancet Publishing Group",
number = "6",

}

TY - JOUR

T1 - Pomalidomide, bortezomib, and dexamethasone for patients with relapsed or refractory multiple myeloma previously treated with lenalidomide (OPTIMISMM)

T2 - a randomised, open-label, phase 3 trial

AU - OPTIMISMM trial investigators

AU - Richardson, Paul G.

AU - Oriol, Albert

AU - Beksac, Meral

AU - Liberati, Anna Marina

AU - Galli, Monica

AU - Schjesvold, Fredrik

AU - Lindsay, Jindriska

AU - Weisel, Katja

AU - White, Darrell

AU - Facon, Thierry

AU - San Miguel, Jesus

AU - Sunami, Kazutaka

AU - O'Gorman, Peter

AU - Sonneveld, Pieter

AU - Robak, Pawel

AU - Semochkin, Sergey

AU - Schey, Steve

AU - Yu, Xin

AU - Doerr, Thomas

AU - Bensmaine, Amine

AU - Biyukov, Tsvetan

AU - Peluso, Teresa

AU - Zaki, Mohamed

AU - Anderson, Kenneth

AU - Dimopoulos, Meletios

AU - Abildgaard, Niels

AU - Adler, Howard

AU - Altuntas, Fevzi

AU - Akay, Olga Meltem

AU - Amin, Bipinkumar

AU - Anagnostopoulos, Achilleas

AU - Anderson, Larry

AU - Anttila, Pekka

AU - Araujo, Carla

AU - Arce-Lara, Carlos

AU - Aydin, Yildiz

AU - Basu, Supratik

AU - Battini, Ramakrishna

AU - Beeker, Thaddeus

AU - Benboubker, Lotfi

AU - Ben-Yehuda, Dina

AU - Bladé, Joan

AU - Blau, Igor Wolfgang

AU - Boccia, Ralph

AU - Burke, Lillian

AU - Byeff, Peter

AU - Cascavilla, Nicola

AU - Cavo, Michele

AU - Janakiram, Murali

AU - Verma, Amit K.

PY - 2019/6/1

Y1 - 2019/6/1

N2 - Background: As lenalidomide becomes increasingly established for upfront treatment of multiple myeloma, patients refractory to this drug represent a population with an unmet need. The combination of pomalidomide, bortezomib, and dexamethasone has shown promising results in phase 1/2 trials of patients with relapsed or refractory multiple myeloma. We aimed to assess the efficacy and safety of this triplet regimen in patients with relapsed or refractory multiple myeloma who previously received lenalidomide. Methods: We did a randomised, open-label, phase 3 trial at 133 hospitals and research centres in 21 countries. We enrolled patients (aged ≥18 years)with a diagnosis of multiple myeloma and measurable disease, an Eastern Cooperative Oncology Group performance status of 0–2, who received one to three previous regimens, including a lenalidomide-containing regimen for at least two consecutive cycles. We randomly assigned patients (1:1)to bortezomib and dexamethasone with or without pomalidomide using a permutated blocked design in blocks of four, stratified according to age, number of previous regimens, and concentration of β2 microglobulin at screening. Bortezomib (1·3 mg/m2)was administered intravenously until protocol amendment 1 then either intravenously or subcutaneously on days 1, 4, 8, and 11 for the first eight cycles and subsequently on days 1 and 8. Dexamethasone (20 mg [10 mg if age >75 years])was administered orally on the same days as bortezomib and the day after. Patients allocated pomalidomide received 4 mg orally on days 1–14. Treatment cycles were every 21 days. The primary endpoint was progression-free survival in the intention-to-treat population, as assessed by an independent review committee. Safety was assessed in all patients who received at least one dose of study medication. This trial is registered at ClinicalTrials.gov, number NCT01734928; patients are no longer being enrolled. Findings: Between Jan 7, 2013, and May 15, 2017, 559 patients were enrolled. 281 patients were assigned pomalidomide, bortezomib, and dexamethasone and 278 were allocated bortezomib and dexamethasone. Median follow-up was 15·9 months (IQR 9·9–21·7). Pomalidomide, bortezomib, and dexamethasone significantly improved progression-free survival compared with bortezomib and dexamethasone (median 11·20 months [95% CI 9·66–13·73]vs 7·10 months [5·88–8·48]; hazard ratio 0·61, 95% CI 0·49–0·77; p<0·0001). 278 patients received at least one dose of pomalidomide, bortezomib, and dexamethasone and 270 patients received at least one dose of bortezomib and dexamethasone, and these patients were included in safety assessments. The most common grade 3 or 4 treatment-emergent adverse events were neutropenia (116 [42%]of 278 patients vs 23 [9%]of 270 patients; nine [3%]vs no patients had febrile neutropenia), infections (86 [31%]vs 48 [18%]), and thrombocytopenia (76 [27%]vs 79 [29%]). Serious adverse events were reported in 159 (57%)of 278 patients versus 114 (42%)of 270 patients. Eight deaths were related to treatment; six (2%)were recorded in patients who received pomalidomide, bortezomib, and dexamethasone (pneumonia [n=2], unknown cause [n=2], cardiac arrest [n=1], cardiorespiratory arrest [n=1])and two (1%)were reported in patients who received bortezomib and dexamethasone (pneumonia [n=1], hepatic encephalopathy [n=1]). Interpretation: Patients with relapsed or refractory multiple myeloma who previously received lenalidomide had significantly improved progression-free survival when treated with pomalidomide, bortezomib, and dexamethasone compared with bortezomib and dexamethasone. Adverse events accorded with the individual profiles of pomalidomide, bortezomib, and dexamethasone. This study supports use of pomalidomide, bortezomib, and dexamethasone as a treatment option in patients with relapsed or refractory multiple myeloma who previously received lenalidomide. Funding: Celgene.

