Tolerability of Triplet Therapy in Multiple Myeloma

Keith Stewart, MBChB: Noopur, peripheral neuropathy can be nasty, even with subcutaneous bortezomib. Why persist with a drug that causes more toxicity?

Noopur Raje, MD: It’s the convenience of using bortezomib subcutaneously, and you’re getting high response rates. I do want to go back to the ENDURANCE study, the conclusion from Dr Shaji Kumar, who presented it in the plenary session recommended RVd [lenalidomide, bortezomib, dexamethasone] to be the standard of care. In this subset of patients, yes, maybe. But as Tom and Keith have already alluded to, there is a subset of patients where you do want to consider using a carfilzomib-based regimen. In fact, what was most educational about the ENDURANCE trial was the fact that true, high-risk patients were excluded from the trial.

The second important thing is that they had about 30% of patients who were the older patient population. Now, that’s a patient population on whom you’d be very comfortable using RVd [lenalidomide, bortezomib, dexamethasone]. You’re going to get a nice response with that. But that would be the patient population where I would reach out to carfilzomib because of the increasing depth of response.

The other important thing to remember in the ENDURANCE trial was that if you look at the response rates, they favored the KRd [carfilzomib, lenalidomide, dexamethasone] arm. Ultimately, the toxicity is what nullified this response rate. It’s about patient selection. All drugs are not for everybody, and you need to pick the right patient for this.

Keith Stewart, MBChB: Are there twice as many discontinuations with VRd [bortezomib, lenalidomide, dexamethasone]?

Thomas Martin, MD: The discontinuations were higher in KRd [carfilzomib, lenalidomide, dexamethasone] than the VRd [bortezomib, lenalidomide, dexamethasone] arm. A lot were because of the vascular and cardiovascular issues. But the peripheral neuropathy for us is the big thing. The cardiovascular issues can be controlled if we watch it closely.

My take-home for this is 2 things. To Peter’s point, and that was that the Arkansonian way might be better, meaning I don’t know if 9 cycles of KRd [carfilzomib, lenalidomide, dexamethasone] is enough. We must do longer. There’s probably one-third or maybe more of patients who are still responding at the ninth cycle, and then they’re getting converted to maintenance. They need to get to their best response and then continue therapy. I would say that for some of these trials, although it was a wonderful trial, I don’t think it treats them long enough with the induction part of the regimen.

And the second thing in this: In this standard-risk population, these people who don’t have high-risk disease and good features, etc, the other triplet that we haven’t talked about is daratumumab, lenalidomide, and dexamethasone, or DRd, which in fact may be better tolerated than the other 2. And in the MAIA study—although it’s hard to do study-study comparisons—the PFS [progression-free survival] is probably going to be a lot longer than either PFS in the arms of this study. It’s interesting stuff. This is going to bring on more questions and more studies.

Keith Stewart, MbCHB: Peter and Natalie, have you stuck with KRd [carfilzomib, lenalidomide, dexamethasone] or moved to VRd [bortezomib, lenalidomide, dexamethasone]?

Natalie S. Callander, MD: One thing that was a hindrance in this trial is that people outside a trial give bortezomib weekly when they’re giving VRd [bortezomib, lenalidomide, dexamethasone] now. This regimen­—if the panelists do use twice-a-week VRd [bortezomib, lenalidomide, dexamethasone], except maybe in a patient they’re trying to get some sort of prompt response. Given the results of the study, it’s hard to not offer VRd [bortezomib, lenalidomide, dexamethasone]. The PFS benefit was there for older patients. Like Noopur mentioned, one-third of the patients are over 70 years old. There was a big difference in the PFS benefit for patients over 70 who strongly favored VRd [bortezomib, lenalidomide, dexamethasone], I think 38 months versus 28 months. You’re right that the depth of response based on better that VGPR [very good partial response] favored KRd [carfilzomib, lenalidomide, dexamethasone]. But right now, you still have to wonder with time what’s going to happen with that PFS and OS [overall survival].

Transcript Edited for Clarity