Dr Chakra Chaulagain: PFS Is the "Bare Minimum," but OS Is Ideal for Choosing Between MM Therapies

Chakra Chaulagain MD, FACP

Image credit: Maroone Cancer Center of Cleveland Clinic Florida

For transplant-eligible patients with newly diagnosed multiple myeloma, the decision between treatment regimens is based on efficacy as well as patient-specific characteristics, said Chakra Chaulagain MD, FACP, hematologist/oncologist, Maroone Cancer Center of Cleveland Clinic Florida.

Trial data has fully settled the debate that quadruplet therapy should be used upfront for these patients, but there are challenges with translating the clinical trial findings to real-world practice, he said in an interview with The American Journal of Managed Care® (AJMC®). In addition, he discussed the length of time it takes to adopt clinical updates in practice and representation in clinical trials.

AJMC: For transplant-eligible patients with newly diagnosed multiple myeloma, what are the current guideline recommended standards for front-line therapy?

Chaulagain: For this, we have to go back to the phase 2 GRIFFIN trial,¹ which was a randomized trial comparing quadruplet therapy of daratumumab (Darzalex) plus bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (dara-VRd) with VRd, in transplant-eligible patients. These patients received 4 cycles of induction therapy with quadruplet therapy of dara-VRd or VRd followed by autologous stem cell transplant after high-dose melphalan conditioning. Then, they continued with additional 2 cycles of dara-VRd or VRd consolidations, followed by a maintenance therapy with either lenalidomide or a combination of lenalidomide and daratumumab. The phase 2 GRIFFIN trial findings were highly positive for the quadruplet therapy of dara-VRd, in terms of progression-free survival (PFS), minimal residual disease (MRD)–negativity, and depth of response.

Based on that, the phase 3 randomized PERSEUS trial was conducted again comparing the quadruplet of dara-VRd with the triplet of VRd. The findings were presented at American Society of Hematology (ASH) meeting in December 2023 in San Diego, California,² and published simultaneously in New England Journal of Medicine.³ That clinical trial, with over 350 patients in each arm, confirmed in a phase III trial that the quadruplet therapy of dara-VRd, was far more superior to the standard of care the triplet of RVd in terms of depth of response, MRD negativity and PFS. Based on the results of phase 2 GRIFFIN data, followed by the phase 3 PERSEUS trial, the quadruplet therapy of dara-VRd is the current newest standard of care for transplant-eligible, newly diagnosed patients with multiple myeloma.

After the publication of GRIFFIN phase 2 trial, we started using the quadruplet regimen, but now with the positive phase 3 data, there’s much more robust and powerful clinical evidence that the quadruplet therapy, dara-VRd is the way to go for newly diagnosed patients with multiple myeloma who are transplant-eligible.

AJMC: Beyond efficacy, what specific factors play a role in decision making when selecting between therapies for individual patients?

Chaulagain: In terms of efficacy, the response rates are important—the stringent complete response rate and MRD negativity are very important end points. At the same time, PFS is at least a bare minimum, and ideally an improvement in overall survival (OS) would be ideal for us to choose one treatment regimen vs the other. Age, comorbidities, performance status, frailty all are important when we are recommending an individualized therapy to a specific myeloma patient.

AJMC: Findings from the phase 3 PERSEUS and IsKia trials evaluating daratumumab and isatuximab combinations for patients with transplant-eligible multiple myeloma were presented at the 2023 ASH annual meeting. What key efficacy findings and clinical implications from these trials stood out to you regarding the potential to influence future front-line treatment guidelines and practice for transplant-eligible patients?

Chaulagain: In the phase 3 PERSEUS trial, the 4-drug regimen of dara-VRd was much more superior in comparison with VRd in terms of estimated 4-year PFS of 84.3% with the quadruplet regimen versus 67.7% with the triplet regimen. These data are strongly in favor of the quadruplet regimen, and what was very important and interesting with the PFS was that it was consistent across all subgroups including the high-risk myeloma patients, such as International Staging System stage 3 multiple myeloma and patients with high-risk cytogenetics. So, quadruplet therapy was effective both in advanced stage myeloma, as well as those with high-risk genetic features.

