Vemurafenib (VEM) in Relapsed Refractory Multiple Myeloma Harboring BRAFV600 Mutations (V600m): A Cohort of the Histology-Independent VE-Basket Study
Authors: Raje Noopur , Chau Ian , Hyman David M. , Ribrag Vincent , Blay Jean-Yves , Tabernero Josep , Elez-Fernandez Maria Elena , Wolf Jürgen S. , Sirzen Florin , Yee Andrew , Faris Jason , Kaiser Martin , Landau Heather , Michot Jean-Marie , Veronese Luisa , Makrutzki Martina , Lasserre Susan Francis , Puzanov Igor , Baselga Jose 
Published: October 2019

Abstract
Background: Whole-genome sequencing has identified a 4-6% incidence of BRAF mutations in multiple myeloma (MM). We undertook a histology-independent, "basket" study of VEM in BRAF V600m-positive cancers (NCT01524978). Six disease cohorts were prespecified; remaining tumors were classified in a 7th "all-comers" cohort. Here we present preliminary efficacy and safety data for the MM cohort.
Methods: A multicenter, Simon, 2-stage adaptive design in patients with relapsed refractory BRAF V600m-positive MM who were receiving VEM (960 mg bid) until disease progression (PD) or unacceptable toxicity was used. Primary end point is investigator-assessed response rate (RR) at week 8 by International Myeloma Working Group criteria. Secondary objectives include overall RR, clinical benefit rate, duration of response, progression-free survival, overall survival, and safety. Stage 1 was complete after the 7th patient received a minimum of 8 weeks of treatment, died, or withdrew early from the study.
Results: Eight patients had been enrolled in the MM cohort at the time of the data cutoff (December 3, 2014). Data are presented on patients in stage 1. Twelve patients were screened, of which 4 patients did not meet eligibility criteria. Of the 8 patients enrolled in the study, 6 were men and 2 were women, with a median age of 64 years (range, 55-68). High-risk features were seen in 3 patients by cytogenetics and fluorescence in situ hybridization (FISH). Prior treatment included immunomodulators (IMiDs) in 100% of patients, proteasome inhibitors in 75%, and chemotherapy (melphalan, bendamustine, cytoxan, doxorubicin, etoposide, and cisplatin) in 87.5%. Patients had received between 2 and 7 lines of treatment before enrolling in the BASKET trial, and 5 were refractory to IMiDs or proteasome inhibitors, or both. Median duration of treatment was 3.3 months (range, 1-5) at the time of data cutoff; 3 patients continue to be treated and 5 patients discontinued study drug. Response data were available for 7 patients at the end of 2 cycles. One patient achieved partial response (PR); 4 patients had stable disease; 1 patient had progressive disease; and 1 patient response was reported as not evaluable (objective response rate [ORR] week 8, 14%; 95% confidence interval [CI], 0.4-57.9). Of the patients enrolled, 71% (95% CI, 29.0-96.3) had clinical benefit with single-agent VEM. Responses occurred beyond 2 cycles: 1 patient went on to achieve very good PR (after cutoff date, January 2015). Three patients experienced disease progression between study days 57 and 85, and 1 of these patients died as a result of progressive disease. Single-agent VEM was well tolerated, with a safety profile similar to that observed in melanoma patients. Seven patients (88%) had at least 1 adverse event (AE) of grade 3 or 4, and 3 patients (38%) had at least 1 serious AE, including sepsis and lower respiratory tract infection, that was attributable to the underlying disease. Toxicity was manageable, and 1 patient discontinued treatment because of lower respiratory tract infection and skin lesions. Dose modification was necessary in 5 of 8 patients because of toxicity.
Conclusions: This is the first mutation-specific clinical trial in MM. VEM has promising activity in patients with BRAF V600m-positive MM despite these patients being heavily pretreated. Because obvious clinical benefit for patients has been observed, the decision to recruit additional patients was made, and recruitment is ongoing. Updated efficacy results from all patients currently participating in the study will be presented.

Disclosures
Raje: Amgen: Consultancy; Celgene: Consultancy; Astra Zeneca: Research Funding; Eli Lilly: Research Funding; BMS: Consultancy; Roche: Consultancy; Takeda: Consultancy; Onyx: Consultancy. Off Label Use: Vemurafenib is a potent inhibitor of BRAF mutated at codon 600 (BRAFV600). Here we explored the efficacy of vemurafenib in multiple myeloma patients with BRAFV600 mutations.. Chau:Roche: Research Funding. Hyman:Chugai Pharma: Consultancy; Biotherapeutics: Consultancy; Atara: Consultancy, Honoraria. Ribrag:Gilead: Membership on an entity's Board of Directors or advisory committees; Esai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmamar: Honoraria, Membership on an entity's Board of Directors or advisory committees. Blay:roche: Research Funding. Tabernero:Taiho: Consultancy; Millennium: Consultancy; Merck: Consultancy; Amgen: Consultancy; Imclone: Consultancy; Chugai: Consultancy; Merck Serono: Consultancy; Boehringer Ingelheim: Consultancy; Eli Lilly: Consultancy; Celgene: Consultancy; Sanofi: Consultancy; Roche: Consultancy; Novartis: Consultancy; Symphgen: Consultancy. Wolf:Roche: Consultancy, Equity Ownership, Honoraria, Research Funding. Sirzen:F. Hoffmann-La Roche: Employment, Equity Ownership. Faris:Merrimack Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Roche: Research Funding; N-of-One-Therapeutics: Consultancy. Kaiser:Bristol-Myers Squibb: Consultancy; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Honoraria; Chugai: Consultancy. Veronese:F. Hoffmann-La Roche: Employment. Makrutzki:F. Hoffmann-La Roche: Employment. Lasserre:F. Hoffmann-La Roche: Employment, Other: Unspecified, Patents & Royalties. Puzanov:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Baselga:Roche: Consultancy.