COMMENTARY

Four Major Developments in Multiple Myeloma: ASH 2018

'The World of Multiple Myeloma Is Changing Quickly'

Joseph Mikhael, MD, MEd, FRCPC

Disclosures

December 27, 2018

Hello. My name is Dr Joseph Mikhael. I am a professor at Translational Genomics Research Institute (TGen) at the City of Hope Cancer Center and the chief medical officer of the International Myeloma Foundation. Welcome to Medscape Oncology Insights, coming to you from the 2018 American Society of Hematology annual meeting.

Today I am going to briefly share with you four major developments in multiple myeloma that have occurred over this past year and are really being profiled here at the annual meeting.

Frontline Monoclonal Antibody Therapy for Multiple Myeloma

The first is the move toward monoclonal antibody therapy in frontline multiple myeloma. Earlier this year, the US Food and Drug Administration (FDA) approved daratumumab in combination with bortezomib, melphalan, and prednisone in patients who were ineligible for an autologous stem cell transplant, based on a clinical trial that demonstrated its superiority over just melphalan, prednisone, and bortezomib together.

Here at the annual meeting, the late-breaking abstract being presented is looking at daratumumab/lenalidomide/dexamethasone versus lenalidomide/dexamethasone alone.[1] This is a large phase 3 trial that will very likely lead to the use of more daratumumab frontline.

In patients you are treating now with bortezomib/lenalidomide/dexamethasone—or in some cases, just lenalidomide/dexamethasone—we are quite likely going to see in the very near future the addition of daratumumab. This is significant, of course, because we have known that monoclonal antibodies pair very well with just about every myeloma treatment we have. Now we are going to see their use upfront as we try to have a deeper and a more durable response in our patients.

More Approvals for Myeloma

The second major movement looks to two other FDA approvals. The monoclonal antibody elotuzumab, which was previously approved for use in relapsed multiple myeloma with lenalidomide, has now been approved in combination with pomalidomide. We have shrinking options after patients have had two or three relapses. This combination of elotuzumab plus pomalidomide really enhances the activity of just pomalidomide alone and provides another option.[2]

The other FDA approval recently was for carfilzomib. We have been using carfilzomib for many years as a single agent or with dexamethasone, and in combination with lenalidomide or other agents, but now we can actually use the agent once weekly. The ARROW study compared twice-weekly with once-weekly carfilzomib and, interestingly, not only did it demonstrate equivalence, but weekly dosing of 70 mg/m2 demonstrated an improved response rate and improved progression-free survival, while at the same time not increasing toxicity.[3]

In my practice, I have almost exclusively gone to using weekly carfilzomib because it is more convenient for the patient and indeed is more efficacious.

Triple-Refractory Disease

The third movement has to do with the space of patients who we often call "triple refractory." These are patients who have seen a monoclonal antibody, a proteasome inhibitor, and an immunomodulatory drug, and often have seen multiples of those three classes but are now progressing.

Sadly, right now we haven't [got] a lot of choice[s] for those patients, but there is a drug being profiled here (in multiple abstracts) known as selinexor, which is quite likely going to be the next approved agent in multiple myeloma. Selinexor is in a totally new class of drugs called nuclear transport inhibitors. These drugs inhibit tumor-suppressor molecules (which are good, and we want to stay within the nucleus) in their departure from the nucleus, so they can stay there longer and indeed help the cell and the body combat that disease.

We have seen several abstracts with selinexor, initially in the so-called penta-refractory population (ie, refractory to bortezomib, lenalidomide, carfilzomib, pomalidomide, and daratumumab) with a single-agent activity of significance.[4,5,6] That will likely be its indication in the new year. Here at the annual meeting we are also seeing it used in combination with other agents, namely with bortezomib.

CAR T-Cell Therapy

The last movement to talk about is one you are likely familiar with, which is the very exciting field of CAR T-cell therapy. Of course, CAR T-cell therapy is not yet approved in multiple myeloma as it is in certain forms of leukemia and lymphoma, but we are really seeing emerging and encouraging evidence[7] again in patients who are very heavily pretreated, who frankly are estimated to only survive a few months with really great outcomes.

Thankfully, as we have been working in the CAR T-cell world, we have been able to significantly reduce the toxicities and increase the efficacy, and we are now seeing progression-free survival levels of over 12 and even 15 months in this very heavily pretreated population.

Conclusion

The world of multiple myeloma is changing quickly. We now have more FDA approvals of novel agents, or other ways to use the agents we already are using. We have a new class of drug that will quite likely be approved in the very near future [selinexor]. There is another one, venetoclax,[8] which may also make its way to multiple myeloma in the not-so-distant future. We are going to hear a lot more about CAR T-cell therapies and similar therapies, even second-generation CAR T-cell therapies.

I hope this has been helpful to you in your practice and in seeing the future of multiple myeloma.

It has been a privilege to share this with you from San Diego at the annual ASH meeting, and we trust that this will help you in your understanding of this complex disease.

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