Introduction: Daratumumab (DARA) is an anti-CD38 human monoclonal antibody that is approved as a monotherapy and in combination with lenalidomide and dexamethasone, pomalidomide and dexamethasone (pom-dex), or bortezomib and dexamethasone in patients with RRMM. Pom is an immunomodulatory drug that increases CD38 expression on multiple myeloma cells. The addition of Pom to DARA was hypothesized to enhance the efficacy of DARA and improve patient outcomes. A multi-arm, phase 1b study (NCT01998971) evaluated DARA in combination with various backbone therapies; updated data from the DARA + pom-dex arm with an additional 1 year of follow-up are presented.
Methods: Patients in the DARA + pom-dex arm had an Eastern Cooperative Oncology Group score ≤2, an absolute neutrophil count of ≥1×109/L, ≥2 prior lines of therapy including at least 2 consecutive cycles of lenalidomide and bortezomib, and were refractory to their last line of therapy. Only Pom-naïve patients were enrolled. DARA 16 mg/kg was administered intravenously (IV) in 28-day Cycles (weekly for Cycles 1-2, every 2 weeks for Cycles 3-6, and every 4 weeks thereafter until disease progression); Pom 4 mg was administered orally (PO) on Days 1-21; and dex 40 mg was administered IV/PO per week. Safety was the primary endpoint. Efficacy endpoints included overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). Cytogenetic risk was determined from bone marrow aspirates at screening. Minimal residual disease (MRD) was assessed via next generation sequencing (NGS).
Results : A total of 103 patients received ≥1 dose of DARA + pom-dex. Median (range) age was 64 (35-86) years. Median number of prior therapies was 4 (1-13) and 52% of patients had received >3 prior therapies; 89%, 71%, 30%, and 71% of patients were refractory to lenalidomide, bortezomib, carfilzomib, and a proteasome inhibitor + immunomodulatory drug, respectively. Of the 87 patients with available cytogenetic profile, 25% were high-risk (18% del17p, 7% t[4;14], and 1% t[14;16]). 44% of patients had baseline grade 1 or 2 neutropenia (Chari A, et al. Blood . 2017 doi: 10.1182/blood-2017-05-785246; epub, ahead of print).
At the clinical cutoff date of June 16, 2017, a total of 82% of patients discontinued treatment due to progressive disease (51%), adverse events (AEs; 17%), patient withdrawal (4%), physician's decision (4%), death (4%), and other reasons (3%). Most common (>25%) grade 3 or 4 TEAEs were neutropenia (79%; febrile neutropenia [8%]) and anemia (28%). Serious AEs occurred in 57% of patients, and 19%, 22%, and 19% were related to DARA, pomalidomide, and dexamethasone, respectively. TEAEs leading to death occurred in 9% of patients; none were related to DARA.
At a median follow-up of 24.7 (range: 0.2-34.4) months, the ORR was 66% (12% stringent complete response [CR], 11% CR, 26% very good partial response [VGPR], and 18% partial response). The rates of ≥VGPR and ≥CR were 48% and 22%, respectively. Among responders, the median duration of response was 21.4 (95% CI, 13.6-not estimable [NE]) months. In the total study population, MRD-negative rates were 8%, 7%, and 2% at sensitivity thresholds of 10-4, 10-5, and 10-6, respectively. Median PFS was 9.9 months (95% confidence interval [CI], 5.4-15.4) and the 24-month PFS rate was 30% (95% CI, 21-40). Median OS was 25.1 months (95% CI, 15.6-NE) and the estimated 24-month survival rate was 52% (95% CI, 41-62).
Updated safety and efficacy data, including a listing of secondary primary malignancies based on longer follow up, will be presented at the meeting.
Conclusions: Adding DARA to pom-dex resulted in a safety profile consistent with that of the individual therapies. Deep, durable responses were observed, including MRD negativity, and the regimen was associated with encouraging OS in a heavily pretreated patient population. A phase 3 study evaluating DARA + pom-dex versus pom-dex in RRMM patients (APOLLO; NCT03180736) is ongoing.
Facon: Janssen, Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Weiss: Alnylam: Honoraria; Janssen: Research Funding; Janssen: Honoraria; Prothena: Honoraria; Prothena: Research Funding. Suvannasankha: Celgene: Research Funding; Bristol-Myers Squibb: Research Funding; Takeda: Research Funding; Janssen Pharmaceuticals: Research Funding. Arnulf: Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen, Amgen, Celgene: Honoraria. de Boer: Janssen: Employment. Wang: Janssen: Employment. Wu: Janssen: Employment. Chari: Array BioPharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biotest: Other: Research funding (to AC's institution); Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; Acetylon Pharmaceuticals: Other: Research funding (to AC's institution); Pharmacyclics: Research Funding; Bristol-Myers Squibb: Consultancy, Other: Research funding (to AC's institution); travel; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding. Lentzsch: British-Myers Squibb, Celgene, Janssen: Consultancy; Takeda: Speakers Bureau; Caelum BioSciences: Equity Ownership. Schecter: Janssen: Employment. Krishnan: Onyx: Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Celgene: Consultancy, Equity Ownership, Speakers Bureau; Sutro: Consultancy; Takeda: Speakers Bureau.
Asterisk with author names denotes non-ASH members.