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.
Bibliographical noteFunding Information:
PGR reports research funding from Celgene, Takeda, Bristol-Myers Squibb, and Oncopeptides; and advisory board fees from Celgene, Takeda, Janssen, and Oncopeptide. AO reports advisory board fees from Celgene, Janssen, and Amgen. MB reports advisory board fees from Janssen Cilag, Amgen, Takeda, and Sanofi; and speakers bureau fees from Janssen Cilag, Celgene, Takeda, and Amgen. MG reports honoraria from Bristol-Myers Squibb, Celgene, Janssen, and Leadiant (formerly Sigma-Tau). FS reports paid lecturer or advisory board fees from Amgen, Celgene, Takeda, AbbVie, Janssen, Bristol-Myers Squibb, Bayer, and Adaptive. JL reports commercial sponsorship and personal fees from Celgene; and non-financial support from Celgene, Takeda, and Amgen. KW reports grants, personal fees, and non-financial support from Celgene, Amgen, and Janssen; personal fees and non-financial support from Bristol-Myers Squibb and Takeda; and grants and personal fees from Sanofi. DW reports grants and personal fees from Amgen, Celgene, Janssen, and Takeda. TF reports speakers bureau and advisory board fees from Celgene, Janssen, and Takeda; and advisory board fees from Karyopharm, Sanofi, and Oncopeptides. JSM reports advisory board fees from Amgen, Bristol-Myers Squibb, Celgene, Janssen, MSD, Novartis, Takeda, Sanofi, and Roche. KS reports research funding and honoraria from Celgene, Takeda, Bristol-Myers Squibb, and Ono; and research funding from Novartis, GlaxoSmithKline, Janssen, AbbVie, Sanofi, MSD, Alexion, and Daiichi Sankyo. PO'G reports research funding from Celgene. PS reports grants and personal fees from Celgene and Janssen; and grants from Amgen, Takeda, and Karyopharm. PR reports research funding from Celgene. SSe reports research funding from Celgene; and fees from lectures and speakers bureau fees from Celgene, Takeda, Janssen, Amgen, and Novartis. XY, TD, AB, TB and TP report employment with and stock ownership in Celgene. MZ reports employment with Celgene. KA reports advisory board fees from Celgene, Millennium, and Bristol-Myers Squibb; board membership with Gilead; and is the scientific founder of Oncopeptides and C4 Therapeutics. MD reports honoraria, consulting fees, and lecture fees from Amgen, Celgene, Takeda, Janssen, and Bristol-Myers Squibb. AML and SSc declare no competing interests.
This study was supported by Celgene. We thank the study investigators, participating sites, nurses, and study personnel who were involved in this clinical trial, and the patients and their families. We acknowledge Mihaela Marina (MediTech Media) for medical writing assistance, which was funded by Celgene.
© 2019 Elsevier Ltd