Measuring Treatment Response in Transplant-Eligible NDMM
A look at how to measure an adequate treatment response in patients with transplant-ineligible newly-diagnosed multiple myeloma, and treatment regimens for high-risk patients.
Rafael Fonseca, MD: Let me turn to Dr Patel. What’s a good response now? When you have a patient going to transplant, when are you happy? What level of response do you want to see?
Krina Patel, MD: I’m a millennial, so I want that stringent CR [complete response] or MRD [minimal residual disease] negativity if we can get it. But if I can get to the VGPR [very good partial response], it’s always about toxicity vs more therapy. If this patient is doing really well—they get to that VGPR—but they’ve already had 4 or 5 cycles and might run into toxicity, then I’ll send them to stem cell transplant. In the end, I want to get the deepest response possible because multiple studies showed that MRD negativity prognostically still means that patients are going to do the best. Of course, you also want sustained MRD negativity a year or 2 later.
Rafael Fonseca, MD: Your point is so important. An important factor is that monoclonal antibodies aren’t adding much in the way of toxicity. But as I tell my patients, that’s easier said by the doctor. The facts are there. It’s different when you add a PI [proteasome inhibitor] to an IMiD [immunomodulatory imide drug] in older patients vs adding a monoclonal antibody. The threshold for saying, “Yes, I can do it, and it’s safe,” would be pretty good as well.
Amrita Krishnan, MD: But I’ve had a couple of patients, just like my case now, who haven’t gotten a VGPR after quadruplets, and I’m torn about what to do next.
Caitlin Costello, MD: Exactly.
Amrita Krishnan, MD: I’m curious about what you guys would have done in my case.
Caitlin Costello, MD: I like taking that person to transplant because you’ve used some great weapons up front at that point. Maybe you need high-dose chemotherapy at that point to make an even deeper dent in the disease. Then you figure what you’re left with after the fact to make a decision. Do I need to change to second-line therapy at that point to get that deeper response if I haven’t achieved what I want to after transplant?
Rafael Fonseca, MD: Yes, a VGPR is like a C-. We still pass the student, so you might go to transplant, but all of us want very deep responses. The data are very clear that CR isn’t going to be enough. We need to get very deep responses. One thing that’s important that we also think about is what we do on the back end, as we were talking about with the CASSIOPEIA trial. In a patient who completes transplant and still has MRD-positive disease, that’s a critically important conversation, particularly for those who have high-risk disease. The data are very clear that if you can make a high-risk patient MRD negative, you might ameliorate or even totally eliminate the prognostic implications of being a high-risk disease. Dr Patel, are you doing consolidation in the posttransplant period?
Krina Patel, MD: It depends on the patient. For high-risk patients, we do. We’ll do consolidation or doublet maintenance, with either a PI and an IMiD or a CD38 and an IMiD. I don’t think we have an answer for which one is better, but we do what makes the most sense for that patient. For standard-risk patients who haven’t had the best response, such as this patient of yours, if they had a PR [partial response], get a transplant, and then get a VGPR, I’m still worried about that patient because they got the PR only with a quadruplet. I’d consolidate and then potentially do maintenance, even with a doublet, until they’re MRD negative. We don’t have data of when you can stop things, but I want to get that best response after you’ve had the initial response, because that’s when it’s the most vulnerable and you can get that deepest response.
Rafael Fonseca, MD: Dr Costello always says the first cut is the deepest, and that’s so true for first-line therapy for myeloma. That’s when we have the biggest opportunity to make a difference. Dr Costello, how do you walk through that logic in the post-transplant setting?
Caitlin Costello, MD: What you just said is so true. We know that myeloma is at more of a naïve state when we’re initially diagnosing patients, so to make the greatest impact, that first PFS [progression-free survival] is incredibly important. The attrition rates continue to drop off as lines pass by, so we need to have great success up front as much as we can with the future in mind so that we don’t work our way through multiple lines of therapy very quickly.
Amrita Krishnan, MD: Can I can plug my own study, Rafael? I feel like I’m coming on a talk show.
Rafael Fonseca, MD: Sure, please.
Amrita Krishnan, MD: We’re moving into the area of MRD-directed decision-making in terms of maintenance. The SWOG DRAMMATIC study is going to put everyone on maintenance daratumumab–Revlimid [lenalidomide] vs Revlimid, and those who are MRD negative at 2 years get randomized to stopping or continuing maintenance. To your point, maintenance is important. But to the patient’s point, staying on maintenance for the rest of your life is also challenging.
Rafael Fonseca, MD: Very much so. There’s a significant burden with maintenance, particularly with IMiDs. More patients have fatigue, can’t work as well as they normally could, and the diarrhea is a big problem. We’ll have to see how that evolves. Thank you for putting a plug in for that study. We’re committed to doing those studies, and it will answer very important questions as we go into the future.
Dr Krishnan, what are your thoughts about the addition of an antibody like daratumumab in patients with high-risk disease? How does that play out in your mind?
Amrita Krishnan, MD: That’s the million-dollar question. Certainly, in the SHN-03 study, we have a group formed to look at the cytogenetic data because that’s the question people always ask us: “What about high-risk patients?” In a meta-analysis of daratumumab, there seems to be a benefit of adding daratumumab in the high-risk group. It probably doesn’t reach the same degree that we saw initially when we had the studies of bortezomib, but one could argue that was a different era.
Rafael Fonseca, MD: Of course.
Amrita Krishnan, MD: As far as the magnitude of benefit, the challenge is now much greater.
Rafael Fonseca, MD: It’s hard to prove, but PIs were thought to be good for high risk and have been shown to be better for high risk for translocation (4;14) and deletion 17p. But they were being compared with thalidomide and lenalidomide. We see the meta-analysis data. We’ve seen that with other drugs, even selinexor and deletion 17p. Were PIs good for high-risk or were IMiDs not sufficient for high-risk patients? We’ll have to sort through all that.
Thank you very much. That takes us to the conclusion of this first case. Let’s go on to the second one.
