Standard Induction for Newly Diagnosed Symptomatic Myeloma

Keith Stewart, MD, ChB, MBA: What is the standard of induction for a patient with newly diagnosed symptomatic multiple myeloma? Joe, I’m going to start with you, and ask what are you using as your standard backbone in both transplant eligible and ineligible patients?

Joseph Mikhael, MD: That’s a great question, Keith. I’ll keep it simple. In the transplant eligible, VRd [bortezomib, lenalidomide, dexamethasone] has remained the general standard of care. But now we’re starting to see that we can have 2 modifications for that. I agree with Sagar’s thinking that we have mounting evidence for the use of KRd [carfilzomib, lenalidomide, dexamethasone] in the high-risk patient. I think we know when not to use KRd [carfilzomib, lenalidomide, dexamethasone], in transplant ineligible and standard-risk patients. But KRd [carfilzomib, lenalidomide, dexamethasone] is an option, and evidence is mounting for a quadruplet with DVRd [daratumumab, bortezomib, lenalidomide, dexamethasone]. The question with time will be, when do you use KRd [carfilzomib, lenalidomide, dexamethasone] and when do you use DVRd [daratumumab, bortezomib, lenalidomide, dexamethasone]? Are we just going to blanket everybody with DVRd [daratumumab, bortezomib, lenalidomide, dexamethasone]? Furthermore, as I’m sure we’ll discuss, how much D [daratumumab] should someone get? The recent CASSIOPEIA study made us question, in patients who didn’t have dara [daratumumab] in their induction therapy but had it in maintenance therapy did well, but those who had daratumumab in their frontline therapy didn’t need daratumumab in maintenance therapy.

Keith Stewart, MD, ChB, MBA: Let me put you on the spot. If you saw a 60-year-old patient tomorrow, what would you start them on? A patient with standard risk.

Joseph Mikhael, MD: Standard risk? I would still plan to use VRd [bortezomib, lenalidomide, dexamethasone]. But if there’s anything that makes me more concerned about this patient, I would like to try to add DVRd [daratumumab, bortezomib, lenalidomide, dexamethasone]. Insurance-wise, we can’t always get it. There are still some challenges with that. But at the minimum, VRd [bortezomib, lenalidomide, dexamethasone] and likely, DVRd [daratumumab, bortezomib, lenalidomide, dexamethasone].

Keith Stewart, MD, ChB, MBA: Nina, in San Francisco what are you doing for younger patients?

Nina Shah, MD: You said a 60-year-old patient, right?

Keith Stewart, MD, ChB, MBA: I said “younger.”

Nina Shah, MD: It’s a moving target. VRd [bortezomib, lenalidomide, dexamethasone] is still the standard. I will say, I was bummed about the ENDURANCE trial. I thought it was going to be positive and I would have an excuse to use KRd [carfilzomib, lenalidomide, dexamethasone].

Keith Stewart, MD, ChB, MBA: When you mention the ENDURANCE trial, what was that?

Nina Shah, MD: That was the upfront trial looking at KRd [carfilzomib, lenalidomide, dexamethasone] vs VRd [bortezomib, lenalidomide, dexamethasone] in nonplanned transplant patients with newly diagnosed multiple myeloma. It didn’t show a PFS [progression-free survival] difference for patients who got KRd [carfilzomib, lenalidomide, dexamethasone] vs VRd [bortezomib, lenalidomide, dexamethasone]. Basically, the major differences were toxicities. So if you have a patient who has known heart disease, you wouldn’t want to give them KRd [carfilzomib, lenalidomide, dexamethasone]. And with known peripheral neuropathy, you wouldn’t want to give them VRd [bortezomib, lenalidomide, dexamethasone]. The answer that I’ll give you is that we’re still doing VRd [bortezomib, lenalidomide, dexamethasone].

Keith Stewart, MD, ChB, MBA: Why aren’t you adding daratumumab?

Nina Shah, MD: As I always say, I’m a PFS girl, as Joe knows, and we don’t have the PFS data from the GRIFFIN study yet. It’s a randomized phase 2 trial with stringent complete response, sCR, as its end point after consolidation. But if the PERSEUS trial is positive, then I would consider doing that.

