New England Journal of Medicine April 28, 2016

Oral Ixazomib, Lenalidomide, and Dexamethasone for Multiple Myeloma

Philippe Moreau, Tamás Masszi, Norbert Grzasko, Nizar J. Bahlis, et al.

Bottom Line

The addition of the oral proteasome inhibitor ixazomib to lenalidomide and dexamethasone significantly improved progression-free survival in patients with relapsed or refractory multiple myeloma, with limited additional toxicity.

Key Findings

1. The addition of ixazomib to lenalidomide and dexamethasone significantly prolonged median progression-free survival (PFS) to 20.6 months compared to 14.7 months in the placebo group (HR 0.74, 95% CI 0.59-0.94; P=0.01).

2. The overall response rate (ORR) was higher in the ixazomib group (78% vs. 72%), with a significantly greater proportion of patients achieving a very good partial response (VGPR) or better (48% vs. 39%).

3. The median time to response was faster in the ixazomib arm (1.1 months vs. 1.9 months), and the median duration of response was longer (20.5 months vs. 15.0 months).

4. At the time of publication (median follow-up of 23 months for overall survival), median overall survival (OS) had not been reached in either group.

5. Adverse events of grade 3 or higher occurred in 74% of the ixazomib group and 69% of the placebo group, with grade 3/4 thrombocytopenia (19% vs. 9%) and any-grade rash (36% vs. 23%) being more frequent with ixazomib.

6. The incidence of peripheral neuropathy was similar between the two groups (27% with ixazomib vs. 22% with placebo), with severe (grade 3) events occurring in just 2% of patients in both arms.

Study Design

Design

Phase 3 RCT

Double-Blind

Sample

722

Patients

Duration

14.7 mo

Median

Setting

Multicenter, global

Population Adult patients with relapsed, refractory, or relapsed and refractory multiple myeloma who had received 1 to 3 prior lines of therapy.

Intervention Ixazomib (4 mg orally on days 1, 8, and 15) plus lenalidomide (25 mg on days 1-21) and dexamethasone (40 mg on days 1, 8, 15, and 22) per 28-day cycle.

Comparator Placebo plus lenalidomide and dexamethasone per 28-day cycle.

Outcome Progression-free survival (PFS)

Study Limitations

• The trial excluded patients who were refractory to lenalidomide or proteasome inhibitors, limiting the applicability of these results for patients who have already progressed on these agents in the frontline setting.

• Overall survival data were immature at the time of the primary analysis, making it unclear if the progression-free survival advantage would translate into a long-term survival benefit.

• The addition of a third agent inevitably introduces slightly higher rates of certain toxicities, such as gastrointestinal events, rash, and thrombocytopenia, and increases the financial cost of therapy.

Clinical Significance

TOURMALINE-MM1 established ixazomib, lenalidomide, and dexamethasone (IRd) as a highly efficacious, all-oral triplet therapy for relapsed or refractory multiple myeloma. By extending progression-free survival with a manageable toxicity profile—specifically without dramatically increasing the burden of peripheral neuropathy compared to standard regimens—it provided a convenient and sustainable treatment option, which is particularly valuable for minimizing clinic visits and improving patient quality of life.

Historical Context

Historically, the treatment of relapsed or refractory multiple myeloma relied on doublet regimens or triplets requiring parenteral administration, such as intravenous or subcutaneous bortezomib and carfilzomib. These treatments necessitated frequent clinic visits, adding significant logistical burden. The development of ixazomib, the first oral proteasome inhibitor, offered a way to deliver continuous proteasome inhibition while shifting the paradigm toward an entirely oral, outpatient regimen when combined with lenalidomide and dexamethasone.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

Ixazomib is an oral proteasome inhibitor used in combination with lenalidomide. What is the mechanistic rationale for combining a proteasome inhibitor with an immunomodulatory imide drug (IMiD) in multiple myeloma, and how does proteasome inhibition specifically trigger apoptosis in myeloma cells?

Key Response

Proteasome inhibitors block the degradation of ubiquitinated proteins, leading to the accumulation of misfolded proteins and fatal endoplasmic reticulum (ER) stress. They also prevent the degradation of I-kappa-B, thereby keeping the survival factor NF-kappa-B inactive. IMiDs like lenalidomide bind cereblon to promote the ubiquitination and degradation of transcription factors Ikaros and Aiolos. Combining them synergistically disrupts protein homeostasis and dual survival signaling pathways in myeloma cells.

Resident

The TOURMALINE-MM1 trial demonstrated an improvement in progression-free survival with the addition of ixazomib to lenalidomide and dexamethasone (IRd). Given that bortezomib is another commonly used proteasome inhibitor, what are the primary differences in the toxicity profiles and route of administration between ixazomib and bortezomib that might influence your choice in a relapsed/refractory patient?

Key Response

Ixazomib is administered orally, offering a highly convenient all-oral triplet regimen (IRd). Bortezomib is given subcutaneously or intravenously and is notoriously associated with high rates of dose-limiting peripheral neuropathy. Ixazomib has a significantly lower rate of severe peripheral neuropathy, making it an excellent choice for patients with pre-existing neuropathy or those who cannot tolerate frequent clinic visits.

