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Three-Drug Combos, Immunotherapy Mark Future of Myeloma Management

Laura Panjwani
Published: Wednesday, Apr 08, 2015

Sundar Jagannath, MD

Sundar Jagannath, MD

New drug combinations and immunotherapies have significantly expanded treatment options for myeloma. Numerous studies, including the ASPIRE and ELOQUENT-2 trials, have shown positive results for triple drug combinations. Additionally research into natural killer cells and monoclonal antibodies has further solidified the potential for immunotherapy to advance myeloma treatment.

In an interview with OncLive, Sundar Jagannath, MD, director of the Multiple Myeloma Program at the Tisch Cancer Institute, professor of Medicine (Hematology and Medical Oncology), Mount Sinai School of Medicine, discusses the latest research advances in myeloma, and how these steps will impact the future treatment paradigm for the disease.

OncLive: What recent advances in relapsed myeloma treatment are the most significant?

Dr Jagannath: The last ASH meeting (December 2014) was like a watershed period.  We heard about the ASPIRE trial results. It was lenalidomide and dexamethasone with or without carfilzomib in relapsed myeloma patients. This was the first trial that showed a three-drug combination—a proteasome inhibitor, lenalidomide and dexamethasone—was better than using lenalidomide and dexamethasone alone.

This was important because, often, we’ve all been using bortezomib, lenalidomide, and dexamethasone in newly diagnosed myeloma patients without a clear-cut randomized trial giving us evidence-based medicine that the three drugs are better than the two. More importantly, the complete response rate was very high, the response duration or progression-free survival was better, and there was a trend for improvement in overall survival.

At the same ASH meeting, another study showed that pomalidomide with dexamethasone was also given to relapsed myeloma patients with or without cyclophosphamide. Here, the three-drug combination was again better than the two.  Moreover, the three-drug combination actually showed a trend in improvement in survival, showing that you have to do the best therapy upfront, especially in relapsed patients. If you wait for the patient to relapse again, the patient’s general condition is not good and the disease is more refractory, so it is better to use optimal therapy upfront.

The same thing was repeated with pomalidomide, dexamethasone and bortezomib in another trial that was positive. The ELOQUENT-2 trial also came out positive. This looked at the three-drug combination of lenalidomide and dexamethasone with or without elotuzumab. This is an important theme right now.

Based on these studies, how would you best select therapy for a myeloma patient, especially a relapsed myeloma patient?

Only about 10% of patients in the United States participate in clinical trials. Therefore, the evidence-based medicine is generally for a patient population who is fit, healthy, and meets the eligibility criteria for that trial. When you go out into the general population you have comorbidities, patients who are unfit or frail, and you have different prior therapies than shown in these trials.

All of the trials I mentioned before that I was excited about have limitations as to who can participate. The choice of therapy in the general population will depend upon what the previous therapy was. Whether we use the same drugs as the patient has taken before or switch to another combination will depend on how long their prior response duration was. If the patient relapses after 2 years, they could be challenged with the same combination. If a patient progresses on that treatment, then you need to switch to another class of drugs.

How do natural killer cells play a role in the treatment of myeloma?

The importance of natural killer cells came out in the elotuzumab trial when the ELOQUENT-2 became positive. It is clear that natural killer cells are playing an important role because elotuzumab binds to SLAMF7, which is expressed in the myeloma cells, but also in the natural killer cells.  On the natural killer cells, the SLAMF7 has an adaptive protein, so when the antibody binds to it, it actually stimulates the natural killer cells. When elotuzumab binds to SLAMF7 on the myeloma cells, it doesn’t have an adaptive protein; therefore, it is not a signaling molecule, it is just expressed in the cancer cells. Here, when the antibody binds, it targets the myeloma cells and the natural killer cells can destroy them. Because of this, you have an antibody-dependent cell-mediated cytotoxicity (ADCC) mechanism.

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