Subcutaneous Daratumumab Plus Pomalidomide and Dexamethasone (D-Pd) Versus Pomalidomide and Dexamethasone (Pd) Alone in Patients with Relapsed or Refractory Multiple Myeloma (RRMM): Overall Survival Results from the Phase 3 Apollo Study

Introduction: Daratumumab (DARA) is a human IgGκ monoclonal antibody targeting CD38 with a direct on-tumor and immunomodulatory mechanism of action. DARA is approved in combination with standard of care in patients with newly diagnosed multiple myeloma (NDMM) and as monotherapy and in combination with standard of care for patients with RRMM. In the phase 3 ALCYONE, MAIA, CASTOR, and POLLUX studies, the addition of intravenous (IV) DARA to standard of care significantly improved overall survival (OS) versus standard of care alone in patients with NDMM or RRMM. The subcutaneous (SC) formulation of DARA (DARA SC) is associated with a reduced rate of infusion-related reactions and a substantially shorter administration duration compared to the IV formulation. In the primary analysis of the phase 3 APOLLO study (median follow-up, 16.9 months), D-Pd significantly improved progression-free survival (PFS) versus Pd alone (median, 12.4 months vs 6.9 months; hazard ratio [HR], 0.63; 95% confidence interval [CI], 0.47-0.85; P=0.0018), representing a 37% reduction in the risk of disease progression or death with D-Pd in patients with RRMM (Dimopoulos MA, Lancet Oncol 2021). Here, we report final OS and updated safety results from APOLLO after a median follow-up of 39.6 months.

Methods: Patients with RRMM who had received ≥1 prior line of therapy (including both lenalidomide and a proteasome inhibitor) and had responded to prior treatment were randomized 1:1 to receive Pd ± DARA SC. Randomization was stratified by International Staging System disease stage (I vs II vs III) and number of prior lines of therapy (1 vs 2-3 vs ≥4). All patients received 28-day cycles of Pd (P: 4 mg orally [PO] on Days 1-21; d: 40 mg [20 mg for patients ≥75 years of age] PO on Days 1, 8, 15, and 22). In the D-Pd arm, patients also received DARA SC (DARA 1,800 mg co-formulated with recombinant human hyaluronidase PH20 [rHuPH20; 2,000 U/mL; ENHANZE® drug delivery technology, Halozyme, Inc.]) or, prior to a protocol amendment, DARA 16 mg/kg IV (n=7) QW in Cycles 1-2, Q2W in Cycles 3-6, and Q4W thereafter. Patients receiving DARA IV were allowed to switch to DARA SC on or after Cycle 3 Day 1. In both treatment arms, patients were treated until disease progression or unacceptable toxicity. PFS was the primary endpoint; OS was a secondary endpoint.

Results: A total of 304 patients were randomized (D-Pd, n=151; Pd, n=153). The median (range) age was 67 (35-90) years, and patients had received a median (range) of 2 (1-5) prior lines of therapy. 79.6% of patients were refractory to lenalidomide, 48.0% were refractory to a proteasome inhibitor, and 42.4% were refractory to both lenalidomide and a proteasome inhibitor. After a median (range) follow-up of 39.6 (0.1-56.9) months, median OS was longer in the D-Pd arm versus the Pd arm (median, 34.4 [95% CI, 23.7-40.3] months vs 23.7 [95% CI, 19.6-29.4] months; HR, 0.82; 95% CI, 0.61-1.11; P=0.1989). Of the patients who received subsequent therapy, 68.6% of patients in the Pd arm versus 9.7% of patients in the D-Pd arm received anti-CD38-targeted therapy as subsequent therapy. PFS on next line of therapy (PFS2) was improved with D-Pd versus Pd (median, 24.4 months vs 17.6 months; HR, 0.73; 95% CI, 0.55-0.98; P=0.0340).

