Recap: MRD Negativity, Frailty, and Emerging Therapies in Multiple Myeloma

At an Around the Practice^® program hosted by CancerNetwork^®, a panel of experts wrangled with the roles of minimal residual disease (MRD) negativity and patient frailty in multiple myeloma and also discussed the traditional and emerging therapies in this space. The conversation was led by Sagar Lonial, MD, FACP, who is chief medical officer of the Winship Cancer Institute, professor and chair of the Department of Hematology and Oncology, and the Anne and Bernard Gray Family Chair in Cancer at Emory University in Atlanta, Georgia.

The panelists were Timothy Schmidt, MD, an assistant professor in the Department of Medicine at the University of Wisconsin – Madison; Sandy W. Wong, MD, a hematologic oncologist at the University of California, San Francisco; Caitlin Costello, MD, an associate clinical professor of medicine at the University of California, San Diego Health; and Samuel M. Rubinstein, MD, a clinical assistant professor of medicine and hematologist/oncologist at the University of North Carolina, Chapel Hill, and an associate member of the Lineberger Comprehensive Cancer Center.

The Present Treatment Paradigm

LONIAL: What is the current state of the research in this disease space?

COSTELLO: It’s an exciting time in multiple myeloma. We’ve seen an explosion of new medicines in the relapsed/refractory setting, but I would argue that the developments in the newly diagnosed setting have been equally exciting. We’ve seen a significant evolution in the treatment of these patients in the [past] 5 years. We’ve seen [the standard of care] change from doublets to triplets, and we’re wondering now if a 4-drug regimen is better than a 3-drug [regimen], given that 3 is better than 2. There are good long-term data examining quadruplets.

The historical norm of breaking [patient populations into] transplant-eligible vs transplant-ineligible groups is also evolving. We now might examine frail vs fit patients to help us make some clinical decisions. Among fit patients, for example, we’re now examining whether we should be giving quadruplets to everyone. There are long-term data from the phase 2 GRIFFIN study [NCT02874742] examining the addition of the CD38-targeting monoclonal antibody [daratumumab (Darzalex)] to the triplet backbone we’ve become comfortable with: lenalidomide [Revlimid], bortezomib [Velcade], and dexamethasone [RVd].¹ It’s hard to ignore those long-term follow-up data, [which indicate that] patients who are fit and transplant eligible should be experiencing deep and durable responses. GRIFFIN met its primary end point regarding stringent complete responses. We see very deep responses, high MRD negativity rates, and a progression-free survival [PFS] benefit [with this quadruplet].

LONIAL: Does everyone use a quadruplet as their standard therapy?

RUBINSTEIN: At our center, we offer a frontline quadruplet to all patients who are eligible for transplant regardless of risk stratification. Our standard is to use daratumumab plus RVd.

SCHMIDT: We were one of the centers that continued using triplets for a long time, even after some of the GRIFFIN data emerged. We were waiting for more of the longer-term data. The GRIFFIN data had a small caveat in that the continuous daratumumab was used in [a single] arm, [which led to the question of] whether the longer PFS in that arm originated from [the use of daratumumab in the] induction or maintenance setting. As data have emerged from other studies examining CD38-targeting agents in addition to an immunomodulatory-drug backbone in newly diagnosed myeloma, we’ve seen a consistent benefit in terms of response, depth of response, [and] MRD negativity. A PFS [benefit] is also starting to emerge. [An analysis of] the GRIFFIN study showed that pain scores improved more rapidly [with the quadruplet] as well.² This is a regimen we should use for any patients who are candidates for more intensive therapy.

Risk vs Reward: Transplantation and MRD Negativity

LONIAL: The elephant in the room is the role of high-dose therapy in the context of these highly effective triplet or quadruplet therapies. It seems that every patient I see has heard about the phase 3 DETERMINATION trial [NCT01208662].³ They normally interpret the findings differently than I do. How should we address this question?

