Oral Ixazomib, Lenalidomide, and Dexamethasone for Multiple Myeloma
Article summary written by Patrick Brooks, PharmD, Medical Director, Oncology
Ixazomib, an orally administered peptide boronic acid proteasome inhibitor (PI), was approved by the Food and Drug Administration (FDA) in November 20151 in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma (MM) who have received at least one prior therapy.2 In April 2016, results from a phase 3 randomized, double-blind, placebo-controlled study (TOURMALINE-MM1) were published in The New England Journal of Medicine, which investigated the efficacy and safety of ixazomib, lenalidomide, and dexamethasone (IRd) versus placebo, lenalidomide, and dexamethasone (Rd).
Patients were eligible for enrollment if they had:
- Relapsed, refractory, or relapsed and refractory multiple myeloma (RRMM) with measurable levels of disease, even by serum free light chain assay only;
- Eastern Cooperative Oncology Group (ECOG) performance status score of zero to two;
- Receipt of one to three prior therapies; and
- Adequate hematologic and hepatic function
Patients with a creatinine clearance ≥30 mL/min were permitted. Criteria excluding patients from the study included grade 1 peripheral neuropath (PN) with pain, ≥ grade 2 PN, or disease refractory to prior lenalidomide- or PI-based therapy; however, patients with primary refractory disease were permitted.
Patients were randomized 1:1 to ixazomib 4 mg orally (PO) (n=360) or matching placebo (n=362) on days 1, 8 and 15 of 28-day cycles, plus lenalidomide 25 mg PO on days 1 through 21, and dexamethasone 40 mg PO on days 1, 8, 15 and 22. Patients received treatment until disease progression or unacceptable toxicity, and thromboprophylaxis was required of all patients. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS) in the intention-to-treat population, survival in patients with high-risk cytogenetic abnormalities [del(17p), t(4;14), or t(14;16)], overall response rate (ORR), change in global health status, and safety.
At a median follow-up of 14.8 months, the median PFS was 20.6 months versus 14.7 months in the IRd and Rd groups, respectively (HR 0.74; 95% CI: 0.59, 0.94; P=.01). The PFS benefit with IRd was experienced in all key pre-specified patient subgroups, including age >75 years (HR 0.87), International Staging System (ISS) stage 3 (HR 0.72), high-risk cytogenetics (HR 0.54), and two (HR 0.75) or three (HR 0.37) prior therapies. The ORR was 78.3% in patients who received IRd, compared to 71.5% in patients who received placebo (P=.04). At a median follow-up of 23 months, the median OS had not been reached in either group (81 deaths in the IRd group and 90 deaths in the Rd group).
The rates of adverse events (AEs) at the 23-month analysis were similar in each treatment arm, with the rate of serious adverse events (SAEs) being 47% and 49% in the IRd and Rd groups, respectively. Of the patients treated, 17% discontinued treatment with IRd due to the study regimen, compared to 14% in the placebo group. The most significant hematologic toxicity was thrombocytopenia, which was the only ≥ grade 3 AE for which there was ≥5% difference between treatment arms; grade 3 and grade 4 thrombocytopenia occurred in 12% and 7% of patients treated with IRd, compared to 5% and 4% of patients that received placebo, respectively.
The most significant non-hematologic AEs were gastrointestinal (GI) events and rash. The incidence of diarrhea was 45% and 39% of patients treated with IRd and Rd, respectively. GI events occurred primarily in the first three months, but were low-grade and manageable with supportive care, which included antidiarrheal medications and dose-adjustment of ixazomib or lenalidomide. Rash, which occurred in 36% and 23% of patients treated with IRd and placebo, respectively, also occurred primarily in the first three months. Of the patients who experienced rash, 21% and 12% in the IRd and placebo groups, respectively, reported resolution of rash without any intervention. For those patients who required intervention, the use of antihistamines, topical glucocorticoids, and dose-adjustment of study drugs effectively managed rashes.
The incidence of PN and PN with pain was 27% and 4%, respectively, in patients treated with IRD, compared to 22% and 3% in the placebo group. The rate of grade 3 PN was 2% in both treatment arms, and no grade 4 or 5 PN events occurred. With respect to cardiovascular events for patients who received IRd versus Rd, there were no significant differences in the rates of heart failure (4% in both groups), arrhythmias (16% vs. 15%), hypertension (6% vs. 5%), or myocardial infarction (1% vs. 2%). There was no difference between treatment arms with respect to global health status via the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire-Core 30 module (EORTC QLQ-C30) and the myeloma-specific module (EORTC QLQ-MY20), demonstrating a sustained quality of life with the addition of ixazomib.
Ixazomib, in combination with lenalidomide and dexamethasone, demonstrated a PFS benefit and higher response rates, compared to lenalidomide and dexamethasone in patients with RRMM. The addition of ixazomib to the two-drug standard regimen resulted in limited increase in toxicities, with thrombocytopenia, GI effects, and rash identified as the greatest concerns. A demonstrable efficacy across key subgroups is important to note, including high-risk cytogenetics irrespective of positivity cut-offs [eg, 20% or 60% del(17p)-positive],3 and IRd may be a preferred regimen in elderly patients with rapid clinical relapse, where an oral regimen is preferred.4 However, the convenience of an all-oral regimen must be weighed against the risk of patient nonadherence; thus providers should appropriately assess a patient’s current and historical adherence to therapy.
Journal Club Article - Moreau P, Masszi T, Grzasko N, et al. Oral Ixazomib, Lenalidomide, and Dexamethasone for Multiple Myeloma. N Engl J Med. 2016;374(17):1621-1634.
- Food and Drug Administration. FDA approves Ninlaro, new oral medication to treat multiple myeloma. November 20, 2015. Accessed on August 22, 2016.
- Ninlaro® [prescribing information]. Cambridge, MA: Takeda Pharmaceutical Company Limited; 2015.
- Richardson PG, Avet-Loiseau H, Palumbo A, et al. Efficacy and safety of ixazomib plus lenalidomide-dexamethasone (IRd) vs placebo-rd in patients (pts) with relapsed/refractory multiple myeloma (RRMM) by cytogenetic risk status in the global phase III Tourmaline-MM1 study. J Clin Oncol. 2016;34:(suppl; abstr 8018).
- Usmani SZ, Lonial S. Novel drug combinations for the management of relapsed/refractory multiple myeloma. Clin Lymphoma Myeloma Leuk. 2014;14 Suppl:S71-7.