Jonathan L. Kaufman, MD, considers updates from the GRIFFIN trial, the MAIA trial, and the PEGASUS study and comments on factors to consider for daratumumab-containing induction regimens.
Jonathan L. Kaufman, MD: The Griffin trial was a phase 2 randomized trial that compared transplant eligible patients 70 years old and younger with RVd [bortezomib, lenalidomide, and Dexamethasone] as the standard arm and the combination of Dara [daratumumab] RVd as the experimental arm. The RVd was given for 4 cycles, followed by stem cell collection and single auto transplant, then 2 more cycles and lenalidomide maintenance. The study was conducted for 2 years; after the 2 years the investigator and the patient could continue to choose ongoing maintenance therapy. That was the standard arm; the experimental arm daratumumab was included as part of induction, consolidation, as well as part of maintenance therapy for up to 2 years after transplant or 24 doses or months after transplant. Then at the end of that 24 month period for those patients who had been getting daratumumab, the daratumumab would stop and they could continue lenalidomide maintenance. The primary endpoint of this study was sCR [serum creatinine] rate after consolidation, and there was a clear improvement in stringent, complete response rate after induction, transplant and consolidation with the Dara RVd arm versus RVd with 42% versus 32%. This met the primary endpoint as designed by the study, hence the study was considered a positive study. At the initial time point, there was no difference in overall and progression free survival. The reality is, we wouldn't expect that at this early time point. We did see an improvement in MRD [minimal-residual disease testing] negativity. At ASH 2020, I presented a 12-month update where we saw an improvement in sCR over time with the Dara lenalidomide maintenance over lenalidomide alone, and a significant improvement in MRD negativity rates both at the 6 month up post-transplant and the 12 month follow-up post-transplant. This was also with a maintaining MRD negativity at a significantly higher level across all subsets, including high-risk patients in the Dara RVd versus RVd. One comment about the high-risk patients: it was a very small number and the data would not be considered definitive, but we now have additional evidence that adding daratumumab to a comprehensive RVd transplant and Len [lenalidomide] maintenance can be associated with increased MRD negativity in high-risk patients.
The MAIA trial was a phase 3 trial in newly diagnosed myeloma patients who are not transplant candidates with the standard arm being the combination of lenalidomide and Dexamethasone, with treatment to progression. It is important to remember that the Dexamethasone for those patients under 75 years old was 20 mg once per week. The experimental arm was the same Len Dex [lenalidomide and dexamethasone] with the standard dose and schedule of daratumumab. Again, in this study all 3 drugs were treatment to progression. We found in this study there was a significant improvement in response rate, particularly deep responses, and an improvement in progression-free survival. From a safety perspective, we did see more neutropenia with the 3 drug combination, Dara, Len, Dex [daratumumab, lenalidomide, dexamethasone] versus Len Dex. We did see an increase in the number of upper respiratory infections, but we did not see an increase in the number of major and serious life-threatening infections. When we saw that the data of the combination of Dara, Len, Dex versus Len Dex come out, this really impacted treatment decisions across the United States as that Len/Dex was a very common regimen given for non-transplant candidates. Now with the MAIA data, there's an increased use of daratumumab and Len/Dex. Now, there has been no study of Dara, Len, Dex or DRd [daratumumab, lenalidomide, Dexamethasone] versus bortezo [bortezomib]/Len/Dex or RVd, or an RVd-lite. I think both of those regimens remain very effective. However, there's been no study that directly compared those 2 regimens. While there's no direct comparison in the context of a clinical trial of DRd versus standard regimens, the real-world analysis in the PEGASUS study showed favorable progression-free survival looking at dara-Rd versus a real-world experience of standard regimens such as RVd.
My experience with daratumumab-containing induction therapies is consistent with what we saw on the clinical trials; we've seen a higher and deeper responses at a cost of some toxicity. The toxicity is consistent with what we saw in the context of the clinical trials. Increased cytopenias, particularly neutropenia, often in the first several cycles when the daratumumab intensity is highest and the myeloma disease burden is highest. We have seen an increase in upper respiratory tract infections, but have not seen an increase in serious and life-threatening infections. Very importantly, with the approval of subcutaneous daratumumab, once the patient's beyond 6 months of therapy in the nontransplant setting, now the patient's only coming into the infusion center once per month. That visit to the infusion center using the subcutaneous daratumumab is short.
When we think about managing toxicities for patients on daratumumab, first we have to think about what we're going to do before dosing. It is very important to get a type-and-screen to make sure you know blood typing; it can be a challenge after daratumumab. It is also very important to get a hepatitis B profile because we know a hepatitis B reactivation is possible. If a patient has a history of hepatitis B, and then monitoring LFTs [liver function tests] will be important. Consideration of using antivirals for hepatitis B suppression could be considered. In the first several cycles using daratumumab, the other thing that we have to think about when is the development of cytopenias, particularly neutropenia, and monitoring that carefully. Then with daratumumab, you have to think about infusion-related reactions. With the use of subcutaneous daratumumab from the start, infusion-related reactions are about half of what we see with IV. With IV, you have any infusion-related reaction at approximately 50%, and when you use subcutaneous it's somewhere in the range of 20% to 25%.
Transcript edited for clarity.
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