Do you recommend utilizing daratumumab in the maintenance phase after a quadruplet induction for transplant eligible multiple myeloma?

Great question as always - both the Phase 2 GRIFFIN study (Dara-VRd vs VRd using IV Dara and 21-day induction cycles) and the Phase 3 PERSEUS study (Dara-VRd vs VRd using subQ dara and 28-day induction cycles) went on to use dara + lenalidomide for all patients in the post-transplant maintenance setting who had received Dara-VRd during induction.

Well, should we be doing the same in real-world practice? A few words of caution:

1. The CASSIOPEIA second randomization of dara versus observation in patients who had received either Dara-VTd or VTd (yes, thalidomide) showed no real difference in PFS between the Dara-VTd --> observation and the Dara-VTd --> dara maintenance arms. See Figure S4 in the appendix of the trial: Moreau et al., PMID 34529931.
   1. Here, the benefit of dara monotherapy as maintenance was most profound in the patients who had only received VTd induction.
   2. The caveat is that CASSIOPEIA used q8wk daratumumab maintenance and not q4wk dosing, which is what we're more used to.
2. We have many ongoing trials looking more specifically at CD38 + lenalidomide versus lenalidomide only, since CASSIOPEIA did not incorporate lenalidomide at all.
   1. The AURIGA trial (clinicaltrials.gov NCT03901963) of patients who are MRD+ after ASCT has finished accrual and is investigating whether dara+len leads to more MRD negativity achievement compared to len. Of note, this trial excluded prior daratumumab so not directly relevant to the question at hand.
   2. The GMMG-HD7 trial (clinicaltrials.gov NCT03617731) has already shown that adding isatuximab (another CD38 monoclonal antibody) to VRd improves MRD negativity). They have a second randomization of isa-len maintenance versus len maintenance that will be a more direct answer to the question at hand (albeit with a different CD38 mAb).
   3. The SWOG S1803 trial (clinicaltrials.gov NCT04071457), more properly known as DRAMMATIC, is also looking at the dara-len versus len question and includes dara-treated patients.

I am prepared to change my answer to this question based on the results of any of the ongoing trials (AURIGA, GMMG-HD7, DRAMMATIC) or more.

However, as of now - December 19, 2023 - I'd favor withholding dara as a component of maintenance in most patients. My typical approach is lenalidomide monotherapy in standard-risk patients, and lenalidomide plus a proteasome inhibitor (PI) in high-risk patients. Daratumumab does have a risk of URIs and prolonged COVID shedding, and the CASSIOPEIA trial (albeit with q8wk daratumumab maintenance) did not clearly show a benefit to prolonged daratumumab in patients who had received it during induction.

I have, however, occasionally used daratumumab in high-risk patients who cannot tolerate a PI alongside lenalidomide. It does seem reasonable to try 2 tolerated drugs over 1 in this particular setting, albeit I still am eagerly awaiting the results of the trials above.

What do others think?

The trials that we use to guide our practice for using daratumumab in newly diagnosed transplant eligible myeloma (PERSEUS and GRIFFIN prior to that), do not isolate the role of daratumumab in induction versus maintenance. A trial that isolated the role of any maintenance in the era of quads (CASSIOPEIA) showed a very marginal role of any maintenance therapy in people who received quadruplets.

Some other trials are looking at this question in more detail. Currently, however, I think that daratumumab maintenance in addition to lenalidomide following a transplant is likely excessive and unnecessary. I would be more likely to consider it in certain populations, such as those with a significant amount of residual disease after transplant, or those with high-risk disease.

I think Dr. @Dr. First Last has summarized things well. One additional point I will make is that the Emory group presented on a very large series of patients treated with Dara-VRd and transplant, after which standard-risk patients received only lenalidomide and high-risk patients received a PI/IMiD. The PFS curve thus far looks quite similar to what we have seen with GRIFFIN and now PERSEUS. 

I also think we should wait to see a longer-term follow-up from CASSIOPEIA which may inform on the utility of daratumumab maintenance more than it has thus far.

Dr. @Dr. First Last has summarized the data well. The phrase "standard-risk cytogenetics" has not aged well, and I am hoping that more precise language will be more commonplace, incorporating the influence of increased LDH, 1q+, del 1p, circulating plasma cells, etc.

While Dara+Len is not yet as well supported in the literature as Len, Len+Vel, or Len+CFz, the risk of heart failure with prolonged carfilzomib is documented. The risk of peripheral neuropathy with bortezomib is no joke. Dara+Len is a clear contender for maintenance, especially based on the data from MAIA leading the way in an older and more frail population.

The struggle with 2-drug maintenance is that the combination requires a side effect profile that is acceptable for YEARS of therapy, yet it has to be MORE effective than lenalidomide alone. This acknowledges that there are patients with myeloma for whom any combination of PI, IMiD, alkylator, and steroid will be inadequate and they will quickly progress within a year of transplant no matter what.

I hope that detailed studies of both the pharmacokinetics and immune-focused pharmacodynamics will allow us to incorporate bispecifics into maintenance regimens.

The MSK SOC is based on MRD at 10⁻⁶. If patients achieve it post-transplant in standard risk, then Len maintenance. For MRD-positive post-ASCT and high-risk patients, dual-drug maintenance.

While lenalidomide remains the standard maintenance in the U.S., emerging evidence supports daratumumab maintenance as an effective alternative or addition; however, optimal sequencing and long-term outcomes (including overall survival) require further study. (Moreau et al., PMID 38889735) The benefit of daratumumab-based quadruplet induction followed by daratumumab-containing maintenance seems to be consistent across studies, including GRIFFIN and PERSEUS, with a favorable safety profile and no new safety concerns. (Sonneveld et al., PMID 38084760.)

Phase 3 trials of CASSIOPEIA and PERSEUS have shown that adding daratumumab to induction regimens (D-VTd, D-VRd) and continuing daratumumab as maintenance significantly improves depth of response, MRD-negativity, and progression-free survival in this population. CASSIOPEIA has shown further prolongation of progression-free survival compared to observation with daratumumab maintenance of 16 mg/kg IV every 8 weeks for up to 2 years after daratumumab-containing induction/consolidation. (Moreau et al., PMID 34529931)

Until we have more data, for transplant-eligible newly diagnosed multiple myeloma patients who have received a daratumumab-containing quadruplet induction regimen, daratumumab maintenance is a reasonable evidence-based option for improving progression-free survival.