COSTELLO: I believe in transplantation. The reality is that every trial in the modern era of myeloma [testing for whether] we still need transplants [is driven by] our hope that we can eliminate [the need for] transplants with an effective, cheaper therapy. The answer we keep seeing is that they complement each other. The [major] transplant studies, whether it’s the phase 3 IFM 2009 study [NCT01191060; NCT03679351] or DETERMINATION, show us the same answer.^3,4 [Transplantation] continues to be an effective strategy that we should offer our eligible patients.

There’s been much debate over the lack of an overall survival [OS] benefit, and that’s what my patients walk in [knowing]. They’re very well-informed; they come in and say, “Well, the study showed no OS benefit, but I’ve heard the argument that OS wasn’t the primary end point. It wasn’t statistically designed for OS. The statistical design was to show a PFS benefit, and it did that: [It showed a benefit of] almost 2 years.” How do we argue with that? That PFS benefit matters.

RUBINSTEIN: The counterargument is that, in our practice, this is an individualized discussion. How much does a patient value an extra 2 years of PFS against the risks of an autologous transplant? [There’s a] nonzero [chance of] transplant-related mortality [and up to a] 1 in 30 rate of secondary hematologic malignancies. [There was also] more therapy-related myeloid disease, which is generally more challenging to treat, in the transplant arm [of DETERMINATION].

COSTELLO: I say to some of my patients, “Yes, there’s a very small risk of death from a transplant. It’s very small. There’s a reasonably small risk of getting secondary malignancies. There’s an extremely high—almost 100%—risk of your myeloma recurring.” The patient’s quality of life will take a hit for a short while, but I think we’ve all heard our patients say, “I feel fine. I’m back to work. I feel good,” at the 3-month mark. That short-term struggle for long-term benefit is worth it, in my mind.

SCHMIDT: There are also much higher rates of MRD negativity and long durable responses after transplant. You’re giving your patients a better chance at that deep and durable response.

[Of course], we don’t yet have data to show that MRD is the be-all and end-all of myeloma therapy, but we’re heavily exploring MRD-adapted treatment durations and strategies. If these end up panning out, these patients may be more likely to benefit from strategies in which we deescalate therapy or [something similar].

RUBINSTEIN: How do you think about the outcomes observed in those DETERMINATION patients who are MRD negative prior to their transplant? They did not seem to derive much PFS advantage. I’m not yet intentionally deferring transplant in patients who achieve MRD negativity beforehand, but it’s a tempting idea in light of those data.

LONIAL: That analysis was conducted at 1 year [of follow-up], not pretransplant. It showed that if you were MRD negative, it didn’t matter which arm you were part of in terms of PFS. The problem is that, at 1 year, you’ve already made the decision on transplant vs no transplant. The fraction of patients who are MRD negative at 1 year is double in the transplant group compared with the nontransplant group.

SCHMIDT: In the long-term analysis of the IFM 2009 trial, even among MRD-negative patients, there was still a benefit to transplantation. There’s certainly plenty of nuance, but still, overwhelmingly more evidence suggests that transplant is a great option for our patients.

WONG: I would also add that underlying risk is still a major factor. I feel better about a standard-risk patient who is MRD negative than a high-risk patient who is MRD negative. Some of the subset analyses from IFM 2009 and DETERMINATION [showed that] those high-risk patients still don’t do very well, even if they achieve MRD negativity. I’m especially reticent about those patients.

Chimeric antigen receptor [CAR] T-cell therapy comes up all the time when my patients come to the clinic. They don’t ask survival questions, but they know a lot about CAR Ts. Many patients say, “I don’t want a stem cell transplant. I’ll save myself for CAR Ts.” How do you respond to that?

COSTELLO: They’re not mutually exclusive. These patients will receive all these therapies. If our goal is to kick the can down the road—to keep these patients in remission as long as possible—it will give them the opportunity [to receive] CAR T.

LONIAL: You never have [a better] chance [to treat] the most sensitive disease than at the time of the initial diagnosis. Prolonging the initial PFS is a major goal. When they’re hesitant about a transplant, I tell patients that their disease is never as sensitive as it is at initial diagnosis. In DETERMINATION, only around 30% of patients received a salvage transplant, whereas, in IFM 2009, it was around 80%. I worry about losing a very important tool. It might not be the best tool for everyone, but it does benefit the majority of the population.

