Determining How to Incorporate MRD Into Care Decisions for Myeloma

Kathleen A. Dorritie, MD

Minimal residual disease (MRD) has the potential to become a key component of the decision-making process for selecting the optimal treatment for transplant- eligible patients with multiple myeloma, according to Kathleen A. Dorritie, MD.

The utility of MRD was demonstrated in the phase 2 FORTE study (NCT02203643), which examined carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone (KRd) followed by autologous transplant in patients with transplanteligible multiple myeloma. In this trial, MRD appeared to correlate with survival, with patients who underwent stem cell transplantation achieving higher rates of MRD negativity at 1 year compared with those who did not undergo transplant.

“This highlights the importance of MRD and following this when we’re looking at overall outcomes in patients,” Dorritie said. “Certainly, in these high-risk patients, that’s particularly important if we know that it correlates with survival.” However, Dorritie noted that questions remain with regard to the optimal utility of this marker.

“When, where, and how we should incorporate MRD into our decision-making [process] is at the forefront right now, similar to where we were with some leukemias a few years ago,” Dorritie added. “Outside of the research setting, we’re not really using MRD in terms of dictating our plans of care. It’s important that our research guides us in terms of where this [will be] most useful. It certainly appears to be [beneficial], but as clinicians, we don’t currently know the best way to utilize this information.”

In an interview with OncLive® during a 2020 Institutional Perspectives in Cancer webinar on hematologic malignancies, Dorritie, a hematologist/medical oncologist at the University of Pittsburgh Medical Center’s Hillman Cancer Center , detailed the utility of MRD as shown by the results of numerous trials in the multiple myeloma space.

OncLive®: What was exciting about the results of the MAIA trial?

Dorritie: The MAIA trial was based off of another trial that had demonstrated the benefit of lenalidomide and dexamethasone in the first-line [treatment of] patients with multiple myeloma who were transplant ineligible; this led to [the establishment of] lenalidomide plus dexamethasone as the standard of care.

The MAIA trial [NCT02252172] was aimed at trying to improve upon that benefit further with the addition of daratumumab [Darzalex] to lenalidomide/ dexamethasone in the frontline setting for patients who are transplant ineligible. In fact, the addition of daratumumab did seem to improve outcomes in patients in terms of who achieved a progression-free survival [PFS] benefit, which really had not been reached in the daratumumab arm at the time of the trial, but also across all key subgroups. Particularly for high-risk patients, [this] really changes the standard of care.

In clinical practice, how do you determine transplant eligibility?

That has been a moving target that differs a bit depending on where you practice. In Europe, they have different criteria based on age [and other factors] that [can be used to] determine whether a patient is eligible. In general, [the decision is] based not only on age but also on comorbid conditions. If a patient has extensive cardiac history or renal disease, [we] may be concerned [about] toxicities related to transplant; these patients would be deemed ineligible. In general, most patients are transplant eligible, but there is certainly a subset who are not. These types of trials really expand our thinking as to whether transplant will be included as an early treatment option in the first place. That remains to be seen.

In terms of treatment selection, where does MRD factor into the decision-making process? What has been learned so far from the FORTE trial?

The ongoing FORTE trial is composed of 3 arms. [One arm] included the combination of carfilzomib, cyclophosphamide, and dexamethasone [KCd], followed by an autologous stem cell transplant, followed by KCd maintenance. This was compared with 2 different arms that incorporated lenalidomide in place of the cyclophosphamide. [The second was] KRd, followed by autologous stem cell transplant, followed by KRd. The final arm was KRd alone without an autologous transplant. The initial analysis came out in 2018 and showed that both of the lenalidomide- containing arms outperformed the cyclophosphamide- containing arms. The updated analysis from FORTE that was [recently] presented focused on the 2 lenalidomide-containing arms; namely, KRd followed by autologous transplant followed by KRd consolidation compared with KRd without a transplant. The results were quite interesting. As expected, patients who had higher-risk disease going in did not do as well in general [in terms of] complete response [CR] rates and, importantly, MRD-negativity rates.

The updated analysis from FORTE that was [recently] presented focused on the 2 lenalidomide-containing arms, namely KRd followed by autologous transplant followed by KRd consolidation compared with KRd without a transplant. The results were quite interesting. As expected, patients who had higher-risk disease going in did not do as well in general [in terms of] complete response [CR] rates, and importantly, MRD negativity rates.

However, when looking at MRD negativity, which seems to correlate with survival, [investigators] found that patients who were high risk in the autologous-transplant arm did have a higher rate of MRD negativity at 1 year compared with those who had high-risk disease who did not receive an autologous transplant.

What are the next steps for this research?

