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A few thoughts on GRIFFIN study:
D-RVD vs RVD for frontline treatment of myeloma. Phase 2, randomized, unblinded, about 100 each arm.
D-RVD vs RVD for frontline treatment of myeloma. Phase 2, randomized, unblinded, about 100 each arm.
Primary outcome was sCR rate, which was significantly improved in intervention arm, as were numerous secondary endpoints MRD(-), ORR, achieving at least vgpr, etc.
Safety: More cytopenias in intervention arm, particularly neutropenia. Didn’t see data on febrile neutropenia listed. Despite dara arm having more AEs overall and serious infection rate the same, RVD arm ended up with more total serious AEs, unclear how, maybe less dz control 
So this was a study to see if using more aggressive upfront therapy for myeloma leads to deeper responses which, unsurprisingly, it does. The next question is how is this information going to be used.
This is not a study design to look for an overall survival benefit. Phase 2, not powered for OS, and OS often takes a while to accumulate in myeloma because people live for a long time, and in this cohort 50% had low risk disease.
So a couple questions are:
-how well will these deeper responses in this phase 2 predict OS, particularly we have such good agents including dara in the relapse setting?
-Can we identify a subset of patients respectively who may benefit from a more aggressive induction?
-how well will these deeper responses in this phase 2 predict OS, particularly we have such good agents including dara in the relapse setting?
-Can we identify a subset of patients respectively who may benefit from a more aggressive induction?
Regarding the first question, we will need to see more mature data from this study, we would need a larger phase 3 design to look at clinical outcomes, we would also want to make sure that control patients at relapse are getting appropriate therapy including Dara at some point.
In terms of prospectively identifying subset who benefit from more aggressive therapy: most worried about are the people who have high risk genetics/disease, and those who do not achieve at least a VGPR. The former can be identified perspectively, the latter cannot.
In the study, the high-risk group did not seem to drive a disproportionate benefit w/r/t response. This was part of a planned subgroup analysis. Worth noting that small number of high risk people, only 15%. Also, high risk can have good initial response but relapse sooner.
On a positive note, proportion of people who achieved at least a VGPR was significantly higher in the intervention group. Previous work has shown that getting at least to a GPR seems to be prognostically important.
So my 2c
Good:
-randomized phase 2
-deeper response, less refractory dz with Dara
-identified subsequent therapies
-safety wasn’t clearly worse with Dara
Good:
-randomized phase 2
-deeper response, less refractory dz with Dara
-identified subsequent therapies
-safety wasn’t clearly worse with Dara
Meh
-Control arm had more SAE despite less cytopenias, similar rate of serious infections, and most other AE equivalent. What were these additional serious events?
-not many patients got dara at relapse
-not many high risk patients
-Control arm had more SAE despite less cytopenias, similar rate of serious infections, and most other AE equivalent. What were these additional serious events?
-not many patients got dara at relapse
-not many high risk patients
Still meh
-Seemingly did not permit any prior tx. Not uncommon to have a myeloma patient present with an urgent complication like renal failure, symptomatic bone dz. Some myeloma trials allow steroids and/or a single cycle of rescue therapy prior to enrollment. Griffin did not.
-Seemingly did not permit any prior tx. Not uncommon to have a myeloma patient present with an urgent complication like renal failure, symptomatic bone dz. Some myeloma trials allow steroids and/or a single cycle of rescue therapy prior to enrollment. Griffin did not.
Questions yet to be answered, possibly by other studies:
-duration of response, particularly in high-risk patients
-Infection rates over time, since Dara is more aggressively depleting humoral compartment
-duration of response, particularly in high-risk patients
-Infection rates over time, since Dara is more aggressively depleting humoral compartment
-Could we see similar results with less Dara? Given with induction, consolidation and maintenance. Phase 3 could have a crossover after transplant or after consolidation to answer this. Obviously, far more lucrative if the only studied regimen gives a ton of Dara.
A theory in myeloma is that maximizing frontline depth of response could lead to OS benefit, since you are beating down the disease when it is most chemo sensitive. Seeing longer-term data from this trial and MASTER, as well as an eventual phase 3, will be interesting.
Glad to receive any feedback. I was reading this paper on my cell phone during a long drive, figured I’d deposit my thoughts here.