A total of 132 (88.6%) patients in the D-Pd arm and 123 (82.0%) patients in the Pd arm experienced grade 3/4 treatment-emergent adverse events (TEAEs); the most frequently reported (≥15% in both arms; D-Pd/Pd) were neutropenia (69.1%/50.7%), anemia (18.1%/21.3%), and thrombocytopenia (18.1%/18.7%). Grade 3/4 pneumonia occurred in 21 (14.1%) patients in the D-Pd arm and 11 (7.3%) patients in the Pd arm. Serious adverse events occurred in 80 (53.7%) patients in the D-Pd arm and 60 (40.0%) patients in the Pd arm. 2.0% of patients in the D-Pd arm and 4.0% of patients in the Pd arm discontinued treatment due to TEAEs.

Conclusions: After >3 years of follow-up in APOLLO, a clinically meaningful improvement in median OS of 10.7 months was observed with D-Pd versus Pd. The addition of DARA to Pd improved PFS2 compared to Pd alone. No new safety concerns were identified with longer follow-up. Our results, together with the OS benefit observed with DARA-containing regimens in the ALCYONE, MAIA, CASTOR, and POLLUX studies, continue to support the use of DARA in patients with multiple myeloma.

Dimopoulos:Janssen: Honoraria; Beigene: Honoraria; Takeda: Honoraria; BMS: Honoraria; Amgen: Honoraria. Terpos:Amgen: Honoraria, Other: Travel Expenses, Research Funding; BMS: Honoraria; EUSA Pharma: Honoraria, Other: Travel Expenses; Genesis: Honoraria, Research Funding; GSK: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria; Takeda: Honoraria, Other: Travel Expenses, Research Funding; Sanofi: Honoraria, Research Funding. Boccadoro:Amgen: Honoraria, Research Funding; Mundipharma: Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding. Delimpasi:Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Beksac:Janssen: Consultancy, Honoraria, Other: Advisory Boards, Speakers Bureau; Sanofi: Consultancy, Honoraria, Other: Advisory Boards, Speakers Bureau; Oncopeptides: Consultancy, Honoraria, Other: Advisory Boards, Speakers Bureau; Amgen: Consultancy, Honoraria, Other: Advisory Boards, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: Advisory Boards, Speakers Bureau. Katodritou:Abbvie: Honoraria, Other: travel expenses, Research Funding; Karyopharm: Research Funding; Integris Pharma: Honoraria; Sanofi: Research Funding; Takeda: Honoraria, Other: research expenses, Research Funding; GSK: Honoraria, Other: travel expenses, Research Funding; JANSSEN: Other: travel expenses, Research Funding; AMGEN: Honoraria, Research Funding. Moreau:AbbVie, Janssen, Celgene, Amgen, and Sanofi: Honoraria. Symeonidis:Servier SOBI: Membership on an entity's Board of Directors or advisory committees; Roche: Research Funding; Demo/Apopharma: Research Funding; Vianex: Research Funding; Rafarm: Honoraria; Astellas: Research Funding; WinMedica: Research Funding; Abbvie, Amgen, Astra-Zeneca, BMS, GenesisPharma, Gilead, Glaxo, Integris, Janssen, Novartis, Pfizer, Sanofi, Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Bila:Janssen Amgen, Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Oriol:Sanofi: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; GlaxoSmithKline: Consultancy, Speakers Bureau; Janssen: Consultancy; BMS: Consultancy, Speakers Bureau. Mateos:Janssen Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Einsele:BMS/Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grants, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grants, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grants; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grants; Sanofi: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Other: travel grants. Orfanidis:Health Data Specialists S.A.: Current equity holder in publicly-traded company. Kampfenkel:Janssen: Current Employment. Liu:Janssen Research & Development, LLC: Current Employment. Kosh:Janssen: Current Employment. Tran:Janssen Research & Development, LLC: Current Employment, Current equity holder in publicly-traded company. Carson:Janssen: Current Employment. Sonneveld:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding.