Myeloma developing regimens using genomics (MyDRUG) trial: Results from the RAS mutation targeting arm.
Authors: Kumar Shaji , Bianchi Giada , Biran Noa , Hultcrantz Malin , Richter Joshua Ryan , Vij Ravi , Ye Jing Christine , Zonder Jeffrey A. , DiLello Lauren , Yesil Jen , Cho Hearn J. 
Published: June 2022

8055 Background: Multiple myeloma (MM) is characterized by somatic mutations involving cancer-associated genes. The most commonly mutated genes are N- and K-Ras, which increase in prevalence as the disease progresses. Case reports and retrospective data suggest efficacy of targeting the MAPK pathway in N/K-Ras mutated MM. The MyDRUG trial was initiated to explore the efficacy of specific molecularly-targeted therapies in combination with standard therapies in MM. Methods: MyDRUG (NCT03732703) is a genomically-guided umbrella trial for patients with functional high-risk MM, defined as early relapse following primary therapy (3 years for transplant with maintenance, 18 months without), with specific genetic abnormalities. Subjects undergo molecular profiling of their MM cells and are assigned to a targeted arm if a variant allele frequency (VAF) over 25% is identified. The targeted mutated genes and respective agents (approved for non-MM indications and with a known phase 2 dose) are: KRAS/NRAS/BRAF (cobimetinib), FGFR3 (enasidenib), IDH (erdafitinib), CDKN2C (abemaciclib), t(11;14) (venetoclax). Patients receive the investigational drug for 2 cycles as a single agent followed by addition of an active MM combination (ixazomib, pomalidomide and dexamethasone, IPd). Limited dose escalation was performed with the single agent followed by dose assessment in combination with IPd. Here we present the results of the dose escalation portion of C1 arm exploring cobimetinib in patients with N/K-RAS or BRAF mutations. Cobimetinib was administered at 40 mg daily in combination with standard doses of IPd. Results: Eleven subjects with BRAF/RAS mutations were screened between August 2019 and October 2020, with 4 screen failures. Seven were enrolled, 5 males, median age 65 years, and median time from diagnosis of 30 months. N-RAS, K-RAS or BRAF mutations were seen in 4, 2, and 1 subject(s), respectively, with VAF ranging from 33-93%. Median number of prior lines of therapy was 1 (1-3), 3 patients had extramedullary disease, and 1 patient had high risk cytogenetics. Median duration of therapy was 12 months. One patient was not evaluable for dose limiting toxicity. All but 1 patient had at least one cycle delayed due to adverse events (AEs), but no dose reductions were required. No dose limiting toxicities were observed across the cycles, either during single agent therapy (Cycles 1-2) or in combination with IPd (Cycles 3 and 4). Six patients responded to therapy (4 PR, 2 VGPR). One patient was not response evaluable. Fatigue was the most common non-hematological AE followed by diarrhea. Conclusions: Here we report on the feasibility of genomically-guided, precision medicine therapy in K/N-RAS/BRAF-mutated MM. The MEK inhibitor cobimetinib in combination with IPd appears safe in functionally high-risk patients. Ongoing study will provide more information regarding the efficacy of this approach. Clinical trial information: NCT03732703.