Management of Relapsed/Refractory Multiple Myeloma

Keith Stewart, MBChB:How about the treatment of patients with relapsed or refractory myeloma, can you provide some key updates on recent data and practice patterns? Tom, let me start with you. What principles do you use when you’re selecting your relapse therapy or subsequent therapy after induction?

Thomas G. Martin, MD: There are 3 things that I consider. First is, what are their current and residual toxicities or comorbidities that I must worry about when choosing the regimen? The second is what have they been on in the past and what they may be either refractory to or what I think they may be most sensitive to. And then the third, which is part of the patient’s part of this, is convenience, is which one, can they come to the center relatively easily to get a subcutaneous injection or to get an IV [intravenous] medication? That’s how I choose it. If there’s a fourth thing, it’s how they present. If they present aggressive, then I know I have to choose a regimen that’s going to provide a substantial improvement in their aggressive disease.

Keith Stewart, MBChB: In terms of your thinking around the course that you’re going to pursue with that patient, is a second transplant on your radar? Or are you committing to long-term use of a relapse regimen?

Thomas G. Martin, MD: I’m not a big fan of second transplants right out of the gate in first and second relapse. Some of the salvage regimens that we have provide a significant progression-free survival [PFS] advantage, without having to use a transplant. For me, it’s a triplet-based regimen and not a transplant at that time.

Keith Stewart, MBChB: Peter, let’s assume our patient has had what we just all described as standard of care, which is VRd [bortezomib, lenalidomide, dexamethasone], transplant, and lenalidomide maintenance. Now they’re progressing on lenalidomide. What are you doing for those patients? What’s your choice of regimen, assuming that they’re eligible to come into the hospital and everything else?

Peter Voorhees, MD: The 2 regimens that are the most attractive in this situation would be daratumumab, pomalidomide, dexamethasone, and daratumumab, carfilzomib, dexamethasone, given the biologic rationale of incorporating an IMiD [immunomodulatory drug]with a monoclonal antibody. A lot of us gravitate toward the daratumumab, pomalidomide, dexamethasone triplet over the daratumumab, carfilzomib, dexamethasone triplet. It would be very interesting to do a randomized trial of this exact patient population comparing the two. I think that they would both perform very well.

Keith Stewart, MBChB: You’re sticking with an IMiD, even though they’ve just progressed on lenalidomide.

Peter Voorhees, MD: We have good data that pomalidomide has activity in lenalidomide-refractory patients, even when they’ve become refractory in their most recent line of therapy.

Keith Stewart, MBChB: And what data would that be?

Peter Voorhees, MD: That would be pomalidomide, dexamethasone doublet in patients with lenalidomide refractory disease, whether the lenalidomide refractoriness is on the most recent therapy or previous, there is a benefit to pomalidomide, dexamethasone in that situation.

Natalie S. Callander, MD: I want to highlight Pete’s trial for Alliance. That’s going to be interesting when those results come out. He’s looking specifically at patients progressing on lenalidomide maintenance and then randomizing them to pomalidomide, dexamethasone versus pomalidomide, ixazomib, dexamethasone. Those results will be interesting as to whether they can show a triplet is the better move at that point. And these are patients who largely have indolent relapses more or less, biochemical type?

Peter Voorhees, MD: Yes. This is biochemical progression and with a crossover.

Keith Stewart, MBChB: And Noopur, what are you up to?

Nooper Raje, MD: I do put a lot of patients on Pete’s trials. Ones with the biochemical progression. Most of us would turn to a pomalidomide-based regimen because the data do suggest that it does work in lenalidomide-refractory patients. The partner to the pomalidomide is largely dictated by the nature of the relapse. If we have somebody with high-risk features, aggressive relapse, that’s where I would reach out to the carfilzomib, pomalidomide, dexamethasone combination. And if not, then you could choose between pomalidomide, daratumumab, dexamethasone, which is an effective treatment. And more of those indolent relapses is where I would use Pete’s Alliance trial.

Keith Stewart, MBChB: Tom?

Thomas G. Martin, MD: I do think there’s a lot of regimens that can be used with pomalidomide, dexamethasone as a backbone. We’ve shown many studies. There’s also elotuzumab with pomalidomide, dexamethasone. And sometimes we choose that in patients who may be frailer. The infusion reaction rate is only 10%, which is great. It’s a well-tolerated drug. And the other thing I’ll mention is isatuximab. The other CD38 that now is approved for use is isatuximab, together with pomalidomide and dexamethasone. And if you look at the subset of patients who are lenalidomide-refractory in a subgroup analysis, they still do well on the isatuximab, pomalidomide, dexamethasone versus pomalidomide, dexamethasone. The triplet does better than the doublet.

Keith Stewart, MBChB: For the audience to keep up with us here, isatuximab is another monoclonal antibody targeting a CD38, a second-in-class drug that resembles daratumumab. Tom, you’ve used both of them quite a lot. Do you have any suggestion that one might be better than the other, or there are any advantages to one over the other? They both seem to be quite active.

Thomas G. Martin, MD: Yes, they’ve both been used in the refractory setting as single agents, together with lenalidomide, together with pomalidomide, bortezomib, and carfilzomib. If you compare all the studies, they’re very similar in terms of overall response rates and PFS. They work very similarly and probably have the same overall activity.

Keith Stewart, MBChB: Which one would you choose, and if so, why, if you had all things being equal in your patient?

Thomas G. Martin, MD: Just approved also is subcutaneous dosing of daratumumab. The convenience of subcutaneous dosing, the 5-minute dose, I think is going to be a win-win for infusion centers like ours that are very busy, and also for patients who don’t want to sit in the chair for 2 or 3 hours to get their IV infusion. For me, subcutaneous injection is going to win out.

Keith Stewart, MBChB: Your center did a lot more with subcutaneous daratumumab. Are you using that routinely now?

Peter Voorhees, MD: We’re in the process of getting it on our outpatient formulary. We don’t have access to it yet. But we’re hopeful as long as the economics make sense that we’ll get this on our formulary, and we’ll start converting patients to subcutaneous daratumumab in every situation we can.

Transcript edited for clarity.