Dr Haumschild leads a discussion surrounding key considerations when using anti-CD38 drugs.
Ryan Haumschild, PharmD, MS, MBA: You discussed not only the clinical implications but also some of the operational considerations. I think that’s so important as we’re evaluating therapies. We’re all clinicians here, but thinking about what is the impact on the patient? I think ultimately that’s that bimodal impact. Dr Maples, I’ll turn to you and ask, what are the clinical and operational differences in the anti-CD38 monoclonal antibody therapies used in relapsed/refractory multiple myeloma? If you could, what role does the route of administration play in your therapy selection?
Kathryn Tyler Maples, PharmD, BCOP: Absolutely. I’ll piggyback off what Dr Hossain has already highlighted. We do have our 2 anti-CD38 agents of daratumumab and isatuximab. Then of course the daratumumab also has the subcutaneous product. I think we are always thinking about how we operationalize these agents. A couple of operational considerations that have already been discussed include the observation time with subcutaneous daratumumab, and the intravenous IV administration time with the other 2 products. Isatuximab does have a slightly shorter infusion time compared to IV daratumumab, but then subcutaneous daratumumab is going to be the shortest with that 5-minute push.
Another consideration is with isatuximab-based regimens, the dosing remains biweekly. It’s weekly for the first cycle, and then it’s every other week thereafter vs a daratumumab-based regimen where it is more burdensome up front because it’s weekly for 2 cycles and then most commonly every other week for 4 cycles. We do eventually get to a once-monthly dosing schedule. That is really nice for patients in terms of how often they need to come to the infusion center, when we will reach a period where they’re only coming once a month. I think that’s something to consider.
For the premedications, I completely agree with Drs Hossain and Ali. We have started to omit some of the premedications, and we have shortened our observation period, so I think there’s some room to optimize the operational side of things there. We do prefer the subcutaneous formulation over the IV formulation, not only for the operational side of things but there were significantly fewer infusion-related reactions with subcutaneous daratumumab compared to intravenous daratumumab. I think there are a lot of different things you can think about.
Then from a clinical side of things, getting someone started on an anti-CD38 agent, there are a few other considerations that are worth mentioning. We want to check for any hepatitis B exposure. These agents can cause hepatitis B reactivation, so we would make sure that those laboratory blood tests were drawn ideally before they start their anti-CD38 agent. Then lastly, it can interfere with their blood type and screening, so making sure that we can get that blood type and screen done. Again, it’s not the end of the world if it’s not done before. There is additional testing the blood bank can do, but we try to build those things into our order sets to make sure they get done and check off the clinical side of things as well. As we have seen these anti-CD38s be incorporated, I think we want to make sure we’re considering all of the different operational and clinical considerations as we start a new patient on this type of regimen.
Ryan Haumschild, PharmD, MS, MBA: Excellent. Dr Hanna, we know there are so many different mechanisms of action in multiple myeloma, specifically in the relapsed/refractory setting. Could you give the audience a bit of background about what are the best agents to pair with an anti-CD38 medication?
Kirollos S. Hanna, PharmD, BCPS, BCOP: That’s a great question, Dr Haumschild. I think Dr Maples answered this in terms of, outside of our standard triplets, your PIs [proteasome inhibitors], your IMiDs [immunomodulatory drugs], and maybe a steroid here and there, I’m not sure we really know, to be honest with you. The CASSIOPEIA trial is really interesting. They looked at the various ways to sequence DARA [daratumumab] in terms of anti-CD38 incorporation with a PI, an IMiD, and a steroid. There was a maintenance component, there was a nonmaintenance component. Dr Maples and I presented some of these data together several months back. You look at the Kaplan-Meier curve, regardless of where you incorporated the CD38 agent with those 3 drugs, the Kaplan-Meier curve for each combination that had the daratumumab in it was very similar to a triplet regimen without daratumumab. That is one thing saying the IMiDs, the PIs, and the steroids are probably the best combination.
There are a lot of studies that give us some direction. Obviously, when you talk about GRIFFIN, this is a pivotal trial for your 4-drug regimen or your 4-drug combinations in that frontline setting. That is daratumumab-VRd [bortezomib, lenalidomide, and dexamethasone]. You have your standard VRd, a big backbone regimen for your standard patients with myeloma. I don’t think there’s much that battles your GRIFFIN approach in terms of an induction type of therapy, taking them to transplant, and then maybe putting them on maintenance daratumumab or something after. That I would say in the front line, is certainly a solid treatment option.
In the relapse setting, we have some interesting data. One, we talked about the CASSIOPEIA study and those different approaches, but you have, for example, with isatuximab, you have the IKEMA and ICARIA clinical trials. IKEMA is really interesting. The PFS [progression-free survival] rates we saw from the IKEMA study were some of the highest progression-free survival rates we’ve seen with any combination, and that is combining isatuximab with Kd [carfilzomib and dexamethasone]. Dr Maples said that some of these ongoing studies are looking at combining anti-CD38 agents with KRd [carfilzomib, lenalidomide, dexamethasone]. You’re adding an IMiD, but again, you’re doing your carfilzomib as well as your steroid. ICARIA was good too, but that only incorporated Pd [pomalidomide and dexamethasone]. Again, that trial design and the specific population it looked at was a bit more refractory of a patient population, so it’s hard to say that either a PI combination or an IMiD combination is better than the other. I would say to date, combinations with PIs and IMiDs tend to pan out in terms of the best responses.
Transcript edited for clarity.