The Mydrug Platform Trial: Efficacy and Safety of Daratumumab, Ixazomib, Pomalidomide, and Dexamethasone in Patients with Functionally High-Risk Multiple Myeloma

Background: Multiple myeloma (MM) is an incurable malignant neoplasm with a 5-year relative survival rate of 57.9%. Many new agents have improved overall survival; however, some patients rapidly relapse and develop multidrug resistance, which requires the use of new approaches and drug mechanisms to treat. Precision medicine targeting specific genetic abnormalities has the potential to overcome related inherent and/or acquired resistance in patients with MM, but studying this approach has several limitations. Many different mutations occur in MM, and mutation frequency increases with disease progression and relapse, making it difficult to determine dominant genetic abnormalities and assess their relevance to a particular patient. This is a critical factor, as mutations in certain cancer-associated genes (actionable mutations) are targeted by approved drugs for other cancers. Some mutations are found in only a small number of patients. In addition, a substantial subset of patients appear to lack actionable mutations or have low allelic burden, making recruitment to clinical trials studying one specific mutation operationally difficult. To overcome these challenges and understand the role of novel therapies in precision medicine, the MMRF launched MyDRUG, a platform trial of patients with select actionable genetic mutations.

Methods: MyDrug (NCT03732703) is an open-label, multicenter, phase 1/2 platform study of adult patients with functionally high-risk MM (defined as early relapse after initial MM treatment), who have received 1-3 prior therapies. Through different subprotocols, patients received targeted agents or immunotherapy/novel agents in combination with a backbone regimen of ixazomib, pomalidomide, and dexamethasone (IPd). Each subprotocol planned to enroll up to 38 patients, and treatment assignment was based on individual genetic sequencing results as determined by Next-Generation Sequencing assay performed in a CLIA-certified Molecular Characterization Laboratory. Approximately 75% of subjects were expected to have actionable mutations (BRAF, NRAS, KRAS, FGFR3, IDH2, CDK activating) or t(11;14) based on historic data, although not all of these would have the necessary allelic burden of ≥30% to qualify for the targeted subprotocols. Patients with no actionable mutation or mutations with allelic burden below 30% were assigned to the Y1 arm and received daratumumab at the standard dose and schedule in combination with IPd. The primary objective of the Y1 sub-protocol was to evaluate the overall response rate (ORR) according to the International Myeloma Working Group consensus criteria. Secondary objectives included assessment of adverse events (AEs). Confidence intervals were computed using the Clopper-Pearson (exact) method.

Results: Thirty-eight patients were enrolled to the Y1 daratumumab arm with a median (range) age of 63 (46-79) years, with 16 (42.1%) patients of ages 65-74 and 2 (5.3%) patients ≥75 years. Thirteen (34.2%) patients were female, and 8 (21.1%) patients were Black or African American. The ORR for patients receiving daratumumab plus IPd was 92.1%, and 19 (50%) patients had a very good partial response. Thirty-seven (97.4%) patients experienced treatment-related AEs, 35 (92.1%) of which were related to daratumumab. Among patients receiving treatment, 22 (57.9%) experienced a serious AE; 3 (7.9%) experienced an AE leading to discontinuation; and 2 (5.3%) had fatal AEs.

Conclusions: In this platform study of adult patients with treatment refractory, functionally high-risk MM, patients who received daratumumab plus IPd exhibited significant efficacy and a manageable AE profile.

Kumar:AbbVie,: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: 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; Takeda,: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive,: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE,: Research Funding; MedImmune/Astra Zeneca,: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck,: Research Funding; Novartis,: Research Funding; Roche: Research Funding; Sanofi: Research Funding; Oncopeptides: Other: Independent review committee. Hofmeister:Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; BlueBird Bio: Honoraria; Genzyme: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Sanofi: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees. Biran:Sanofi: Consultancy; Janssen: Consultancy, Research Funding; Amgen: Research Funding; Karyopharm: Research Funding; BMS: Consultancy, Research Funding; Merck: Research Funding; Abbvie: Consultancy. Kaur:UT Southwestern: Consultancy, Current Employment. Ye:Sanofi: Research Funding; Karyopharm Therapeutics: Research Funding; Nektar Therapeutics: Research Funding; Portola Pharmaceuticals: Research Funding; GSK: Research Funding; Regeneron: Research Funding; Janssen: Honoraria, Research Funding; Genmab: Research Funding; Mingsight Pharmaceuticals: Research Funding; BMS: Honoraria. Zonder:Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Current Employment, Research Funding; Alnylam, Amgen, Caelum Biosciences, Celgene, Intellia, Janssen, Prothena, Regeneron: Consultancy; Alexion, AstraZeneca Rare Diseas: Research Funding; Janssen: Research Funding. Cho:Takeda: Other: Receive laboratory research support from the above companies. Salary value is less than $10,000 per company., Research Funding; BMS/Celgene: Other: Receive laboratory research support from the above companies. Salary value is less than $10,000 per company., Research Funding.

Daratumumab is a first-in-class, human immunoglobulin G1 kappa (IgG1k) (mAb) that binds malignant cells expressing CD38 with high affinity and induces tumor cell death through several immune-mediated mechanisms of action, including complement-dependent cytotoxicity, antibody-dependent cellular phagocytosis, antibody-dependent cell-mediated cytotoxicity, induction of apoptosis, and modulation of CD38 enzyme activities.