AB - Background: As lenalidomide becomes increasingly established for upfront treatment of multiple myeloma, patients refractory to this drug represent a population with an unmet need. The combination of pomalidomide, bortezomib, and dexamethasone has shown promising results in phase 1/2 trials of patients with relapsed or refractory multiple myeloma. We aimed to assess the efficacy and safety of this triplet regimen in patients with relapsed or refractory multiple myeloma who previously received lenalidomide. Methods: We did a randomised, open-label, phase 3 trial at 133 hospitals and research centres in 21 countries. We enrolled patients (aged ≥18 years)with a diagnosis of multiple myeloma and measurable disease, an Eastern Cooperative Oncology Group performance status of 0–2, who received one to three previous regimens, including a lenalidomide-containing regimen for at least two consecutive cycles. We randomly assigned patients (1:1)to bortezomib and dexamethasone with or without pomalidomide using a permutated blocked design in blocks of four, stratified according to age, number of previous regimens, and concentration of β2 microglobulin at screening. Bortezomib (1·3 mg/m2)was administered intravenously until protocol amendment 1 then either intravenously or subcutaneously on days 1, 4, 8, and 11 for the first eight cycles and subsequently on days 1 and 8. Dexamethasone (20 mg [10 mg if age >75 years])was administered orally on the same days as bortezomib and the day after. Patients allocated pomalidomide received 4 mg orally on days 1–14. Treatment cycles were every 21 days. The primary endpoint was progression-free survival in the intention-to-treat population, as assessed by an independent review committee. Safety was assessed in all patients who received at least one dose of study medication. This trial is registered at ClinicalTrials.gov, number NCT01734928; patients are no longer being enrolled. Findings: Between Jan 7, 2013, and May 15, 2017, 559 patients were enrolled. 281 patients were assigned pomalidomide, bortezomib, and dexamethasone and 278 were allocated bortezomib and dexamethasone. Median follow-up was 15·9 months (IQR 9·9–21·7). Pomalidomide, bortezomib, and dexamethasone significantly improved progression-free survival compared with bortezomib and dexamethasone (median 11·20 months [95% CI 9·66–13·73]vs 7·10 months [5·88–8·48]; hazard ratio 0·61, 95% CI 0·49–0·77; p<0·0001). 278 patients received at least one dose of pomalidomide, bortezomib, and dexamethasone and 270 patients received at least one dose of bortezomib and dexamethasone, and these patients were included in safety assessments. The most common grade 3 or 4 treatment-emergent adverse events were neutropenia (116 [42%]of 278 patients vs 23 [9%]of 270 patients; nine [3%]vs no patients had febrile neutropenia), infections (86 [31%]vs 48 [18%]), and thrombocytopenia (76 [27%]vs 79 [29%]). Serious adverse events were reported in 159 (57%)of 278 patients versus 114 (42%)of 270 patients. Eight deaths were related to treatment; six (2%)were recorded in patients who received pomalidomide, bortezomib, and dexamethasone (pneumonia [n=2], unknown cause [n=2], cardiac arrest [n=1], cardiorespiratory arrest [n=1])and two (1%)were reported in patients who received bortezomib and dexamethasone (pneumonia [n=1], hepatic encephalopathy [n=1]). Interpretation: Patients with relapsed or refractory multiple myeloma who previously received lenalidomide had significantly improved progression-free survival when treated with pomalidomide, bortezomib, and dexamethasone compared with bortezomib and dexamethasone. Adverse events accorded with the individual profiles of pomalidomide, bortezomib, and dexamethasone. This study supports use of pomalidomide, bortezomib, and dexamethasone as a treatment option in patients with relapsed or refractory multiple myeloma who previously received lenalidomide. Funding: Celgene.

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U2 - 10.1016/S1470-2045(19)30152-4

DO - 10.1016/S1470-2045(19)30152-4

M3 - Article

C2 - 31097405

AN - SCOPUS:85067190733

VL - 20

SP - 781

EP - 794

JO - The Lancet Oncology

JF - The Lancet Oncology

SN - 1470-2045

IS - 6

ER -