Sagar Lonial, MD, FACP, explains the importance of daratumumab/lenalidomide/low-dose dexamethasone (DRd) in several key areas, including progression-free survival versus common standard-of-care regimens in the PEGASUS trial, toxicities, and how active patients fare.
Sagar Lonial, MD, FACP: When we begin to think about head-to-head comparisons or other trials that are treating a similar transplant-ineligible patient population, there was a retrospective analysis done by Dr Brian G.M. Durie and colleagues, the PEGASUS study, where the use of daratumumab/lenalidomide/dexamethasone was compared with lenalidomide/dexamethasone, as we saw in the MAIA study. But it was also compared with VRd [bortezomib, lenalidomide, and dexamethasone] from the SWOG study, as well as bortezomib and dexamethasone from other transplant-ineligible patient trials. What we know about this is that these cross-trial comparisons are always a bit challenging. They are never done with the same patient populations. Even if you have the same eligibility criteria, the number and subtlety of these patients may be different between trials.
In the analysis, they tried to take as much of that into account as they could. They compared the potential HR [hazard ratio] and PFS [progression-free survival] for daratumumab/lenalidomide/dexamethasone with VRd, bortezomib/dexamethasone, and lenalidomide and dexamethasone. What they demonstrated was that the HR favoring the use of daratumumab/lenalidomide/dexamethasone was the highest and had the longest progression-free survival compared to either bortezomib/lenalidomide/dexamethasone, or VRd, lenalidomide/dexamethasone, or bortezomib/dexamethasone. Again, this was a complicated statistical model, but it certainly suggests that the daratumumab/lenalidomide/dexamethasone regimen does have a longer progression-free survival when we look at the curves of these trials separately.
What I think is pretty clear is that for somebody for whom one was going to consider lenalidomide/dexamethasone as a control arm or as a standard treatment, the data from the phase 3 MAIA trial clearly supports the use of daratumumab/lenalidomide/dexamethasone as a triplet in the context of newly diagnosed, frail myeloma. When we begin to think about relative pros and cons of each of these potential treatments, it’s important to note that the proteasome inhibitor may offer significant benefit in the high-risk patient population. And so, when I think about how I’m going to use this for the average transplant-ineligible patient population, daratumumab/lenalidomide/dexamethasone has become the standard of care, except in the high-risk subsets or patients for whom I worry and need a very quick response. The use of a bortezomib-based induction may offer a strategic benefit in that clinical scenario.
What we know about the SWOG study is that it was only 8 cycles of bortezomib and that demonstrated a significant improvement in overall survival. Beyond that, patients can come in once a month. Similarly, when you use daratumumab/lenalidomide/dexamethasone, once you get beyond cycle 6 of therapy patients only have to come in once a month and can get subQ [subcutaneous] daratumumab, which also represents a convenience from a patient perspective.
We’ve certainly treated patients with both regimens. These are the most common regimens used in the transplant-ineligible patient population. One of the patients I put on the MAIA trial regimen was an 82-year-old woman who, in the beginning, came with lots of family members. Everybody was concerned about how she was going to do. After 6 months on daratumumab/lenalidomide/dexamethasone, she quickly went into a response and nobody was there with her anymore. She was doing well. She was able to come to clinic on her own, get her infusion, and leave and do things on her own. Her family became less concerned about her overall prognosis. And she’s continued therapy with daratumumab/lenalidomide/dexamethasone for over 3.5 to 4 years.
I think this certainly is a very reasonable approach to use in an older, frailer patient population. Again, it may be the subtleties of genetics, risks, speed of response, as well as other issues that may factor into choices. But certainly from the MAIA trial and the PEGASUS retrospective analysis, daratumumab/lenalidomide/dexamethasone looks like it is one of the better treatment options for this patient population.
As we think about using daratumumab-based combinations, one of the things to consider is the toxicity profile. We know that with IV daratumumab, the biggest issue is infusion reactions in the first 2 doses. Consequently, the first dose needs to be given on an average of 6 hours and the second dose is somewhere around 3 to 4 hours. At our center, we were giving daratumumab IV over 90 minutes. What we now know about the subcutaneous formulation is it can be given much more quickly. The period of observation is only there for the first and second dose. Beyond that, patients can get their subQ injection and leave the clinic within 15 to 20 minutes. So, I think these really are the major issues.
For patients who are on long-term daratumumab, consideration of prophylaxis or IVIg [intravenous immunoglobulin] if needed for the presence of recurrent infections is something that should be noted. In patients who are receiving daratumumab in combination with lenalidomide, particularly early on, you may see a bit more neutropenia than you might expect with lenalidomide and dexamethasone alone. This is not unexpected and is not a major issue. Patients can be managed with dose adjustments or the concomitant use of Neupogen [filgrastim], or G-CSF [granulocyte colony-stimulating factor], to try and manage some of that neutropenia. Over time, that typically goes away. Or again, the dose of lenalidomide can be modified to allow patients to continue a dosage of both daratumumab and lenalidomide in this situation.
Transcript edited for clarity.
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