Do quadruplet regimens (e.g., Daratumumab (daratumumab), VELCADE (bortezomib), Revlimid (lenalidomide), dexamethasone) or Isatuximab (isatuximab), VELCADE (bortezomib), Revlimid (lenalidomide), dexamethasone) improve progression-free survival (PFS) or overall survival (OS) compared to triplet regimens (e.g., VELCADE (bortezomib), Revlimid (lenalidomide), dexamethasone) in newly diagnosed patients?

From the Guidelines

Quadruplet regimens containing anti-CD38 monoclonal antibodies (daratumumab or isatuximab) combined with bortezomib, lenalidomide, and dexamethasone do improve progression-free survival compared to the standard triplet regimen of bortezomib, lenalidomide, and dexamethasone (VRd) in newly diagnosed multiple myeloma patients. The most recent and highest quality study, the GRIFFIN trial, demonstrated that adding daratumumab to VRd (D-VRd) significantly extends progression-free survival, with studies showing approximately 50-60% reduction in the risk of disease progression or death 1.

Key Points

• Clinical trials have shown that quadruplet regimens achieve deeper responses, including higher rates of minimal residual disease negativity.
• Isatuximab combined with VRd has shown promising results in early studies.
• These quadruplet regimens are generally well-tolerated, though they do increase the risk of infections, neutropenia, and infusion-related reactions compared to triplet therapy.
• The improved efficacy of quadruplet regimens appears to be due to the complementary mechanisms of action, with anti-CD38 antibodies directly targeting plasma cells while enhancing immune-mediated tumor cell killing, working synergistically with the proteasome inhibitor (bortezomib), immunomodulatory drug (lenalidomide), and anti-inflammatory agent (dexamethasone) 1.

Benefits of Quadruplet Regimens

• Particular benefits for patients with high-risk cytogenetics or other adverse prognostic factors who typically have poorer outcomes with standard triplet therapy.
• Substantial progression-free survival benefit, with approximately 50-60% reduction in the risk of disease progression or death.
• Deeper responses, including higher rates of minimal residual disease negativity.

Considerations

• Increased risk of infections, neutropenia, and infusion-related reactions compared to triplet therapy.
• Overall survival data is still maturing for many of these studies due to the relatively recent introduction of these quadruplet regimens. However, based on the current evidence, quadruplet regimens are recommended for newly diagnosed multiple myeloma patients due to their improved progression-free survival and deeper responses.

From the FDA Drug Label

The improvement in PFS represented a 40% reduction in the risk of disease progression or death in patients treated with Isa-VRd

Median follow-up time=60 months.

• Based on ITT population.

Progression-Free Survival* Median (months)[95% CI]NR[NR–NR]54.34[45.21–NR] Hazard ratio † [95% CI]0.60 [0.44–0.81] p-value (Stratified Log-Rank test) †‡0. 0009

Median overall survival was not reached for either treatment group. At a median follow-up time of 60 months, 26% of patients in the Isa-VRd group and 32.6% of patients in the VRd group had died (HR=0.78; 95% CI: 0.55 to 1. 1)

The quadruplet regimen Isa-VRd improves progression-free survival (PFS) compared to the triplet regimen VRd in newly diagnosed patients, with a 40% reduction in the risk of disease progression or death. However, the median overall survival (OS) was not reached for either treatment group, but there was a trend towards improved OS in the Isa-VRd group (HR=0.78; 95% CI: 0.55 to 1.1) 2.

From the Research

Comparison of Quadruplet and Triplet Regimens in Newly Diagnosed Multiple Myeloma

• Quadruplet regimens, such as Daratumumab, VELCADE (bortezomib), Revlimid (lenalidomide), and dexamethasone (DVRd), have been compared to triplet regimens, like VELCADE (bortezomib), Revlimid (lenalidomide), and dexamethasone (VRd), in terms of progression-free survival (PFS) and overall survival (OS) in newly diagnosed patients.
• A study published in 2025 3 found that the addition of daratumumab to VRd (D-VRd) resulted in significantly improved PFS and OS compared to VRd alone in transplant-ineligible or transplant-deferred newly diagnosed multiple myeloma patients.
• Another study from 2024 4 demonstrated that the combination of daratumumab with VRd induction and consolidation therapy, and lenalidomide maintenance therapy, conferred a significant benefit in terms of PFS among transplantation-eligible patients with newly diagnosed multiple myeloma.
• The GRIFFIN trial 5 showed that the addition of daratumumab to RVd induction and consolidation improved the depth of response in patients with transplant-eligible newly diagnosed multiple myeloma, with no new safety concerns.

Efficacy of Quadruplet Regimens

• The CEPHEUS trial 3 reported that the MRD-negativity rate was 60.9% with D-VRd versus 39.4% with VRd, and the risk of progression or death was 43% lower for D-VRd versus VRd.
• A comparative analysis of sequential cohorts with triplet therapy lenalidomide, bortezomib, and dexamethasone (RVd) versus daratumumab with RVD (DRVd) in transplant-eligible patients 6 demonstrated the utility of the D-RVd regimen in real-world clinical practice.
• The PERSEUS trial 4 found that the estimated percentage of patients with PFS at 48 months was 84.3% in the D-VRd group and 67.7% in the VRd group, with a hazard ratio for disease progression or death of 0.42.

Safety and Tolerability

• The studies mentioned above reported that the addition of daratumumab to VRd or RVd was generally well-tolerated, with manageable adverse events 3, 4, 5.
• Grade 3 or 4 adverse events, such as neutropenia and thrombocytopenia, were common in both the D-VRd and VRd groups 4.
• Infections were more common with D-VRd, but grade 3/4 infection rates were similar between the two groups 5.