Selecting Optimal Therapy in Transplant-Ineligible NDMM and Key Takeaways


Expert hematologist-oncologists home in on clinical trial data to consider which regimens are most appropriate for patients with transplant-ineligible NDMM.


Ajai Chari, MD: Rafael, I’m going to ask you a question, which I got from a community doctor when I was at a conference recently. They said: “I’ve been doing VRd [bortezomib, lenalidomide, dexamethasone] for all this time, and my patients aren’t dying. Why should I switch to DRd [daratumumab, lenalidomide, dexamethasone]?”

Rafael Fonseca, MD: That’s a great question. Familiarity is very powerful in this world, and that’s probably what happens. But we did a study that was presented at one of the oral sessions at ASH [annual meeting of the American Society of Hematology], and we asked ourselves, we have 2 regimens. As I mentioned, both had category 1 evidence. How do you choose between them? I will say that I personally have a concern with bortezomib and neuropathy. I always tell my worst stories; “Doctor, you saved my life but I still cannot feel my feet.” And even with subcutaneous weekly, it can happen. Given that we have these regimens, and they’re both perceived to be effective, how do we choose? We went about doing one of those simulations with real-world data, where we actually said, let’s look at the duration of therapy in first line, which could be with either a MAIA regimen or VRd or Rd [lenalidomide, dexamethasone]. Then, importantly, we did a sensitivity analysis with various levels of attrition because we know, and it’s been published by at least 4 papers, [there is] significant loss per line of therapy in the non-transplant-eligible patients. It can be as high as 50%. And the reason that’s important is because sometimes someone says, “Oh, drug A plus B is better than drug A.” Someone could say, “Hey, you need to show me drug A plus B is better than A followed by B.” But what they miss is that A followed by B divided by 2, if you have a 50% attrition. That’s very important. And then we use real-world data for the treatment of patients in the first relapse. If they were in MAIA, we assume it would be carfilzomib or pomalidomide. And if they weren’t RVd or Rd, it would be a daratumumab-containing combination. Everyone gets it. The only way to resolve this completely would be through a randomized phase 3 study, but that is several years out. SWOG [Cancer Research Network] has a study with some differences, but it’s addressing this question. But until then, what? And what we found is this: If you start with the MAIA regimen and follow up by current palm, you have a survival of about 9.1 years projected overall survival. And it’s about 2.5 years longer than if you start with SWOG and then go to a MAIA rescue. Is this definitive? No. But if you’re choosing between the 2 regimens, and with my added comment that you have the neuropathy-free regimen, that makes me think of the MAIA regimen as a preferred choice for our upfront.

Ajai Chari, MD: I think a lot of people want that VRd light vs DRd study to be done. But unfortunately, by the time that is accrued and rolled and resulted, we have very exciting new agents that we’re going to talk about. Just to close this discussion, this is the take-home message slide, if you will, for the transplant-ineligible population.¼Again, the same kind of PFS [progression-free survival] graph on the left. We have the 777 on the left, with a hazard ratio of 0.74. RVd light, which is from our Boston colleagues, a very important study, but only 50 patients, single arm. VelC [bortezomib] or Dara [daratumumab] VMP vs VMP [bortezomib, melphalan, prednisone] has a ratio of 0.42, MAIA hazard of ratio 0.53 and finally IRD [ixazomib, lenalidomide, dexamethasone], 0.83. That was not statistically significant. I think the main question is really this RVd, MAIA, and I just want to call your attention to a few things. First, we’re not comparing the direct numbers. The Rd and MAIA’s PFS is actually very impressive, 34 months, as you pointed out. But what we’re comparing are the hazard ratios. What’s the value of adding bortezomib vs Dara?I think some of the devils are in the details. We want to highlight that the median age of 777 is only 63. I think many of us would not consider that to be a transplant-ineligible patient population. MAIA’s median age is 73. Next, there’s the ability to give the treatment as indicated. SWOG was twice-weekly bortezomib; who’s giving twice-weekly bortezomib to 73-year-olds? That is also not translatable to the patient in clinic. Last but not least, looking at the OS [overall survival] hazard ratio, 0.71 for the SWOG [trial] and 0.68, both are statistically significant. But look what happens to the hazard ratio for SWOG for the patients over 65, it’s not significant. And that’s the population we’re talking about. While we’re not trying to do direct cross-study comparisons, if you’re looking at the ability to give a drug as intended in the study to your older patients sitting in front of you in clinic and expecting that PFS and OS benefit, I think DRd is really hard to beat. And I think to close, it’s with 56-month follow-up, and we’ve still not reached a PFS median. That is a game changer for this population.

Krina Patel MD:It’s amazing.

Ajai Chari, MD: And that’s important; as Rafael mentioned, you may only get 1 shot with these patients.

Krina Patel MD: Only 1 line of therapy.

Ajai Chari, MD: Take your best drug. Thank you for that great discussion.

Transcript edited for clarity.

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