Keith Stewart, MD, ChB, MBA: Again, people won’t know what PERSEUS is.

Nina Shah, MD: Oh, yes. The trial is dara-RVd [daratumumab plus lenalidomide, bortezomib, dexamethasone] vs RVd [lenalidomide, bortezomib, dexamethasone] in patients who are going to transplant, and it’s a randomized phase 3 design instead of a randomized phase 2 trial. So that gives us a better understanding of what the outcomes are and how to apply those outcomes to our patients.

Keith Stewart, MD, ChB, MBA: Cristina, what about older patients? What’s your frontline regimen for an older patient?

Cristina Gasparetto, MD: A nontransplant eligible patient?

Keith Stewart, MD, ChB, MBA: Yes.

Cristina Gasparetto, MD: There aren’t many choices. I think the MAIA study, of course, is my first choice.

Keith Stewart, MD, ChB, MBA: People won’t know what MAIA is.

Cristina Gasparetto, MD: MAIA was the randomized study comparing the dara-RVd [daratumumab plus lenalidomide, bortezomib, dexamethasone], in the front line, for nontransplant eligible patients vs the doublet, lenalidomide plus dexamethasone. Even the longer follow-up is amazing, the durability of response, PFS, etc. However, it was a little inferior for high-risk disease. Thinking about the addition of a proteasome inhibitor, when I have a patient with high-risk disease and nontransplant eligible, I always think about adding the proteasome inhibitor. Of course, here you are stuck in a situation where you have to make adjustments based on comorbidity, such as age, like you mentioned, and frailty. I always think about the possibility that there may be nothing different in the biology of myeloma between younger and older patients. But we don’t treat the older patient as aggressively. We treat them sometimes suboptimally and get an inferior outcome. It’s a balance, right? I like to have the proteasome inhibitor, or bortezomib, weekly if I can, and then go from there.

Keith Stewart, MD, ChB, MBA: If I recall correctly, at EHA [European Hematology Association Annual Meeting] dara-Rd [daratumumab plus lenalidomide, dexamethasone] had a PFS of more than 5 years of therapy, 63 months or something.

Cristina Gasparetto, MD: Yes, it was about 60 months.

Keith Stewart, MD, ChB, MBA: That’s pretty impressive. Do you think you need a proteasome inhibitor when you can get lots of neuropathy in an elderly patient?

Cristina Gasparetto, MD: I thought about that when I saw the longer follow-up, thinking about what I gain. But I still think some of the high-risk genetics perform better with a proteasome inhibitor. I learned a lot from the update of the FORTE trial from Francesca Gay, MD, with all the dissection of the different cytogenetics.

Joseph Mikhael, MD: I would agree with Cristina. I’m pretty much using DRd [daratumumab, lenalidomide, dexamethasone] for all standard-risk patients who aren’t eligible for transplant, but I consider using VRd [bortezomib, lenalidomide, dexamethasone] in high-risk patients. Both the SWOG S0777 study, which was VRd [bortezomib, lenalidomide, dexamethasone] versus Rd [lenalidomide, dexamethasone], and the MAIA study, as Cristina said, which is DRd [daratumumab, lenalidomide, dexamethasone] versus Rd [lenalidomide, dexamethasone], now have survival advantage of the triplet. I think we can push Rd [lenalidomide, dexamethasone] behind us. But I think that in the evaluation of the DRd [daratumumab, lenalidomide, dexamethasone], the only kink in that armor was in high-risk patients. So I tend to favor using VRd [bortezomib, lenalidomide, dexamethasone]. The last thing I’ll say, Keith, is pragmatically for the community oncologists. I try to use VRd [bortezomib, lenalidomide, dexamethasone] a little differently than they did in SWOG, the original study. They started it IV [intravenously] at twice weekly. I plan to use it weekly for 6 months, if there’s no neuropathy, then I’ll back it down and give it every other week for the next 6 months. I think we have justification for a year based on other studies. Hopefully that strikes the balance, as Cristina said, of not giving a lot of neuropathy but holding high-risk disease down for longer.

Transcript Edited for Clarity