When would you add daratumumab to a PI/IMiD/dex backbone for first-line treatment of transplant-eligible multiple myeloma?
Short answer - in patients with low risk disease.
Long answer - CASSIOPEIA enrolled fit patients below 65 years of age with adequate kidney function (greater than or equal to 40 mL/min/1.73 m2) with predominantly stage 1 & 2 disease by the revised international staging system (91% in Dara-VTd, 90% VTd) for the primary endpoints of improvement in stringent complete response (sCR) in part 1 and the PFS benefit in part 2. The addition of Dara created a PFS benefit in all subgroups except for those with high risk cytogenetics; these are the same findings in MAIA and ALCYONE. The second Daratumumab randomization in CASSIOPEIA demonstrated that Dara maintenance was not useful for patients that received Dara upfront. Waiting for survival benefit will take forever, but without a survival benefit it's useless with tools that are all palliative rather than curative.
The addition of Dara led to more infections overall, although the grade 3/4 infections were similar between arms. Are there interventions that we could employ in patients receiving Dara to improve safety, e.g. adding a fluoroquinolone for the first months of therapy as reported in the TEAMM trial? Are such high doses of dexamethasone and even Dara needed? Looking at alternative doses and schedules may attenuate toxicities and improve affordability.
What is the trade-off integrating Dara into the initial treatment of fit myeloma patients? Obviously, it adds more cost, infections, and side effects - there are no free lunches. If the backbone is lenalidomide, bortezomib, and dexamethasone (RVd) or carfilzomib, lenalidomide, and dexamethasone (KRd), the benefit of Dara is not proven.
In patients with high risk disease, nothing works. Add Dara to KRd, do KRd alone, or do RVd. I don't care. The definition of high risk means R-ISS 3, ≥5% circulating PCs, extra medullary disease, hypodiploidy, t(8;22), or ISS-3 plus 1q amp.
In patients with low risk disease, Dara-RVd makes sense in hopes of limiting the time on post-transplant lenalidomide maintenance. I define this group as ISS 1-2 with not high risk IgH translocations, no MYC rearrangements, no gain or amp of 1q, and no del 17.
In patients with intermediate risk disease, defined as ISS 3 and other misfits, I suggest RVd or KRd, pushing patients to whichever toxicity they want to avoid more - neuropathy or cardiac issues, since the triplet combinations are equivalent based on ENDURANCE.
The only published phase 3 study currently using Daratumumab as part of front line regimen is in non-transplant newly diagnosed patients using Dara-VMd vs VMd. In transplant-eligible, the GRIFFIN study comparing Dara -VRD(velcade/revlimid/dex) versus VRD alone as induction in transplant-eligible newly diagnosed MM is still maturing. Until then VRd (or KRd) is frontline in Newly Dx transplant eligible MM. Unless on a clinical trial, insurance will not cover Dara-VRd frontline.