The OS from the PERSEUS study was immature obviously because we need longer follow up. The CR rate and MRD negativity were both much higher in the combination of dara-VRd compared with the VRd group. For example, the CR rate is 87.9% with quadruplet regimen versus 70.1% with the triplet regimen. The MRD negativity rate was much higher at 75.2% for the quadruplet therapy and only 47.5% with VRd. Another important aspect that emerged from the PERSEUS trial was regarding the maintenance therapy with daratumumab in combination with lenalidomide versus lenalidomide alone. Two-thirds of the patients receiving daratumumab plus lenalidomide for maintenance were able to discontinue daratumumab after achieving sustained MRD negativity in 2 different tests at 1 year apart. They could then continue lenalidomide monotherapy for maintenance therapy.

The therapy really could be de-escalated if these patients were able to achieve sustained MRD negativity. This really represents the MRD-guided maintenance therapy era in the treatment of multiple myeloma, and patients are being followed for a follow-up analysis examining the longer-term outcomes of stopping daratumumab after 2 years of maintenance therapy in patients who achieved sustained MRD negativity. We can also have an approach of MRD-based monitoring, based on these findings, meaning the patient can have periodic MRD testing, and daratumumab can be added on to the single agent lenalidomide therapy if they were to lose the MRD negativity (MRD resurgence). This is really a very good era in immunotherapy-based treatment of multiple myeloma, for maintenance guided by MRD negativity.

The IsKia trial⁴ only had about 20 months of median follow-up. The progression-free survival data were just for 1 year at the time of data cut-off, and there was no difference in the quadruplet therapy of isatuximab, carfilzomib, lenalidomide, and dexamethasone (isa-KRd) versus KRd in these patients with transplant-eligible multiple myeloma. Longer-term follow-up is necessary; hopefully, we’ll have more data at the upcoming ASH meeting, and the next few years, for us to have a clear PFS advantage in the isatuximab-based quadruplet arm compared with the triplet of KRd. On the other hand, the very good partial response rate, the CR rate, and the stringent CR rates were similar between isa-KRd in comparison with KRd. Again, the data are still preliminary, and immature, so we will have to wait for the final data to be presented.

In summary, quadruplet therapy of CD38 monoclonal antibodies combined with a triple regimen—for example, dara-VRd, and isa-KRd—were tolerated well. There was some added toxicity to the triplet regimen by adding a CD38 monoclonal antibody—daratumumab or isatuximab—but there was no increased discontinuation of therapy as a result. For example, the discontinuation for toxicity was 6% in isa-KRd, versus 5% in the KRd arm. The discontinuation rate was higher in the VRd arm compared with the dara-VRd arm. So, adding monoclonal antibody therapy does not increase toxicity in a meaningful way and does not lead to increased discontinuation; the therapy is very well tolerated. Those are the take home points.

AJMC: How robust do the efficacy and safety data seem to be and do they support possible changes in clinical guidelines and practice patterns for the initial treatment of multiple myeloma in transplant-eligible patients?

Chaulagain: I think the data on the daratumumab-based quadruplet are robust—it's strong from both the phase 2 trial of GRIFFIN and phase 3 trial of PERSEUS. They have been reproduced with adequate follow-up in a very large number of patients. For newly diagnosed, transplant-eligible patients with multiple myeloma, the quadruplet regimen of dara-VRd is going to be standard of care, and I think the National Comprehensive Cancer Network guidelines and others will reflect that in their upcoming guidelines meetings.

I think the isatuximab-based regimen is still finding its way into the frontline. Isatuximab has been approved for relapsed multiple myeloma, and KRd is also approved for relapsed multiple myeloma—neither isatuximab nor KRd have an up-front approval as of now, but this might change with the follow-up data from the IsKia trial down the road. It is possible that the isatuximab-based quadruplet regimen—isa-KRd—might make it to the frontline in the future, but it might take some time. I want to point out that one unique finding associated with isa-KRd is that patients with high-risk cytogenetics and very high-risk cytogenetics had an excellent MRD negativity and response rate. Again, long-term follow-up data are needed, but if this efficacy holds for a long period of time, it is possible that isa-KRd would be a potentially practice-changing therapy, for high-risk and ultra-high-risk newly diagnosed transplant-eligible patients with multiple myeloma. Again, it’s too early to speculate and make it conclusive, so we need to wait for follow-up data on the IsKia study.

