Ixazomib Regimen Induces High Response Rates, Proves Tolerable in Relapsed/Refractory Multiple Myeloma

Article

The addition of ixazomib to daratumumab, pomalidomide, and dexamethasone has elicited deep and durable response rates with a manageable safety profile as salvage therapy in patients with relapsed/refractory multiple myeloma.

Caitlin L. Costello, MD

Caitlin L. Costello, MD

The addition of ixazomib (Ninlaro) to daratumumab (Darzalex), pomalidomide (Pomalyst), and dexamethasone has elicited deep and durable response rates with a manageable safety profile as salvage therapy in patients with relapsed/refractory multiple myeloma, according to interim findings from stage 2 of a phase 2 trial (NCT03590652) that were presented at the 19th International Myeloma Society Annual Meeting.

As of May 2022, the overall response rate (ORR) was 83% (n = 25) in 30 patients evaluable for response, with 57% achieving a very good partial response (VGPR) or better. Specifically, 20% achieved stringent complete response (CR), 13% achieved CR, and 23% achieved VGPR. Additionally, 27% of patients achieved partial response and 13% achieved stable disease. One (3%) patient had progressive disease (PD).

“The addition of ixazomib to [daratumumab, pomalidomide, and dexamethasone] shows improved ORR and a manageable toxicity profile with a nearly all oral regimen,” Caitlin L. Costello, MD, an associate clinical professor of medicine in the Department of Medicine, Division of Blood and Marrow Transplantation, at Moores Cancer Center, University of California San Diego, said in a presentation of the data.

“The high ORR is particularly compelling for high-risk disease, as more than half of the patients treated to date had at least 1 high risk feature, offering a promising option for the management of early relapse in high-risk patients,” she added.

In previous findings from the phase 3 APOLLO trial (NCT03180736), the triplet combination of daratumumab, pomalidomide demonstrated a 69% ORR and a median progression-free survival (PFS) of 12.4 months in patients with relapsed/refractory multiple myeloma. Additionally, investigations have begun with quadruplet regimens in newly diagnosed multiple myeloma and may provide a benefit in the early relapse setting, as well.

This prospective, open-label, multicenter, single-arm trial is evaluating the efficacy and safety of adding ixazomib to daratumumab, pomalidomide, and dexamethasone in patients with early relapsed/refractory multiple myeloma.

Investigators used a Simon’s optimal 2-stage design, enrolling 6 initial patients to the safety run-in and added 8 patients to complete stage 1. Stage 2 is ongoing and has recruited 22 of the planned 32 patients.

The first 6 patients enrolled to the safety run-in received intravenous daratumumab at 16 mg/kg weekly for 8 doses, then biweekly for 8 doses, then monthly. They also received 4 mg of oral pomalidomide on days 1 to 21 of a 28-day cycle; 4 mg of oral ixazomib on days 1, 8, and 15 of a 28-day cycle; and 20 mg to 40 mg of dexamethasone weekly.

All patients in the safety run-in experienced grade 3/4 neutropenia, leading investigators to reduce the doses of both ixazomib and pomalidomide to 3 mg. Subcutaneous daratumumab at 1800 mg was permitted per an amendment.

Patients are eligible for the trial if they have relapsed/refractory multiple myeloma, an ECOG performance status of 0 to 2, and have received 1 to 3 prior lines of therapy. Patients are excluded if they have previously progressed on pomalidomide or have prior exposure to ixazomib or daratumumab.

The primary end points of this trial are ORR, efficacy, and safety. Secondary end points include PFS, overall survival (OS), and minimal residual disease (MRD)–negativity rate. MRD assessments are ongoing for patients in suspected CR.

As of May 2022, 14 patients were treated in stage 1 of the trial, and 18 patients were treated in stage 2, for a total of 32 treated patients. The median age was 61.5 years (range, 41-87), 50% were female, and 72% were white. Patients had received a median of 1 prior line of therapy (range, 1-3), and 52% (n = 12) had high-risk cytogenetic features, including 17p deletion (35%; n = 8), 1q gain (30%; n = 7), or translocations t(14;16) (17%; n = 4), t(14;20) (4%; n = 1), or t(4;14) (17%; n = 4).

The median time on treatment was 4.8 months (range, 0.4-30.8). Fourteen patients remain on the quadruplet regimen.

Of the 25 patients who responded, plus the 1 patient with PD, the median OS was 38.9 months (95% CI, ≥18.8), and the median PFS was 9.5 months (95% CI, ≥6.04). The median time to response was 1 month.

Investigators performed flow cytometric analysis and cytometry by time of flight analysis on peripheral blood and bone marrow at baseline and during treatment at day 15 of cycle 2 to evaluate pharmacodynamic changes. The immunophenotypic changes in patients treated with the quadruplet were consistent with previously reported data on immune changes with daratumumab, pomalidomide, and dexamethasone, even with added immunosuppression from ixazomib.

These analyses showed an increase in proliferating or acting cytotoxic T cells; a decrease in natural killer (NK) cells, with a general shift toward proliferating or activating NK and NK-T cells; an increase in monocytes; and a decrease in plasmacytoid dendritic cells, with a shift toward classical dendritic cells.

The most common grade 3/4 treatment-related adverse effects (TRAEs) included neutropenia (grade 3, 28%; grade 4, 38%), thrombocytopenia (grade 3, 6%; grade 4, 3%), electrolyte disturbance (grade 3, 3%; grade 4, 3%), respiratory conditions (grade 3, 6%; grade 4, 3%), and leukopenia (grade 3, 9%). Additionally, 22% and 3% of patients experienced grade 3 and 4 infections, respectively, including febrile neutropenia (grade 3 lung infection, 3%; grade 3 unspecified, 3%; grade 4 upper respiratory infection [URI], 4%), and other infections (grade 3 URI, 3%; grade 3 gastrointestinal infection, 6%; grade 3 urinary tract infection, 3%; and grade 3 meningitis, 3%). Other grade 3 TRAEs included infusion reactions (3%), thrombosis (3%), psychiatric conditions (3%), anemia (3%), and vascular access issues (3%). One patient experienced grade 5 febrile neutropenia in the form of a lung infection.

In all, 7 deaths have occurred, 4 from PD, 1 from sepsis, 1 from COVID-19, and 1 from unrelated surgical complications.

Reference

Kumar AD, Rosenberg A, Padilla M, et al. Phase II study of the combination of daratumumab, ixazomib, pomalidomide, and dexamethasone as salvage therapy for relapsed/refractory myeloma: stage 2 interim results. Presented at: 19th International Myeloma Society Annual Meeting. August 25-27, 2022. Los Angeles, CA. P-252

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