Ixazomib-Containing Combinations Signal Potential for More PI-Based Regimens in R/R Multiple Myeloma

The oral proteasome inhibitor (PI) ixazomib (Ninlaro) is gaining traction as a key component of combination regimens for the treatment of patients with relapsed/refractory multiple myeloma in multiple phase 2 studies, according to Andrew Yee, MD, and Krina Patel, MD, MSc.

Yee is the clinical director of the Center for Multiple Myeloma at Massachusetts General Hospital and an assistant professor of medicine at Harvard Medical School, in Boston, Massachusetts. Patel is an associate professor in the Department of Lymphoma/Myeloma, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center in Houston.

During an OncLive® Ask The Expert program on optimizing outcomes in relapsed multiple myeloma moderated by Yee and Patel, expert oncologists discussed the latest data with oral PI-based combinations in relapsed/refractory multiple myeloma, as well as future research directions with these agents.¹

What are the latest data with oral PI combinations in relapsed/refractory multiple myeloma?

The moderators highlighted data from 2 notable clinical trials with oral PIs in relapsed/refractory multiple myeloma: a phase 2 study (NCT03439293) of ixazomib plus daratumumab (Darzalex) and dexamethasone (IDd) in patients with relapsed/refractory multiple myeloma and the phase 2 I2D IFM2021_03 trial (NCT04998786) evaluating ixazomib plus iberdomide and dexamethasone (I2D) in elderly patients at first relapse.^2,3

The former phase 2 study enrolled patients who had not been previously exposed to ixazomib and daratumumab and had received 1 to 3 prior lines of therapy.² Patients also needed to have an ECOG performance status between 0 and 2, adequate hematologic and organ function, and have achieved at least a partial response (PR) to at least 1 prior line of treatment. The primary end point was very good PR (VGPR) or better rate; secondary end points included progression-free survival (PFS), duration of response (DOR), time to response, and safety.

Findings from the final analysis of the trial revealed that the VGPR or better rate was 30.5% (95% CI, 19.2%-43.9%), including a complete response (CR) rate of 13.6%, among efficacy-evaluable patients (n = 59). The overall response rate (ORR) was 64.4%. At a median follow-up of 30.9 months (95% CI, 27.9-33.8), the median time to progression was 21.1 months (95% CI, 10.2-27.9). The median overall survival (OS) was not reached (NR) at a median follow-up of 32.5 months (95% CI, 30.6-33.6).

Subgroup analysis data demonstrated that the ORRs among patients with high-risk cytogenetics (n = 15), expanded high-risk cytogenetics (n = 24), those 75 years old or older (n = 12), lenalidomide (Revlimid)–refractory (n = 21), and those who received a prior PI and/or immunomodulatory drug (n = 58) were 53.3%, 58.3%, 50.0%, 61.9%, and 65.5%, respectively. The respective VGPR rates were 16.9%, 13.3%, 12.5%, 8.3%, 9.5%, and 17.2%.

“[There were] responses across a range of different patient profiles,” Yee said. “[Additionally], the tolerability was favorable, as you would expect from the individual components.”

I2D IFM2021_03 evaluated the efficacy and safety of I2D in patients who were at least 70 years old and had received 1 prior line of therapy.³ Patients were required to be refractory to lenalidomide and/or anti-CD38 therapy, have an ECOG performance status between 0 and 2, have no higher than grade 2 peripheral neuropathy, and adequate hematologic and organ function. The study’s primary end point was ORR. Secondary end points included PFS, DOR, OS, and safety.

Findings from I2D IFM2021_03 showed that the median PFS among patients who received I2D (n = 70) was 13 months (95% CI, 8.2-NR) and the median OS was NR (95% CI, 78%-95%). The ORR was 64%, including VGPR and CR rates of 27% and 9%, respectively.

“We're starting to think about the next class [of] future myeloma therapies [such as] CELMoDs,” Yee explained. “There are several examples of CELMoDs, [including] iberdomide. I would have personally thought that there'd be a little bit more juice to this regimen. But bear in mind that this [study comprised] an older patient population.”

References

1. Ask the expert: optimizing outcomes in relapsed multiple myeloma: integrating guidelines, data, and real-world experience. OncLive. December 15, 2025. Accessed January 26, 2026.
2. Delimpasi S, Dimopoulos MA, Straub J, et al. Ixazomib plus daratumumab and dexamethasone: final analysis of a phase 2 study among patients with relapsed/refractory multiple myeloma. Am J Hematol. 2024;99(9):1746-1756. doi:10.1002/ajh.27382
3. Touzeau C, Leleu X, Tiab M, et al. Iberdomide, ixazomib and dexamethasone in elderly patients with multiple myeloma at first relapse. Br J Haematol. 2025;206(5):1366-1372. doi:10.1111/bjh.19978