Meletios A. Dimopoulos, MD
An all-oral triplet therapy of ixazomib (Ninlaro), cyclophosphamide, and dexamethasone demonstrated promising early response rates in elderly patients with newly diagnosed multiple myeloma, according to phase II data presented at the 2015 ASH Annual Meeting.
Across all doses explored in the early study, the complete response (CR) or very good partial response (VGPR) rate was 26%. The overall response rate (ORR) with the triplet was 71%. The 12 month progression-free survival (PFS) rate was 80% and adverse events (AEs) were manageable.
"After a median follow up of only 9 cycle, any early overall response rate of 71% indicates that ixazomib, cyclophosphamide, and dexamethasone is an active, all-oral, IMiD [immunomodulatory agent]-free PI [proteasome inhibitor]-based combination in frontline, elderly multiple myeloma patients," said lead investigator Meletios A. Dimopoulos, MD, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece. "New responses are continuing to occur late in induction, and new VGPR occurring in maintenance suggests that increased responses may be expected as data mature."
In the study, 70 patients were randomized to receive ixazomib and dexamethasone with cyclophosphamide at 300 mg/m2
(ICd-300; n = 36) or 400 mg/m2
(ICd-400; n = 34). Ixazomib was given orally at 4 mg on days 1, 8, and 15 and dexamethasone was administered orally at 40 mg on days 1, 8, 15, and 22. For those over the age of 75 years, the steroid dose was reduced to 20 mg.
The median age of patients was 73 years. ISS stages were well balanced, with 62% of patients having stage II or III disease. The primary endpoint of the study was combined complete response (CR plus VGPR) during induction. Secondary endpoints included ORR, PFS, and safety.
The combined CR and VGPR rate was 28% in the ICd-300 arm and 21% for those treated with ICd-400. The ORR was 78% with ICd-300 and 65% with ICd-400. The CR rates were 10% and 9%, in the ICd-300 and 400 groups, respectively. The stable disease rate was 23%, across both doses.
After a median follow-up of 9.2 months, the 12-month PFS rate with ICd-300 was 68%. In the ICd-400 arm, the 12-month PFS rate was 91%. A ≥50% M-protein reduction was seen for 93% of patients treated with ICd-300 and in 76% of those receiving ICd-400.
All-grade AEs occurred in 92% of patients treated with ICd-300 and in 97% of those receiving ICd-400. Drug-related all-grade AEs occurred in 69% and 82% of patients, for the 300 and 400 mg/m2
doses, respectively. Additionally, higher incidences of serious AEs were seen with the larger dose of cyclophosphamide (39% vs 50%).
The most frequently reported all-grade gastrointestinal AEs with ICd-300 and 400, respectively, were diarrhea (22% and 15%), constipation (17% and 15%), vomiting (14% and 24%), and nausea (14% and 24%). More patients in the ICd-400 arm required anti-emetic therapy compared with the lower dose (39% vs 50%).
The most frequently reported grade ≥3 hematologic AEs with the 300 and 400 doses, respectively, were neutropenia (14% vs 35%), anemia (11% vs 15%), and thrombocytopenia (3% vs 10%). G-CSF therapy was required for 53% of patients in the ICd-400 arm versus 11% in the ICd-300 group.
The most common non-hematologic AEs were peripheral neuropathy, fatigue, and pneumonia. All-grade rash occurred in 25% of patients treated with ICd-300 and for 21% of those in the ICd-400 arm. Grade ≥3 cardiac events were seen in 8% and 9% of patients, in the 300 and 400 groups, respectively. There were no occurrences of cardiac failure.
"Toxicity, including myelosuppression, was manageable and in line with previous ixazomib studies," said Dimopoulos. "Toxicity appeared higher in the ICd-400 arm, and ICd-300 may be preferable for elderly patients."
On November 20, 2015, the FDA approved a triplet regimen of ixazomib, lenalidomide (Revlimid), and dexamethasone, based on data from the TOURMALINE-MM1 trial. In this phase III study, the median PFS was 20.6 months with ixazomib plus lenalidomide and dexamethasone compared with 14.7 months for lenalidomide and dexamethasone alone.
In addition to the MM1 study, the TOURMALINE clinical trial program contains four other phase III studies. In the MM2 trial, the combination of ixazomib, lenalidomide, and dexamethasone is being explored in newly diagnosed patients with multiple myeloma. The MM3 and MM4 studies are investigating maintenance therapy with ixazomib in patients who have or have not undergone an autologous stem cell transplant.
Dimopoulos MA, Grosicki S, Jedrzejczak WW, et al. Randomized Phase 2 Study of the All-Oral Combination of Investigational Proteasome Inhibitor (PI) Ixazomib Plus Cyclophosphamide and Low-Dose Dexamethasone (ICd) in Patients (Pts) with Newly Diagnosed Multiple Myeloma (NDMM) Who Are Transplant-Ineligible (NCT02046070). Presented at: 57th American Society of Hematology Annual Meeting; Orlando, Florida; December 5-8, 2015. Abstract 26.
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