Sarah Holstein, MD, PhD

Question

How is the treatment of multiple myeloma changing, particularly as newer agents receive approval or expanded indications (eg, daratumumab granted Priority Review for the first line, denosumab approved to prevent skeletal-related events [SREs])?

Answer

The treatment landscape is changing quickly. While the ALCYONE trial was important, as it was the first phase 3 study to incorporate daratumumab into induction therapy, it is not practice-changing in the US because VMP [bortezomib, melphalan, and prednisone] is rarely used as a regimen.

Having said that, I do believe it is likely that over the next several years as trials evaluating the addition of daratumumab to more commonly used regimens such as RVd [lenalidomide, bortezomib, and dexamethasone], KRd [carfilzomib, lenalidomide, and dexamethasone], and Rd [lenalidomide and dexamethasone] read-out, that the standard of care for both transplant-eligible and transplant-ineligible patients will include daratumumab as part of the induction regimen.

Denosumab provides an important addition to the bone-modifying armamentarium, particularly for patients with renal insufficiency. It appears to be associated with the same risk of osteonecrosis of the jaw as zoledronic acid, and it remains to be determined whether denosumab confers a similar potential survival benefit as has been observed with zoledronic acid.v

Question

How has maintenance therapy changed, and what is its role now for patients with multiple myeloma?

Answer

There is now very compelling evidence that lenalidomide maintenance after autologous stem cell transplant (ASCT) not only significantly prolongs progression-free survival, but also confers an overall survival benefit.

Results from the Myeloma XI study presented at ASH [American Society of Hematology] 2017 demonstrate that lenalidomide maintenance benefits patients regardless of cytogenetic risk and regardless of minimal residual disease (MRD) status. There is also increasing evidence that lenalidomide maintenance after induction therapy for non-transplant patients improves outcomes.

Thus, at this time, lenalidomide maintenance is the current standard of care. Having said that, there are many unresolved issues. For example, it is clear that for patients with high-risk disease, lenalidomide maintenance, while beneficial, is still insufficient. Determining which agents could be combined with lenalidomide (or used instead of lenalidomide) to overcome the adverse outcomes associated with high-risk disease is very important.

The Myeloma XI study clearly demonstrates that even if patients achieve MRD-negativity following completion of initial therapy, they do better with lenalidomide maintenance than without it. However, we need to determine whether patients who have achieved sustained MRD negativity over a period of time (2 years? 3 years?) can be safely taken off maintenance therapy or whether treatment until progression should remain the standard of care.

Finally, we also need to learn how to identify those patients who are at highest risk for the development of lenalidomide-associated secondary primary malignancies and determine alternative maintenance strategies for these patients.

Question

Answer

Where are we now with CAR-T therapy for multiple myeloma? What can be expected in the near future, in terms of incorporating it into practice?

Question

Do you think immune checkpoint inhibition will have a place in the treatment landscape for multiple myeloma, given the increased risk of death in clinical trials? Is the mechanism for the increased risk of death known?

Answer

The results of the 2 phase 3 studies involving checkpoint inhibitor/immunomodulatory drug (IMiD) combinations were very surprising, given the previously encouraging results from phase 1/2 studies of these same combinations. We really do not understand the mechanisms underlying the increased risk of death.

There are still many unanswered questions at this time — whether these results translate to all checkpoint inhibitors, whether it is the checkpoint inhibitor/IMiD combination which is particularly problematic, or whether patients who are less heavily pretreated are at higher risk for complications.

With respect to the latter, it should be noted that 1 of the studies involved patients with newly diagnosed myeloma. It is very clear that the immune system dysfunction induced by the presence of malignant plasma cells is significant and complex and that there are changes that occur after repeated lines of therapy. It is also clear that IMiDs have pleiotropic effects on the immune system. I believe a great deal more basic/translational research needs to be performed to understand the effects of checkpoint inhibitor therapy in myeloma.

Question

What new approaches are you excited about for the treatment of multiple myeloma in the future?

Answer

I am excited about anti-BCMA therapy, which includes not only the BCMA CAR-T cells, but also the anti-BCMA antibody-drug conjugate (GSK2857916). The latter demonstrated significant single-agent activity in a phase 1 study and, of course, the next step will be to evaluate this agent in combination with other myeloma drugs. I am also excited about the potential for other cellular therapies, including natural killer cell therapy.