A Phase I Study of Ruxolitinib, Lenalidomide, and Steroids for Patients with Relapsed/Refractory Multiple Myeloma

Abstract

Purpose: Ruxolitinib with lenalidomide and dexamethasone shows antimyeloma effects in vitro and in vivo. MUC1 leads to lenalidomide resistance in multiple myeloma cells, and ruxolitinib blocks its expression. Thus, ruxolitinib may restore sensitivity to lenalidomide. Therefore, a phase I trial was conducted to determine the safety and efficacy of ruxolitinib with lenalidomide and methylprednisolone for patients with relapsed/refractory multiple myeloma (RRMM) who had been treated with lenalidomide/steroids and a proteasome inhibitor and showed progressive disease at study entry.Patients and Methods: A traditional 3þ3 dose escalation design was used to enroll subjects in four cohorts with planned total enrollment of 28 patients. Subjects received ruxolitinib twice daily, lenalidomide daily on days 1-21 of a 28-day cycle, and methylprednisolone orally every other day. Primary endpoints were safety, clinical benefit rate (CBR), and overall response rate (ORR).Results: Twenty-eight patients were enrolled. The median age was 67 years and received a median of six prior treatments including lenalidomide and steroids to which 93% were refractory. No doselimiting toxicities occurred. The CBR and ORR were 46% and 38%, respectively. All 12 responding patients were refractory to lenalidomide. Grade 3 or grade 4 adverse events (AE) included anemia (18%), thrombocytopenia (14%), and lymphopenia (14%). Most common serious AEs included sepsis (11%) and pneumonia (11%).Conclusions: This phase I trial demonstrates that a JAK inhibitor, ruxolitinib, can overcome refractoriness to lenalidomide and steroids for patients with RRMM. These results represent a promising novel therapeutic approach for treating multiple myeloma (ClinicalTrials.gov number, NCT03110822).

Ruxolitinib reverses checkpoint inhibition by reducing programmed cell death ligand‐1 (PD‐L1) expression and increases anti‐tumour effects of T cells in multiple myeloma

“…Lastly, preclinical studies have shown that combining RUX with the immunomodulatory agent LEN led to reduced proliferation of MM cell lines and primary tumour cells derived from patients with MM 18 . These findings were supported by the results from a Phase I clinical trial, evaluating the safety and efficacy of RUX, LEN and steroids for treating patients with heavily previously treated MM 38 . RUX overcame refractoriness to LEN in nearly half of patients 38 .…”

“…18 These findings were supported by the results from a Phase I clinical trial, evaluating the safety and efficacy of RUX, LEN and steroids for treating patients with heavily previously treated MM. 38 RUX overcame refractoriness to LEN in nearly half of patients. 38 We have recently reported that one potential mechanism through which RUX may provide anti-MM effects is inhibition of M2 polarisation of macrophages.…”

“…Notably, JAK inhibitors have not been associated with the frequent and clinically significant IRAEs of other checkpoint inhibitors, which have limited their clinical utility. [31][32][33][34]38 Thus, JAK inhibitors may help overcome the immune resistance generated among patients receiving immune-based anti-MM therapy, perhaps allowing these treatment approaches to be more effective without the deleterious side-effects associated with checkpoint inhibitors.…”

Janus Kinase Signaling: Oncogenic Criminal of Lymphoid Cancers

“…In MM, Ruxolitinib treatment decreased expression of genes including JAK2, TYK2, IL-6 and IL-18, driving disease progression and inducing antophagosome accumulation [101]. In a phase I clinical trial, Ruxolitinib was able to overcome lenalidomide and steroid resistance for relapsed/refractory MM patients, with a clinical benefit rate of 46% and an overall response rate of 38%, respectively [102]. Hypersensitivity of Ruxolitinib was noted in one patient with CSF3R T618I mutation, in which there were decreased white cell numbers and neutrophil counts as well as a normalization of the platelet count [103].…”

Novel Non-Immunologic Agents for Relapsed and Refractory Multiple Myeloma: A Review Article

“…After preclinical models showed that ruxolitinib-a JAK 1 and 2 inhibitor-was active on MM cells and could restore sensitivity to lenalidomide, a phase I trial (n = 28, median of 6 prior treatments) with ruxolitinib, lenalidomide, and corticosteroids was therefore designed for RRMM patients. The ORR was 38%, and all of the responding patients were lenalidomide-refractory [65]. A phase I/II study investigating ruxolitinib with carfilzomib is also ongoing (NCT 03773107).…”