For Newly Diagnosed Myeloma, Are Four Drugs Better Than Three?

With a recent expansion in the availability of treatments for multiple myeloma (MM), several regimens have been shown to improve survival outcomes in patients with newly diagnosed disease. Three-drug regimens have been accepted as the standard frontline management of myeloma, but the advent of four-drug regimens has raised the question of whether certain patients would benefit from the addition of another drug. Clinical trials have showed varying results, depending on the exact combination of drugs used during induction or maintenance.

In this edition of Drawing First Blood, ASH Clinical News invited Brea Lipe, MD, from the University of Rochester Medical Center in New York, and Peter Voorhees, MD, of Atrium Health and Levine Cancer Institute in Charlotte, North Carolina, to debate whether patients with newly diagnosed MM should be treated with three- or four-drug combinations as induction. Dr. Lipe was asked to argue in favor of triplet regimens and Dr. Voorhees was asked to argue in favor of quadruplet therapies.

Dr. Lipe: Triplet regimens are considered stan-dard of care for patients with newly diagnosed MM, with long-term data showing that triplet combinations – such as bortezomib, lenalidomide, and dexamethasone (VRd) and daratumumab, lenalidomide, and dexamethasone (DRd) – can improve overall survival (OS), progression-free survival (PFS), and overall responses in this population versus doublet regimens.

While the data for quadruplet regimens are promising, these regimens are not quite ready for prime time. I think we are moving on to evaluating quadruplet regimens even before we have optimized triplet combinations with the appropriate maintenance therapy. Historically, we’ve seen that not all quadruplet combinations have succeeded. For example, there was no difference in outcomes between RVd and RVd plus elotuzumab in the randomized S1211 trial.¹ Overall, research suggests that appropriate maintenance therapy improves duration and depth of response. Optimized and appropriate maintenance therapy may help avoid the need for adding a fourth drug.

Dr. Voorhees: For patients with newly diagnosed, transplant-ineligible myeloma, a strong case can be made for three-drug combinations, particularly DRd or RVd. However, I would argue in favor of four-drug combinations for these patients. The two U.S. Food and Drug Administration-approved quadruplets so far are daratumumab plus bortezomib, thalidomide, and dexamethasone (VTd) and daratumumab plus bortezomib, melphalan, and prednisone (VMP).

Daratumumab plus VTd was validated in the phase III CASSIOPEIA trial, which compared VTd as induction and post-transplant consolidation with or without the anti-CD38 antibody daratumumab.² The rates of stringent complete response, measurable residual disease (MRD) negativity, and PFS were all improved when daratumumab was added to pre-transplant induction and post-transplant consolidation therapy. The most recent analysis, presented at the 2021 American Society of Clinical Oncology Annual Meeting, revealed an OS trend beginning to emerge in favor of quadruplets.³

The randomized phase II GRIFFIN trial that we spearheaded at the Alliance Foundation was constructed in the same vein as CASSIOPEIA.⁴ We looked at RVd as pre-transplant induction therapy and post-transplant consolidation with or without the incorporation of daratumumab. By the end of consolidation therapy, the quadruplet group showed improvement in stringent complete response, and that difference has become increasingly obvious with longer follow-up. At the 2020 American Society of Hematology Annual Meeting, we reported a complete response rate of 82% in the quadruplet arm versus 61% in the triplet arm. Moreover, we showed an MRD negativity rate of 62.5% in quadruplet-treated patients, versus 27.2% for those on the triplet combination in an intent-to-treat analysis.⁵

Because research has shown that, in patients with myeloma, achievement of MRD negativity is associated with improvement in longitudinal outcomes such as PFS and OS, National Comprehensive Cancer Network (NCCN) guidelines now list daratumumab with RVd as a standard frontline regimen for newly diagnosed, transplant-eligible patients with myeloma.

Hopefully, the phase III PERSEUS trial, which is designed similarly to the GRIFFIN trial, will verify the results that we’ve obtained thus far. Additionally, there are two ongoing studies in the transplant-ineligible patient population: CEPHEUS, looking at the RVd backbone with or without daratumumab for transplant-ineligible patients, and IMROZ, evaluating the incorporation of the anti-CD38 antibody isatuximab with the RVd backbone for patients with transplant-ineligible, newly diagnosed myeloma.

