Saad Z. Usmani, MD: Let me first talk about the GRIFFIN trial. We had several abstracts that were highlighting quadruplet regimens. The GRIFFIN trial was first presented almost 2 years ago. It is a randomized phase 2 study that was done in transplant-eligible patients up to the age of 70. The standard of care arm of this trial was RVd [lenalidomide, bortezomib, and dexamethasone] as part of induction followed by autologous stem cell transplant. Then, RVd was given for 2 cycles of consolidation post-transplant and patients moved on to receive LEN [lenalidomide] maintenance. On the experimental arm, daratumumab was added to RVd, so RVd with daratumumab for 3 cycles of induction then 2 cycles of post-transplant consolidation, followed by daratumumab, lenalidomide as maintenance. The primary end point for this study was stringent CR [complete response] post-consolidation. That was what it was powered for. However, secondary end points include rates of MRD [minimal residual disease] negativity, overall response rate, VGPR [very good partial response] or better, stringent CR, PFS [progression-free survival], as well as overall response rates.

It was a well-designed study asking an important question, keeping in line with a similar kind of a study that was done in Europe, the CASSIOPEIA trial, where daratumumab was added to VTd [bortezomib, thalidomide, and dexamethasone] as part of conduction and consolidation. The original data that were presented by my colleague before had demonstrated that the study met its primary end point. Stringent CR post-consolidation was statistically significant and superior in the daratumumab-containing arm. At ASH [American Society of Hematology annual meeting], what was reported was a 2-year follow-up update and specifically data looking at what was happening to the response deepening over time, specifically up to 2 years of maintenance. What was important at that time point, you have 2 years of maintenance, stringent CR or better was seen in 82% of the patients in the daratumumab arm of the study compared to 61% in the standard of care arm. The 2-year PFS rate, again, the median follow-up on the study is now 38.6 months, was not reached for either group.

There’s a trend emerging at the 3-year PFS rate for the daratumumab arm, but again, these are early data and premature data, I guess. MRD negativity rates were significantly high, both at 10-5 and 10-6, in the daratumumab-RVd followed by daratumumab, lenalidomide maintenance arm. What we are seeing is sustained MRD negativity beyond 6 months and beyond 12 months being higher, including in subgroups that were high risk for gain 1q21 [chromosome] as an example. These data are practice informing, and there’s a phase 3 trial that’s ongoing called the PERSEUS study, which is following the same kind of schema in transplant-eligible patients as a follow-up to GRIFFIN. We are really looking forward to those results.

How do I utilize the GRIFFIN data in clinical practice? What we are trying to do for newly diagnosed patients is picking therapies that give our patients the best likelihood of the deepest response, especially during that first year of diagnosis. Based on that information, I am more comfortable utilizing daratumumab-VRd [bortezomib, lenalidomide, dexamethasone] as part of induction in a transplant-eligible patient. For our upfront patients who are either standard or high risk, both VRd and daratumumab-VRd are reasonable choices. I’m leaning more toward daratumumab-VRd for majority of patients, and that’s where the field is likely headed. For high-risk patients, typically, any PI-IMiD [proteasome inhibitor-immunomodulatory drug] induction regimen like VRd is OK. There are data with single-arm phase 2 and randomized phase 2 trials showing good responses and PFS benefit for KRd [carfilzomib, lenalidomide, dexamethasone] in high-risk patients, and that’s something that I would use for certain high-risk patients.

When it comes to maintenance strategies for standard-risk patients, it’s lenalidomide maintenance, and then it’s an IMiD-PI based maintenance for high-risk patients. That’s the general approach. Again, I’m an early adapter, what it’s looking like is for the vast majority of patients, we are going to be utilizing a quadruplet regimen that incorporates an anti-CD38 monoclonal antibody. There were some very interesting data with the other anti-CD38, isatuximab, being combined with the PI-IMiD induction regimen by the German myeloma group that was presented at ASH as well, which aligns with what we’ve seen with GRIFFIN.

Transcript edited for clarity.