Recap: Treatment Options in Transplant-Eligible and -Ineligible Multiple Myeloma

In this special edition of Around the Practice: Institutional Insights, physicians from Memorial Sloan Kettering Cancer Center in New York, New York, discuss topics in multiple myeloma.

The experts included Saad Z. Usmani, MD, MBA, FACP, chief of myeloma service; Neha S. Korde, MD, a hematologic oncologist; Sham Mailankody, MBBS, a medical oncologist; and Urvi A. Shah, MD, a hematologic oncologist.

Transplant Eligibility Criteria in Multiple Myeloma

To begin their discussion, the clinicians evaluated the case of a patient with transplant-eligible multiple myeloma. Usmani moderated the narrative, commencing with asking how each participant would handle this patient’s treatment.

CASE

• A 51-year-old man presented with revised International Staging System stage II multiple myeloma.
• Laboratory values Hemoglobin: 7.0 g/dL
• β2-Microglobulin: 6 mg/dL
• Albumin: 3.2 g/dL
• Bone marrow: 22% clonal plasma cells
• Serum κ free light chain: 24 mg/dL
• Serum IgG: 5 g/dL
• Cytogenetic abnormalities: none
• ECOG performance status: 1
• PET/CT: multiple vertebral bone lesions
• No extramedullary disease
• His diagnosis was IgG κ myeloma, and he was identified as being transplant eligible.

Usmani: How do you determine if a patient is transplant eligible?

Mailankody: At our center we have almost everybody see a transplant doctor for a consultation before we determine if the patient is eligible. In many cases like this, the patient is clearly transplant eligible. There are patients who may be older and have comorbidities. But we’ve [become] much better with transplants, so the default status for most of our patients should be that they’re transplant eligible unless there are glaring exclusions. We also find it helpful that patients meet with a transplant doctor, in addition to their primary
myeloma doctor, to get a second perspective about the role of transplant, collection, and up-front vs delayed transplant.

Shah: It’s important to start with induction. Now that we have so many options, that becomes a big conversation. Once the patient has finished about 3 to 4 cycles, that’s helpful because you know how they tolerate those cycles. This helps you determine transplant eligibility and if they tolerate it well, especially for those you’re on the fence about.

Usmani: Would your engagement with the transplant physicians be different if this patient had high-risk disease? If he had high-risk cytogenetics, would
you be worried about having a gap between finishing induction, collection, and transplant?

Korde: I take a different approach with my patients. I like to get that seed planted early because that’s the best thing for them. If there’s this ongoing discussion about whether they’re up for it, it helps to address it as we go through the induction. For my high-risk patients, I’m very transplant forward. I introduce the concept to them quickly, usually at first visit. I’m pretty up front and honest in terms of why and where the data are.

Usmani: We have [several] choices of first-line induction treatment. What are
your thoughts on picking triplet vs quadruplet regimens?

Mailankody: There should be few patients, if any, treated with doublets in modern times. Obviously, there are patients in our clinic who may need doublet treatment for various reasons, but the default position should be to go with a triplet or a quadruplet regimen.

I’ll go with a triplet regimen at a minimum. For patients who have aggressive disease presentation or high-risk cytogenetics, there may be more of an inclination to go with a quadruplet—for instance, [regarding the] updated results from GRIFFIN [NCT02874742].¹ We’re recognizing more that [although] we’ve made significant progress for patients with high-risk myeloma, we continue to need new approaches and innovations in how we treat them. It would be reasonable to consider a quadruplet regimen like daratumumab [Darzalex] and RVd [lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone] based on [data from] the GRIFFIN study.

This patient has standard-risk cytogenetics and is a young person. Any of these choices would be reasonable. He has a creatinine clearance of 45 mg/dL, which would not preclude him from getting lenalidomide, but that may be one reason why some physicians would consider CyBorD [cyclophosphamide, bortezomib, dexamethasone] for a cycle or 2 until the renal function stabilizes; but any of the mentioned choices would be quite reasonable.

