Role of IMiD-based Strategies for RRMM

Paul G. Richardson, MD: David, I want you to talk about something you and I have worked on for many years together, and that’s IMiD [Immunomodulatory imide drug]-based strategies in relapsed/refractory disease. I want to especially acknowledge the work you’ve done with POM [pomalidomide], and all the work that has followed from that with pomalidomide. In that spirit, I wondered if you could touch on your impressions from your own work with [trial] MM-014, joint work with OPTIMISMM, and the APOLLO study. Notably, there was a nice abstract from the Canadian groups with ASH [the American Society of Hematology annual meeting] 2020, abstract 413, which was DARA/CYCLO/DEX [daratumumab, cyclophosphamide, dexamethasone]. Additionally, there was ICARIA-MM from our own group. Most encouragingly, there was the STOMP data, which Christine Chen, MD, did a nice job on with abstract 726. Overall, there is a lot there to talk about. Finally, the other piece is that there are a lot of questions from community doctors asking why wouldn’t we use pomalidomide early? Why would it not be in newly diagnosed patients? We would love your thoughts, David.

David Siegel, MD, PhD: The answer to the last question is that we weren’t allowed to use it in newly diagnosed patients, not that it shouldn’t have had a role. I think you bring up an excellent topic. I think that pomalidomide is a very underutilized drug. Obviously, all of us have a fair amount of experience with pomalidomide-based combinations, but in the community, you see it used relatively sparingly. Paul and I were co-authors on the first paper that led to pomalidomide’s approval, so we do have a long history of working together on pomalidomide. However, there was a whole section of abstracts from the 2020 ASH meeting that brought more to the forefront. Specifically, several pomalidomide-based regimens that were used relatively early during relapse.

The first of them was presented by you, Paul, the OPTIMISMM trial, which is the combination of bortezomib, pomalidomide, and dexamethasone. As Nina pointed out, there are many patients out there who get into second- and third-line therapy, and they may have been exposed to bortezomib, but were never refractory bortezomib, particularly patients who went onto transplant. As such, the combination of bortezomib, pomalidomide, and dexamethasone should be on everybody’s short list of second-line salvage regimens. Bortezomib is safe and relatively easy. I don’t use a lot of bortezomib because of my concerns in relation to peripheral neuropathy, but this is certainly a legitimate combination that needs to be used.

The MM-014 trial was designed to address a very specific problem in the multiple myeloma [MM] community, but in the more global oncology community as well, and that is this instinct that if a patient is on lenalidomide, that pomalidomide is not a legitimate choice. This was a 2-arm trial. The initial arm of this trial was to take patients who were progressing on lenalidomide-containing first-line therapies or second-line therapies and treat them with pomalidomide and dexamethasone.

Refractoriness…the response to pomalidomide, then refractoriness to lenalidomide. The point being, that pomalidomide is a legitimate and basically fully active drug even in patients who had gotten previous lenalidomide. The arm that was presented at ASH was the combination of pomalidomide and daratumumab, one of the most popular combinations. Overall, the point was that patients who were progressing on lenalidomide have about the same response rate to that DARA/POM [daratumumab, pomalidomide] combination as patients who had not been exposed to lenalidomide in immediate prior lines. Therefore, lenalidomide to POM/DARA [pomalidomide, daratumumab] doesn’t compromise the activity of that combination, and I think that’s something very important to understand. Pomalidomide is its own drug; it is not an extension of lenalidomide.

The APOLLO trial was interesting because it confirms that the DARA/POM/DEX [daratumumab, pomalidomide, dexamethasone] combination using subcutaneous administration of daratumumab is active, is well tolerated, is certainly a premier regimen and one that is growing in popularity in the United States as well.

The Canadian trial that you were talking about is a little more complex. They use a lot more cyclophosphamide for the management of multiple myeloma in Canada than they do in the United States. This was a trial to look at whether the 4-drug combination with the addition of pomalidomide to DARA/CYCLO/DEX [daratumumab, cyclophosphamide, dexamethasone] had activity. In fact, response rates were close to 90% in relapsed patient populations. Certainly, it is a combination that is a feasible one. How much the cyclophosphamide adds in that, the trial didn’t really address that. However, a 90% response rate in a relapsed patient population is impressive no matter how you look at it.

ICARIA-MM, this is always a difficult topic. Certainly, isatuximab is a viable drug. It is extremely active; it is well tolerated. Its early schedule is better than the schedule of daratumumab, but it is an intravenous [IV] drug with similar both toxicity and efficacy profile to daratumumab. Specifically, whether an IV drug that is given slightly less frequently can push aside a subcutaneous drug, I think this is going to end up being a financial question much more than it is going to end up being a clinical question. Nonetheless, there is no suggestion that isatuximab is in any way clinically inferior to daratumumab, and they are both monoclonal antibodies against CD38. Overall, it depends on payer issues as to how attractive that combination is, but certainly it is at least as effective in my opinion as the daratumumab-based combination.

I think STOMP is going to turn out to be one of the important studies. The part of this that I’m speaking to now is that one of the arms of this trial included selinexor. Selinexor is a very exciting drug that Paul touched on, and one that we’ve all touched on to some extent. A unique mechanism of action, it is a nuclear pore inhibitor and theoretically traps TP53 and perhaps some other tumor suppressor proteins in the nucleus, which makes the cell more easily convinced to undergo apoptosis, than if that TP53 was not trapped in the nucleus. As such, whether this drug is going to be uniquely active in some of the high-risk populations, I certainly hope so.

One of the arms of this trial was selinexor, pomalidomide, and dexamethasone, and it was very effective. If people had some early experiences that were negative with selinexor when it was being used as a single agent or with dexamethasone, where emesis and GI [gastrointestinal], weight loss kind of issues were prohibitive, they’re going to be very surprised about the new iteration of selinexor at lower doses with third compounds, where the toxicities are much more manageable. Moreover, even in very heavily treated patients, there are some surprising responses that are quite durable.

Particularly now in the COVID-19 [coronavirus disease 2019] world, the selinexor, pomalidomide combination is a very exciting one, very well tolerated once you get used to the antiemetic regimens and you’re using the selinexor at lower doses. Specifically, this treatment is 60 mg, not the 100 mg that people got scared of in the past. As a result, selinexor is going to turn out to be a very important drug, and we’re just starting to figure out how to use it now.

I think the moral to the story is use pomalidomide if you’re out there in the community. It’s an easy drug. If you’ve used Revlimid [lenalidomide], you’re going to know how to use pomalidomide, and it certainly has significant efficacy advantages over lenalidomide.

Paul G. Richardson, MD: I think you’re absolutely right, David, that’s it’s a partner drug that’s underappreciated in terms of its add-on value, and from those days 10 years ago together when we started just with POM/DEX [pomalidomide, dexamethasone], look at where we are now. I do agree with you about SELI [selinexor]. Obviously, the original STORM [trial] experience reflected just that. We had to go in as a monotherapy eventually with steroid. I was so impressed by what we’re now starting to see in terms of the once-a-week dosing and lower dose, recognizing the adverse effect profile is very real, but it is manageable, and especially with that lower dose weekly. Certainly, in my own practice, I’m using selinexor 20, 30, 40 mg once a week, and when you combine it with a PI [proteasome inhibitors], we see some real excitement.

Transcript edited for clarity.