A Phase 1 Study of Ruxolitinib, Steroids and Lenalidomide for Relapsed/Refractory Multiple Myeloma (RRMM) Patients

Multiple myeloma (MM), a plasma cell dyscrasia, is the most common primary malignancy of the bone marrow.The etiology of myeloma is largely unknown, although genetic predisposition and environmental factors have been speculated. MM arises from malignant plasma cells that clonally expand and accumulate in the bone marrow. These clonal plasma cells produce high levels of monoclonal immunoglobulins. Plasma cell dyscrasias are classified as monoclonal gammopathy of undetermined significance, solitary plasmacytoma, smoldering myeloma, active myeloma, extra-skeletal myeloma, or plasma cell leukemia.

In 2015 an estimated 26,850 adults (14,090 men and 12,760 women) in the United States will be diagnosed with multiple myeloma. It is estimated that 11,240 deaths (6,240 men and 5,000 women) from this disease will occur this year.

In recent years, new and more effective drugs have become available for the treatment of MM. Such drugs have been evaluated together and in combination with older agents, rapidly increasing the number of therapeutic options available to MM patients, and resulting in an improvement in their overall survival (OS) rates. Among the drugs that have been FDA approved specifically for myeloma are the immunomodulatory agents (IMiDs) thalidomide, and its newer analogs lenalidomide and pomalidomide.

IMiDs exert their anti-neoplastic action by affecting various cancer cell functions and the microenvironment, including cytokine production, immune cell function, and in some instances, inflammation, cell proliferation and cell death. The IMiD thalidomide has been found to be effective as an anti-MM agent in one-third of myeloma patients; notably, higher response rates have been observed when combined with steroids. Lenalidomide is an analog of thalidomide that has shown more potent anti-MM activity than thalidomide in preclinical studies, and has been FDA-approved for the treatment of previously untreated as well as relapsed or refractory MM (RRMM) in combination with dexamethasone. Recently, an analog of thalidomide and lenalidomide, pomalidomide, has also been approved for RRMM patients.

The 5-year survival rate for MM patients has increased from 25% in 1975 to 34% in 2003 and is currently closer to 40% due to these newer and more effective treatment options. Unfortunately, even with these newer agents, responses to therapy are transient, and MM remains an incurable disorder with an eventual fatal outcome; and, therefore, new therapies are urgently needed.

JAK2 is an intra-cytoplasmic tyrosine kinase that belongs to the Janus kinase family. JAK kinases play a major role in the transmission of signals from cytokine and growth factor receptors into the nucleus. JAK kinases activate several intracellular signaling proteins, among which the STAT transcription factors are well defined. The JAK/STAT pathway mediates diverse cellular events that affect cell growth, differentiation and cell survival.