Ixazomib Combo Exhibited Less Toxicity in Non-Transplant Eligible, Intermediate-Fit Newly Diagnosed Multiple Myeloma

The phase 2 HOVON 143 study (EudraCT 2016-002600-90) demonstrated that patients who are non-transplant eligible and intermediate-fit and are newly diagnosed with multiple myeloma (NDMM) derive benefit from the combination of ixazomib (Ninlaro), daratumumab (Darzalex), and low-dose dexamethasone with an objective response rate (ORR) of 71%, according to a presentation from the 2021 American Society of Hematology Annual Meeting.¹

In the single-arm study, which was designed to explore the potential for a less-toxic regimen for intermediate-fit patients with NDMM, there were clinically significant improvements seen in global health status, role functioning, and future perspective from baseline to the end of the induction regimen; however, there was also a worsening of clinically significant polyneuropathy. Overall, 46% of patients did not proceed to maintenance therapy after induction, primarily due to progressive disease (63%) and toxicity (13%).

“We think that maybe it is important to combine immune therapy with IMiDs [immunomodulatory drugs], and maybe look into whether T cell-directed therapy is feasible in intermediate patients," lead author Kaz Groen, MD, of Amsterdam UMC, Vrije Universiteit Amsterdam, Cancer Center Amsterdam, said during a presentation of the results. “It's important to keep in mind that we need agents with less toxicity, especially neurotoxicity. Low-grade neurotoxicity is what commonly leads to discontinuation of treatment.”

International Myeloma Working Group Frailty Index (IMWF-FI) intermediate-fit patients comprise one-third of new diagnoses of non-transplant eligible multiple myeloma. When compared with fit patients, intermediate fitness is associated with inferior overall survival (OS) and higher treatment discontinuation due to toxicity, which prompted the conduct of the trial, Groen noted.²

In the phase 2 HOVON 143 study, 65 patients with NDMM were treated with ixazomib, daratumumab, and dexamethasone in nine 4-week induction cycles. For the study, ixazomib was administered at 4 mg on days 1, 8, and 15 along with 16-mg/kg of daratumumab on days 1, 8, 15, and 22 of cycles 1 and 2, days 1 and 15 of cycles 3 to 6, and then on day 1 only for cycles 7 to 9. Additionally, patients received dexamethasone on the same days as daratumumab at 20 mg for cycles 1 and 2 followed by 10 mg for cycles 3 to 9. Following induction, maintenance therapy consisted of ixazomib at 4 mg on days 1, 8, 15, 29, 36, and 43 of an 8-week cycle along with daratumumab at 16 mg/kg and dexamethasone at 10 mg on day 1 for up to 2 years. Prophylactic cotrimoxazole and valaciclovir were also administered, to avoid infections.

“After induction, just over half of patients received maintenance. This was mostly due to progressive disease in two-thirds of cases but also partially to toxicity or noncompliance,” said Groen. “Seven patients, or 11%, discontinued ixazomib alone during treatment, which means they were only treated with daratumumab and dexamethasone.”

The median age of patients enrolled was 76 years (range, 65-80), with most being between 76 and 80 years of age (57%). The most common World Health Organization performance status was 0 (38%) and 1 (43%). At baseline, all patients had an activity of daily living (ADL) score of 5 or greater. Most patients had an instrumental ADL (IADL) score of 6 or greater at baseline; however, there were 14% of patients with a score 5 or lower. The Charlson Comorbidity Index (CCI) was at least 2 for 29% of patients enrolled in the study.

Most patients had International Staging System (ISS) stage II disease (57%), with 18% having stage III and 25% having stage I. By the revised criteria, stage II jumped to 75%, with 5% having stage III, 15% stage I, and 5% unknown. Fourteen percent of patients had high-risk cytogenetic disease and lactate dehydrogenase was normal in 94% of patients.

The ORR of 71% consisted primarily of very good partial responses (23 patients; 35%) and partial responses (22 patients; 34%). There was 1 complete response (2%). In addition to ORR, there was a minimal response in 17% of patients and stable disease in 11%. One patient was not evaluable.

At a median follow up of 18.1 months (range, 9.4-27.8 months), the median progression-free survival (PFS) was 17.4 months. There was no difference in PFS for those deemed less likely to be fit because of age or due to CCI/IADL, Groen noted. The median PFS for those deemed to have intermediate fitness due to age was 16.6 months. The median PFS was 18.2 months for those who were categorized due to CCI/IADL score.

The median OS was not yet reached. There had been 8 deaths at the time of the analysis, due to relapse (n = 3) and non-relapse mortality (n = 5), which included 2 sudden deaths, 1 case of mesothelioma, and 2 of unknown causes. The median event-free survival was 5.3 months. The most common events were non-hematologic adverse events of grade 3/4 (59%) followed by progressive disease (31%).

Hematologic adverse events (AEs) were most commonly grade 2/3 in severity, with grade 3/4 events consisting of anemia (3%), thrombocytopenia (5%), and neutropenia (6%). Overall, 51% of patients experienced a grade 3/4 non-hematologic AE with the combination. The most common grade ≥2 non-hematologic AEs were gastrointestinal events (36%) and infections (37%). All-grade peripheral neuropathy was experienced by 41% of patients (18% with grade 1, 15% with grade 2, and 8% with grade 3).

References

1. Groen K, Stege CAM, Nasserinejad K, et al. Ixazomib, daratumumab and low dose dexamethasone in intermediate-fit patients with newly diagnosed multiple myeloma (NDMM); results of induction treatment of the phase II HOVON 143 study. Presented at: 2021 ASH Annual Meeting and Exposition; December 11-14, 2021; Atlanta, GA. Abstract 80.

2. Palumbo A, Bringhen S, Mateos M-V, et al. Geriatric assessment predicts survival and toxicities in elderly myeloma patients: an International Myeloma Working Group report. Blood. 2015;125 (13): 2068–2074. doi:10.1182/blood-2014-12