Exploring the Potential Role of JAK Inhibitors in Multiple Myeloma

CancerNetwork® spoke with James R. Berenson, MD, about the potential role that JAK inhibitors may play in the treatment of patients with multiple myeloma. The conversation focused on the rationale for researching this drug class as well as ongoing initiatives to assess the utility of agents like ruxolitinib (Jakafi) for this patient population.

Berenson, founder, medical and scientific director, and president and chief executive officer of the Institute for Myeloma and Bone Cancer Research and private practitioner in West Hollywood, California, described the factors associated with the overexpression of JAK in the bone marrow, which may constitute a prime survival factor for multiple myeloma. This overexpression may affect the checkpoint inhibitor proteins in the body, resulting in resistance to standard anti-myeloma therapies such as immunomodulatory drugs. 

Additionally, he mentioned a patient case that had involved a scenario in which JAK-mutated multiple myeloma progressed following prior treatment with lenalidomide (Revlimid). According to Berenson, the disease’s resistance to lenalidomide was primarily associated with proteins driven by JAK; subsequent treatment involving JAK inhibition proved successful in restoring the efficacy of lenalidomide. 

Based on a rationale to target JAK overactivity in the bone marrow and results from this patient case, Berenson and colleagues have focused on researching ruxolitinib as a therapeutic candidate for potentially improving outcomes in multiple myeloma via JAK inhibition. Findings from a phase 1 trial (NCT03110822), for example, have demonstrated that the efficacy and tolerability of ruxolitinib plus methylprednisolone can be extended with lenalidomide in those with multiple myeloma. Additionally, other ongoing trials aim to combine ruxolitinib with agents such as selinexor (Xpovio).

“The question is, where will ruxolitinib sit in the sequencing of treatment of [patients with] multiple myeloma? Where will selinexor be?” Berenson stated. “At this point, there's certainly been low use of these drugs, especially ruxolitinib in multiple myeloma. We hope, with a more positive signal, these drugs will move further up in the algorithm of how you treat multiple myeloma.”

Reference

Berenson JR, Limon A, Rice S, et al. A phase I trial evaluating the addition of lenalidomide to patients with relapsed/refractory multiple myeloma progressing on ruxolitinib and methylprednisolone. Target Oncol. 2024;19(3):343-357. doi:10.1007/s11523-024-01049-w