RUBINSTEIN: I suppose, [out of all of us], I’m the least pro-transplant. I tell patients that, if I were a younger man and were to develop myeloma tomorrow, I would want an upfront autologous transplant. [However], you have to weigh the pros and cons. I do wonder if sustained MRD negativity may someday enable us to defer an increasing number of patients and still derive some benefit.

LONIAL: The big topic is MRD-directed therapy. We heard from the FDA at the International Myeloma Society/FDA Joint Workshop that the data are all over the map. Some research examines [the outcomes at treatment] cycle 4; others examine cycle 6. Some data examine [MRD at] 1 year, and some use 10^–5 sensitivity whereas some use 10^–6. I’ve been advocating for rigor in the time points. Let’s look at 6 months and 12 months, and which patients are MRD negative at which depth, and then [observe if] that’s sustained.

RUBINSTEIN: I agree. MRD is most useful as a biomarker in a sustained capacity as opposed to a single time point. Patients with high-risk myeloma are not necessarily less likely to achieve very deep remissions; they’re just not always sustainable. If we move toward using MRD to drive advances in therapy and regulatory decisions, [our methods] need to be more standardized across the community.

WONG: We also need to standardize how we define MRD, because there’s next-generation sequencing [NGS] and next-generation flow [NGF], and some clinicians add imaging on top of [those— different] types of imaging. Obviously, on the cutting edge of technologies in development, [we could] use immuno-mass spectrometry. [Regardless], we really have to come together to figure out which tests we should use for MRD testing, and [we need to] conduct them at defined time points.

LONIAL: At our center, we perform MRD testing and PET/CT imaging at 1 year. How does this compare with your practice?

SCHMIDT: We typically check MRD at a posttransplant restaging on day 90 or 100. Our institution hasn’t been conducting bone marrow biopsies on every patient on a recurring basis because it has very rarely impacted our management decisions.

If we come together as a community and agree that, based upon these specific time points, we can have more informed discussions with our patients and make more informed decisions [based on this testing], then I would certainly be open to routine testing.

COSTELLO: For the sake of debate, [let’s ask this]: Does every patient need to be MRD negative? We do see patients who regress back to a kind of smoldering phenotype, or a monoclonal gammopathy of undetermined significance–like state. Are we overtreating those patients to achieve a goal that we don’t need to meet? That’s another unanswered question. Yes, we need to agree on whether to use NGF or NGS, on the [appropriate] time points, on [the most useful] depth [of testing]. [However], we also have to answer whether everybody needs to achieve MRD negativity.

LONIAL: [At our practice], we don’t change [treatment] if a patient is MRD positive. If they’re positive [according to] PET/CT, we might. That’s probably a bit of a different situation, but I’m with you. We use it to track outcomes, and then we go back and ask if these patients did well even though they didn’t achieve MRD negativity.

WONG: At day 90 post transplant, we always perform bone marrow biopsies. We always [check for] MRD. We use NGS, but we don’t routinely do [PET/ CT] imaging. A lot of the reason has to do with insurance because they’ll ask for data showing that it’s useful. [However, the data are] scattered and inconsistent. We need studies to show [necessity].

Transplant Ineligibility and Frailty

LONIAL: What treatments are currently used for the frailer, older, transplant-ineligible patient population?

RUBINSTEIN: We’ve seen much excellent drug development in recent years, but disproportionately in a population of patients that may not reflect the real-world population of patients with myeloma. The average patient in some of these frontline transplant trials is [aged] in their mid-50s, whereas the typical patient in the United States with newly diagnosed myeloma is [aged] nearly 70 [years]. Many patients aren’t eligible for autologous transplant in the frontline, and the question is: Has this drug development benefited that patient population?