Korde: For my standard-risk patients who are young, because of [findings from] the ENDURANCE study [NCT01863550], I’ll often choose KRd [carfilzomib (Kyprolis), lenalidomide, dexamethasone] if I have a clear understanding of their cardiac history.² In this patient, if he has a relatively benign cardiac history, I’ll choose carfilzomib up front. In my older standard-risk patients, I tend to go with RVd because it’s tolerable.

Shah: I tend to agree with what everyone has said, but some things call for a discussion with the patient about the toxicities of these drugs. Patients
sometimes have very strong preferences about carfilzomib, which has a slight increased cardiotoxicity, vs bortezomib, which has neuropathy. I tend to bring up the basics of the data. The ENDURANCE study [data] showed no difference between VRd and KRd, but there may be some [findings from] phase 2 studies that suggest that this combination is good. It’s important to see what the patient is leaning toward. I tend to prefer bortezomib options, given the ENDURANCE trial results, the cost, and also because it’s [intravenous] vs subcutaneous. I find that having to come in weekly for an [intravenous] therapy vs just having a shot is a significant [improvement in] quality-of-life benefit unless neuropathy is an issue.

Mailankody: For somebody with a mild to moderate degree of cardiac history, you may want to go with [bortezomib]. Many times what patients tell us will influence what regimens we use, but we can feel comfortable that both treatments are equally effective, at a minimum, based on the ENDURANCE study [data]. They have somewhat different safety profiles, so that may play a role, but the [important aspect is the use of a] triple regimen, at least, for most patients. Then consider a quadruplet regimen in the coming years as well while more data emerge from GRIFFIN and other studies.

Induction and Consolidation in Transplant-Ineligible Patients

Usmani: In your clinical practice, how do you guide the number of cycles of [induction and consolidation]?

Mailankody: If you engage the transplant doctors early, the delay in taking a break for collection is usually not very long. The caveat is to have the patient see the doctors proactively and early.

We have studies of transplant vs delayed transplant. The idea is that if those patients defer for various reasons and do [progress eventually], then there would be a strong consideration for transplant. I’d probably resume some form of induction therapy for a few more cycles. After [stem cell] collection in those patients who decide not to do transplant up front, I try to get as deep of a response as possible before maintenance therapy.

Shah: I also ask if [their response is plateauing or what their response is to how many cycles. It should depend on the deepening of cycles for the individual, which we don’t see in clinical trials because they’re fixed in terms of the number of cycles. With a patient, I make sure that with every cycle there’s some added response. Once they’ve plateaued, I do 1 more cycle. I don’t see a point in continuing cycles indefinitely or for a certain number that I’ve defined. I refer them to the transplant [department] and think about whether they need to go to transplant sooner than later if necessary.

Usmani: The only patients that I’m [recommending] consolidation for, and I try to introduce this idea before transplant, are the high-risk patients. If they’re not getting better than a VGPR [very good partial response] post transplant, I would negotiate with them to have a couple of postconsolidation cycles or posttransplant cycles with consolidation before going into a maintenance phase.

Transplant Ineligible in Multiple Myeloma

Usmani: Can you talk about first-line treatment options for transplant-ineligible multiple myeloma.

Shah: As we have more data coming along, we have options for the transplant-ineligible patients. RVd-lite used to be the standard that many doctors used across the United States, where they would do reduced doses of lenalidomide and bortezomib with a 35-day cycle or adapted to a 28-day cycle. This was based on [results from] a small study from Massachusetts General Hospital in Boston. Now, with the new phase 3 randomized MAIA study [data (NCT02252172)], we also see that there’s an overall survival benefit.³ That study looked at daratumumab, lenalidomide, and dexamethasone [DRd] compared with lenalidomide and dexamethasone.

Then the randomized phase 3 [TOURMALINE-MM2] study [NCT01850524] in the transplant-ineligible group looked at ixazomib [Ninlaro], lenalidomide, and dexamethasone compared with lenalidomide and dexamethasone.⁴ This was not a statistically significant study, but there was a clinically significant benefit in some ways. If a patient didn’t want to come in for visits and wanted a completely oral regimen, then for those certain patients ixazomib could be added to [Rd].

Usmani: Would you think about the high-risk patients when you would consider that?