AJMC: What additional evidence or confirmatory findings would you still require from these or other studies to fully shift standards of care in this setting?

Chaulagain: I think the quadruplet therapy data on dara-VRd for up front, induction therapy in newly diagnosed multiple myeloma is fully settled. I don't think we need any additional study findings or efficacy or follow-up data. But for isa-KRd we do need longer-term follow-up data, because the IsKia trial was interesting, but it was a smaller trial; there were only about a little over 300 patients (151 patients in each arm), so that is why I would like to see the longer-term follow-up data. The median follow-up was only about 20 months, and we need at least 4 years of follow up, similar to the PERSEUS trial, to see whether this data will be conclusive, and whether they will hold for a long period of time.

AJMC: In your experience, where have you seen the biggest barriers in translating clinical trial findings around novel combinations or emerging agents in real-world clinical practice?

Chaulagain: In my mind, clinical trials do not reflect on how we use anti-myeloma drugs in clinic in the real-world setting. For example, in the PERSEUS trial, the patients received 160 mg of dexamethasone weekly, which is excessive, in my mind. In the real-world clinical practice, in the US, typically we use 20 mg to 40 mg of dexamethasone weekly, because a very high dose of dexamethasone can have an adverse impact on patients’ endocrine and cardiovascular health. We need to be cautious there. Similarly, bortezomib was used twice weekly in the PERSEUS clinical trial, and in our real-world clinical practice, we use it once a week. Several retrospective studies have shown that once weekly bortezomib is as effective as twice weekly bortezomib, as far as PFS, response rate, and OS. So, twice weekly bortezomib is not necessary; it only increases the risk of neuropathy.

Based on this, you can see there is a little bit of disconnect between how clinical trials are designed and how patients are treated in the real-world practice. Why the clinical trial designs do not match, or do not account for how these drugs are given in real-world practice, is still unclear.

What I would like to also highlight is that clinical trial designs should include feedback from treating physicians including community oncologists. And the patients participating in trials should also represent our population. There has to be enough representation of ethnic minorities to account for cancer disparities as ethnic minorities have not had adequate representation in myeloma clinical trials, historically.

Another point I want to highlight is that adoption of clinical trial findings to the real-world setting can take several years, and the transition to quadruplet therapy and its wide-spread adoption might take several years. For example, transitioning from doublet to triplet therapy in newly diagnosed, transplant-eligible multiple myeloma took a long time, and is still occurring. In the same manner, the triplet to quadruplet transition will take a long time. I'm thinking about the next 5 to 10 years. It's a slow process and it's a moving target, but hopefully we'll get there soon.

References

1. Voorhees PM, Sborov DW, Laubach J, et al. Addition of daratumumab to lenalidomide, bortezomib, and dexamethasone for transplantation-eligible patients with newly diagnosed multiple myeloma (GRIFFIN): final analysis of an open-label, randomised, phase 2 trial. Lancet Haematol. 2023;10(10):e825-e837. doi:10.1016/S2352-3026(23)00217-X

2. Sonneveld P, Dimopoulos MA, Boccadoro M, et al. Phase 3 randomized study of daratumumab (DARA) + bortezomib, lenalidomide, and dexamethasone (VRd) versus VRd alone in patients (pts) with newly diagnosed multiple myeloma (NDMM) who are eligible for autologous stem cell transplantation (ASCT): primary results of the PERSEUA trial. Blood. 2023;142(suppl 2):LBA-1. doi:10.1182/blood-2023-191911

3. Sonneveld P, Dimopoulos MA, Boccadoro M, et al; PERSEUS Trial Investigators. Daratumumab, bortezomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2024;390(4):301-313. doi:10.1056/NEJMoa2312054

4. Gay F, Roeloffzen W, Dimopoulos MA, et al. Results of the phase III randomized Iskia trial: isatuximab-carfilzomib-lenalidomide-dexamethasone vs carfilzomib-lenalidomide-dexamethasone as pre-transplant induction and post-transplant consolidation in newly diagnosed multiple myeloma patients. Blood. 2023;142:(Supp 1):4. doi:10.1182/blood-2023-177546