Treating Transplant-Eligible and -Ineligible MM

Keith Stewart, MBChB: Let’s talk about 4-drug regimens if we’re looking toward the future. Peter, since you’re the lead investigator on the GRIFFIN clinical trial, can you tell the audience what the trial is all about and what you found?

Peter Voorhees, MD: This was a randomized phase 2 study looking at the addition of daratumumab into the RVd [lenalidomide, bortezomib, dexamethasone] backbone for transplant-eligible myeloma patients. They received 4 cycles of RVd [lenalidomide, bortezomib, dexamethasone] induction, transplant, 2 cycles of post-transplant RVd [lenalidomide, bortezomib, dexamethasone] consolidation, and then went on to lend maintenance until disease progression. The dara arm received daratumumab, both with induction and consolidation, as well as the first 2 years of maintenance therapy. And what we found up to this point is that by the end of consolidation therapy, the stringent CR [complete response] rates and the CR and nonstringent CR rates are better when you add daratumumab into the RVd [lenalidomide, bortezomib, dexamethasone] backbone. We’ve also shown an increased rate of MRD [minimal residual disease] negativity with the addition of daratumumab as well. At this point, with close to 2 years of median follow-up, progression-free survival is very good and similar between the 2 arms of the trial. We have yet to see a progression-free survival advantage with the addition of daratumumab. But we clearly have shown an improvement in the depth of response.

Keith Stewart, MBChB: Tom, are you using 4-drug cocktails yet?

Thomas Martin, MD: Unfortunately, we’re not able to do that because of insurance purposes. I think we are going to all move to 4-drug regimens—especially in the transplant-eligible population—and that we’re going to get a very deep remission in 3 to 4 cycles and then go right to transplant, just like what’s done in the GRIFFIN study. That’s the wave of the future, to try to get an even deeper response using 4-drug regimens quicker. But right now, we can’t do it just from insurance purposes.

Keith Stewart, MBChB: When you say that, there are FDA-approved regimens that contain 4 drugs from the ALCYONE trial and I think CASSIOPEIA too. For the audience, these drugs are using melphalan or thalidomide as 1 of the 4 drugs. Is it across all 4 drug combinations or just the 1 that Peter talked about?

Thomas Martin, MD: That’s a great question. In terms of the ALCYONE trial, using melphalan as a front-line therapy induction is certainly in a transplant-ineligible population. In the MAIA study with a three-drug, it looks more impressive than a four-drug regimen using melphalan and bortezomib instead of lenalidomide. I would still go with the three-drug with dara as front-line.

In terms of thalidomide as part of the therapy, I don’t think I’ve used thalidomide since maybe 2004 or 2005. And I’m not ready to go back.

Keith Stewart, MBChB: Anybody better able to use four drugs, and are you?And if so, in who?

Natalie S. Callander, MD: We’ve only used it in trials. Right now we are holding back and seeing, one of the things that we noticed in some of the trials--and I don’t know if the other panelists have--is that at least our impression in some of the dara-containing regimens that there’s a more difficulty with stem-cell collection. I don’t know if other people have noticed that, but it just seems sometimes we’re taking more time to collect stem cells.

Keith Stewart, MBChB: I’ve seen some data on that which seems to suggest their yields are lower, but still quite adequate for transplant most of the time.

Peter Voorhees, MD: There’s a higher rate of use of combination with GCSF for mobilization. And as long as you’re doing that, the stem cell yields are similar. They’re a little lower, but it’s not a clinically significant difference. And time to engraftment is the same. But if you do go beyond four cycles of four-drug therapy, whether it’s RBd/dara or KRd/dara, you’re potentially asking for trouble.I would collect after four cycles.

Keith Stewart, MBChB: That’s an excellent point to make. Noopur, what’s happening in Boston? Are you moving to four drugs?

Nooper Raje, MD: Not quite. We’re doing that in the context of clinical trials, for a lot of the reasons which all of the panelists have mentioned. But I just want to point one thing out there. We are all using four-drug regimens. And sure, four-drug regimens are going to show us a depth of response. I think what we need to start doing is using that depth of response to really tailor therapy in these four-drug regimens, because along with deep responses comes two things, both real toxicity to our patients and financial toxicity as well.

Keith Stewart, MBChB: I have had a bad experience. When I was still at Mayo Clinic, we started using four drugs for younger, higher risk patients. I didn’t find it easy. The infection rate and other complications in my early experience was high. We do need to approach with a little bit of conservatism and wait for final results from Peter’s work.

Transcript edited for clarity.