P-090: BRAF V600E multiple myeloma patient salvaged with triple MAPK inhibition after CAR T relapse

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<h3>Background</h3> Despite a growing arsenal of treatment choices, patient relapse post-BCMA-targeted CART therapy remains a challenge and the therapeutic path is still undefined. Among the most frequently observed actionable mutations, BRAF V600E, is present in ~7% of multiple myeloma (MM) patients. The availability of selective inhibitors of BRAF V600E makes this a valuable therapeutic target. However, the clinical efficacy of these inhibitors has been limited and short-lived, frequently due to feedback-induction of BRAF dimers. Novel studies revealed that the multi-kinase inhibitor regorafenib is a potent and selective inhibitor of dimeric BRAF. They have further demonstrated relief of these negative outcomes by inhibiting BRAF in both its monomeric and dimeric form in combination with MEK inhibition leading to more efficacious and tolerable treatment. (Adamopoulos C. et al. Cancer Discov. 21). We present a case of a MM patient with BRAF V600E mutation salvaged with a triple therapy inhibition strategy after relapsing following anti-BCMA CART therapy. <h3>Method</h3> A 61-year-old male with penta-refractory MM (IgA lambda), ISS stage 3 with hyperdiploidy, gain of 1q21 and del13 was treated with anti-BCMA CART therapy, achieving a best response of VGPR, and disease progression after 6 months. He was temporarily salvaged with BCNU/Mel ASCT and achieved a best response of PR until progression with extramedullary disease (subcutaneous skin lesions in lower extremities) and elevated lambda free light chains (FLC, 126.4mg/l) at 6 months. <h3>Results</h3> Targeted sequencing showed a BRAF V600E mutation was present prior to CART therapy in his bone marrow and persisted in his bone marrow and a plasmacytoma with a VAF of 41% at this current relapse. A western blot analysis of bone marrow aspirate confirmed BRAF V600E with a specific antibody, and showed phosphorylation of ERK, which was diminished with trametinib. Longer exposure to trametinib confirmed a feedback loop activating MAPK which was abrogated with the BRAF dimer inhibitor regorafenib. With these findings the patient was started on targeted therapy based on combination of a BRAF monomer-inhibitor, dabrafenib (100mg, orally twice daily), a MEK-inhibitor, trametinib (1.5mg, orally for 21/28 days daily), and a BRAF dimer inhibitor, regorafenib (40mg, orally once daily). Within 3 months of treatment initiation, prompt reduction in subcutaneous skin lesions and 80% reduction in free lambda FLC (27.5 mg/l) was observed. Furthermore, the patient had good tolerance to all three medications with minimal side effects (grade 1 fatigue) and continues treatment. The treatment regimen allowed the patient to carry out activities of daily living and return to work. <h3>Conclusion</h3> Post-CART failure treatment is a challenging and unmet need. NGS may identify targeted therapy that would be able to salvage patients with a tolerable side effect profile.