The potential benefit of adding daratumumab to either induction and/or maintenance is an important question in our field. Daratumumab is an effective anti-myeloma therapy and is well tolerated and now even easier to administer in the subcutaneous formulation. The recently published PERSEUS study has established D-RVd as a standard of care induction therapy in NDMM, and this analysis can provide further information on this regimen in a real-world population with underrepresented subgroups, as well as additional insight into the role of daratumumab in the maintenance setting.

While no retrospective analysis can replicate the balance of a randomized clinical trial, in this comparison, patient characteristics were similar in terms of age, sex, and race between the RVd and D-RVd cohorts. Risk-stratified maintenance therapy was used in both patient populations, with a vast majority of standard-risk patients receiving lenalidomide monotherapy until progression, and high-risk patients receiving triplet maintenance therapy with a PI and IMID backbone. There was a higher percentage of patients in the D-RVd group with carfilzomib-based maintenance strategies when compared to RVd, but this accounted for a very small number of patients overall.

In terms of response rates, we saw improved depth of response favoring the D-RVd group with a higher ORR as well as higher ≥VGPR rates. The sCR/CR rates were lower in the D-RVd group, but again, this is almost certainly due to the daratumumab interference with the serum immunofixation assay. Unfortunately, MRD data was not routinely available yet post-transplant for all patients, though this analysis is ongoing. However, the depth of response benefit with quadruplets did translate to an early PFS benefit for all patients, and this benefit was seen for both the standard- and high-risk patient groups.

Beyond the GRIFFIN and PERSEUS trials, multiple randomized phase 3 studies have also shown the benefit of quadruplet induction regimens with the utilization of an anti-CD38 monoclonal antibody, either daratumumab or isatuximab, in combination with a PI and IMID backbone [9, 10]. The GMMG-HD7 trial was a randomized phase 3 trial comparing isatuximab and RVd versus RVd, and post-induction rates favored the quadruplet arm with a ≥VGPR rate of 77% versus 61% and improved MRD negativity rate of 50% versus 36% [10]. Several phase 2 trials have also investigated the use of quadruplet induction with daratumumab, as well as the use of the more potent proteasome inhibitor, carfilzomib, in lieu of bortezomib. However, given the increased toxicity seen with carfilzomib as compared to bortezomib and the small number of patients included in these trials, though the early data is quite impressive, we support the use of Dara-RVd for both standard and high-risk patients [11,12,13].

It is important to clarify the differences in the dosing schedule utilized in our analysis and in the GRIFFIN and PERSEUS trials. Induction was administered in 21-day cycles in contrast to 28-day cycles with weekly dosing of daratumumab, lenalidomide on days 1–14, and bortezomib twice weekly on days 1, 4, 8, and 11. Dexamethasone was dosed at our center at 40 mg weekly unless split dosing was required due to patient toxicity versus 20 mg on days 1, 2, 8, 9, 15, and 16. Furthermore, post-transplant, per our institutional protocol, we initiated maintenance therapy without the requirement of two additional cycles of consolidation, as was done in both the GRIFFIN and PERSEUS trials. We also did not use daratumumab during maintenance therapy as was done in the D-RVd arms in the GRIFFIN and PERSEUS trials and instead utilized the previously described risk-stratified maintenance approach per our standard institutional practice [14].

There are several limitations to this analysis, namely that it is a retrospective study and is a comparison of two sequential cohorts separated by time with varying availability of supportive care and novel treatment options. We tried to mitigate this potential difference with our subgroup analysis of the last 326 patients included in RVD 1000, which clearly shows the superiority of the quadruplet regimen. We do not have specific data on adverse events, quality of life, or dose reductions/holds during induction and/or maintenance therapy. Additionally, as some of the patients were induced in the community and then subsequently transplanted at our center, though we recommended our standard dosing of D-RVd, we do not have confirmation that this is how the regimen was administered.

Despite these limitations, this is the largest real-world database of transplant-eligible NDMM patients treated with RVd versus D-RVd, and importantly, the control arm (RVd) has historically mimicked the RVd arm from randomized trials providing further confidence to the validity of this data. Though we now have data on D-RVd from a large, randomized phase 3 trial, there are key differences between our datasets and the clinical trial experience that lend additional perspective on the treatment of NDMM. Importantly, both the RVd and the D-RVd datasets offer valuable insight into response and outcomes in black patients as they include a much larger number than seen in randomized prospective trials (36.3% in the RVd dataset and 41.7% in the D-RVd dataset). There was no statistically significant difference in PFS between black and white patients treated with either D-RVd or RVd. Moreover, black patients benefited from D-RVd induction with a similar magnitude of benefit as compared to RVd as their white counterparts, suggesting that if black patients are afforded the same access to care, they can experience the same outcomes.

Another unique aspect of our treatment algorithm as compared to GRIFFIN and PERSEUS is our risk-adapted maintenance approach. Though it is clear multiagent maintenance is necessary for some patients, it remains unclear which patients actually benefit from this more intensive approach, and thus we currently reserve this strategy for higher-risk patients. Despite this difference between our treatment approach and the randomized data, we found that our daratumumab arm has a similar estimated 4-year PFS rate compared to the PERSEUS trial. This raises the question about the necessity of daratumumab in both induction and maintenance for all patients. Our analysis suggests good outcomes with daratumumab in induction, but longer follow-up is needed to confirm which subsets of patients truly benefit from daratumumab in the maintenance setting as well. This question has previously been raised in the CASSIOPEIA trial, as patients who received daratumumab as induction did not seem to benefit from daratumumab as maintenance therapy and vice versa. Again, longer-term follow-up will be needed to evaluate the true benefit of the addition of daratumumab during maintenance.

Looking forward, we feel that these results, in conjunction with the GRIFFIN and PERSEUS data, as well as other randomized trials evaluating the addition of daratumumab to triplet induction regimens, support the use of Dara-RVd as the standard of care induction therapy for both standard- and high-risk NDMM patients, followed by ASCT and maintenance therapy. We acknowledge that for particular subsets of high-risk MM patients, such as double-hit disease, this strategy is likely suboptimal and supports the ongoing clinical investigation of the use of novel immune-based strategies, including earlier use of bispecific T-cell engagers and possibly CAR-T cell therapy for this patient group.