Shah: I rarely use the ixazomib/lenalidomide/dexamethasone triplet. I recently had a patient who loved to travel and was otherwise fit but refused to come in weekly for treatment. For that patient, it worked out well. But if a patient is willing to come in, I would prefer either RVd or DRd for them. I’ll add that many transplant-ineligible patients are obviously frail, and I often see doctors considering a doublet therapy, but I would argue that we should try to do a triplet therapy at a reduced dose rather than do 2 drugs for those [patients]. With that, you can start with 1 cycle of a doublet, see how they tolerate it, and then add the next drug with the second cycle.

Usmani: The point you’re trying to make here is that it’s the same heterogeneous disease. It has many different clones and subclones. You can’t treat myeloma with a single mechanism of action, but you can combine different mechanisms of action to get them in a dose-attenuated fashion so that you can get better outcomes for your patients.

I’ve always been struck by the fact that [data from] most of the ixazomib studies, whether it’s in the newly diagnosed or early-relapsed setting, have shown some early promise but that promise hasn’t come through. Many of us have felt that maybe it’s the weaker of the 3 PIs [proteasome inhibitors]. Another way of looking at this would be if K [carfilzomib] and V [bortezomib] were comparable in the frontline setting, based on the ENDURANCE study [results]. This may be a reasonable replacement for older patients but may not have the same kick.

When you’re thinking about frontline treatment for transplant-ineligible patients, how are you thinking about the treatment options?

Korde: I’m looking at whoever is sitting in front of me. For that transplant-ineligible group, looking at the recently updated MAIA data [shows me that] this regimen is the standard of care in this group. It’s hard to compare the 2 [therapies] head to head, but when you look at the DRd—the tolerability, how easy it is to give, and the lack of neuropathy—that tends to come to the forefront of my mind.

I’m also thinking about who the patient is. For the person sitting in front of you, there can be a whole range of frailty and comorbidity considerations. Look at the support system [and] the providers helping the patient. What I usually find is that the DRd tends to go very smoothly with those patients. It seems to work with few adverse effects and lower rates of neuropathy. I tend to prefer that over RVd.

Mailankody: The data would suggest that as long as we don’t have randomized comparison data, any differences between the 2 triplets are somewhat marginal. There are very few patients who should be getting doublets with newly diagnosed myeloma in 2021. For most people, transplant eligible or ineligible, you will be able to administer a triplet.

Korde: Do you end up switching your patients to lenalidomide alone after maintenance?

Usmani: I wait for patients to get to a response plateau, and it also depends on how well they’ve tolerated it. If they have any issues [with their lab results], my typical preference is to wean off the lenalidomide and keep the daratumumab to once a month. Yes, it used to be more cumbersome when it was an infusion, but now it’s subcutaneous. When they come in for labs, you can take care of the subcutaneous injection. There are other patients who are standard risk and have tolerated lenalidomide whom you can wean off the daratumumab. That’s real-world practice.

When you initiate the 3-drug regimens for your newly diagnosed transplant-
eligible patients, we talk about whether you continue maintenance with 1 drug vs continuing on all drugs. Does cytogenetic risk, or high-risk vs standard risk, influence your choice? How confident are you of one strategy vs the other?

Mailankody: We talked a lot about the ENDURANCE study. It’s a large study with 1000 patients that didn’t include those with high-risk myeloma or high-risk cytogenetics; those patients were excluded. The results, very strictly speaking, are relevant or applicable primarily to patients with standard-risk myeloma. I think the clinical scientific question about the role of carfilzomib in patients with frontline [disease and] high-risk cytogenetics is still an open question.

That said, I do believe that of the many treatments for myeloma, there are very few treatments that work for high-risk but do not work in standard-risk patients. You have treatments that work well in low-risk patients, but do not work in high-risk [patients]. It’s reasonable to consider carfilzomib, lenalidomide, and dexamethasone for high-risk patients. The responses tend to be somewhat earlier with carfilzomib vs bortezomib. If you have a patient [with high-risk cytogenetics] who has a large mass in the spinal column or another lesion for which you would like to get an early, quick response, I would probably lean toward KRd.

