Case 4: Treatment Considerations for High-Risk and Standard-Risk R/R Myeloma

EXPERT PERSPECTIVE VIRTUAL TUMOR BOARD

Ola Landgren, MD, PhD:Thinking about how we have discussed high-risk disease and standard-risk disease, although we have slight differences in our approach, which is great—that drives the science forward and brings us back to these meetings to continue discussing.

Ajai Chari, MD:Everybody know that joke? If you ask 4 myeloma doctors, you’ll get 6 opinions, probably.

Ola Landgren, MD, PhD:One thing I do still think we agree on, from what I have heard so far here today, is that we agree that the high-risk disease patients need better therapies. The standard-risk patients can benefit, but some of us are maybe slightly more conservative; some of us are more aggressive.

Nina Shah, MD:Early adopters.

Ola Landgren, MD, PhD:Early adopters. Let’s think about that concept in the relapsed setting here. If you have a patient who has a complete response and it turns into biochemical relapse, and the patient is feeling fine otherwise, and there is this reoccurrence on the M-spike, would you use a different therapy compared with patients who start having symptoms after presentation of the relapse? Alfred, would you kind of give a less-intense treatment for the biochemical relapse, or would you do full speed there?

Alfred Garfall, MD:Again, there’s not a lot of evidence to guide this decision, so this is very stylistic. But for patients who have biochemical-only progression without a lot of complications and at a slow pace, this is a case where I especially consider using elotuzumab. I don’t have much hope that later on it’s going to turn to rapidly progressing disease, but it could be modified by the effect of Revlimid [lenalidomide]. So if someone is on Revlimid maintenance, consider increasing the dose of Revlimid and adding elotuzumab. Sometimes it works; sometimes it doesn’t. But if it doesn’t work and a couple of months have gone by, you can usually pick up where you left off with something more potent at that point.

On the other hand, if it is somebody who you worry about getting sick quickly, I think either a potent IMiD [immunomodulatory imide drug]—PI [proteasome inhibitor] combination like carfilzomib and Pomalyst [pomalidomide], or a daratumumab-based combination, is most appropriate.

Ola Landgren, MD, PhD:Ajai, what’s your thinking here?

Ajai Chari, MD:This is a very uncommon in a US patient, right? Because the patient is not on lenalidomide maintenance. I think that’s super important because we have 4 great RD [lenalidomide, dexamethasone] backbone studies, right? ERD [elotuzumab, lenalidomide, dexamethasone], IRD [ixazomib, lenalidomide, dexamethasone], the daratumumab-RD [lenalidomide, dexamethasone], and also KRd [carfilzomib, lenalidomide, dexamethasone].

There’s a role for each of those, right? For somebody who wants only oral therapy, IRD [ixazomib, lenalidomide, dexamethasone] is great. If somebody really wants a very well-tolerated therapy, such as the older, fragile patient, elotuzumab is a great option. And if it’s somebody who wants the daratumumab convenience, especially if it’s subcutaneous, that might be great. And carfilzomib is obviously probably a little harder of a sell, with a twice-weekly label. I think a lot of us are doing weekly, but maybe for a biochemical relapse it seems like a lot. To be giving that forever at that schedule is challenging. But there’s a role for all of them.

I agree with Alfred that elotuzumab was really prominent for biochemical relapse. But now that elotuzumab is also approved with pomalidomide, I’m not as worried about that sequencing issue. It used to be a use-it-or-lose-it issue. Now there is downstream use of it as well.

Ola Landgren, MD, PhD:What I was trying to bring up here is in the standard-risk patients, the newly diagnosed. Many years back there were people who said you could do some form of risk-adapted treatment. You could even give 2 drugs. You remember the old days, when that was kind of on the table. The people who communicated that approach said that if you’re high risk, then you need to have the 3 drugs.

We talked about the SWOG study here, which is an old study. It was published in 2017. That shows that if the standard-risk patients get 3 drugs, that’s really where you see the great benefit. In fact, if you look carefully at the data, you see that the standard-risk patients treated with 2 drugs have a worse progression-free survival than the high-risk patients with 3 drugs. If you want to be a little silly here, you could say that if you follow the risk-adapted paradigm of treatment, that was worse for the patient than having a bad FISH [fluorescence in situ hybridization] signature.

So how about this biochemical relapse here? Are we talking about the same thing—that you could go for the best therapies or the biochemical relapse to try to maximize the benefit? Is that an opportunity?

Ajai Chari, MD:You bring up a really important point. Right now in the relapsed setting, the FDA is probably not going to allow RD [lenalidomide, dexamethasone] doublet therapies anymore, right? If triplet after triplet after triplet is showing superiority, what is the role of a doublet in the relapsed setting?

Ola Landgren, MD, PhD:Exactly. That’s the point I’m trying to get at.