Dr. Lipe: All those data are encouraging. However, one of the concerns that came out of the CASSIOPEIA trial was the lack of clinically or statistically significant difference in MRD rates or PFS for patients who received daratumumab plus VTd and those who received the VTd upfront followed by daratumumab maintenance.

It’s reasonable to say that daratumumab definitely adds something, but we aren’t sure whether it needs to be given as part of the upfront quadruplet regimen, which can increase toxicity, or whether it can be given as maintenance later on, when we can manage the potential toxicity by tapering doses according to response. Studying that question may give us the opportunity to identify patients who really need a quadruplet.

Dr. Voorhees: I agree that the updated analysis from the second randomization of the CASSIOPEIA trial is important. The three groups of patients who received daratumumab in induction, consolidation, and maintenance all had better outcomes than those who did not receive daratumumab. However, in the second randomization, comparing daratumumab plus VTd with or without daratumumab maintenance certainly confounded those findings. There was a clear difference in PFS in the second randomization.

Additionally, patients in this study received maintenance therapy with daratumumab as a single agent just once every eight weeks, without the standard backbone of lenalidomide. The impact of having an immunomodulatory agent in maintenance remains to be seen. The SWOG maintenance trial provides an opportunity to look at the relative value of adding daratumumab to lenalidomide maintenance for patients who receive daratumumab-containing induction compared with those who do not.

Dr. Lipe: I agree. The data are still immature at this point. The SWOG study is looking at MRD-directed maintenance, the impact of daratumumab plus lenalidomide versus lenalidomide, and whether we can stop maintenance for patients who achieve MRD negativity. However, results from these trials won’t necessarily tell us what happens when patients receive daratumumab for induction therapy, because that isn’t a mandated part of the induction.

As we move forward and study other quadruplet combinations, we need to be mindful of the risks of financial and physical toxicity and how we can appropriately use these quadruplet regimens in the patients who stand to gain the most.

Dr. Voorhees: I agree. The financial toxicity issue is real, and we need to be thoughtful as we develop four- and even five-drug regimens.

Regarding side effects, there are several important issues that arose in the CASSIOPEIA and GRIFFIN trials. Unsurprisingly, there is a higher rate of grade 3 and higher neutropenia when the anti-CD38 antibody is incorporated into the backbone. In the CASSIOPEIA trial, the rate of grade 3 and higher neutropenia was 28% with daratumumab plus VTd versus 15% with VTd alone. In the GRIFFIN trial, it was 22% versus 41%. There was also an increased rate of overall infection in the four-drug arms of the CASSIOPEIA and GRIFFIN trials, but not for grade 3 or higher infections.

Dr. Lipe: Another question to answer is, when we use quadruplet combinations up front, what are the long-term implications for the bone marrow environment and for future treatment options. Are we limiting ourselves moving forward?

Dr. Voorhees: When you add an anti-CD38 antibody into the regimen, it does impact stem cell localization and collection. In the CASSIOPEIA trial, the median stem cell yield for those receiving the triplet was 8.9×10⁶ CD34 cells/kg, versus 6.3×10⁶ in the quadruplet arm. The rate of plerixafor utilization was also higher in the quadruplet arm (22% vs. 8%). A similar pattern emerged in the GRIFFIN trial.

Looking at quadruplet regimens in the transplant setting, I always encourage clinicians to collect those stem cells after four cycles. The longer you go, the higher the risk of suboptimal stem cell mobilization.

Dr. Lipe: It’s important to note that the rate of dropout and the ability to stay on trial is also a bit different. If part of the benefit of the quadruplet is getting people on therapy and keeping them on therapy, then we need to make sure that quadruplets are not impairing our ability to do so.

Taking in the data provided by all of these trials, overall, I would say that DRd should remain the standard frontline option in the transplant-ineligible population. The “light” version, RVd, has also shown promising response rates and efficacy in this population. An upcoming trial will be looking at comparing these two approaches, which might give us some better indication of which is the best option in real-world practice.