The historical standard of care for transplant-ineligible patients with newly diagnosed myeloma has been a doublet: lenalidomide and dexamethasone. In the [past] 5 to 7 years, we’ve seen good outcomes [in this population] using triplet therapy of RVd. The phase 3 SWOG S077 study [NCT00644228] included both transplant-eligible and transplant-ineligible patients and showed an OS advantage with the addition of bortezomib to induction [chemotherapy].⁵

More recently, the phase 3 MAIA trial [NCT02252172] assessed daratumumab, lenalidomide, and dexamethasone [DRd], and it showed an impressive median PFS in excess of 5 years.⁶ Multiple recent updates [also showed an] OS advantage to this addition of daratumumab. We now have multiple options for triplet induction therapy that have been shown to be effective, and we have data showing it to be safe and well-tolerated even in a frail subgroup of the transplant-ineligible population.⁷

We have formal ways to categorize patients as frail or not frail. The International Myeloma Working Group [IMWG] has a simple, often-used metric based on age, performance status, and comorbidities.⁸ Patients categorized as frail by that scoring system still derive an OS advantage from DRd and, maybe more importantly, tolerate it very well, preserving an excellent quality of life.

LONIAL: How do we approach the question of duration of therapy?

COSTELLO: We’ve learned that continuous therapy matters. When European studies compared a fixed duration of lenalidomide vs continuous therapy until progression, we saw that [transplant-ineligible] patients benefited from [continuous therapy]. MAIA [also indicated] that continuous treatment matters, and DRd is a very tolerable combination.

We all know our patients have trouble with lenalidomide, but you can use dose modifications to make it more tolerable in the long run. Some patients want to get off it and stay on daratumumab instead, and, without any data, that’s not wrong either. [However, if you have] a good conversation with your patient to understand the barriers to continuous therapy, adjustments can be made to allow it to happen, because it does matter.

WONG: I also believe in continuous therapy. It’s important to suppress [clonal proliferation] quickly and decrease clonal heterogeneity. Taking pressure off the cancer clone increases the chance of greater clonal heterogeneity, and that’s the problem. If you allow that to happen, the patient relapses. Any time you give the myeloma a chance to relapse, it can become much cleverer. Then you move patients to your second line of therapy, and obviously [that] can produce, in a transplant-ineligible patient, a fracture.

There’s [also] a big difference between transplant ineligibility and frailty. We need to be using the IMWG scoring system more [often] to better define these populations because transplant ineligibility doesn’t [imply] frailty. [Doing so] will help us better tailor our treatments to frail populations. We’re very worried about these patients—they’re much more difficult to treat.

Bispecific T-cell Engagers

LONIAL: Bispecific T-cell engagers were the belle of the ball at the 64th American Society of Hematology [ASH] Annual Meeting & Exposition. What were some of the findings regarding these?

WONG: This was an amazing meeting. The T-cell engagers were central, as [they were] the prior year. It’s an exciting time [in myeloma] because we have 3 targets. We have BCMA [B-cell maturation antigen], and we have the recently approved agent teclistamab-cqyv [Tecvayli].⁹ In that class, multiple other options are under development, including elranatamab, which is also subcutaneous. [This is great for] ease of administration. At ASH, we also saw [data] regarding alnuctamab, which is also given subcutaneously.¹⁰ We hadn’t seen an update since the 2019 meeting, so it was great to see those findings. We also have intravenous BCMA T-cell engagers, like ABBV-383 and Regeneron’s linvoseltamab. A lot of exciting activity exists in that class of drugs, and the overall response rates are generally around 60% to 70%.

However, we’re starting to see some potential differences in terms of toxicity. It’s difficult [to say for sure] because teclistamab has had the longest median follow-up at around 14 months, quite a long time.¹¹ The one with the second-longest is probably elranatamab, and then the other ones [follow]. I’m very excited that we have teclistamab now.

LONIAL: I think we’re all excited. I’ve not given teclistamab [to any patients]. Have any of us given it commercially?

SCHMIDT: Commercially, no.

WONG: Yes. We just started this week. We dosed 2 patients.

RUBINSTEIN: Our first [patient to receive it] is coming in this week.

Final Thoughts

LONIAL: What are some prospects for the future in this space? What do you want to see in the coming years?

RUBINSTEIN: It’s a very exciting time to be taking care of patients with multiple myeloma. We have several highly effective therapies that have novel targets. The biggest unmet need is [that we need to] figure out how to stop these therapies while preserving disease control.

