Ruxolitinib and methylprednisolone for treatment of patients with relapsed/refractory multiple myeloma

Abstract

Multiple myeloma (MM) is a bone marrow (BM)-based malignancy that causes uncontrolled clonal development of malignant plasma cells. 1,2 In the United States, approximately 35 000 new cases of MM were projected in 2021, with an estimated 12 500 deaths. 1 The malignant cells and other cells in these patients' BM are linked to the clinical manifestations of MM. These cells produce monoclonal immunoglobulins and cytokines that affect patients' bones, BM and associated blood counts, immunological system and kidneys. 2 Janus kinase (JAK) inhibitors have shown efficacy in treating auto-immune disorders and myeloproliferative neoplasms, including polycythaemia vera (PV) and myelofibrosis. Specifically, ruxolitinib, an oral JAK1 and JAK2 selective inhibitor, was approved by the Food and Drug Administration (FDA) for the treatment of intermediate and high-risk myelofibrosis as well as

Preclinical and clinical evaluation of the Janus Kinase inhibitor ruxolitinib in multiple myeloma

“…In a recent preclinical study, we have shown that treatment with RUX is capable of increasing MM cell apoptosis when combined with IL-2-stimulated T cells [23]. This is similar to the effects of anti-PD-1 or anti-PD-L1 antibodies but does not appear to be associated with the immune-related adverse events (IRAEs) that commonly occur with the administration of these types of antibodies [18,19,25]. We have shown that treatment of MM patients' BM mononuclear cells (MCs) with RUX, even at low concentrations, reduces both the proportion of PD-L1 expressing cells and levels of PD-L1 expression [23].…”

“…Success in preclinical research using JAK inhibitors for the treatment of MM has further prompted early-phase clinical studies. For example, RUX is being studied as part of an all-oral treatment regimen [18][19][20] that addresses many of the current issues that occur with regimens containing IMiDs, PIs, and monoclonal antibodies. The following sections of this article will be focused on studies of RUX in the preclinical [21][22][23][24] and clinical settings [18][19][20] focused on the treatment of relapsed/refractory (RR) MM.…”

“…Considering these observations, the phase 1 study was amended to assess the efficacy of RUX with steroids alone for treating RRMM patients [ 18 ]. The study enrolled and treated 29 patients who had previously undergone extensive prior treatments, including a median of 6 (range 3–12) lines of therapy, all with prior exposure to PIs and LEN.…”

Case report: Refractory Evans syndrome in two patients with spondyloenchondrodysplasia with immune dysregulation treated successfully with JAK1/JAK2 inhibition

“…There is no documented association between STAT-1 loss-of-function and multiple myeloma ( 36 ). In contrast, recent clinical approaches have demonstrated some success in treating refractory multiple myeloma using a combination of ruxolitinib, corticosteroids, and lenalidomide ( 37 ). Given the scarcity of literature specifically addressing baricitinib in the context of multiple myeloma, we have elected to continue treatment with ruxolitinib in patient #1.…”

Definers and drivers of functional high-risk multiple myeloma: insights from genomic, transcriptomic, and immune profiling

“…For example, the aforementioned JAK/STAT3 pathway has been shown to be activated preferentially in cells from patients with FHRMM ( 36 , 37 ). Ruxolitinib, a known inhibitor of the JAK/STAT3 pathway approved for myelofibrosis, has been shown in a Phase 1 trial to lead to responses in approximately a third of patients with relapsed/refractory MM ( 94 ). Interestingly, preclinical studies suggest that ruxolitinib may also lower PD-L1 expression on MM cells and interfere with other pro-growth pathways ( 95 , 96 ).…”