Faster Corticosteroid Tapering Safe in Relapsed/Refractory MM
Ajai Chari, MD, Icahn School of Medicine, Mount Sinai, New York, NY, discusses the phase 1b PAVO study, which evaluated the safety of faster corticosteroid tapering in patients with relapsed/refractory multiple myeloma (MM) receiving subcutaneous daratumumab.
Hi. My name is Ajai Chari. I'm professor of medicine at the Icahn School of Medicine at Mount Sinai in New York. It's my pleasure to be presenting the "Corticosteroid Tapering in Patients with Relapsed or Refractory Myeloma Receiving Subcutaneous Daratumumab." This is part 3 of the open‑label, multicenter phase 1b PAVO study.
We all know that steroids are used in multiple regimens in the treatment of multiple myeloma. However, they also happen to be probably one of the least favorite drugs from a patient perspective because of the psychiatric effects of fluid retention, insomnia, etc.
This study was looking at the ability to potentially taper that faster, given that we know from prior publications and studies that subcutaneous daratumumab is very well‑tolerated. The typical intravenous daratumumab has anywhere between 40 to 50% rate of infusion‑related reactions with the first dose, where subcu dara is less than 10%.
The median infusion time for the IV dara is 7 hours for the first infusion, and eventually can get to about 3 hours if somebody is getting rapid infusion dara, which is also done in many centers in 90 minutes. However, in comparison, subcu dara is a 3 to 5‑minute injection, so very convenient, very well‑tolerated.
The question being asked in this particular part of the study is, do we really need those steroids given that the risk of allergic reactions is so much lower? The eligibility were similar to the other dara studies. This is an open‑label, non‑randomized, multicenter phase 1b study.
Daratumumab is given at a fixed dose 1800 milligrams. It has the recombinant hyaluronidase, which allows this subcutaneous administration to be absorbed systemically, and the standard dosing schedule.
In terms of the steroid tapering, the 3‑week methylprednisolone is a typical premedication given for dara. Some of the patients got a 3‑week tapering schedule, where they got the 100 milligrams per dose one, 60 milligrams on day 8, and 30 milligrams on day 15, with the post‑dose medications of 2 days on week 1, 1 day each on the subsequent 2 weeks.
A second group of patients had a 2‑week tapering, where they got 100 milligrams in the first week and 60 milligrams in second week with, again, 20 milligrams post‑dose day 1 for 2 days, and for cycle 1 day 8, 1 day. Basically, the steroid tapering effect. There was a 2+2 design. The DLT was for this 3‑ and 2‑week tapering period with the DLT definition being IRR.
What we found in this study, the patient population was similar to other studies in terms of prior lines of therapy, age, etc. 30 patients were enrolled. 15 in the 3‑week taper, 15 in the 2‑week taper, with the median of 2 prior lines of therapy and about 40% refractory to PI and an IMID.
The duration follow‑up was 7.7 months, and 5.6 months for the 3‑week and 2‑week taper respectively. The median number of doses ranged from 14 to 12 for 3‑week and 2‑week respectively.
In terms of the safety, the grade 3 and 4 treatment‑emergent adverse events was in eight patients, 53%. They were the typical, what we see with dara in terms of infection, fatigue, nausea. Importantly, with respect to the IRRs, there were no IRRs reported in the 3‑week group.
In the 2‑week group, there was 3 patients, which is 20%, all occurring in the first dose. That was a pyrexia, sore throat, and increased blood pressure. All of those were grade 1, except the blood pressure that was grade 3. There was also chills grade 2 and tachycardia grade 1. The median time to IRR was 65 minutes.
The efficacy was what we expect in terms of VGPR or better rate was 32%. The overall response rate was 52%, so comparable or even more favorable. The median duration of response was not reached.
The conclusion here is that in 30 relapsed/refractory myeloma patients, the methylprednisolone can be tapered quickly over 3 weeks and as well as 2 weeks without an increased rate of infusion‑related reactions.
This will be particularly helpful in the future when daratumumab containing combination studies, such as perhaps T‑cell redirectors, also known as bispecific, CAR‑Ts, checkpoint inhibitors. All of those agents, the use of steroids can be contraindicated or decrease the efficacy of those drugs.
What we see here is that we can combine those safely with only a 2‑week taper. Actually, currently, 1‑week taper is also ongoing.