First-Line Quadruplet Regimens Continue to Enhance Outcomes in Myeloma


Muhamed Baljevic, MD, FACP, discusses the evolution of quadruplet combination therapies in frontline multiple myeloma.

Muhamed Baljevic, MD, FACP

Muhamed Baljevic, MD, FACP

The utility of treatment with quadruplet regimens has continued to carve out a role in the frontline treatment of multiple myeloma following readouts of data from trials such as the phase 2 GRIFFIN study (NCT02874742), as well as the phase 3 GMMG-HD7 (NCT03617731), PERSEUS (NCT03710603), and IsKia (NCT04483739) trials, according to Muhamed Baljevic, MD, FACP, who added that quadruplet-based initiatives are continuing to push the envelope for progression-free survival (PFS) outcomes.1-4

“It's always been important in myeloma to do the best we can at every stage [of treatment], particularly [in the frontline setting, we need to] give our best effort because, unfortunately, many different studies have shown that not every [patient] gets a chance to [utilize] every single initiative for the treatment of their disease, such as stem cell transplant. Down the line, they may lose their ability to [receive a transplant],” Baljevic said in an interview with OncLive® following the Vanderbilt Stem Cell Transplant and Cellular Therapy Symposium.

In the interview, Baljevic discussed significant advancements in treatment strategies for newly diagnosed multiple myeloma, including the efficacy demonstrated by quadruplet regimens; highlighted notable trials evaluating the utility of these regimens compared with standard-of-care treatment; and emphasized the importance of initiating the most effective treatments early in the disease course for patients with multiple myeloma.

Baljevic is a hematologist and medical oncologist, an associate professor of medicine in the Division of Hematology/Oncology, the director of Plasma Cell Disorders Research, and director of the Vanderbilt Amyloidosis Multidisciplinary Program at Vanderbilt-Ingram Cancer Center, and co-chair of the Vanderbilt-Ingram Cancer Center Protocol Review and Monitoring System in Nashville, Tennessee.

OncLive: How have updates in multiple myeloma from the 2023 ASH Annual Meeting affected current practice?

Baljevic: The 2023 ASH Annual Meeting was momentous in regard to the newly diagnosed space, with [data reported for] several keynote studies. It's important to understand and appreciate that over the last 10 to 15 years, we have made major strides in our ability to induce very deep responses and maintain those responses for prolonged periods of time.

When looking at PFS in patients with newly diagnosed disease, if you look at the history of some of the studies that have tried to push the needle forward, [we now utilize] quadruplet combinations in newly diagnosed patients. Quadruplet combinations for induction therapy consist of a proteasome inhibitor, an immunomodulatory drug, an anti-CD30 monoclonal antibody, and a steroid. [Using quadruplet combinations], we have been able to [extend] PFS from [approximately] 30 and 40 months. We've seen the long-term reports from trials such as GRIFFIN and some of the other quadruplet-based initiatives that are pushing the PFS to 80, 90, and perhaps 100 months. We don't even have a long-term follow-up of some of these studies yet, and medians have not been reached when it comes to the ultimate duration of PFS.

What are your primary considerations when deciding how to treat patients in the first-line setting?

We don't have equal opportunity to impact disease at every single disease stage. Our ability to treat disease more successfully is always better earlier rather than later.

It's important to understand your patients [when determining a frontline treatment]. We are in an era of personalized medicine, and it's important to understand a patient’s comorbidities and factors that could impact the choice of therapy. It's also important to understand a patient’s preferences and capabilities in terms of the logistics of delivering therapy.

We are still emerging from the COVID-19 pandemic that has upended everything in our lives, including how we treat patients in terms of agents and choices. Although we try not to compromise any capabilities of treating people successfully, sometimes people have a different [interpretation] of what is important and what quality of life means for them.

I would argue that quadruplet regimens are standard of care [in the frontline setting]. The GRIFFIN study—a randomized phase 2 study of daratumumab [Darzalex] plus bortezomib [Velcade], lenalidomide [Revlimid], and dexamethasone [D-RVd] vs RVd alone—recently had long-term follow-up reported. The 4-year PFS [rate] was significantly better [with the quadruplet (87.2% vs 70.0%)]; however, PFS wasn't the primary end point of GRIFFIN. One of the reasons why some of these phase 3 studies have been run with this exact combination or some variations of how these drugs are given is because the PFS was not the primary end point [in the phase 2 study].

There was a significant improvement in PFS with the 4-drug vs 3-drug regimen. There were no differences in overall survival [OS], where the curves were overlapping. However, clearly, we were able to see that the depth of responses with both the triplet and quadruplet [combinations] continued deepening and improving over time, from the end of induction to post-autologous transplant consolidation to the final analysis. Certainly, the ability to induce deep minimal residual disease [MRD] responses [was also encouraging].

What is the importance of evaluating for MRD in this patient population?

In the GMMG-HD7 trial—which looked at isatuximab [Sarclisa] plus RVd vs RVd [alone]—the primary end point was MRD negativity rate by next generation flow [NGF] at 10-5 [sensitivity] after the induction in the intention-to-treat population. [In this population], 50.1% of patients reached a MRD-negative response before undergoing stem cell transplant, which is amazing.