COSTELLO: We [also] don’t know what to do with [high-risk and functional high-risk] patients. So much [more] effort needs to be put forth for them.

WONG: Those who have already received BCMA-directed therapy don’t have further options. In the coming year, I’m excited to see what comes of the teclistamab submission. We need another target to [engage with].

SCHMIDT: Yes, an ultra-high–risk population [exists] in which we see early progression even with very active combination therapies. Figuring out who these [ultra-high–risk] patients are, and identifying them for early enrollment in clinical trials aimed at overcoming the adverse effect of this high-risk biology early in their disease course, is an unmet need that we need to address.

References

1. Sborov DW, Laubach JP, Kaufman JL, et al. Daratumumab (DARA) + lenalidomide, bortezomib, and dexamethasone (RVd) in patients (pts) with transplant-eligible newly diagnosed multiple myeloma (NDMM): final analysis of GRIFFIN. Presented at: 19th International Myeloma Society Annual Meeting; August 25-27, 2022; Los Angeles, CA. Abstract OAB-057.
2. Silbermann R, Laubach J, Kaufman JL, et al. Health-related quality of life in transplant-eligible patients with newly diagnosed multiple myeloma treated with daratumumab, lenalidomide, bortezomib, and dexamethasone: patient reported outcomes from GRIFFIN. Blood. 2022;140(Suppl 1):1146-1149. doi:10.1182/blood-2022-162313
3. Richardson PG, Jacobus SJ, Weller EA, et al; DETERMINATION Investigators. Triplet therapy, transplantation, and maintenance until progression in myeloma. N Engl J Med. 2022;387(2):132-147. doi:10.1056/NEJMoa2204925
4. Perrot A, Lauwers-Cances V, Cazaubiel T, et al. Early versus late autologous stem cell transplant in newly diagnosed multiple myeloma: long-term follow-up analysis of the IFM 2009 trial. Blood. 2020;136(Suppl 1):39. doi:10.1182/blood-2020-134538
5. Durie BGM, Hoering A, Sexton R, et al. Longer term follow-up of the randomized phase III trial SWOG S0777: bortezomib, lenalidomide and dexamethasone vs. lenalidomide and dexamethasone in patients (pts) with previously untreated multiple myeloma without an intent for immediate autologous stem cell transplant (ASCT). Blood Cancer J. 2020;10(5):53. doi:10.1038/s41408-020-0311-8
6. Kumar SK, Moreau P, Bahlis NJ, et al. Daratumumab plus lenalidomide and dexamethasone (D-Rd) versus lenalidomide and dexamethasone (Rd) alone in transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM): updated analysis of the phase 3 MAIA study. Blood. 2022;140(Suppl 1):10150-10153. doi:10.1182/blood-2022-163335
7. Facon T, Cook G, Usmani SZ, et al. Daratumumab plus lenalidomide and dexamethasone in transplant-ineligible newly diagnosed multiple myeloma: frailty subgroup analysis of MAIA. Leukemia. 2022;36(4):1066-1077. doi:10.1038/s41375-021-01488-8
8. International Myeloma Working Group. Myeloma Frailty Score Calculator. Accessed February 15, 2023. http://www.myelomafrailtyscorecalculator.net
9. FDA approves teclistamab-cqyv for relapsed or refractory multiple myeloma. FDA. October 25, 2022. Accessed February 14, 2023. https://bit.ly/3Xj3dex
10. Wong SW, Bar N, Paris L, et al. Alnuctamab (ALNUC; BMS-986349; CC-93269), a B-cell maturation antigen (BCMA) x CD3 T-cell engager (TCE), in patients (pts) with relapsed/refractory multiple myeloma (RRMM): results from a phase 1 first-in-human clinical study. Blood. 2022;140(Suppl 1):400-402. doi:10.1182/blood-2022-159009
11. Moreau P, Garfall AL, van de Donk NWCJ, et al. Teclistamab in relapsed or refractory multiple myeloma. N Engl J Med. 2022;387(6):495-505. doi:10.1056/NEJMoa2203478