Initial Therapy for High-Risk Myeloma

Transcript: Paul G. Richardson, MD: If I may Amrita, when you think of molecular risk and when you think of ISS [International Staging System] staging and R-ISS [revised-ISS] staging, because we’ve touched in a way on CRAB [high calcium, renal dysfunction, anemia, bone lesions] features, how does that influence what you think about? This isn’t just obviously for the frail or older population, this is more broadly.

Amrita Y. Krishnan, MD: Well, I think we’ve been seeing changes now, and we are better at incorporating that into our initial frontline induction strategy. I think most of us would agree that now in the younger patient and in the high-risk patient we’ve heard a lot of data at this meeting about integrating carfilzomib as an up-front induction therapy. I would see that, and I think we’re going to discuss even moving beyond that into the quadruplets, and the discussion is a quadruplet regimen overcoming high risk or not. I think that’s very controversial actually.

Paul G. Richardson, MD: In terms of your practice, Nina, do you look at ISS stage and molecular risk features? How do you integrate that? Obviously recognizing these are symptomatic patients, they meet CRAB, or less in fact, how do you use those tools?

Nina Shah, MD: I think that simplicity of course wins the day. R-ISS is a great, easy thing to do if people get the LDH [lactate dehydrogenase], which of course a lot of people don’t. If you have information with the high-risk people I’d give them at least something different than VRd [bortezomib, lenalidomide, dexamethasone], which is great, but we haven’t done enough for high-risk patients. So I usually go with KRd [carfilzomib, lenalidomide, dexamethasone].

I’m not sure if DARA/VRd [daratumumab plus bortezomib, lenalidomide, dexamethasone] is going to be better than that. Right now I still do [carfilzomib, lenalidomide, dexamethasone], and I definitely do length of treatment longer, so [carfilzomib, lenalidomide, dexamethasone], transplant, consolidations, modified maintenance, and a very long course of treatment.

Paul G. Richardson, MD: Right.

Nina Shah, MD: We again don’t have prospective data to know, and now we’ll have more immunotherapies available for high risk up front with clinical trials being planned.

Paul G. Richardson, MD: The older patient who may not be a transplant candidate, how do you approach them?

Nina Shah, MD: Now we have a lot of options I think. We have VRd [bortezomib, lenalidomide, dexamethasone]-Lite, if they’re standard risk. DRd [daratumumab, lenalidomide, dexamethasone] I think is a great option. Then there’s people that might want to get the ALCYONE [daratumumab plus bortezomib, melphalan, prednisone]. That’s not what I normally do in my practice. I think it would be between VRd [bortezomib, lenalidomide, dexamethasone]-Lite and [daratumumab, lenalidomide, dexamethasone]. Sometimes even CyBorD [cyclophosphamide, bortezomib, dexamethasone] is not a horrible option, depending on what’s going on with the patient.

Paul G. Richardson, MD: Depending on the clinical context. Of course also there is no reason, to Ajai’s point, in the frailer, older patient to not think about if you’ve got a patient you’re particularly worried about, you know, an RVd [lenalidomide, bortezomib, dexamethasone]-Lite plus a monoclonal antibody.

Amrita Y. Krishnan, MD: If I could ask something, I’d be interested to hear from everyone how comfortable are they with the MAIA trial data of just using [daratumumab, lenalidomide, dexamethasone] in a high-risk patient.

Kenneth H. Shain, MD, PhD: In my opinion, if they’re transplant ineligible and they’re standard risk, then [daratumumab, lenalidomide, dexamethasone] is where I put all those patients at this point. The higher-risk patients, I still want to make sure there’s a proteasome inhibitor [PI] that’s part of their story. I think the data tell us we have to be a little bit more careful about that. I’m not whether we were a little surprised by that; at least I was a little surprised, but it does. It’s still a majority of patients, but I think that’s where they deserve that therapy, and a PI still needs to be sitting in part of a high-risk patient, whether they’re eligible or not.

