What is your preferred approach to a patient with myeloma who has refractory disease to Dara-VRd in the frontline setting?

Unless the patient is not actually receiving some or all of the Dara-RVd (lenalidomide compliance can be challenging), this functionally defines high risk disease. Most patients don't usually have disease stability for autologous transplant, or even if they are stable for a hot second, transplant provides little disease control for all its toxicity. Investigational treatment becomes more appealing and I often recommend patients set up an account at https://sparkcures.com/.

Assuming no therapeutic clinical trials are available, I tend to move on to Carfilzomib+Pomalidomide+Dex-Cyclophosphamide [KPCd] as "bridging" to CARVYKTI. Again, stability for a CART may not be possible, If this occurs, then shuttling the patient to a BCMA BsAb +/- Poma...

Agreed with @Dr. First Last's and @Dr. First Last's excellent comments. I'd favor KPd as my general option here. And I agree wholeheartedly re: oral Cytoxan not being so useful and hyperCVAD/DCEP being very intense.

UPDATE, SEPTEMBER 2024: The remainder of this response below presumes that second-line cilta-cel (Carvykti CAR-T) is not an option practically, but after the updated FDA approval I'd agree with CAR-T here. (Ide-cel is now approved for lines 3+). I will note that the "brain-to-vein" period between discussing CAR-T and getting CAR-T - including both 'holding' therapy before leukapheresis and 'bridging' therapy thereafter - is >3 months even in the most optimistic scenario. So if you don't think disease control is possible during th...