MRD May Predict Improved Outcomes in Multiple Myeloma

Meet the experts

Updated results from the phase 3 PERSEUS trial (NCT03710603) at the 2024 American Society of Clinical Oncology Annual Meeting in Chicago, Illinois, were the focus of the discussion for the recent Between the Lines program.¹

Colleagues Cesar Rodriguez Valdes, MD, and Frits van Rhee, MD, PhD, met to discuss the results of the trial and how they affect the current treatment landscape for patients with transplant-eligible multiple myeloma in the frontline setting. After the data were presented, the clinicians gave their impressions on the efficacy updates and whether there were any clinical implications for patients.

Rodriguez is associate professor of medicine at the Icahn School of Medicine at Mount Sinai, The Tisch Cancer Institute, and the Center of Excellence for Multiple Myeloma and is clinical director of multiple myeloma at The Mount Sinai Hospital, all in New York, New York. van Rhee is professor of medicine and clinical director of the University of Arkansas for Medical Sciences Myeloma Center in Little Rock. Throughout the discussion, the pair also discussed the adverse effects (AEs) observed, how to best manage AEs, and key takeaways for their colleagues.

Frontline Treatment Options in Multiple Myeloma

The current standard of care for this patient population is a 3-step approach including an induction phase, a consolidation phase, and either transplant or additional therapy. If a patient is not transplant eligible, they will receive additional chemotherapy as consolidation and then maintenance treatment.

Currently, proteasome inhibitors and immunomodulatory agents are used in combination with dexamethasone. Studies are underway to assess whether monoclonal antibodies can be used in this population.

Rodriguez asked van Rhee what he believed to be some unmet needs in the current population. “The overall outcome still needs to be improved. We’re doing well, but we can do better. Then there are the patients with high-risk myeloma with 1 or more cytogenetic aberrations, which reclassifies them as high risk, who historically have had worse outcomes,” van Rhee said.

van Rhee emphasized that this is where monoclonal antibodies can come into play. Rodriguez wondered whether there were specific areas of improvement. van Rhee highlighted the importance of complete remissions, assessing minimal residual disease (MRD), and maximizing tumor reduction.

PERSEUS Trial Updates

The trial assessed daratumumab (Darzalex), bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (D-VRd), with DR maintenance for patients with transplant-eligible, newly diagnosed multiple myeloma. A total of 709 patients were randomly assigned 1:1 and began induction therapy. In the D-VRd arm, patients were given 1800 mg of subcutaneous (SC) daratumumab every week during cycles 1 and 2 and every 2 weeks during cycles 3 and 4. SC bortezomib was given at 1.3 mg/m2 on days 1, 4, 8, and 11; lenalidomide at 25 mg orally on days 1 to 21; and dexamethasone at 40 mg orally or intravenously on days 1 to 4 and 9 to 12. The VRd arm had matched dosing.

Patients went on to single transplant and then consolidation, which matched the induction arm. During maintenance, patients in the VRd arm were given lenalidomide at 10 mg orally on days 1 to 28 until progressive disease. Patients in the D-VRd arm were given SC daratumumab at 1800 mg every 4 weeks plus lenalidomide at 10 mg orally on days 1 to 28 for a minimum of 2 years. If patients had MRD-positive status, they could continue DR until progressive disease. If they had MRD-negative status, they would stop daratumumab, continue with lenalidomide, and restart daratumumab per the specified criteria.

The median follow-up was 47.5 months, and the median time to postconsolidation was 9.7 months. At 48 months, the progression-free survival (PFS) rates were 84.3% in the D-VRd arm and 67.7% in the VRd arm (HR, 0.42; 95% CI, 0.30-0.59; P < .0001).

The MRD negativity rate at 10–5 in the D-VRd arm was 75.2% vs 47.5% in the VRd arm (OR, 3.40; 95% CI, 2.47-4.69; P < .0001). The MRD negativity rate at 10–6 was 65.1% in the D-VRd arm and 32.2% in the VRd arm (OR, 3.97; 95% CI, 2.90-5.43; P < .0001). At 12 months or more, the sustained MRD negativity rate at 10–5 was 64.8% in the D-VRd arm and 29.7% in the VRd arm (OR, 4.42; 95% CI, 3.22-6.08; P < .0001).

