‘Virtually All Patients’ with Newly Diagnosed Transplant-Ineligible Myeloma Achieve Response With Addition of Daratumumab to Lenalidomide-Dexamethasone Combo

Thierry Facon, MD, Hematology Division head and assistant professor of hematology at Lille University Hospital in France

The addition of daratumumab (Darzalex) to a combination regimen of lenalidomide (Revlimid) and dexamethasone (Decadron; D-Rd) is nearly universally beneficial to all patients with newly diagnosed transplant-ineligible multiple myeloma (NDMM), according to an expert.

“This regimen is rapidly active. For example, the median time to achieve PR [partial response] is less than 4 months. At the end of the day, more than 90% of patients will achieve response,” Thierry Facon, MD, Hematology Division head and assistant professor of hematology at Lille University Hospital in France, said in a recent interview with CancerNetwork^®.

During the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting, CancerNetwork^® spoke with Facon about the high likelihood of favorable treatment responses and reduction in pain resulting from the use of D-Rd in patients with NDMM.

Facon supported his conclusions citing findings from the phase 3 MAIA study (NCT02252172), which was designed to assess end points such as progression-free survival (PFS), time to response, and duration of response observed in the D-Rd regimen compared with lenalidomide and dexamethasone alone (Rd).

Overall, median time to complete response (CR) was 20.8 months for patients receiving D-Rd and 47.9 months for those receiving Rd in the total patient population (HR, 1.72; 95% CI, 1.36-2.18; P <.0001).¹ Median time to CRs were also shorter for D-Rd than Rd across patient subgroups based on factors such as renal function and cytogenetic risk status. Overall, the study indicated that D-Rd produced more durable responses and improved patient-reported outcomes than Rd among patients with transplant-ineligible NDMM regardless of renal function or cytogenetic risk statuses.

Facon spoke more about the rationale behind the MAIA study, the safety profiles of the studied regimens, patient subgroup analyses, and what future research may look like for the treatment of transplant-ineligible NDMM.

CancerNetwork^®: What are some important efficacy findings from the trial?

Facon: The good news is that the PFS benefit was unprecedented. I know that the word 'unprecedented' has been said many times in myeloma, but to be honest, it's likely true for this particular study. At the time of the Lancet Oncology paper in 2021, the median PFS was still not reached.² At 5 years, the PFS rate was 52.5%, so we were close to the median. The median PFS has now been reached at 61.9 months. That's quite a long time, and that is the best median PFS achieved in elderly patients with myeloma. And so, the median OS has still not been reached in either arm, but the expectation is to have a median PFS of more than 7 years. We still don't know, but it's reasonable to think that we may achieve more than 7 years in terms of median OS. That will be a great achievement for elderly patients with multiple myeloma.

What did the safety profile look like for the studied treatments?

Safety is fine; it's very manageable. As of today, we still have a lot of patients in the MAIA study, especially patients [receiving daratumumab]. Some of these patients have already received more than 60 cycles. So, it's tolerable. The dexamethasone has been discontinued for many patients, so the majority of patients stay on lenalidomide. Usually, I would say lenalidomide [in 10 or] 15 milligrams, and daratumumab given subcutaneously because the study has accepted to switch from [intravenous] to [subcutaneous infusion]. So, the MAIA patients today receive subcutaneous daratumumab, and it's mostly daratumumab.

Then, we presented quality of life and all patient-reported outcomes. The frailty analysis is something important, and it has shown that there is also a benefit for the addition of daratumumab for the frail patients. It's true that the frail patients still have a less favorable outcome as compared to the non-frail patients, but more than 80% of these patients can achieve response, and the median PFS is quite nice. Of course, we did see more adverse events in the frail patients, and in general, more serious adverse events and more discontinuation of therapy. That's the usual stuff. D-Rd study results are also good for the frail patients.

No regimen is perfect. You cannot say, 'this is just wonderful; you just keep it like this.' [D-Rd is] not a miracle, but it's still the best regimen we have today. And most importantly, this is a kind of reset for the elderly. As of today, many countries have D-Rd available for older patients.

What are the next steps for improving this treatment regimen?

What should we do if you want to have more than 5 years of median PFS and more than 8 years of median OS in older patients? It's not so easy, but the good news is that we have several new drug candidates. We have bispecific antibodies which are currently under investigation for [patients with] relapsed or refractory myeloma. And so, these bispecific antibodies may play a role. You may say that CAR T-cell strategies, at least for the non-frail patients, may be interesting, as well. We may have new agents as well, so iberdomide, for example, instead of lenalidomide.

