Daratumumab plus pomalidomide and dexamethasone versus pomalidomide and dexamethasone alone in previously treated multiple myeloma (APOLLO): an open-label, randomised, phase 3 trial.

BACKGROUND

In a phase 1b study, intravenous daratumumab plus pomalidomide and dexamethasone induced a very good partial response or better rate of 42% and was well tolerated in patients with heavily pretreated multiple myeloma. We aimed to evaluate whether daratumumab plus pomalidomide and dexamethasone would improve progression-free survival versus pomalidomide and dexamethasone alone in patients with previously treated multiple myeloma.

METHODS

In this ongoing, open-label, randomised, phase 3 trial (APOLLO) done at 48 academic centres and hospitals across 12 European countries, eligible patients were aged 18 years or older, had relapsed or refractory multiple myeloma with measurable disease, had an Eastern Cooperative Oncology Group performance status of 0-2, had at least one previous line of therapy, including lenalidomide and a proteasome inhibitor, had a partial response or better to one or more previous lines of antimyeloma therapy, and were refractory to lenalidomide if only one previous line of therapy was received. Patients were randomly assigned (1:1) by an interactive web-response system in a random block size of two or four to receive pomalidomide and dexamethasone alone or daratumumab plus pomalidomide and dexamethasone. Randomisation was stratified by number of previous lines of therapy and International Staging System disease stage. All patients received oral pomalidomide (4 mg, once daily on days 1-21) and oral dexamethasone (40 mg once daily on days 1, 8, 15, and 22; 20 mg for those aged 75 years or older) at each 28-day cycle. The daratumumab plus pomalidomide and dexamethasone group received daratumumab (1800 mg subcutaneously or 16 mg/kg intravenously) weekly during cycles 1 and 2, every 2 weeks during cycles 3-6, and every 4 weeks thereafter until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival in the intention-to-treat population. Safety was analysed in all patients who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov, NCT03180736.

FINDINGS

Between June 22, 2017, and June 13, 2019, 304 patients (median age 67 years [IQR 60-72]; 161 [53%] men and 143 [47%] women) were randomly assigned to the daratumumab plus pomalidomide and dexamethasone group (n=151) or the pomalidomide and dexamethasone group (n=153). At a median follow-up of 16·9 months (IQR 14·4-20·6), the daratumumab plus pomalidomide and dexamethasone group showed improved progression-free survival compared with the pomalidomide and dexamethasone group (median 12·4 months [95% CI 8·3-19·3] vs 6·9 months [5·5-9·3]; hazard ratio 0·63 [95% CI 0·47-0·85], two-sided p=0·0018). The most common grade 3 or 4 adverse events were neutropenia (101 [68%] of 149 patients in the daratumumab plus pomalidomide and dexamethasone group vs 76 [51%] of 150 patients in the pomalidomide and dexamethasone group), anaemia (25 [17%] vs 32 [21%]), and thrombocytopenia (26 [17%] vs 27 [18%]). Serious adverse events occurred in 75 (50%) of 149 patients in the daratumumab plus pomalidomide and dexamethasone group versus 59 (39%) of 150 patients in the pomalidomide and dexamethasone group; pneumonia (23 [15%] vs 12 [8%] patients) and lower respiratory tract infection (18 [12%] vs 14 [9%]) were most common. Treatment-emergent deaths were reported in 11 (7%) patients in the daratumumab plus pomalidomide and dexamethasone group versus 11 (7%) patients in the pomalidomide and dexamethasone group.

INTERPRETATION

Among patients with relapsed or refractory multiple myeloma, daratumumab plus pomalidomide and dexamethasone reduced the risk of disease progression or death versus pomalidomide and dexamethasone alone and could be considered a new treatment option in this setting.

FUNDING

European Myeloma Network and Janssen Research and Development.

Informations de copyright

Copyright © 2021 Elsevier Ltd. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests MAD received honoraria for participation in advisory boards from Amgen, Takeda, Bristol Myers Squibb, Janssen, and BeiGene. ET received honoraria from Janssen, Genesis, Celgene, and Bristol Myers Squibb; research funding from Janssen and Genesis; and non-financial support from Genesis. MBo received honoraria and research funding from Sanofi, Celgene, Amgen, Janssen, Novartis, and Bristol Myers Squibb; received honoraria from AbbVie; received research funding from Mundipharma; and served on an entity's board of directors or advisory committees for Janssen and GlaxoSmithKline. MBe served as a member on an entity's board of directors or advisory committees, and on a speakers' bureau for Janssen, Sanofi, Amgen, Bristol Myers Squibb, Oncopeptides, and Takeda. EK received honoraria, research funding, personal fees, and non-financial support from Janssen-Cilag. PM served as a consultant for and received honoraria from Celgene/Bristol Myers Squibb, Janssen, Amgen, AbbVie, and Sanofi. AS served on advisory committees and received research funding from Bristol Myers Squibb; served on advisory committees and speakers' bureaus for, and received research funding from, AbbVie, Amgen, Celgene/Genesis, and Sanofi/Genzyme; and received research funding from Astellas. AO served on advisory committees for Celgene/Bristol Myers Squibb, Sanofi, Amgen, and GlaxoSmithKline. M-VM served as a consultant for, received honoraria from, and served on an entity's board of directors or on advisory committees for Janssen, Bristol Myers Squibb/Celgene, Amgen, Takeda, Oncopeptides, GlaxoSmithKline, Sanofi, Pfizer, Regeneron, AbbVie/Genentech, Seattle Genetics, and Adaptive Biotechnologies. HE served as a consultant for, received honoraria and research funding from, and served on a speakers' bureau for Janssen, Celgene, Amgen, GlaxoSmithKline, and Sanofi; and served as a consultant for, received honoraria from, and served on a speakers' bureau for Takeda. TA is an employee of Genmab and is current equity holder in a publicly traded company. JU was an employee of Janssen and equity holder in a publicly traded company at the time of the study, and is currently an employee of Genmab and equity holder in a publicly traded company. TK, JMS, YQ, and RC are employees of Janssen. HA and JV are employees of Janssen and are current equity holders in a publicly traded company. PS received research funding from Amgen, Celgene, Janssen, and Takeda, and received honoraria and served on advisory committees for Janssen, Celgene, Amgen, Takeda, Bristol Myers Squibb, and Skyline Dx. All other authors declare no competing interests.