Fellow

In the TOURMALINE-MM1 trial, how did the IRd regimen perform in patients with high-risk cytogenetics (such as del(17p), t(4;14), or t(14;16)) compared to standard-risk patients, and how does this influence your sequencing of PI-based versus anti-CD38-based triplets in early relapse?

Key Response

The trial demonstrated that the progression-free survival benefit of ixazomib was maintained across predefined subgroups, importantly including patients with high-risk cytogenetics. In fact, the addition of ixazomib partially overcame the poor prognosis associated with these mutations, yielding a hazard ratio similar to standard-risk patients. Fellows must weigh this data against emerging data from monoclonal antibodies (like daratumumab in the POLLUX trial) to decide on optimal sequencing, often reserving IRd for high-risk patients who prioritize oral therapy or have specific baseline toxicities.

Attending

While the TOURMALINE-MM1 trial established the efficacy of the IRd triplet, real-world application often involves frail, older adults. How does the availability of an all-oral triplet regimen change our paradigm for prolonged, continuous therapy in relapsed/refractory multiple myeloma, and what are the primary pitfalls in managing adherence and toxicity outside a strict trial setting?

Key Response

An all-oral regimen shifts the burden of care from the infusion center to the patient's home, drastically improving quality of life and facilitating prolonged, continuous therapy, which is critical for maintaining remission in myeloma. However, it requires rigorous outpatient monitoring for GI toxicity, rash, and thrombocytopenia, as well as strict adherence assessments, since missed oral doses or unmanaged low-grade toxicities directly compromise the triplet's synergistic efficacy.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The TOURMALINE-MM1 study utilized progression-free survival (PFS) as its primary endpoint rather than overall survival (OS). In the context of relapsed/refractory multiple myeloma trials with long post-progression survival and multiple subsequent lines of therapy, what are the statistical advantages of using PFS, and how does the double-blind, placebo-controlled design strengthen these findings compared to open-label trials?

Key Response

PFS is not confounded by subsequent lines of therapy, allowing for a faster, cleaner readout of a drug's direct effect, which is critical in myeloma where OS can take years to mature. The double-blind placebo design (which was uniquely feasible because all drugs in the regimen are oral) eliminates investigator bias in assessing disease progression, which can sometimes be a subjective radiological or biochemical call, offering a significant methodological advantage over open-label parenteral versus oral trials.

Journal Editor

As a peer reviewer analyzing the TOURMALINE-MM1 manuscript, what specific concerns might you raise regarding the choice of the control arm (Rd alone) given the rapid evolution of standard-of-care at the time of study enrollment, and how might informative censoring rules for patients who discontinued treatment due to toxicity bias the PFS estimation?

Key Response

A critical reviewer would note that while Rd was an acceptable control when the study was designed, triplet therapies (like VRd or KRd) were rapidly becoming the standard of care for early relapse, making a doublet control arm less reflective of contemporary optimal practice. Furthermore, if the experimental arm has higher early toxicity leading to asymmetrical dropout, informative censoring could artificially inflate the PFS if not handled with rigorous statistical sensitivity analyses.

Guideline Committee

Based on the TOURMALINE-MM1 data, how should the IRd regimen be positioned within current NCCN or IMWG guidelines for relapsed/refractory multiple myeloma, and what level of evidence supports its specific recommendation over other lenalidomide-based triplets (such as KRd or DRd) for specific patient phenotypes?

Key Response

IRd is incorporated into NCCN and IMWG guidelines as a Category 1 preferred regimen for patients with 1-3 prior lines of therapy. The committee must position it alongside other highly efficacious triplets like carfilzomib/Rd (KRd) or daratumumab/Rd (DRd). While cross-trial comparisons often show deeper responses with DRd or KRd, IRd is specifically recommended with high-level evidence for patients who require or strongly prefer an all-oral regimen, live far from infusion centers, or have pre-existing cardiovascular risks or neuropathy that preclude carfilzomib or bortezomib use.

Clinical Landscape

Noteworthy Related Trials

2015

ASPIRE Trial

n = 792 · NEJM

Tested

Carfilzomib, lenalidomide, and dexamethasone

Population

Relapsed/refractory multiple myeloma patients

Comparator

Lenalidomide and dexamethasone

Endpoint

Progression-free survival (PFS)

Key result: The addition of carfilzomib to lenalidomide and dexamethasone significantly prolonged progression-free survival (26.3 months vs. 17.6 months) and improved overall response rates.

2015

ELOQUENT-2 Trial

n = 646 · NEJM

Tested

Elotuzumab, lenalidomide, and dexamethasone

Population

Relapsed/refractory multiple myeloma patients

Comparator

Lenalidomide and dexamethasone

Endpoint

Progression-free survival (PFS) and overall response rate (ORR)

Key result: Adding elotuzumab to lenalidomide and dexamethasone provided a significant and clinically meaningful improvement in progression-free survival compared to doublet therapy.

2016

POLLUX Trial

n = 569 · NEJM

Tested

Daratumumab, lenalidomide, and dexamethasone

Population

Relapsed/refractory multiple myeloma patients

Comparator

Lenalidomide and dexamethasone

Endpoint

Progression-free survival (PFS)

Key result: Daratumumab combined with lenalidomide and dexamethasone significantly reduced the risk of disease progression or death by 63 percent compared to the control group.

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