[Notably], the PERSEUS trial looked at D-RVd vs RVd alone, with the primary end point being PFS. What's important and unique about PERSEUS is that in the second part of the study, patients who achieved sustained MRD negativity for 12 months after at least 2 years of maintenance daratumumab and lenalidomide had the ability to discontinue daratumumab and continue with lenalidomide alone. Upon losing MRD-negative status or losing complete response, they had the ability to restart daratumumab. This was a particularly important aspect of this study because we are in the era of trying to come up with more instructive approaches on how to treat patients more effectively, and perhaps how to identify situations where we may deescalate [treatment].

Quadruplet combinations, which are standard of care in North American practice, are not ubiquitously and equally available and present for every patient [globally], and they are extremely expensive. These are important things to keep in mind, but nonetheless, PERSEUS was a positive trial with a comparative PFS benefit with quadruplet to triplet after 48 months. There are important differences in terms of depth of response and MRD negativity rates [at sensitivities of] 10-5 and 10-6.

Another angle that was valuable were data on sustained MRD negativity after at least 12 months. That's important because it is 1 of the points that the FDA’s Oncologic Drugs Advisory Committee highlighted when voting on the role of MRD as an end point in multiple myeloma.

PERSEUS showed that 64% of patients receiving maintenance in the D-RVd group discontinued daratumumab after achieving sustained MRD negativity; this is what we want to see. We want to see data that can ultimately help guide [our treatment decisions]. What are the situations where we can de-escalate and to what point can we de-escalate? What type of approaches should we follow in further steps for maintenance? When do we have to worry about resuming therapy and what extent of therapy [is this]?

What other notable trials have included MRD data readouts?

The [phase 2] GMMG-CONCEPT trial [NCT03104842] looked at Isa-RVd as a quadruplet treatment for both transplant-eligible and -ineligible populations. This is neat because it looked at high-risk patients who were the focus; these patients with high-risk features were eligible to join this study. The primary end point was [MRD negativity by] NGF at 10-5 [sensitivity] after consolidation, [which was met]. It was a non-randomized phase 2 trial. In transplant-eligible patients, 67.7% of patients achieved MRD negativity and in the non-transplant group, [that number] was 54.2%.5

The phase 3 IsKia trial is also important and was the first randomized phase 3 trial with carfilzomib [Kyprolis], lenalidomide, and dexamethasone [KRd] as a backbone of a quadruplet-based therapy. It's important to mention that KRd still doesn't have [approval] for frontline utility. Many places in the United States have used [KRd] for a while now, [along with] dara-KRd or even isa-KRd [based on] available data. We generally have the ability to do that without too much resistance from payers. However, It's important to mention that even KRd as a triplet still doesn't have a label.

[IsKia] was an important phase 3 trial that looked at transplant-eligible patients who were under 70 years old and received isa-KRd vs KRd, transplant, and 4 cycles of post-transplant consolidation, as well as further light consolidation for 12 cycles thereafter.

The primary end point was MRD negativity rate at a 10-5 [sensitivity]. The secondary end points were MRD negativity rate after induction and PFS, as well as sustained MRD negativity. Here, we also saw positive trial results with 77% vs 67% of patients in the quadruplet and triplet groups, respectively, achieving MRD negative status by next-generation sequencing at 10-5 [sensitivity]. If you look a level deeper at 10-6 there are even stronger results; 67% vs 48% of patients were able to achieve this incredibly deep response, [respectively]. The MRD compliance and sample quality were excellent in this study.


  1. Silberman R, Laubach J, Kaufman JL, et al. Health-related quality of life in transplant-eligible patients with newly diagnoses 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
  2. Goldschmidt H, Mai EK, Bertsch U, et al. Addition of isatuximab to lenalidomide, bortezomib, and dexamethasone as induction therapy for newly diagnosed, transplantation-eligible patients with multiple myeloma (GMMG-HD7): part 1 of an open-label, multicentre, randomised, active-controlled, phase 3 trial. Lancet Haematol. 2022;9(11):e810-e821. doi:10.1016/S2352-3026(22)00263-0
  3. Sonneveld P, Dimopoulos MA, Boccadoro M, et al. Phase 3 randomized study of daratumumab + bortezomib, lenalidomide, and dexamethasone (VRd) versus VRd alone in patients with newly diagnosed multiple myeloma who are eligible for autologous stem cell transplantation: primary results of the PERSEUS trial. Blood. 2023;142(suppl 2):LBA1. doi:10.1182/blood-2023.191911
  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(suppl 1):4. doi:10.1182/blood-2023-177546
  5. Leypoldt LB, Tichy D, Besemer B, et al. Isatuximab, Carfilzomib, Lenalidomide, and Dexamethasone for the Treatment of High-Risk Newly Diagnosed Multiple Myeloma. J Clin Oncol. 2024;42(1):26-37. doi:10.1200/JCO.23.01696
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