What is the progression-free survival (PFS) of Daratumumab (daratumumab) plus Lenalidomide (lenalidomide) as maintenance therapy?

From the Guidelines

Daratumumab plus lenalidomide maintenance therapy significantly improves progression-free survival (PFS) in multiple myeloma patients compared to lenalidomide maintenance alone. According to the most recent study from 2023 1, the combination of daratumumab and lenalidomide resulted in a higher PFS rate, with a hazard ratio of 0.31, representing a 69% reduction in the risk of progression or death. This combination is typically continued until disease progression or unacceptable toxicity. The study also reported that the most common adverse events of grade 3 or 4 in patients treated with the daratumumab regimen versus lenalidomide/dexamethasone were neutropenia, thrombocytopenia, and anemia.

Some key points to consider when using daratumumab plus lenalidomide maintenance therapy include:

• Monitoring for infusion reactions with daratumumab and for cytopenias, fatigue, and infection risk with both medications
• Prophylaxis for herpes zoster is recommended
• The improved efficacy is likely due to the complementary mechanisms of action: daratumumab targets CD38 on myeloma cells inducing direct and immune-mediated killing, while lenalidomide enhances immune function and has direct anti-myeloma effects
• Though this combination increases cost and potential side effects, the significant PFS benefit makes it an important consideration for maintenance therapy in eligible multiple myeloma patients.

It's worth noting that another study from 2020 1 discussed the efficacy and safety of lenalidomide/dexamethasone in elderly patients with MM, but the most recent and relevant study for daratumumab plus lenalidomide maintenance PFS is the one from 2023 1.

From the FDA Drug Label

14 CLINICAL STUDIES 14. 1 Newly Diagnosed Multiple Myeloma Combination Treatment with Lenalidomide and Dexamethasone in Patients Ineligible for Autologous Stem Cell Transplant MAIA (NCT02252172), an open-label, randomized, active-controlled trial, compared treatment with DARZALEX 16 mg/kg in combination with lenalidomide and low-dose dexamethasone (DRd) to treatment with lenalidomide and low-dose dexamethasone (Rd) in patients with newly diagnosed multiple myeloma ineligible for autologous stem cell transplant.

Efficacy was evaluated by progression free survival (PFS) based on International Myeloma Working Group (IMWG) criteria. MAIA demonstrated an improvement in Progression Free Survival (PFS) in the DRd arm as compared to the Rd arm; the median PFS had not been reached in the DRd arm and was 31.9 months in the Rd arm (hazard ratio [HR]=0.56; 95% CI: 0.43,0.73; p<0. 0001), representing 44% reduction in the risk of disease progression or death in patients treated with DRd. After a median follow-up of 64 months, the median PFS was 61.9 months (95% CI: 54.8, NE) in the DRd arm and 34.4 months (95% CI: 29.6,39. 2) in the Rd arm.

The combination of Daratumumab and Lenalidomide as maintenance therapy showed an improvement in Progression Free Survival (PFS) compared to Lenalidomide alone, with a median PFS of 61.9 months in the DRd arm and 34.4 months in the Rd arm 2.

• Key points:
  • The study demonstrated a 44% reduction in the risk of disease progression or death in patients treated with DRd.
  • The median PFS had not been reached in the DRd arm and was 31.9 months in the Rd arm.
  • After a median follow-up of 64 months, the median PFS was 61.9 months in the DRd arm and 34.4 months in the Rd arm.

From the Research

Daratumumab plus Lenalidomide Maintenance PFS

• The combination of daratumumab and lenalidomide has been shown to improve progression-free survival (PFS) in patients with relapsed or refractory multiple myeloma 3, 4.
• In the POLLUX study, daratumumab plus lenalidomide and dexamethasone (D-Rd) reduced the risk of disease progression or death by 63% and increased the overall response rate (ORR) versus lenalidomide and dexamethasone (Rd) alone 3.
• The median PFS was 44.5 months with D-Rd versus 17.5 months with Rd, with a hazard ratio of 0.44 (95% CI, 0.35-0.55; P < 0.0001) 3.
• Similar results were seen in the CASTOR trial, which demonstrated a significant improvement in PFS with daratumumab plus bortezomib and dexamethasone versus bortezomib and dexamethasone alone 5.
• The addition of daratumumab to lenalidomide and dexamethasone has also been shown to improve overall survival (OS) in patients with relapsed or refractory multiple myeloma, with a median OS of 67.6 months versus 51.8 months with Rd alone (hazard ratio, 0.73; 95% CI, 0.58-0.91; P = 0.0044) 5.

Subgroup Analysis

• Prespecified analyses demonstrated an improved PFS and OS with D-Rd versus Rd in most subgroups, including patients aged 65 years or older, patients with one, two, or three prior lines of therapy, and patients with high-risk cytogenetic abnormalities 3, 5.
• The combination of daratumumab, lenalidomide, and dexamethasone has also been shown to be effective in patients with newly diagnosed multiple myeloma, with a high rate of minimal residual disease (MRD) negativity and improved PFS and OS rates 6, 7.

Safety and Tolerability

• The most common grade 3 or 4 adverse events with D-Rd were neutropenia, anemia, pneumonia, thrombocytopenia, and diarrhea 3, 5.
• The addition of daratumumab to lenalidomide and dexamethasone was associated with a higher rate of infusion-related reactions and neutropenia, but no new safety concerns were reported 3, 4.