So, there are different ways to improve on D-Rd, and that could be important for some subgroups — especially the patient with high-risk cytogenetics. They still do a little bit worse as compared to the patient with standard cytogenetics, so the high-risk patients remain a concern. This is true for the younger and older patients.

D-Rd provided some improvement for the high-risk patient, but not that much. The odds ratio for survival in the high-risk subgroup is 0.8. This is not perfect, but this is some benefit. We have to improve the outcome of high-risk patients. This is something we have to do, and we still have to improve the outcome of the frail patients. Again, this is not a perfect regimen, but this is the best balance between efficacy, safety, and ease of administration.

And so, the next step, again, is to possibly implement or to find a place for CAR T-cell strategies, but probably more for bispecific antibodies. The way to manage bispecific antibodies in elderly patients and especially in the frail patient is still not defined. This is something we have to work on. If you look carefully at the New England Journal [of Medicine] paper and the Lancet Oncology paper, you understand that the duration of response will be better for D-Rd patients.³ It is also true that the time to response is shorter with D-Rd as compared to lenalidomide and dexamethasone alone. Duration of CR has been achieved in approximately 50% of patients receiving D-Rd; that's almost 200 patients.

Can you go into more detail about the subgroup analysis for the trial?

We did look at two subgroups: the first one was for patients with renal impairment. Considering the cutoff of 60 [mL/min,] which is the traditional cutoff, it's always the same story because you have approximately 40% to 50% of patients below 60 and more than 50% of patients over 60.

From a clinical point of view, it's likely not the most important cutoff. The most important cutoff would be possibly 30, not 60. Still, D-Rd is better than lenalidomide and dexamethasone for patients with renal impairment. We looked at patients with high-risk cytogenetics, [which is] approximately 15% of patients. And again, D-Rd did better as compared to lenalidomide and dexamethasone for these patients. And finally, we looked at patient-reported outcomes; especially the pain symptom scores. And again, D-Rd was better as compared to lenalidomide and dexamethasone as early as cycle 6, and this was, in a certain extent, a sustained benefit as well.

I like the analysis for pain, because sometimes when you report on quality of life, you report on the scales or questionnaires. For quality-of-life experts, it means something, but for the clinicians and for the patients, it's a little bit different.

Are there any important future trials related to this regimen?

Probably at the end of this year or early next year, we will have two additional studies in the newly diagnosed elderly patient with multiple myeloma looking at 4 drugs: basically the combination of daratumumab or isatuximab, which is the other CD38 [added [onto] the VRd. The one way to improve on D-Rd would be to just have the old bortezomib moving forward with either isatuximab or daratumumab-VRd. The read out is planned for the end of this year or next year. So, that will likely be a positive study, at least for some subgroups. These studies considering 4 drugs have excluded the frail patients in general, so what we may have in the next few years is to have 4 drugs for the elderly [patients] and the D-Rd for the elderly, frail [patients]. And again, this is not the more innovative way to move forward. The most innovative way will be to combine either a bispecific [antibody] and a CD38, or combining the lenalidomide on a bispecific [antibody,] or possibly combining a bispecific lenalidomide on daratumumab, for example. Moving forward with 4 drugs, the D-Rd will move to D-Rd plus a bispecific antibody for some patients.

In summary, what do you hope that your colleagues take away from this analysis?

This regimen is rapidly active. For example, the median time to achieve PR [partial response] is less than 4 months. At the end of the day, more than 90% of patients will achieve response. Virtually all patients will achieve response, and time to response is very short; even the time to high-quality responses is short. It likely has something to do with the pain reduction. For those patients who can achieve high quality responses, these responses are durable. This is true for patients with some degree of renal impairment. This is true for patients with high-risk cytogenetics, as well. But as we know, response in patients with high-risk cytogenetics is not the best end point. The majority of patients will have response, but for patients with high-risk [cytogenetics,] the duration of response and the PFS is more challenging and not that good.

References

1. Facon T, Kumar SK, Plesner T, et al. Time to response, duration of response, and patient-reported outcomes (PROs) with daratumumab (DARA) plus lenalidomide and dexamethasone (D-Rd) versus lenalidomide and dexamethasone (Rd) alone on transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM): subgroup analysis of the phase 3 MAIA study. Presented at: 2022 American Society of Clinical Oncology (ASCO) Annual Meeting; June 3-7, 2022; Chicago, IL. Accessed October 21, 2022.
2. 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):P1582-1596. doi:10.1016/S1470-2045(21)00466-6
3. Facon T, Kumar SK, Plesner T, et al. Daratumumab plus lenalidomide and dexamethasone for untreated myeloma. N Engl J Med. 2019:380:2104-2115. doi:10.1056/NEJMoa1817249