Ixazomib-Based Regimens Expand Options in Relapsed/Refractory Multiple Myeloma

The inclusion of ixazomib (Ninlaro)–containing regimens in the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for multiple myeloma has allowed for better treatment personalization in the relapsed/refractory setting due to the oral administration of the agent and its differentiated toxicity profile, according to Andrew Yee, MD, and Krina Patel, MD, MSc.

“Ultimately in multiple myeloma, we have a good problem of having so many options to choose from. When I think about these different options, there’s a lid for every pot,” Yee noted.

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. 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, the experts discussed the latest updates to the NCCN guidelines in multiple myeloma and data updates with proteasome inhibitor (PI)–based regimens in the second- and third-line settings.¹

What have been the notable recent updates to the NCCN guidelines in multiple myeloma?

The moderators began their discussion by reviewing the NCCN Clinical Practice Guidelines in Oncology for multiple myeloma.² They highlighted that in patients who are anti-CD38 refractory, ixazomib in combination with pomalidomide (Pomalyst) and dexamethasone is listed as a preferred treatment option following 2 prior lines of therapy, including an immunomodulatory drug (IMiD) and a PI. The triplet is also listed as a preferred regimen in lenalidomide (Revlimid)–refractory patients after 2 prior lines of therapy, including an IMiD and a PI. In both cases, eligible patients must have experienced disease progression on or within 60 days of the completion of their last therapy.

“[Ixazomib] has 2 key features,” Yee explained. “One, it’s an oral drug. In some patients, having oral drugs is a huge [advantage]; they don’t have to come into clinic as often. It [also] doesn't have that risk of peripheral neuropathy that bortezomib [Velcade] has and, unlike carfilzomib [Kyprolis], it doesn't have that risk of cardiac toxicity. For many patients, ixazomib [treatment] can provide the right balance of having the efficacy of a PI, but without the [adverse] effects [AEs] of peripheral neuropathy and…the potential risks of cardiac dysfunction and shortness of breath. There are specific patient segments where those are important priorities.”

Ixazomib plus pomalidomide and dexamethasone is also listed as a category 1 other recommended therapy in patients with relapsed/refractory disease following 1 to 3 prior lines of treatment. Additionally, ixazomib plus cyclophosphamide and dexamethasone is categorized as another recommended regimen in the same disease setting.

“I don’t believe that every patient [should] get these therapies, but there’s a population [for whom these regimens] can help to keep them on their treatments,” Patel commented. “If patients can’t stay on their treatments, then their myeloma becomes more refractory [and] they get more tumor burden.”

What are the latest updates in oral PI-based therapies in the second- and third-line settings?

After reviewing the notable updates to the NCCN guidelines, the moderators shifted their discussion to focus on data from the phase 2 Alliance A061202 (NCT02004275) and IFM 2014-01 (NCT03683277) trials.

Alliance A061202 evaluated pomalidomide and dexamethasone with or without ixazomib for the treatment of patients with PI-sensitive or naive multiple myeloma.³ Patients were required to have received at least 2 prior lines of therapy, an ECOG performance status of 0 to 2, and adequate organ and hematologic function. The primary end point was progression-free survival (PFS); overall survival (OS), overall response rate (ORR), and safety were evaluated as secondary end points.

Findings from Alliance A061202 revealed that patients who received the triplet (n = 38) experienced a median PFS of 20.3 months compared with 7.5 months among patients who received only pomalidomide and dexamethasone (n = 39; HR, 0.437). The 2-year OS rates were 78.6% (95% CI, 66.2%-92.8%) and 79.5% (95% CI, 67.8%-93.2%), respectively (HR, 0.774; 95% CI, 0.33-1.80). The respective ORRs were 63.2% and 43.6%.

Notably, ixazomib plus pomalidomide and dexamethasone conferred a PFS benefit in both patients with standard- and high-risk disease. Specifically, patients with high-risk disease who received the triplet experienced an over 48% reduction in the risk of disease progression or death compared with those treated with only pomalidomide and dexamethasone (HR, 0.417; 95% CI, 0.17-1.06). A significant PFS benefit was also reported with the triplet compared with the doublet in patients with standard-risk disease (HR, 0.45; 95% CI, 0.21-0.99).

“With the triplet [vs the doublet], there was a bit more neutropenia. [Rates of] grade 3 [neutropenia] were 31.6% vs 15.4%, [respectively], and then 5.3% vs 2.6% [for grade 4, respectively],” Patel noted.

IFM 2014-01 was a single-arm study that evaluated ixazomib plus pomalidomide and dexamethasone in patients with relapsed/refractory multiple myeloma harboring high-risk cytogenetic features.⁴ The primary end point was time to progression (TTP). Secondary end points included PFS, OS, ORR, and safety.

Findings from IFM 2014-01 showed that the median TTP among patients who received ixazomib plus pomalidomide and dexamethasone (n = 26) was 10.5 months (95% CI, 7.9-not estimable [NE]). The median OS was NE (95% CI, 27.1-NE).

“Patients who had both deletion 17p [del(17p)] and t(4;14) didn’t do as well as those that had t(4;14) or del(17p) by itself,” Patel said. “[However], these patients, in general, were able to continue on therapy as long as they were responding.”

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. NCCN. Clinical Practice Guidelines in Oncology. Multiple myeloma, version 5.2026. Accessed January 26, 2026. https://www.nccn.org/professionals/physician_gls/pdf/myeloma.pdf
3. Vorhees P, Suman V, Efebera Y, et al. Alliance A061202: ixazomib, pomalidomide, and dexamethasone for patients with lenalidomide-refractory MM in first relapse. Blood Adv. 2024;8(19):5039-5050. doi:10.1182/bloodadvances.2024013623
4. Bobin A, Manier S, De Keizer J, et al. Ixazomib, pomalidomide and dexamethasone in relapsed or refractory multiple myeloma characterized with highrisk cytogenetics: the IFM 2014-01 study. Haematologica. 2025;110(3):758-763. doi:10.3324/haematol.2024.285916