Ruxolitinib and Methylprednisolone for Treatment of Patients with Relapsed/Refractory Multiple Myeloma

Although JAK inhibitors alone have demonstrated efficacy for treating a variety of autoimmune diseases and hematologic disorders, including myelofibrosis and polycythemia rubra vera, clinical studies have not shown their effectiveness for treating cancer patients. Preclinical data from our laboratory and others show that the selective JAK1/2 inhibitor ruxolitinib (RUX) inhibits multiple myeloma (MM) growth both in vivo and in vitro. We have recently shown in a phase 1 trial that heavily previously treated MM patients who were refractory to the immunomodulatory agent lenalidomide and glucocorticosteroids often achieve responses with the addition of RUX (Berenson et al. Clin Cancer Res. 2020;26:2346-2353). No dose-limiting toxicities were observed at the maximally administered doses of this all oral regimen of RUX 15 mg twice daily continuously, methylprednisolone (MP) 40 mg every other day, and lenalidomide 10 mg daily for 21 days of a 28-day cycle. Because RUX and glucocorticosteroids without lenalidomide showed anti-MM activity preclinically, we amended the trial to evaluate RUX and MP at these same doses and schedules without lenalidomide for MM patients with progressive disease who had all received glucocorticosteroids, a proteasome inhibitor and lenalidomide, ≥ 3 prior regimens, and had a CrCl ≥60 mL/min. Planned enrollment was 29 MM patients. Exploratory objectives included determination of predictors of outcomes through univariate and multivariate Cox proportional hazard models. The univariate Cox proportional hazard model was run utilizing variables including the levels of baseline serum B-cell maturation antigen (sBCMA), serum monoclonal protein and serum free light chains, prior number of treatments, age, gender, and cytogenetic markers. Further analysis was done using the multivariate Cox proportional hazard model for these variables. All patients have been enrolled with follow up until April 28, 2022. The median age was 64 years (range, 46-85) with 62% male (n = 18). Median lines of prior therapy were 6 (range, 3-12). Cytogenetics and FISH were evaluable in 28 patients; 70% had high-risk cytogenetic markers. Overall response rate was 31% (1 VGPR and 8 PR). Two-thirds of responding patients had high-risk cytogenetic markers. The median duration of response was 13.1 mo (range, 2.8-22.0). Progression-free survival (PFS) ranged from 0.5-24.6 mo (median 3.4); responders and non-responders had medians of 15.6 mo (range, 3.5-24.6) and 1.6 mo (range, 0.5-9.9), respectively. Baseline sBCMA levels were lower among responders compared with non-responders (median 65.28 ng/mL vs. 172.5 ng/mL). Previous retrospective studies have shown that baseline sBCMA levels predict PFS among relapsed/refractory (RR)MM patients who started a new therapy, and this was also shown in a prospective study for those treated with RUX, MP and lenalidomide. The results in this study among patients who received RUX and MP without lenalidomide also showed that higher baseline sBCMA levels (p = 0.0096) and, in addition, t(14;16) (p = 0.0071) predicted shorter PFS. Overall, the treatment was well tolerated, and only 1 patient reduced their dose of RUX. The results of this clinical trial showed that the combination of RUX 15 mg twice daily with methylprednisolone 40 mg every other day was well tolerated and demonstrated significant clinical activity among heavily previously treated patients with multiple myeloma. Notably, responses were achieved among many patients who had high-risk cytogenetics. This study is the first to show that JAK inhibitors alone have clinical activity for treating cancer patients. Based on these promising results, we are further evaluating higher doses of RUX in combination with methylprednisolone for the treatment of RRMM patients.