When, if ever, would you select a three-drug regimen instead of four-drug regimen in patients with newly diagnosed Multiple Myeloma?

Thank you for this question. For older, transplant-ineligible patients, there is no data that patients live longer or better (the true goals of treatment) with four drugs instead of three drugs. Yes, the responses are better, and we hope this may translate to longevity over time, but we do not know that. PFS in the frontline setting does not correlate well with OS, because patients can get therapies subsequently.

For frail patients, I would absolutely use three drugs rather than four. Given the safety profile of daratumumab compared to bortezomib, my choice would be daratumumab/lenalidomide/dexamethasone for such patients, with sparing use of dexamethasone and prompt omission. For some really frail patients, I start off without lenalidomide ...

In the setting of a very frail older-aged adult with multi-pharmacy and several significant co-morbid conditions that would prohibit the use of certain medications. An example would be someone over the age of 75 yo with severe peripheral neuropathy at diagnosis, DRd (MAIA) would be tolerated better than DRVd (PERSEUS). The goal is to gain optimal deep response (ideally MRD-) in such a patient, the rate of achieving the deep response may be slightly delayed but the added consolidation and sustainability of the response are key. In such a patient, the trade-off would be triplet vs quad induction with less toxicity to allow for the best QoL while aiming to achieve optimal treatment response.

Our institution has participated enthusiastically in ECOG protocol EAA181, which starts out with daratumumab, lenalidomide, and dexamethasone induction for 9 cycles, then a randomization to add in bortezomib for 9 additional cycles or not. The study was designed for patients who are transplant ineligible or transplant deferred. The study excludes R-ISS III patients by design. As we are still learning the kinetics of MRD negativity, I think it is still reasonable to complete this trial to figure out if lower risk NDMM will benefit from the addition of a fourth drug. We also have this study open at our VA affiliate, which tends to have a more frail population.

Our site will preferentially use quads for all high risk, but continue to use tripl...