Daratumumab in transplant regimens for myeloma?

When autologous transplantation is chosen in patients newly diagnosed with multiple myeloma, the standard pretransplant induction and posttransplant consolidation therapy is the triple combination of lenalidomide, bortezomib, and dexamethasone (RVd). In this issue of Blood, however, Voorhees et al show that the addition of daratumumab to this regimen increased rates of stringent complete response (CR) and minimal residual disease (MRD) negativity at the end of consolidation. Because the safety profile of this new combination was acceptable, the authors state that this combination may be a potential new standard for transplant-eligible myeloma patients.¹ 

It is already known that, in transplant noneligible patients, the addition of the anti-CD38 antibody daratumumab to standard regimens such as bortezomib, melphalan, and prednisone (ALCYONE [Daratumumab Plus Bortezomib, Melphalan, and Prednisone for Untreated Myeloma] trial)²  or lenalidomide and dexamethasone (MAIA [Daratumumab Plus Lenalidomide and Dexamethasone for Untreated Myeloma] trial)³  has dramatically improved the response rate and progression-free survival (PFS). The question now is whether the addition of daratumumab may also be useful in the transplantation paradigm.

Autologous transplantation is the standard of care for eligible patients with newly diagnosed multiple myeloma. The pretransplant induction therapy consists of 3 to 6 cycles of a bortezomib-containing triplet regimen, followed by high-dose therapy plus autologous transplantation. Usually, 2 courses of consolidation with the same regimen are administered posttransplant, before maintenance therapy. Triplet therapy with bortezomib, thalidomide, and dexamethasone has been used mostly in Europe. The CASSIOPEIA (Bortezomib, Thalidomide, and Dexamethasone With or Without Daratumumab Before and After Autologous Stem-Cell Transplantation for Newly Diagnosed Multiple Myeloma) trial showed that the addition of daratumumab to induction and consolidation triplet therapy with bortezomib, thalidomide, and dexamethasone improved the depth of response after consolidation, as assessed by the stringent CR and CR or better rate but also by the MRD negativity rate at the level of 10^–5.⁴  The RVd triplet is currently considered standard induction/consolidation treatment. The phase 2 randomized study by Voorhees et al of 207 patients also shows that the addition of daratumumab to 4 cycles of induction and 2 cycles of consolidation with RVd improved the postconsolidation stringent CR rate (42.4% vs 32%), the CR or better rate (51.5% vs 42.3%), and, importantly, the MRD negativity rate at the level of 10⁻⁵. With longer follow-up and the addition of maintenance therapy, the responses continue to deepen, with a significant benefit in favor of the daratumumab arm, especially in terms of MRD negativity rates (51% vs 20.4%). Except for slightly increased hematologic toxicity that had no major clinical consequences, the combination was well tolerated with no new safety concerns. However, in this phase 2 randomized study, one may question the robustness of the statistical analysis, or the potential biases in the control group (eg, a lower percentage of patients underwent transplant in the control arm vs the experimental arm). Also, the study was not sufficiently powered and the follow-up was too short to show significant benefit in terms of PFS, particularly because PFS is already very good with RVd induction and consolidation plus autologous transplantation and maintenance.⁵  However, we know that there is a strong relation between MRD negativity and outcome,^6,7  and we can reasonably postulate that the deeper response rate observed in the daratumumab arm will translate into an improved PFS with longer follow-up.

If the international phase 3 randomized PERSEUS trial (Bortezomib, Lenalidomide, and Dexamethasone [VRd] ± Daratumumab [DARA] in Patients [pts] With Transplant-Eligible [TE] Newly Diagnosed Multiple Myeloma [NDMM]: A Multicenter, Randomized, Phase III Study; clinicaltrials.gov #NCT03710603) confirms these data in a larger number of patients and, in addition, shows a PFS advantage due to the addition of daratumumab, the quadruplet daratumumab-RVd regimen will become a new standard in the transplantation programs for patients newly diagnosed with multiple myeloma. Isatuximab, another anti-CD38 that also yields excellent results in the relapsed setting,⁸  could also be used in this indication (clinicaltrials.gov #NCT03617731).

However, several questions should be addressed. First, the number of induction courses seems to be important. The Spanish PETHEMA group recently published results on 458 transplant-eligible patients treated with 6 cycles of a 28-day bortezomib, lenalidomide, and dexamethasone regimen (instead of 21-day) plus 2 cycles of consolidation. The postconsolidation results were also excellent, with a 50.2% CR or better rate and a 45.2% MRD negativity rate at the 3 × 10⁻⁶ level.⁹  The total number of cycles (induction plus consolidation) may also be important. Preliminary results with 4 cycles of induction therapy and 4 cycles of consolidation therapy with another triplet, carfilzomib, lenalidomide, and dexamethasone (FORTE [Efficacy of Carfilzomib Lenalidomide Dexamethasone [KRd] With or Without Transplantation in Newly Diagnosed Myeloma According to Risk Status] trial), also showed a postconsolidation CR or better rate of 62% (including 41% stringent CR) and a 58% MRD negativity rate at the 10^–5 level.¹⁰  Although cross-trial comparisons may be inaccurate, these results seem similar to those achieved with the daratumumab-RVd regimen, and these approaches may be considered viable alternatives. Results of combination therapies with or without daratumumab are shown in the table.

Second, it remains to be determined if the results of the daratumumab-RVd regimen discussed in this article can be further improved by either replacing bortezomib with carfilzomib or by continuing induction therapy to 6 cycles. This question is addressed by ongoing studies.

Finally, if 6 courses of daratumumab-RVd prove to be well tolerated and induce a higher incidence of deep responses than 4 courses, we could then again address the question of the role of frontline autologous transplantation in patients newly diagnosed with myeloma. In particular, if a patient achieves MRD negativity after induction quadruple therapy, is autologous transplantation still necessary, with maintenance therapy to follow? It should be stressed, however, that because current results are improving so rapidly, it will be increasingly difficult to design randomized studies to show a significant difference between 2 arms, as such studies will need very large number of patients and long follow-up times.