In a phase I/IIa clinical trial, researchers, led by Kevin Kelly, MD, examined the safety, activity, and pharmacokinetics of indatuximab ravtansine when combined with immunomodulatory drugs in patients with relapsed or refractory multiple myeloma (MM). The study, published in The Lancet Haematology, reported that the combination therapy showed preliminary antitumor activity and was tolerated in the test population.
The open-label study took place at nine U.S. hospitals. Adults with relapsed or refractory MM and Eastern Cooperative Oncology Group (ECOG) performance status or Zubrod score of 2 or below were eligible for enrollment. Patients who received the lenalidomide-containing regimen had failure of at least one previous therapy. Patients treated with the pomalidomide-containing regimen had failure of at least two previous therapies (including lenalidomide and bortezomib) and had progressive disease within 60 days of their last treatment.
In phase I, patients received indatuximab ravtansine intravenously on days one, eight, and 15 of each 28-day cycle in escalating dose levels, alongside lenalidomide and dexamethasone. In phase II, the recommended phase II dose of indatuximab ravtansine was given to an expanded cohort of patients in combination with lenalidomide and dexamethasone. The primary endpoint of phase I was determining the dose-limiting toxicities and the maximum tolerated dose of indatuximab ravtansine. The primary outcomes assessed in phase II were the objective response rate (ORR; defined as partial response or better) and clinical benefit response (ORR plus minor response). All patients were analyzed for safety and all patients with post-treatment response assessments were analyzed for activity.
Sixty-four patients were enrolled between July 3, 2012, and June 30, 2015. A total of 47 (73%) patients received the lenalidomide combination with a median follow-up of 24.2 months (interquartile range [IQR] 19.9-45.4), while 17 (27%) patients received the pomalidomide regimen with a median follow up of 24.1 months (17.7-36.7). The maximum tolerated dose of indatuximab ravtansine plus lenalidomide was 100 mg/m2, and informed the recommended phase II dose for indatuximab ravtansine plus pomalidomide.
The ORR in the indatuximab ravtansine plus lenalidomide group was71.7% and 70.6% in the indatuximab ravtansine plus pomalidomide group. The clinical benefit response rates were85% and 88%, respectively.
The most common grade III/IV adverse events in both groups were neutropenia (14 [22%] of 64 patients), anemia (10 [16%]), and thrombocytopenia (7 [11%]). Treatment-emergent adverse events that led to discontinuation occurred in 35 (55%) of the 64 patients. Five patients died during the study from causes unrelated to indatuximab ravtansine treatment.
The study’s authors posited that the indatuximab ravtansine and immunomodulatory drug regimens showed promising early results and suggested that the treatment “could be further evaluated in patients with relapsed or refractory MM.”