Daratumumab for maintenance in myeloma

In this issue of Blood, Badros and colleagues present the results from AURIGA, the first phase 3 randomized trial comparing daratumumab lenalidomide (DR) to lenalidomide alone (R) as posttransplant maintenance therapy.¹ 

Induction therapy followed by autologous stem cell transplantation and R maintenance remains the standard of care for transplant-eligible (TE) patients with newly diagnosed multiple myeloma (NDMM).² However, many patients have persistent detectable disease using this standard approach. Therefore, efforts have focused on enhancing the efficacy of single-agent oral lenalidomide maintenance, while preserving safety and convenience. The anti-CD38 antibody daratumumab has been approved in combination with lenalidomide in transplant-ineligible NDMM and in the relapse setting.^3,4 More recently, posttransplant maintenance with DR has been assessed in 2 randomized trials, GRIFFIN and PERSEUS.^5,6 However, in both studies, patients were randomized to receive upfront daratumumab or not during bortezomib lenalidomide dexamethasone (VRD) induction, VRD consolidation, and lenalidomide maintenance. As a result, the specific benefit of adding daratumumab during the maintenance phase is difficult to ascertain.

The AURIGA study enrolled patients with NDMM who achieved at least very good partial response and had minimal residual disease (MRD)-positive status (threshold 10-5) assessed by next-generation sequencing (NGS) following induction and transplant. The primary end point was the MRD negativity rate (NGS, 10-5) at 12 months from the start of maintenance. A total of 200 patients were randomized 1:1 to receive DR or R for up to 3 years. The study met its primary objective with a significantly higher MRD conversion in the DR arm (50.5%) compared with the R arm (18.8%) (odds ratio = 4.51, 95% confidence interval [CI], 2.37-8.57, P < .0001). After a median follow-up of 32.3 months, a progression-free survival (PFS) benefit was observed in the DR arm with a 47% reduction in the risk of disease progression or death (hazard ratio = 0.53, 95% CI, 0.29-0.97). The DR regimen was well tolerated with no new safety signal reported. Although the results of this randomized study support the addition of daratumumab to standard lenalidomide maintenance in TE patients with NDMM, several important questions remain.

First, because daratumumab was not approved for TE NDMM at the time of study design, patients enrolled in AURIGA were daratumumab naive. Now that anti-CD38-based induction and consolidation is standard of care, the benefit of the addition of D to R during maintenance must be validated in patients who received quadruplet upfront. The impact of daratumumab maintenance in this population has been only suggested by the phase 3 study CASSIOPEIA,⁶ and the study designs of both GRIFFIN and PERSEUS preclude the ability to evaluate the specific benefit of the addition of D to R during maintenance.

The second consideration pertains to the study population. AURIGA focused exclusively on patients with detectable MRD (NGS, 10-5) before maintenance. MRD positivity is associated with poorer outcomes in TE NDMM, making dedicated studies for this high-risk population particularly important.⁷ However, AURIGA does not address whether DR offers any benefit over R in patients who achieved MRD negativity prior to maintenance. The ongoing German Myeloma Multicenter Group (GMMG)-HD7 trial, which is comparing isatuximab plus R to R alone as posttransplant maintenance, should help clarify the value of adding an anti-CD38 antibody in an all-comer TE NDMM population.

The final point concerns the study primary end point. To date, PFS and overall survival remain the validated end point for maintenance trials. Although the study successfully met its MRD-based primary end point, longer follow-up with more PFS events is required to confirm the superiority of DR in terms of survival. That said, numerous studies have now demonstrated the prognostic value of MRD in MM, and the Oncologic Drugs Advisory Committee recently endorsed MRD as a valid surrogate end point to support accelerated approvals.

In conclusion, AURIGA demonstrated a significant advantage in MRD conversion with DR over R in a population of daratumumab-naive patients who had suboptimal response to induction and transplant (ie, MRD⁺). Alongside data from the GRIFFIN, PERSEUS, and CASSIOPEIA trials, these findings support the use of daratumumab during maintenance in TE patients with NDMM.^5,6,8 However, results from other ongoing phase 3 randomized trials, such as the GMMG-HD7 study, will likely be required to obtain a potential approval for the combination of anti-CD38 and lenalidomide as maintenance therapy in TE patients with NDMM.

Conflict-of-interest disclosure: C.T. and A.P. are advisory board members and received honoraria from Bristol Myers Squibb, Janssen, and Sanofi.