Three-Drug Combos, Immunotherapy Mark Future of Myeloma Management

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.

This is also true when we use anti-CD38 monoclonal antibodies. CD38 is highly expressed in plasma cells. When you use anti-CD38 monoclonal antibodies and they bind to the myeloma cells, they also engage the natural killer cells and the CD8 cells and get ADCC mechanism and kill the cells. They could also be directly cytotoxic. These antibodies are also powerful and very effective. For the first time, we realize that we can control myeloma by immune mechanism. The checkpoint inhibitors are soon going to be tried in myeloma, and we are anxious to see how they are going to play in the management of it.

What do you see as the role going forward with immunotherapy for myeloma?

From doing the genome analysis and following the patient from the time of diagnosis through multiple relapses until death, we realize that the immune mechanism is going to play an important role.

Every time a patient presents with newly diagnosed myeloma, they have multiple clones. The current available drugs are only suppressing the predominant clone. Another clone then emerges, which is resistant to the current therapy and you switch treatment, but then the patient develops more mutations and, eventually, the patient dies. The immune mechanism is completely independent of the molecule mutation. It is genome naïve. What is happening in the nucleus doesn’t matter, because the antibody binds to the cell surface and gets stripped of the cancer cells completely.

The immune mechanism is very important if you have to make a quantum leap toward a cure for myeloma. We are all excited with monoclonal antibodies and all of these immune therapies that are coming into the treatment of myeloma.