BENEFIT Trial Results Show Quadruplet Regimen for NDMM TI May Require Weighing Efficacy vs Safety


The quadruplet regimen added bortezomib to the current standard of care, which is a triplet regimen of isatuximab, lenalidomide, and dexamethasone for patients with transplant-ineligible, newly diagnosed multiple myeloma (NDMM TI).

The phase 3 BENEFIT trial (NCT04751877) looked at a triplet regimen (the current standard of care) vs a quadruplet regimen in patients with transplant-ineligible, newly diagnosed multiple myeloma (NDMM), explained James A. Davis, PharmD, BCOP, clinical pharmacy specialist in malignant hematology at the Medical University of South Carolina (MUSC) Hollings Cancer Center and an assistant professor at MUSC College of Pharmacy, during a presentation at the Oncology Pharmacists Connect (OPC) meeting in Austin, Texas. The triplet combination assessed, which is the current standard of care for this patient population, is isatuximab (Isa, Sarclisa; Sanofi) plus lenalidomide (Revlimid; Bristol Myers Squibb) and dexamethasone (Rd), while the quadruplet regimen assessed the addition of bortezomib (Velcade; Pfizer) to the IsaRd triplet regimen.1,2

Notably, finding the best treatment combinations for patients with NDMM is critical, as outcomes worsen with each successive line of therapy. Presented at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, the BENEFIT trial investigators noted that they added bortezomib to the current standard of care for NDMM to assess the prolonged use of bortezomib at a duration of 18 months with a reduced intensity weekly schedule to IsaRd. Specifically, the investigators noted that they intended to assess the impact of a proteasome inhibitor in a quadruplet regimen to improve the depth of response.2

“Kudos to the investigators for doing once weekly [for this quadruplet regimen],” Davis said during the OPC session. “Once weekly [sic] is the standard of care in that patients have less neuropathy and as good outcomes, and they don't have to come in twice a week to clinic. So once weekly here is a good thing.”1

The phase 3 BENEFIT trial is a prospective, multicenter, randomized, parallel trial that included patients aged 65 to 79 years. Traditionally, patients with MM who are identified as TI are often of older age and frailer, Davis explained. However, patients who were TI and included in the BENEFIT trial were non-frail, with a median age of 73 years, and approximately 30% of patients were over the age of 75 years.1

During the trial, patients were randomized 1 to 1 and stratified by age, high-risk cytogenetic, and center. The primary end point was minimal residual disease (MRD) 10-5 negative rate (NGS) at 18 months from treatment start analyzed in intention-to-treat (ITT).1,2 “10-5 NGS is the deepest level of response that you can measure via blood or bone marrow,” Davis said.1

Key secondary end points included overall survival (OS), progression-free survival (PFS), event-free survival, time to next treatment, response rates and durations, other minimal residual disease end points, and safety (using the National Cancer Institute’s Common Terminology Criteria for Adverse Events v5.0).2

At the study data cutoff date of February 2, 2024, 270 patients (135 per arm) were recruited, with baseline characteristics well balanced in each arm. Among these patients, 23 (9%) had high-risk cytogenetic (Intergroupe Francophone du Myelome score >1), 181 (76%) had Revised International Staging System 2+3, and 47 (17%) had impaired renal function (epidermal growth factor receptor of <60 mL/min).1,2

At 18 months, MRD negativity rates at 10-5 were significantly higher in the quadruplet regimen arm compared to the triplet regimen arm (47% vs 24% [95% CI. 1.73 – 5.07, p<0.001], with the MRD benefit consistent across patient subgroups. At 21.2 months median follow-up, 33 (12%) patients had relapsed and 20 (7%) had died, with no significant difference in each arm. Additionally, the investigators noted that the addition of the weekly “lighter” schedule of bortezomib did not significantly affect relative dose intensity of IsaRd. Further, 44 (33%) patients presented with neurological adverse events (AEs) of grade 2 or higher in the quadruplet vs 27 (20%) in triplet arm.1,2

“Not surprisingly, the quadruplet had better rates of MRD 10-5 and MRD 10-6, and complete response rates were higher,” Davis said. “Those differences were all statistically significant. However, at 18 month follow up, there were no differences that were statistically significant in PFS or OS. And the safety here, or AEs, especially neurological, which we considered peripheral neuropathy most likely, were 33% vs 20%, [the former being in] the quad arm.”1

The full paper on the BENEFIT study was published simultaneously with the ASCO presentation, and the data published in the paper showed rates of grade 3 peripheral neuropathy at 10% in the triplet and 27% in the quadruplet regimen, Davis explained.1

neuropathy multiple myeloma

Peripheral neuropathy can be debilitating and can make it too painful for patients to use their hands for daily activities. Image Credit: © sania -

“If you don't know what grade 3 peripheral neuropathy is, it’s peripheral neuropathy that sucks so bad that you can't use your hands and do activities of daily living like make coffee or texting,” Davis said. “These patients are elderly, and if they've got neuropathy, it's not a good thing. They can trip and break a hip. Patients [with MM] have brittle bones anyway most of the time, so it's not good.”1

Although the BENEFIT trial results showed that the quadruplet regimen induced deeper responses when compared with the triplet regimen, the differences in PFS and OS require longer follow up time, Davis explained.1

“With the quadruplet vs the triplet, we have higher response rates, but that hasn’t translated into OS or PFS at 18 months,” Davis said. “The full paper also didn't have criteria spelled out, even in the supplement, as to how the investigators defined who is transplant ineligible or not. And does this efficacy benefit really outweigh the rate of neuropathy?”1

Davis noted that bortezomib is a great drug in MM and is one of the only approved drugs that shows OS benefit for patients.1

“However, there is a cost to every drug and the cost for bortezomib is, unfortunately, peripheral neuropathy, which can be debilitating. I've had patients transferred to our center that have been on that drug for 12 or 24 months that are wheelchair-bound, and because of neuropathy and not because of myeloma,” Davis said. “I think the use of bortezomib in this quadruplet regimen is really not going to be for everyone, and [should be used] on a patient by patient basis, maybe not based on age, but based on a frailty score.”1


  1. Davis JA. Insights Into Evolving Treatment Modalities in Multiple Myeloma. Oncology Pharmacists Connect; June 20-21; Austin, Texas.
  2. Leleu XP, Hulin C, Lambert J, et al. Phase 3 randomized study of isatuximab (Isa) plus lenalidomide and dexamethasone (Rd) with bortezomib versus isard in patients with newly diagnosed transplant ineligible multiple myeloma (NDMM TI). J Clin Oncol. 2024;42(suppl 16). doi:10.1200/JCO.2024.42.16_suppl.7501
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