Newer Approaches Show Potential to Reduce Need for Transplant in NDMM

Several pivotal trials in patients with newly diagnosed multiple myeloma (NDMM) have reshaped frontline treatment and offered a glimpse into the future of minimal residual disease (MRD)-based treatment paths. In a recent virtual Case-Based Roundtable meeting, Hans Lee, MD, director of Myeloma Research at the Sarah Cannon Research Institute in Nashville, Tennessee, presented trial data in transplant-eligible NDMM and asked participants how they use the novel regimens and whether there is potential to reduce the role of autologous stem cell transplant (ASCT) following induction chemotherapy or avoid unnecessarily toxicity with maintenance regimens.

DISCUSSION QUESTIONS

• With the introduction of novel induction therapies, is there a continued role for transplantation in patients with NDMM?​
  • Do the results from the DETERMINATION (NCT01208662), GRIFFIN (NCT02874742), PERSEUS (NCT03710603), and IsKia (NCT04483739) studies influence how you consider ASCT? ​
• How do you manage adverse events (AEs) for patients receiving induction therapy? ​
  • Does it differ for triplet vs quadruplet therapy? ​

Hans Lee, MD: What is the continued role of high-dose chemotherapy and ASCT in newly diagnosed myeloma, especially with the introduction of some of these novel four drug induction regimens?

Andrew Jallouk, MD: It’s still my standard to do an ASCT after [induction] for transplant eligible patients, but I don't push it as hard, especially if somebody has standard risk and a fantastic response. If there are logistical caregiver issues or they're borderline from a functional status perspective, then I don't push it as hard for those patients.

Jeremy Pantin, MD: I think it's a tough question, but I think in the future if we can trade off toxicities of transplant with better chimeric antigen receptor [CAR] T-cell therapy, we may end up getting rid of transplant altogether in the future.

Lee: I think Dr Pantin is referring to the CARTITUDE-6 study [NCT05257083], for which we are awaiting the results. This is ciltacabtagene autoleucel [Carvykti] vs ASCT for NDMM and so we'll await the results. I think it's finished enrolling and it has a coprimary end point of MRD negativity and progression-free survival. There's historically been a lot of things tried and everything has failed. We can't be too premature and say that CAR T will win because lots of things have tried to beat transplant as far as the DETERMINATION study, but nothing has, at least, currently beaten transplant.

David Chism, MD: From my local standpoint, I'm still referring to the transplant team for consideration when the patient's eligible, particularly for a high-risk disease. I think in the future, there is a possibility for people who have standard risk and have had a great response to avoid financial toxicity…with a transplant, so it might be an option for those patients, but that would require more standardization for MRD at 10^-6 and doing more testing in the community. I think we're on the right road there, but we have a way to go in terms of that.

Michael Hemphill, MD: On the community oncology side where we see patients so often right after the ASCT and follow them and see them either monthly or every other month, the cumulative toxicity of lenalidomide [Revlimid] is still going to be one of the biggest issues as far as the quality of life. A lot of these patients are already a little bit older to begin with. They're already accumulating other comorbidities, not even myeloma related, some of which can be things like heart failure and kidney function getting worse because of the hypertension and diabetes. If you add some lenalidomide and more swelling, etc, and they end up with a knee replacement on lenalidomide and then they get a clot a month later, all these things add up. I like the idea of going on the front end if we inevitably are going to see a higher chance of MRD 0, hopefully after 2 years, possibly even coming off [maintenance].

Lee: That's a great point. I think if the patient's eligible for transplant you can go hard early on, hopefully have a higher probability of getting to an MRD-negative state and then consider early discontinuation of therapy if they get to that point. I think generally speaking, the mantra in myeloma is don't undertreat, treat adequately in the beginning to hopefully obtain the deepest and most durable response.

What about AEs? We’ve talked about some of the AEs with the addition of daratumumab [Darzalex] to VRd [bortezomib (Velcade), lenalidomide, and dexamethasone], but of course some of the other drugs have AEs. Lenalidomide has AEs; bortezomib has AEs. What's your general strategy, practically speaking, when you administer Dara-VRd to your newly diagnosed patients?

Chism: Generally, they're on an antiviral [medication]. I start them on a low dose of rivaroxaban [Xarelto] because they're high risk for clot on lenalidomide. Sometimes we do the pneumocystis jirovecii pneumonia prophylaxis or sulfamethoxazole/trimethoprim [Bactrim]. Most of the times it's rivaroxaban rather than aspirin for most of these patients in the community. We give immunoglobulin G [IgG] if they are very low and have recurrent infections and those types of things.

Lee: Great, I think those are all fairly standard.

Nina Arhin, MD: For bortezomib, usually what I've noticed is the neuropathy, so I reduce the dose of the medication. Then for people with kidney dysfunction, sometimes we need to reduce the dose of lenalidomide as well.

Lee: Even though the PERSEUS and GRIFFIN studies used twice weekly bortezomib on days 1, 4, 8 and 11, are most people using weekly bortezomib to mitigate the neuropathy risk or are some people using twice weekly?

Chism: For me, it is weekly because it's just more convenient for the patients and I don't think the data [showed] that much difference when they did weekly vs twice weekly in terms of that, but the toxicity was higher.¹ I generally prefer weekly, and the patients can adhere more to that regimen.

Lee: I completely agree. I generally dose patients with weekly bortezomib instead of twice weekly bortezomib unless they have very high disease burden where I might do twice weekly for cycle 1. But it does seem to be a significant benefit with neuropathy mitigation with the weekly schedule over the twice weekly schedule.

Hemphill: In the induction of Dara-VRd, if the IgG levels are low, but you haven't seen any infections, are you empirically giving intravenous immunoglobulin [IVIG] in those patients?

Lee: That's a great question. In certain contexts, [such as] if they're getting a bispecific antibody, I'd definitely give IVIG preemptively regardless of history of infections to keep IgG levels more than 400 mg/dL. If a patient's receiving Dara-VRd and they have hypogammaglobulinemia without any recurrent infections, I oftentimes hold off. If you ask what I do in my practice at the IgG level is less than 200 mg/dL even in the absence of infection, then I would consider preemptive IVIG. But if it's between 200 and 500 mg/dL, I don't necessarily give IVIG unless the patient has having recurrent infections.

DISCLOSURES: Lee previously reported consulting or advisory roles with Takeda, GlaxoSmithKline, Sanofi, Bristol Myers Squibb, Genentech, Allogene Therapeutics, AbbVie, Janssen Research & Development, Regeneron; research funding from Takeda, Amgen, Janssen, GlaxoSmithKline, Regeneron, Bristol Myers Squibb/Celgene. Jallouk previously reported consulting for Kite/Gilead. Pantin previously reported speaker’s bureau work for Sanofi, Bristol Myers Squibb and Omeros Corporation and honoraria and consultancy from Legend Biotech and Novartis Pharmaceuticals.

REFERENCE:

Hoff FW, Banerjee R, Khan AM, et al. Once-weekly versus twice-weekly bortezomib in newly diagnosed multiple myeloma: a real-world analysis. Blood Cancer J. 2024;14(1):52. doi:10.1038/s41408-024-01034-6