Multiple Myeloma Drug Resistance: New Immunotherapies May Improve Survival

Increasing genetic complexity over time allows multiple myeloma to acquire drug resistance, but immunotherapies that overcome this hurdle might improve overall survival.
Increasing genetic complexity over time allows multiple myeloma to acquire drug resistance, but immunotherapies that overcome this hurdle might improve overall survival.

Multiple myeloma evades and disables antitumor immunity. Unmasking this disease to immune cells and stimulating antitumor immunity might yield better survival outcomes for this daunting diagnosis, experts told Cancer Therapy Advisor.

“Immune dysregulation has an important role in the pathogenesis of multiple myeloma,” explained Irene M. Hutchins, MD, of the Scripps Clinic in La Jolla, California. “Novel therapies are focused on restoring immune response against myeloma cells and overcoming the tumor's immune escape mechanisms.”

Immunotherapy should be particularly well-suited to treating multiple myeloma, agree experts like Sagar Lonial, MD, FACP, chief medical officer and chair of the department of hematology and medical oncology at Emory University's Winship Cancer Institute in Atlanta, Georgia.

“One of the main reasons for this is the number of cell surface markers on myeloma cells that are unique,” Dr Lonial said. “That makes them attractive targets for immunotherapy.”

These cell surface markers tend to be more stable through time than tumor signaling-pathway gene targets. This stability might allow clinicians to circumvent acquired tumor drug resistance — a frequent problem for targeted therapies.1

Molecular rearrangements like RAS mutations cause abnormal signaling within tumor cells. Because tumors become more genomically unstable and acquire more and different gene mutations over time, an anticancer agent that targets a particular tumor signaling pathway can become ineffective.

A hallmark of multiple myeloma is immunosuppression or tumor-mediated “immune paralysis.” Agents that reverse this paralysis could allow patients' immune systems to recognize and attack myeloma cells. Used in combination, different types of immunotherapy agents might work in concert by blocking different mechanisms by which cancer cells disable and evade immune cells.

Immunotherapy comes in “different flavors,” Dr Lonial noted. “There's immunotherapy that's as simple as monoclonal antibodies [mAbs], like elotuzumab, which target something specific. Those are in some ways ‘immunotherapy' because they have impacts on immune function.”

Elotuzumab and daratumumab have both “significantly improved response rates in the relapsed and refractory setting, with minimal added toxicity,” Dr Hutchins noted.2 “The optimal sequencing of these agents has not yet been established; future data will determine if they have a role in frontline or maintenance therapy.”

The list of mAbs that are under study for multiple myeloma is long and growing. Tabalumab is undergoing phase 2 clinical study, and isatuximab, indatuximab, pidilizumab, pembrolizumab, and atezolizumab are undergoing clinical study in combination with lenalidomide. Elotuzumab is under study in combination with lirilumab and urelumab in phase 1 trials.

Numerous other immunotherapeutic strategies are also under investigation for treating myeloma, including immune checkpoint inhibitors, chimeric antigen receptor T cells (CAR-T) therapies, bi-specific antibodies such as bi-specific T-cell engagers (BiTES), and vaccines.1-5

Engineered to target myeloma cell surface antigens to stimulate immune T-cell attacks and to kill myeloma cells, CAR-T therapies are particularly promising.1-3 CD19 (CTL019)-targeting CAR-T therapy may prolong time to relapse following complete response (CR).1

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