Frontline therapy for multiple myeloma

In this video, Dr Rutger Callens, haematologist at the AZ Delta hospital in Roeselare, talks us through the highlights of the oral abstract session at EHA 2024 discussing innovations in the frontline treatment of patients with multiple myeloma (MM).

CASSIOPEIA is randomized phase III trial including 1,085 transplant eligible, newly diagnosed MM patients (NDMM). Patients were initially randomized to 4 cycles of pre-ASCT induction (ind) and 2 cycles of post-ASCT consolidation (consol) therapy with daratumumab (D) + bortezomib-thalidomide-dexamethasone (VTd) or VTd alone. In a second phase, patients with a partial response or better were randomized to D maintenance for up to 2 years or observation. After >6.5 years of median follow-up, D-VTd ind/consol, prolonged the median progression-free survival (PFS) with ~2.5 years vs. VTd alone, corresponding to a 39% lower risk of disease progression or death (median: 83.7 vs. 52.8 months; HR[95%CI]: 0.61[0.52-0.72]; p< 0.0001). Also the overall survival (OS) was significantly improved with D-VTd, with a hazard ratio of 0.55 (95%CI: 0.442-0.73). In part II of the study, D maintenance reduced the risk of progression or death by 51%, with a 20% higher 72-month PFS rate compared to observation (57.1% vs. 36.5%). The incorporation of D in the different treatment phases also led to high rates of durable MRD-negativity.¹

In the phase III PERSEUS study, adding D to bortezomib, lenalidomide, and dexamethasone (VRd) ind/consol followed by maintenance therapy with D + lenalidomide (R) significantly delayed disease progression and increased the depth of response compared to VRd alone followed by R maintenance in patients with transplant eligible NDMM. EHA 2024 featured the presentation of a detailed analysis of MRD in this trial. The rate of MRD-negativity proved to be consistently higher with the D-based therapy and this rate gradually increased over time. With D-VRd, the percentage of patients with sustained MRD-negativity (i.e., ≥12 months) at a level of 10^-6 was 47.3% as compared to 18.6% in the control arm (p< 0.0001). Among patients who were MRD positive at the end of consol therapy, D-VRd was associated with a significantly higher proportion of patients achieving MRD negativity at10^–6 during maintenance therapy (62.3% vs. 31.0%; p<0.0001).²

In the phase III GMMG-HD7 trial, the addition of isatuximab (Isa) to ind therapy with lenalidomide, bortezomib, and dexamethasone (RVd) significantly increased the rates of MRD negativity in patients with transplant eligible NDMM. During EHA 2024, data on MRD negativity and depth of response following high-dose therapy (HDT) and an ASCT were presented. Isa-RVd proved to be associated with a higher rate of very good partial responses or better (≥VGPR) compared to RVd alone (82.8% vs. 68.7%; OR[95%CI]: 2.19[1.49-3.23]; p< 0.0001). In addition, also the rate of MRD negativity was significantly higher with Isa-RVd than with RVd alone at 66.2% and 47.7%, respectively (OR[95%CI]: 2.13[1.56-2.92]; p< 0.001).³

In contrast to the studies above, the phase III BENEFIT trial investigated a quadruple regimen in transplant ineligible NDMM patients. In this trial, non-frail, transplant ineligible NDMM patients were treated with Isa-Rd with or without bortezomib (V). At the 18-month landmark, the rate of MRD negativity (10 ^-5) with Isa-VRd was reported at 47%, which was significantly better than the 24% seen with Isa-Rd (OR[95%CI]: 2.96[1.73-5.07; p< 0.001). At this timepoint, no significant difference in OS or PFS was observed. The regimen was well-tolerated, with only 10% of patients who discontinued V due to adverse events.

Dr Callens concludes that these studies consistently demonstrate a benefit of quadruple therapy in patients with NDMM, both in the transplant eligible and transplant ineligible setting. As such, it is to be expected that these regimens will become standard of care in the years to come.