Paul G. Richardson, MD: Exactly. Specifically when we think of PIs, obviously now bortezomib is generic, it has a cost implication as well. I think all of those factors are real.

Sagar, obviously together we’ve been pioneers of that triplet platform and an RVd [lenalidomide, bortezomib, dexamethasone] and so on. How would you approach this? Because I certainly am not a reductionist. I strongly feel the proteasome inhibitor has a role.

Sagar Lonial, MD, FACP: I think in the standard-risk transplant-eligible patient, our group after almost a decade has now changed our guidelines. We’re RVd/DARA [lenalidomide, bortezomib, dexamethasone plus dexamethasone] for the standard risk, and then for the high risk we’re [carfilzomib, lenalidomide, dexamethasone].

Paul G. Richardson, MD: Fantastic, great. Ajai, any other points?

Ajai Chari, MD: I think it’s important to distinguish between improving and overcoming. I think no drug has consistently overcome high risk; they’re all improving it. One of the key questions though is, yes, SWOG showed a response rate PFS [progression-free survival] and OS [overall survival] benefit without the intent to transplant, but the median age was only 63, and it was a twice-weekly bortezomib.

When we’re talking about the older patient and we want to give a PI, is a weekly PI adequate to overcome high risk, or improve high risk? We have to get into that granularity of dosing and schedule. I think the challenge also is we know that in the real world, particularly where these frail elderly patients aren’t even coming to us or going on study, they may not be able to tolerate a lot of PI until progression. I think that also has to be considered. I think if somebody is transplant ineligible and truly high risk we have an IIT [Investigator Initiated Trial] for [daratumumab plus bortezomib, lenalidomide, dexamethasone]-Lite. I think that’s what I would do. The question of which drug, which triplet, it depends on patient factors.

Paul G. Richardson, MD: I think what’s interesting, and Sagar and I have discussed this, the frequency of a proteasome inhibition is relevant. The original RVd [lenalidomide, bortezomib, dexamethasone]-Lite regimen that we studied was obviously 35 days, with an interruption in the bortezomib exposure over 2 weeks.

We christened this, it’s really a regimen that everyone sort of embraced, which is the 28-day cycle. We’ve christened it RVd [lenalidomide, bortezomib, dexamethasone]-Premium Lite because essentially what you do is pop the bortezomib in days 1, 8, 15, and 22 so there’s no interruption. Say a patient’s 1Q magnified, where proteasome inhibition may really matter, and we think that’s a reasonable strategy.

Ken, how do you think of this when you’re embracing additional risk in a patient who may not be a candidate for transplant, for example?

Kenneth H. Shain, MD, PhD: We follow the same kind of principle. It’s slightly less Velcade heavy. We do day 1, 4, 8, and we do 1, 8, 15 dosing of Velcade, give them that extra week off with the Velcade dosing. That’s an RVd [lenalidomide, bortezomib, dexamethasone]-Lite model, so it’s the same concept. There is a little more of a space in the Velcade dosing, but I think it’s friendlier to patients. I think the proteasome inhibitor dosing is still adequate. Again, we need to prove those kind of things. But it’s the same concept. If we want to keep things moving as best we can, not too long a break from a PI, make sure those things are there. That’s how I look at the transplant-ineligible patient who has high risk because we want to make sure there’s that PI in there, but it’s not quite as regimented, and the 35 days of the bigger break was nothing that we wanted to adopt. It seems a bit more complicated to be able to figure out.

Paul G. Richardson, MD: You have more symmetry so you do 28 but just the 1, 8, and 15.

Kenneth H. Shain, MD, PhD: Cesar Rodriguez MD also had a nice abstract at the IMW [International Myeloma Workshop] talking about how that was very nice. It did almost as well or as well as you would predict it would do.

Paul G. Richardson, MD: In Cesar’s schedule, as he explained it to me, I think they dosed every week, I think.

Kenneth H. Shain, MD, PhD: I think it was 1, 8.

Paul G. Richardson, MD: I don’t recall, but that’s fine.

Transcript Edited for Clarity