[We need to follow] the duration of this MRD negativity. We know that at 1 year, the risk of relapse in [those who fall in] the high cytogenetic risk category seems to be higher in those who did not undergo an autologous transplant. However, we don’t know how long that benefit is going to hold. It’ll be interesting to see the data as time goes on to see at what point these patients will relapse.

What was unique about the findings from the CASSIOPEIA trial?

CASSIOPEIA [NCT02541383] aimed to move daratumumab into earlier lines of therapy. We know that daratumumab is efficacious in [patients with] relapsed/refractory myeloma, both alone and in combination regimens. [These trials were] specifically [done] in patients who are transplant eligible compared with the MAIA study, where we were looking at patients who were transplant ineligible.

In Europe, bortezomib [Velcade], thalidomide [Thalomid], and dexamethasone [VTd] is the standard of care. CASSIOPEIA is a phase 3 trial comparing VTd alone versus daratumumab and VTd followed by autologous transplant. For this trial, the upper age limit was 65 years. This is due to differences in practice in Europe with regard to autologous transplantation. In the GRIFFIN trial [NCT02874742], you’ll see that the age limit is a little bit different.

Just to summarize, the number of patients who achieved a stringent CR [sCR] and achieved MRD negativity was higher in the group who received daratumumab compared with [those given] VTd alone. Importantly, responses seemed to deepen over time, both with regard to the response rates and MRD-negativity rates.

When looking across all subgroups, more patients in the daratumumab-VTd arm seemed to do better. The only subgroups where this did not necessarily seem to be the case were in the high-risk cytogenetic group and the high-risk International Staging System [ISS] group, which has been consistent across many trials. Daratumumab/VTd seemed to have PFS benefit across every subcategory or stratification category. [Here, we saw] higher rates of sCR, higher rates of MRD negativity, and, importantly, no increase in overall toxicity other than expected hematologic toxicities. To reiterate, this is important because deep responses such as sCR and MRD negativity really correlate with overall survival [OS].

The GRIFFIN trial was the companion study that was done in the United States. What was the significance of this trial, and how has it affected practice?

This was the US companion study to CASSIOPEIA. The backbone was lenalidomide, bortezomib, and dexamethasone [RVd], compared with VTd. Essentially, this was the same study looking at daratumumab/RVd versus RVd alone. When looking at overall response rates, sCR rates, and MRD negativity rates, the arm that contained daratumumab did better. Responses deepened over time and MRD negativity improved over time.

Importantly, the GRIFFIN trial doesn’t have as long of follow-up, so at the time when results were updated at [the 2020] American Society of Clinical Oncology [Virtual Scientific Program], the median PFS had not been yet reached in either group; that was [observed] at around 24 to 30 months, although we did start to see a separation of the PFS curves. No difference in OS rates [were observed either]. Again, we may just need longer follow-up.

Certainly, daratumumab/RVd significantly improved response rates and depth of response. Importantly, the steps of mobilization were not affected by the addition of daratumumab, nor was engraftment. PFS and OS data are not mature, but in the United States, it is thought that daratumumab and RVd might become the new standard of care.

How does this affect the high-risk subgroup?

It’s unclear whether this will hold true for the high-risk subgroup, but the high cytogenetic risk and ISS high- risk groups did not show benefit from the addition of daratumumab, although the number of patients in this group was quite small—only 29 patients. This is the group of patients we’ll need to focus our research on going forward.

Where should future efforts be focused?

Other important areas for research include follow-up with these patients who are receiving some of our later lines of therapy incorporated earlier, particularly daratumumab. While we know daratumumab lends benefit to patients earlier on, is this going to affect their response to treatments later? We don’t quite know. The best sequencing for these patients also remains an important question in myeloma, which we don’t have an answer for yet.

Would you like to add anything else?

For patients not eligible for transplant, the shift is toward incorporating novel agents earlier, and we’ve seen benefit from incorporating daratumumab earlier. For transplant- eligible patients, the benefit of transplant may ultimately shift with the ever-increasing therapies, but it is still the standard of care at the current time.

It may be that a few years down the road we’ll be collecting stem cells but saving them for a later line of therapy, but as of right now, autologous stem cell transplant remains the standard of care. The best way to sequence our therapy options remains unclear, and incorporation of MRD is likely to become more standardized. I think a big benefit to participating in research studies is to see where this information will be most useful, so we can translate it into improvements in care for our patients.

Reference

1. Gay F, Cerrato C, Scalabrini DR, et al. Carfilzomib-Lenalidomide-Dexamethasone (KRd) induction-autologous transplant (ASCT)-Krd consolidation vs KRd 12 cycles vs carfilzomib-cyclophosphamide-dexamethasone (KCd) induction-ASCT-KCd consolidation: analysis of the randomized Forte trial in newly diagnosed multiple myeloma (NDMM). Blood. 2018;132(suppl 1):121. doi:10.1182/blood-2018-99-112093