# Ibrutinib in Combination with Lenalidomide Revlimid/Dexamethasone in Relapsed/Refractory Multiple Myeloma (AFT-15)

## TL;DR

This study tested a new drug combination for treating relapsed or refractory multiple myeloma and found it to be well-tolerated with some clinical benefits.

## Contribution

The study evaluates the safety and efficacy of combining ibrutinib with lenalidomide and dexamethasone in relapsed/refractory multiple myeloma patients.

## Key findings

- The combination was well tolerated with manageable toxicities and one patient had stable disease for 4.6 years.
- The overall response rate was 15.4% and the clinical benefit rate was 61.5%.
- Five patients maintained stable disease for at least two cycles.

## Abstract

We conducted a 3 + 3 phase Ib trial to determine the tolerability and efficacy of Ibrutinib (IBR) in combination with lenalidomide (LEN) + dexamethasone (DEX) in patients with relapsed/refractory (RR) MM with at least one prior line of therapy. Thirteen patients were eligible for disease response. The median number of prior lines of therapy was 3 (2–9). Ten patients (76.9%) had an autologous stem cell transplant. All were exposed to an immunomodulatory drug (IMID; LEN [92.3%], pomalidomide [30.8%] or thalidomide [7.7%]) and a proteasome inhibitor (bortezomib [100%], carfilzomib [38.5%] or ixazomib [15.4%]). In total, 53.8% of patients were exposed to an anti-CD 38, and 7.7% were exposed to chimeric antigen receptor T cell therapy. The combination was well tolerated, with clinical activity seen. The overall response rate (partial response and better) was 15.4%. One patient maintained stable disease (SD) for 4.6 years. Five patients maintained SD for ≥2 cycles. The clinical benefit response (SD and better) was 61.5%. The all-oral combination of LEN with IBR was feasible and well tolerated, with evidence of clinical activity. Future directions for an all-oral combination with IBR and the accompanying real-world advantages include next-generation IMiDs such as pomalidomide, and the potent oral degraders in the CELMod category, specifically iberdomide and mezigdomide.

Background: Studies have suggested a synergism between lenalidomide (LEN) and ibrutinib (IBR) in multiple myeloma (MM). Both downregulate IRF4, a key target and master transcriptional factor regulating myeloma cell survival. Method: A 3 + 3 phase I trial was conducted to determine the maximum tolerated dose (MTD) of IBR in combination with LEN + dexamethasone (DEX) in patients with relapsed/refractory (RR) MM who had at least one prior line of therapy. Three dose levels (DLs) were planned. The cycle length was 28 days. IBR was administered orally daily in doses of 560 mg on DL1-2 and 840 mg on DL3, LEN was administered orally on days 1–21 in doses of 15 mg on DL1 and 25 mg on DL2-3, and DEX was administered orally on days 1, 8, 15, and 22 in a dose of 40 mg if age < 75 years or in a dose of 20 mg if it was ≥75 years for DL1-3. Patients with a glomerular filtration rate (GFR) <60 but ≥30 mL/min were treated in accordance with the manufacturer’s instructions with LEN 10 mg. Dose-limiting toxicities (DLTs) included the following: grade 4 neutropenia lasting more than 5 days, thrombocytopenia, febrile neutropenia, nausea, vomiting or diarrhea; grade 3 thrombocytopenia with bleeding or platelet transfusion; and grade 3–4 hyperglycemia or a thrombotic/embolic event, and other nonhematologic toxicities. The overall response rate (ORR) was defined as the percentage of patients with a partial response (PR), very good partial response (VGPR), or complete response (CR) according to IMWG criteria on two consecutive evaluations at least 4 weeks apart. The clinical benefit rate (CBR) was defined as the percentage of patients with stable disease (SD) or a better outcome on two consecutive evaluations at weeks apart. Results: Fourteen patients (DL1: six patients; DL2: three patients; DL3: five patients) were registered for the study from March 2019 to May 2023, prior to its closure due to limited accrual. Thirteen patients are included in the summary of toxicities and response as one patient on DL3 halted participation prior to the start of the treatment. Two patients on DL3 were excluded from the determination of MTD: one having discontinued cycle 1 treatment due to COVID-19 infection and the another having mistakenly taken 280 mg/day of IBR instead of the assigned 840 mg/day dose during cycle 1. Only one patient developed a DLT, on DL1 with grade 3 non-viral hepatitis. The median number of cycles administered was 4 (range: 1–56). Severe toxicities reported included grade 4 lymphocytopenia (1), grade 4 thrombocytopenia (1), and grade 5 sepsis in the setting of PD (1). Disease responses included a VGPR on DL1 and CR on DL3. Thus, the ORR was 15.4% (90% CI: 2.8–41.0%). One patient on DL1 maintained SD for 4.6 years before discontinuing the treatment to undergo an alternative therapy. Another five patients maintained SD for ≥ 2 consecutive cycles. Thus, the CBR was 61.5% (90% CI: 35.5–83.4%). Conclusions: The combination of LEN with IBR in RR MM proved feasible, with manageable toxicities and the majority of discontinuations being due to disease progression.