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Ruxolitinib (rux) is an orally administered agent that selectively inhibits both JAK1 and JAK2, and is currently approved by the FDA for the treatment of myelofibrosis and polycythemia vera. It has been shown to enhance the activity of lenalidomide and dexamethasone in suppressing the growth of both multiple myeloma cell lines, primary cell lines derived from patients, and in xenograft models in immunodeficient mice. In an oral abstract presented at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting, data from a phase I study of ruxolitinib, lenalidomide, and methylprednisolone to treat relapsed and refractory multiple myeloma (RRMM) patients, was shown. The study was conducted by James R. Berenson from the Institute for Myeloma and Bone Cancer Research, California, US, and colleagues.
Dr Berenson began with an explanation as to the rationale behind this combination. It has been shown that MUC1 expression is increased in the bone marrow (BM) of myeloma patients, especially when these cells are bound to stromal cells, leading to translocation of beta-catenin to the nucleus and up-regulation of CD44, and in turn, this leads to lenalidomide resistance. Stromal cell interactions also drive increased expression of CXCL12, CXCR4, and TRIB1, leading to M2 polarization and further tumor cell stimulation. Ruxolitinib acts to suppress MUC1, PDL1/PD-1, CD44, and CX12/CXCR4, and down-regulates TRIB1, leading to a marked reduction of M2 expression. Overall, the outcome is depression of tumor stimulation and warranted further exploration of ruxolitinib a phase I trial in combination with lenalidomide, and methylprednisolone. The primary endpoint was to determine the maximum-tolerated dose (MTD) and to establish safety and tolerability at this dose; secondary endpoints include progression-free survival (PFS) and duration of response (DoR). The trial used a classic 3 + 3 dose escalation and recruited patients (pts) with progressive disease that had received 3 or more prior lines of therapy, and failed treatment with both lenalidomide and a proteasome inhibitor (PI).
This preliminary data is extremely promising in terms of both efficacy and safety and it is particularly encouraging that benefits were observed in heavily pre-treated patients that were refractory to lenalidomide. As an all-oral regimen, this offers convenience for patients and warrants further evaluation in a phase II trial. Interestingly, baseline BCMA measurements correlated with PFS and response, suggesting that BCMA could be a useful biomarker to track response to treatment. BCMA has the advantage of a higher turnover rate allowing quick assessment of response, is independent of renal function, and is more reliable than serum free light chain (SLFC) measurements.
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