Responses After ASCT Were Extended With Daratumumab Maintenance and Standard Consolidation/Induction

The use of daratumumab (Darzalex) as maintenance therapy for patients with newly diagnosed multiple myeloma who received autologous stem cell transplant (ASCT) plus induction and consolidation therapy with bortezomib, thalidomide, and dexamethasone (VTd) was beneficial, according to findings presented during the 2021 European Hematology Association (EHA) Congress.¹

The results were taken from the randomized, open-label phase 3 CASSIOPEIA trial (NCT02541383) in patients with transplant-eligible multiple myeloma (N = 1085), which compared the combination of daratumumab plus VTd (dara-VTd) versus VTd alone as consolidation/induction in this patient population and led to the approval of dara-VTd for this indication.² The current analysis looked at the addition of daratumumab maintenance for patients who had a response to therapy in part 1 of the trial.

“CASSIOPEIA part 2 met its primary end point with a 47% reduction in the risk of disease progression or death with daratumumab maintenance compared with observation,” Philip Moreau, MD, head of the Hematology Department and the unit for early Phase I/II trials in clinical hematology at the University Hospital of Nantes, Nantes, France, said during a presentation of the data. “In patients who received VTd in part 1, daratumumab also improved progression-free survival and depth of response.”

Part 2 of the trial looked at daratumumab maintenance vs observation in patients who achieved a partial response (PR) or better in part 1, regardless of therapy arm. Moreau noted that at the time of trial initiation, there was no approved or established standard of care for maintenance therapy. However, current treatment guidelines now recommend the use of maintenance to prolong initial therapy response.

Following PR, patients were re-randomized to daratumumab 16 mg/kg as maintenance every 8 weeks until progression up to 2 years or observation. Stratification factors included induction treatment of VTd or dara-VTd and depth of response.

The primary end point of the research was progression-free survival (PFS) after second randomization, with 281 events assessed at the interim analysis with an efficacy boundary of P <.0166. Interaction between initial therapy and maintenance were evaluated. Key secondary end points were time to progression (TTP) from second randomization, rate of complete response (CR) or better, minimal residual disease (MRD) negativity, and overall survival (OS). In addition, updates to PFS, OS, and time to PFS on second-line therapy (PFS2) were performed.

In total, 886 patients underwent re-randomization to daratumumab (n = 442) or observation (n = 444). Patient characteristics were well balanced in the 2 groups, with patients having a median age of 59 years, with the majority being men (59.0% with daratumumab vs 57.2% with observation). Most patients had an ECOG performance status of 0 (57.0% and 58.6%, respectively) or 1 (39.4% vs 38.7%) and International Staging System I (42.8% vs 38.5%) or II (41.0% vs 48.2%).

The majority of patients in both groups had high-risk cytogenetics, at 87.0% of the daratumumab group and 84.2% in the observation group. About three-quarters of both groups (76.2% and 75.9%, respectively) had at least a very good PR (VGPR) with MRD negativity.

At a median follow-up of 35.4 months, the median PFS was not reached in those receiving daratumumab maintenance vs 46.7 months in those on observation (HR, 0.53; 95% CI, 0.42-0.69; P <.0001).

“The PFS benefit of [daratumumab] versus observation was also observed in all prespecified subgroups, except those who received dara-VTd consolidation in part 1,” Moreau said. “Longer follow-up is needed to look at the benefit that patients may receive following [initial dara-VTd].”

Daratumumab was also associated with significant benefits in TTP (HR, 0.49; 95% CI, 0.38-0.62; P <.0001) and a trend toward improvement in PFS2 (HR, 0.62; 95% CI, 0.40-0.96; P = .0298). Patients who had daratumumab versus observation had high rates of CR or better (72.9% vs 60.8%, respectively; OR, 2.17; 95% CI, 1.54-3.07; P <.0001) and MRD negativity (58.6% vs 47.1%; P = .0001). Data regarding OS were immature at the time of analysis.

The safety profile of daratumumab was manageable and only 3.0% of patients discontinued treatment due to adverse effects. About half of patients (54.5%) had an infusion-related reaction, mostly grade 1 or 2 in severity. Second primary malignancies occurred in 5.5% of the daratumumab group and 2.7% of the control group.

Although PFS did not differ significantly between the daratumumab and observation groups who were initially treated with dara-VTd, there was a significant benefit to active maintenance versus observation in patients who first received VTd (HR, 0.32; 95% CI, 0.23-0.46; P <.0001).

“Similarly, daratumumab improved rates of CR or better and MRD negativity compared with observation in patients who received VTd induction, but these outcomes were similar among patients who received dara-VTd induction/consolidation irrespective of maintenance therapy,” Moreau said. “The highest rates of deep responses were seen in patients who received dara-VTd induction/consolidation in part 1 followed by daratumumab maintenance in part 2.”

Updated data from part 1 of the trial showed that the median PFS was still not reached with dara-VTd at 44.5 months of follow-up versus 51.5 months in the VTd group (HR, 0.58; 95% CI, 0.47-0.72; P <.0001). Although the median OS was not reached in either arm, dara-VTd reduced the risk of death by 42% vs VTd alone, confirming its value as an induction and consolidation regimen in this setting (HR, 0.54; 95% CI, 0.37-0.79).

In patients who did not undergo second randomization, poor outcomes in terms of median PFS were observed in the dara-VTd (30.7 months) and VTd alone (25.4 months) arms. Although PFS2 data were immature, similar trends were noted in those who were not re-randomized.

“The optimal daratumumab-containing maintenance regimen remains to be determined,” Moreau said. “We looked forward to the results of ongoing trials such as GRIFFIN [NCT02874742], PERSUES [NCT03710603], and AURIGA [NCT03901963] that will provide additional information about the role of daratumumab in the maintenance setting.”

_References

_{1. Moreau P, Hulin C, Perrot A, et al. daratumumab maintenance vs observation in patients with newly diagnosed multiple myeloma treated with bortezomib, thalidomide, and dexamethasone ± daratumumab and asct: CASSIOPEIA part 2 results. Presented at: 2021 European Society of Hematology Congress; June 9-17, 2021. Virtual. Abstract S180. Accessed June 11, 2021. https://bit.ly/3pI5QHG}

_{2. FDA approves daratumumab for transplant-eligible multiple myeloma. FDA. September 26, 2019. Accessed June 11, 2021. https://bit.ly/35fT7T6}