BRAF V600E Mutations in Multiple Myeloma: Clinical and Therapeutic Implications

Activating mutations of the serine/threonine kinase BRAF are observed in various solid and hematologic malignancies with the point mutation V600E being the most common. However, both frequency and relevance of the mutation differ greatly between entities. This year, a small molecule inhibitor specifically targeting V600E-mutated BRAF has been approved for metastatic melanoma. Recently, BRAF mutations in multiple myeloma (MM) have been reported by several groups in the context of next generation sequencing projects. However, the clinical relevance of these mutations remains unclear.

We report on frequency and clinical characteristics of MM patients harboring the BRAF V600E mutation. Furthermore, first clinical data on treatment with vemurafenib in MM with BRAF V600E mutation is presented.

A V600E-mutation specific monoclonal antibody was recently developed at our institution. We screened 338 tissue samples by immunohistochemistry (315 bone marrow, 23 soft tissue plasmocytoma) from 310 patients with monoclonal gammopathy collected at out center between April 1999 and May 2011. Positive results were verified by direct sequencing. Of 310 analyzed patients, 205 had symptomatic MM, 12 symptomatic light chain amyloidosis, 45 smoldering MM and 48 MGUS. MM subtypes comprised 174 IgG, 60 IgA, 55 Bence Jones, 14 IgM, 4 IgD, 1 biclonal, 4 asecretory. From 25 patients serial bone marrow samples or tissue from different compartments were available. Median age at biopsy was 61.4 years (range 29–87) and 244 samples were obtained at from newly diagnosed patients.

Six patients (2%) were positive for BRAF V600E mutation both by immunohistochemistry and by confirmatory sequencing. A brief overview of patient characteristics is shown in Table 1. Five patients received bortezomib-based first line treatment whereas one received conventional chemotherapy. Four patients underwent autologous transplantation. Interestingly, PFS after start of first-line treatment was relatively short with a median PFS of 10.5 months. Remarkably, four of these six patients developed extramedullary myeloma in their disease course (soft tissues in 2, CNS in 1, both soft tissues and CNS in 1). In two of these patients a re-biopsy after two and three lines of therapy, respectively, was available. In both cases the mutation remained present in all cells without signs of clonal evolution in regard to BRAF V600E.

One of the BRAF V600E positive patients had relapsed with multiple soft tissue plasmocytomas after autologous transplantation followed by multiple treatment lines containing bortezomib, lenalidomide and bendamustine. After informed consent we started the patient on vemurafenib 480mg BID and increased the dosage to 720mg BID after one week. Vemurafenib was well tolerated and no grade III/IV adverse events were noted. Already after the first cycle (four weeks), a partial response was achieved according to IMWG and RECIST criteria for serological and radiological assessment, respectively. As assessed by immunohistochemistry, a dramatic decrease in proliferative activity (MIB-1) accompanied by a sharp increase in apoptosis, as well as loss of MAP kinase signaling (p-ERK) could be observed in tumor samples under treatment with vemurafenib.

Immunhistochemistry is a rapid and reliable method for the detection of BRAF V600E and provides a useful tool especially if applied to entities with low mutation frequency, such as MM. In our cohort, however small, patients harboring the mutation show a conspicuous course of disease with a comparably short PFS and an unusually high frequency of extramedullary myeloma. Individualized treatment with vemurafenib seems feasible and rapid response was observed. A detailed follow-up of the clinical course will be presented at the meeting.

Off Label Use: Vemurafenib is a BRAF inhibitor FDA approved for treatment of metastatic melanoma.