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Ixazomib maintenance after transplant extends PFS in newly diagnosed multiple myeloma
SAN DIEGO — Maintenance therapy with ixazomib significantly extended PFS compared with placebo among patients with newly diagnosed multiple myeloma who underwent autologous stem cell transplantation, according to results of the phase 3 Tourmaline-MM3 trial presented at ASH Annual Meeting and Exposition.
Maintenance with ixazomib (Ninlaro, Takeda) appeared associated with deeper responses and increased conversions to minimal residual disease negativity. The regimen also exhibited a favorable safety profile.
The findings support ixazomib as “a valuable option for maintenance therapy” for patients on response after autologous stem cell transplant, Meletios A. Dimopoulos, MD, chairman of the department of clinical therapeutics at National and Kapodistrian University of Athens School of Medicine, and colleagues wrote.
The potential of maintenance therapy to prolong disease control and extend survival after autologous stem cell transplant has been studied extensively. Lenalidomide (Revlimid, Celgene) is the only agent approved for this indication; however, lenalidomide maintenance has been associated with development of second primary malignancies, and tolerability issues also have emerged, according to study background.
Proteasome inhibitors such as bortezomib (Velcade, Takeda) are a standard backbone of myeloma treatment, and bortezomib-based maintenance regimens have demonstrated promising activity among patients who underwent autologous stem cell transplant.
However, no phase 3 trial has demonstrated a benefit of proteasome inhibitor-based maintenance compared with placebo. In addition, the clinical utility of maintenance bortezomib may be limited due to the need for regular parenteral administration and tolerability concerns, Dimopoulos and colleagues wrote.
“There is a need for an oral proteasome inhibitor maintenance therapy that can be administered for a prolonged period, improve depth of response without cumulative or late-onset toxicity, and improve convenience for patients,” Dimopoulos and colleagues wrote.
The double-blind, placebo-controlled Tourmaline-MM3 study compared weekly ixazomib maintenance with placebo among patients with newly diagnosed multiple myeloma.
The study included 656 patients (median age, 57 years; range, 24-73) who achieved at least a partial response to induction therapy with a proteasome inhibitor and/or an immunomodulatory drug followed by single autologous stem cell transplant. Eighteen percent of patients had high-risk cytogenetics, such as 17p deletion, t(4;14) translocation or t(14;16) translocation.
Researchers randomly assigned patients 3:2 to ixazomib (n = 395) or placebo (n = 261) on days 1, 8 and 15 of each 28-day cycle. Ixazomib was dosed at 3 mg during the first four cycles and, if tolerated, was increased to 4 mg starting in the fifth cycle.
Treatment continued for up to 2 years, or until disease progression or unacceptable toxicity.
Investigators stratified randomization by induction regimen — proteasome inhibitor without immunomodulatory drug (59%), immunomodulatory drug without proteasome inhibitor (11%), or both (30%) — as well as preinduction International Staging System stage (37% stage I vs. 63% stage II or stage III), and response after autologous stem cell transplant (34% complete response, 45% very good partial response and 21% partial response).
Patients who underwent tandem autologous stem cell transplant or received consolidation after autologous stem cell transplant were excluded.
PFS assessed by independent review committee served as the primary endpoint. OS served as a key secondary endpoint.
Median follow-up was 31 months.
Patients assigned ixazomib achieved significantly longer median PFS (26.5 months vs. 21.3 months; HR = 0.72; 95% CI, 0.58-0.89). A landmark analysis from the time of autologous stem cell transplant also showed a significant PFS benefit for ixazomib-treated patients (median, 30.7 months vs. 24.9 months; HR = 0.68; 95% CI, 0.55-0.84).
Researchers observed the PFS benefit across subgroups, including those with International Scoring System stage III disease (HR = 0.66), proteasome inhibitor-exposed patients (HR = 0.75), proteasome inhibitor-naive patients (HR = 0.49) and those with high-risk cytogenetics (HR = 0.62).
Median OS had not been reached in either treatment group.
Results showed ixazomib was associated with a significantly higher rate of deepened response (relative risk = 1.41; 95% CI, 1.1-1.8), as well as a higher rate of conversion from documented minimal residual disease positivity at study entry to minimal residual disease negativity (12% vs. 7%).
A similar percentage of patients assigned ixazomib and placebo discontinued treatment due to adverse events (7% vs. 5%).
A higher percentage of ixazomib-treated patients experienced grade 3 or higher adverse events (42% vs. 26%) or serious adverse events (27% vs. 20%). One patient assigned ixazomib died on treatment compared with none assigned placebo.
The most common grade 3 or higher adverse events that occurred at greater frequency in the ixazomib group included infections (15% vs. 8%), gastrointestinal disorders (6% vs. 1%), neutropenia (5% vs. 3%) and thrombocytopenia (5% vs. < 1%).
Rates of peripheral neuropathy (19% vs. 15%) and second primary malignancies (3% each) were similar between the ixazomib and placebo groups, as were quality of life scores as assessed by the EORTC QLQ-C30 questionnaire. – by Mark Leiser
Reference:
Dimopoulos MA, et al. Abstract 301. Presented at: ASH Annual Meeting and Exposition; Dec. 1-4, 2018; San Diego.
Disclosures : Dimopoulos reports honoraria from Amgen, Bristol-Myers Squibb, Celgene, Janssen and Takeda. Please see the abstract for all other authors’ relevant financial disclosures.