In the intent-to-treat population, the sustained MRD negativity rates were compared at 10^–5 and 10^–6. In the D-VRd arm, at 12 months or more, the MRD negativity rate at 10^–5 was 64.8% and the negativity rate at 10^–6 was 47.3% vs 29.7% and 18.6% in the VRd arm, respectively. At 18 months or more, in the D-VRd arm, the MRD negativity rate at 10^–5 was 59.4% and the negativity rate at 10–6 was 42% vs 25.1% and 15% in the VRd arm, respectively.

PFS status by MRD at 10^–6 was assessed between both arms. In the D-VRd arm, those with MRD-positive status had a PFS rate of 34.9% and those with MRD-negative status had a PFS rate of 65.1%. In the VRd arm, the resulting rates were 67.8% and 32.2%. In conclusion, the study findings highlighted that there is potential for a cure in the population with newly diagnosed multiple myeloma if the MRD negativity at 10^–6 is reached and sustained.

Importance of MRD in Clinical Trials

MRD has been found to improve outcomes and is now accepted as an early surrogate end point by the FDA.² To assess MRD, either flow cytometry or next-generation sequencing is used.

“With this new technology, we can see in more detail how much more residual disease there is, which is the one that’s going to make the disease want to come back. Now we aim for MRD-negative status when we treat patients with myeloma,” Rodriguez said.

Rodriguez asked van Rhee whether MRD-negative status was enough or whether a sustained MRD-negative status was something to strive for. At van Rhee’s institution, MRD is analyzed multiple times over different years, and if a patient continues to have MRD-negative status, they will be less likely to experience relapse. He emphasized the need for sequential assays, as they are a powerful predictor.

The PERSEUS study findings highlighted that rates of MRD negativity at 10–6 were sustained for 12 months or longer and were doubled with D-VRd vs VRd. Additionally, the conversion to MRD negativity was doubled during maintenance with DR vs lenalidomide alone.

Adding Daratumumab to a Quadruplet Regimen

Rodriguez noted that a pressing topic is whether daratumumab is enough for frontline therapy or as part of maintenance. He wanted to know whether the data from PERSEUS answer this question or whether additional studies are needed to confirm this.

“I don’t think it answered the questions definitively. There are other studies…[that] will also try to answer this question of whether daratumumab is better,” van Rhee said.

A frequent conversation about how to best treat those with high-risk cytogenetics and those with functionally high-risk disease. Would these populations benefit from the D-VRd regimen outlined in PERSEUS? van Rhee emphasized that many studies, PERSEUS included, are not designed to investigate these subgroups.

As quadruplet therapies are becoming more acceptable, clinicians are learning the associated AEs and how to best manage them. van Rhee highlighted that he weighs the benefit/risk ratio of tolerating a treatment vs what the outcomes will be.

Adding a fourth drug to a regimen will come with increased AEs. However, adding a drug such as a monoclonal antibody will come with AEs that are manageable, van Rhee noted. He said they typically are not severe, so although there is an increase of AEs, the risk/benefit ratio is skewed toward adding daratumumab.

“The addition of daratumumab [in] the PERSEUS study to our standard [VRd] induction regimen, adding it as part of consolidation, and adding the daratumumab to maintenance [are] improving and capturing the higher response rate, a higher depth of response by seeing a higher [complete response] rate, and a higher MRD-negative status in our patients,” Rodriguez said. Looking at the implications of this study, van Rhee believes D-VRd will become the new standard of care in this population. The results from this trial will help to transform care in both the academic and community settings.

References

1. Rodríguez-Otero P, Moreau P, Dimopoulos MA, et al. Daratumumab (dara) + bortezomib/lenalidomide/dexamethasone (VRd) in transplant-eligible (TE) patients (pts) with newly diagnosed multiple myeloma (NDMM): analysis of minimal residual disease (MRD) in the PERSEUS trial. J Clin Oncol. 2024;42(suppl 16):7502. doi:10.1200/JCO.2024.42.16_suppl.7502
2. April 12, 2024 meeting of the Oncologic Drugs Advisory Committee (ODAC). YouTube. April 12, 2024. Accessed July 2, 2024. https://tinyurl.com/2tbe3f4k