Ajai Chari, MD:I agree, but the difference could be that if you start with a triplet, does everybody need all 3 of those drugs maintained forever? That’s where we, as the practicing physician, with the patient at the bedside can say, “Look, you’ve had an amazing response. You’re standard risk. I’m going to eliminate 1 of these 3 drugs.” I mean, everybody’s least favorite. And then maybe even eliminate 1 of the other drugs but maintain…

I think that’s a really important point, but I would also add that you know 2 of these studies—ASPIRE and ELOQUENT—although mature, not as mature, have shown that that PFS [progression-free survival] benefit is translating into an OS [overall survival] benefit. Although the caveat is always drug access, so…the point is that it’s not that by doing this you’re compromising later outcomes; it actually can translate. But I would just say, even if it’s a standard-risk patient, start with 3 but then maybe taper.

Nina Shah, MD:Yeah, I totally agree. I have stopped giving people 2. It’s better, I think, for synergy to give 3 and dose attenuate, or eventually decrease the dexamethasone or whatever. You’ve got to give them a shot because every single trial has shown 3 is better than 2. Remember that those trials often are based on people coming on with biochemical progression. They meet the eligibility criteria, and their investigator puts them on.

Alfred Garfall, MD:One option that I think is often discounted, though: For someone who has had a good response and may be on Revlimid maintenance and for whom it’s been a long time since their induction therapy, is going back to the induction regimen OK? I don’t think you have to move on to new drugs necessarily at first biochemical progression if somebody—you know, this patient has grade 1 neuropathy, so I’d be reluctant to introduce Velcade [bortezomib]. But in someone who didn’t have any contraindications of going back to their induction therapy, that’s an appropriate option as well if they tolerated it.

Nina Shah, MD:Or a second transplant if it’s been 5 years.

Alfred Garfall, MD:Yeah, for sure.

Ola Landgren, MD, PhD:I think you bring up a very important point, Alfred. Tolerance to prior therapy obviously would impact the different drug options we are thinking about. For patients with neuropathy, you wouldn’t pick drugs that make that worse. If there was renal failure, you would stay away from drugs that were released through the kidney, for example.

The last question I have here is if the patient was found to have a certain risk signature—say, high risk, but the patient didn’t clinically behave as high risk to begin with—and now we’re talking about the relapse situation. Would you look at the old FISH results, Ajai, and say you must do this or that? Or is it really the clinical presentation that matters?

Ajai Chari, MD:That’s a great question. I had a patient, for example, who was labeled as deletion 17p. It turns out it wasn’t plasma cell specific. We repeated the marrow, and there was no 17p in the myeloma cells. It was in the rest of the marrow compartment. So I think we can get these weird issues. As we said, functional risk is much more important. If you had whatever high risk you supposedly had, and you’ve had the induction transplant and lenalidomide maintenance, and now you’ve gotten to the 4 years, that to me is not high risk.

I still think we’re using triplets for everyone, so it wouldn’t, in that sense, make that big of a difference. I guess maybe if somebody was truly high risk, would there be a role for a quad if they had symptomatic disease as well? For now, the functional risk really trumps initial risk.

Alfred Garfall, MD:The further you get from that initial diagnosis, the less relevant those results become. In some ways, everybody has high-risk myeloma. It’s just that people get to it in different amounts of time. Eventually the disease becomes resistant to all available therapies. At some point, people declare themselves becoming more aggressive, and that can happen very unexpectedly and on a moment’s notice.

Ajai Chari, MD:To your point, both the CAR T [chimeric antigen receptor T-cell therapy] and selinexor, which is for these heavily treated populations, about 50% of the patients have molecular high risk. But the rest are functionally high risk, right?

Nina Shah, MD:Yes, they’ve had 7 lines of therapy.

Ajai Chari, MD:Because if you’ve had that in 6 years, then you’re high risk no matter what.

Nina Shah, MD:Yeah.

Ola Landgren, MD, PhD:Do you have any other perspectives, Nina?

Nina Shah, MD:Of treating the high-risk patients at relapse?

Ola Landgren, MD, PhD:Yes.

Nina Shah, MD:Yeah, I would repeat the bone marrow. As Ajai said, sometimes you don’t find the things that you thought were going to be there. But I do think that if they had done really well for 4 years, it would be tough. If I found that 17p again, for sure I’d…

Ajai Chari, MD:But you did such a great job with the maintenance.

Nina Shah, MD:Yes, thank goodness they got a transplant and maintenance. They do so well. But yes, I would definitely repeat the bone marrow and see where we’re at there.

Ola Landgren, MD, PhD:I would like to thank Dr Ajai Chari, Dr Alfred Garfall, and Dr Nina Shah for very thoughtful case presentations and a lively, informative discussion. And to our viewing audience, thank you very much for joining us for thisTargeted Oncology™ Virtual Tumor Board® presentation. We hope today’s discussion was a valuable use of your time and that you acquired some practical knowledge that you can take back to your clinic. Thank you.

Transcript edited for clarity.