Improving Outcomes for Multiple Myeloma Patients through Novel Therapeutic Interventions

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PROJECT SUMMARY Multiple myeloma (MM) is an incurable blood cancer affecting approximately 83,000 people in the United States. Although treatments for MM have improved significantly in recent years, the vast majority of patients experience multiple relapses and ultimately succumb to complications of the disease. For the last 12 years, I, the Research Specialist, have devoted my work toward contributing to improving outcomes for cancer patients. Since 2014, I have worked in the laboratory of Unit Director Flavia Pichiorri, where we exclusively specialize in MM. I am now involved with three National Cancer Institute–funded studies. 1) Radioimmunotherapy/CAR T cells: The use of therapeutic isotopes such as the beta emitter 177Lu or the alpha emitter 225Ac have increased the specific killing of cancer cells, but side effects are clinical concerns. Although CAR T cells may reduce tumor burden, patients remain at risk of relapse. We predict that the use of CD38-directed radioimmunotherapy and CS1-directed CAR T cells will result in more durable remissions while lowering the dose for each agent, with decreased side effects and enhanced immunomodulation. 2) Reolysin: Reolysin, an oncovirus, shows only modest activity in MM patients, likely because of resistance mechanisms to oncoviruses. We observed that carflizomib, a second generation proteasome inhibitor, showed synergic killing of MM cells in vitro when combined with Reolysin. We found that carfilzomib facilitates Reolysin infection through modulation of the antiviral response of the microenvironment. We also discovered that HDAC inhibitors can reduce the surface expression of an important adhesion receptor and upregulate the expression of an oncovirus receptor. 3) Overcoming IMiD research in myeloma: To overcome disease resistance to immunomodulatory drugs (IMiDs) such as lenalidomide (Len), combinatorial therapies may be necessary. I have investigated the safe, orally available drug leflunomide (Lef), which has been used for rheumatoid arthritis for the last 20 years. We demonstrated that Lef directly inhibits several kinases, including the PIM family of serine/threonine kinases in MM cells, negatively affecting c-Myc protein levels, which are commonly upregulated in MM. With this information, we reasoned that a suitable drug to use in combination is the immunomodulatory drug lenalidomide (Len). The completion of the projects’ goals will rely in large part on my qualifications, and the results thus far point to my value as a Research Specialist in the cancer research community.