On the other hand, those patients who have the least to gain from our standard approaches (i.e., those who are either not achieving MRD negativity or are high risk) might have more to gain from risking toxicities with quadruplet therapies. Of course, we’re not necessarily going to know whether they will achieve MRD negativity prior to treatment, so maybe intensification is a better option than starting with four drugs.

Dr. Voorhees: I believe there are two groups of patients for whom we haven’t identified an optimal upfront combination therapy: Frail patients who are ineligible for transplant and typically for clinical trial participation, and for patients with high-risk myeloma. There’s no question that patients with standard-risk myeloma benefit more from the incorporation of an anti-CD38 antibody into their therapy, but it is not clear if adding an anti-CD38 antibodies to standard of care backbones will improve outcomes for patients with high-risk disease. We need to look at novel drug combinations for that group of patients, such as incorporating bispecific antibodies into frontline therapy.

We’ve also discussed the increased infectious risk with the use of anti-CD38 antibodies as we move B-cell maturation antigen (BCMA)-targeted therapy into frontline treatments. Also, if we wind up moving GPRC5D-directed therapy into the frontline, we are going to see more hypogammaglobulinemia and other infectious concerns. Identifying the best ways to manage these patients, particularly in the context of the COVID-19 pandemic, will be critical.

Dr. Lipe: Even with all these trials, the optimal combination therapy for frontline treatment is unknown. As our drugs change and the field moves forward, like with the introduction of the newer BCMA-targeting drugs that are showing impressive responses in relapsed myeloma, this question is always in flux.

We need to re-stratify disease risk and determine how to achieve responses in high-risk patient populations. We also need to identify the optimal duration of therapy, whether it’s induction or maintenance, and how to tailor maintenance. We need to better identify patients who are at risk for toxicity or complications and provide better supportive care for managing those toxicities. Should we start using more granulocyte colony stimulating factor (G-CSF) for our patients on quadruplet combinations to reduce the rate of neutropenia? Do we start using antibiotic prophylaxis to reduce the rates of pulmonary infections with four-drug regimens that incorporate daratumumab? Trials should be designed with these questions in mind so that we know if we can manage the toxicity of quadruplet therapies.

References

1. Usmani SZ, Ailawadhi S, Sexton R, et al. Primary analysis of the randomized phase II trial of bortezomib, lenalidomide, dexamthasone with/without elotuzumab for newly diagnosed, high-risk multiple myeloma (SWOG-1211). J Clin Oncol. 2020;38(suppl 15):8507-8507.
2. Moreau P, Attal M, Hulin C, et al. Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): A randomised, open-label, phase 3 study. Lancet. 2019 Jul 6;394(10192):29-38.
3. Moreau P, Sonneveld M, et al. Daratumumab (DARA) maintenance or observation (OBS) after treatment with bortezomib, thalidomide and dexamethasone (VTd) with or without DARA and autologous stem cell transplant (ASCT) in patients (pts) with newly diagnosed multiple myeloma (NDMM): CASSIOPEIA Part 2. J Clin Oncol. 2021:39(suppl 15):8004-8004.
4. Voorhees PM, Kaufman JL, Laubach J, et al. Daratumumab, lenalidomide, bortezomib, and dexamethasone for transplant-eligible newly diagnosed multiple myeloma: The GRIFFIN trial. Blood. 2020 Aug 20;136(8):936-945.
5. Kaufman JL, Laubach JP, Sborov D, et al. Daratumumab (DARA) plus lenalidomide, bortezomib, and dexamethasone (RVd) in patients with transplant-eligible newly diagnosed multiple myeloma (NDMM): Updated analysis of Griffin after 12 months of maintenance therapy. Abstract #549. Presented at the 2020 American Society of Hematology Annual Meeting, December 7, 2020.
6. ClinicalTrials.gov. S1803, Lenalidomide +/- Daratumumab/rHuPh20 as Post-ASCT Maintenance for MM w/MRD to Direct Therapy Duration (DRAMMATIC). October 12, 2021. Accessed November 7, 2021. https://clinicaltrials.gov/ct2/show/NCT04071457.