A quadruplet would also be an option in those patients based on emerging data from the GRIFFIN study. These studies have not looked specifically at high-risk patients, which is what limits us being more definitive, but I think it would be reasonable to consider daratumumab/RVd in those patients. This is not in trials, but this is how I practice. If I start on a triplet, whatever the choice is, I check again in 2 months to see what the response is like. If you have a patient who has not achieved a PR [partial response] after 2 cycles of RVd and has high-risk cytogenetics, that patient isn’t likely going to get a very deep response. [For those patients], I would be more proactive about adding a fourth drug or changing to a different triplet. It doesn’t happen very often, fortunately, but is something to keep in mind as we tailor these regimens and treatments to our patients.

Usmani: One thing that we haven’t touched upon is the utility of MRD [minimal residual disease] testing in our clinical practice. Should we be defining treatment duration or changing treatments based on MRD results?

Korde: I don’t think we’re yet there. We are in a gathering-data phase at this point. The questions that are being asked, for instance, by the MASTER study [NCT03224507] are fascinating.⁵ This is a roadmap to where we want to go. When I look at our smaller phase 2 study where we tailored treatment around MRD response, even though some of those data are maturing, I don’t think it’s quite there yet. We need more sustainable MRD time points.

Shah: In the MASTER study, they divided the patients into groups of
0 high-risk cytogenetic abnormalities, 1 cytogenetic abnormality, and 2 cytogenetic abnormalities. The high-risk features that they call for are t (4;14), t (14;16), deletion 17p, and gain of chromosome 1q.

Once they stopped maintenance, they looked at patients at the 1-year landmark who relapsed or had a biochemical progression. Of those with 2 high-risk cytogenetic abnormalities, 27%…had a recurrence of disease, whereas in the 0 to 1 cytogenetic abnormality, …almost 0% or 4% of patients…[had]. It’s important to have sustained MRD negativity at 2 time points, and it may not be the same for all patients, depending on risk.

Usmani: Sustained CR is most important for high-risk patients. As our tools are getting better, we’re seeing this recurrent theme in some of those concepts. We are going to be relying on sustained MRD negativity. Lower thresholds may be relevant to standard-risk patients, but I agree, sustained MRD is probably going to be the first time point we’re thinking about.

Mailankody: I generally tell my patients that I would do at least a minimum of 2 years because there are no studies of maintenance less than 1 to 2 years. Beyond that, if they’re tolerating it well and things are going well, maybe continue treatment but have a discussion of the pros and cons of stopping—particularly if they have sustained MRD negativity, are lower risk, or have had adverse effects with the ongoing maintenance therapy. That’s a small group of patients, but those patients may do OK with coming off maintenance at some point and being monitored closely off maintenance.

References

1. Laubach JP, Kaufman JL, Sborov DW, et al. Daratumumab (DARA) plus lenalidomide, bortezomib, and dexamethasone (RVd) in patients (pts) with transplant-eligible newly diagnosed multiple myeloma (NDMM): updated analysis of GRIFFIN after 24 months of maintenance. Blood. 2021;138(suppl 1):79. doi:10.1182/blood-2021-149024
2. Kumar SK, Jacobus SJ, Cohen AD, et al. Carfilzomib or bortezomib in combination with lenalidomide and dexamethasone for patients with newly diagnosed multiple myeloma without intention for immediate autologous stem-cell transplantation (ENDURANCE): a multicentre, open-label, phase 3, randomised, controlled trial. Lancet Oncol. 2020;21(10):1317-1330. doi:10.1016/S1470-2045(20)30452-6
3. Facon T, Kumar SK, Plesner T, et al. Daratumumab, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone alone in newly diagnosed multiple myeloma (MAIA): overall survival results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2021;22(11):1582-1596. doi:10.1016/S1470-2045(21)00466-6
4. Facon T, Venner CP, Bahlis NJ, et al. Oral ixazomib, lenalidomide, and dexamethasone for transplant-ineligible patients with newly diagnosed multiple myeloma. Blood. 2021;137(26):3616-3628. doi:10.1182/blood.2020008787
5. Costa LJ, Chhabra S, Medvedova E, et al. Daratumumab, carfilzomib, lenalidomide, and dexamethasone with minimal residual disease response-adapted therapy in newly diagnosed multiple myeloma. J Clin Oncol. Published online December 13, 2021. doi:10.1200/JCO.21.01935