Ibrutinib–dexamethasone combination effective in relapsed, refractory myeloma

NEW YORK — Ibrutinib plus dexamethasone induced durable responses in patients with heavily pretreated myeloma, according to results of a multicenter phase 2 study presented at Lymphoma & Myeloma 2015.

Outcomes for patients with myeloma have improved, but novel therapies with unique targets are needed to help patients who are refractory to or relapse after standard treatment regimens.

Paul G. Richardson

Prior research indicated Bruton’s tyrosine kinase is overexpressed in myeloma cells and may positively regulate myeloma stem cells, according to study background.

This suggests ibrutinib (Imbruvica; Pharmacyclics, Janssen) — a Bruton’s tyrosine kinase inhibitor that has been “a game changer” in chronic lymphocytic leukemia and also demonstrated effectiveness in Waldenstrom’s macroglobulinemia — could be a viable therapeutic option in myeloma, Paul G. Richardson, MD, clinical program leader and director of clinical research at Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute, said during a presentation.

“There is a strong rationale for why this may have activity,” said Richardson, a HemOnc Today Editorial Board member. “For myeloma, as we move into the next generation of novel agents, single-agent activity of drugs is no longer the norm. Rational, biologically informed combinations provides us with very key constructs for what we can do with therapies for our patients.”

Richardson and colleagues conducted the phase 2 trial to evaluate escalating doses of ibrutinib with or without low-dose dexamethasone in four cohorts of patients (n = 92) with relapsed or relapsed/refractory myeloma.

They presented preliminary findings at the ASH Annual Meeting and Exposition last year.

The current analysis report encompassed results from the expansion cohort, which included 43 patients (median age, 65 years) with relapsed or relapsed/refractory disease. Patients had undergone a median four prior therapies (range, 2-10), including an immunomodulatory agent.

“This was not a good-risk population,” Richardson said. “This population was heavily pretreated and had resistant disease. The majority, unfortunately, were losing benefit to either immunomodulatory or proteasome inhibitor-based therapy, or both.”

The most common immunomodulatory agents administered in prior therapy were lenalidomide (Revlimid, Celgene; 91%), thalidomide (Thalomid, Celgene; 58%) and pomalidomide (Pomalyst, Celgene; 30%).

Most patients (91%) had received bortezomib (Velcade, Millennium), whereas 33% had received carfilzomib (Kyprolis, Onyx) and 77% had undergone autologous stem cell transplantation. Seventy percent of patients were refractory to their last line of therapy.

Four patients (9%) had deletion 17p or translocation of chromosome 4 and 14.

All patients in the expansion cohort received ibrutinib 840 mg daily plus dexamethasone 40 mg weekly.

Clinical benefit rate, defined as minimal response or better, served as the primary endpoint. Secondary endpoints included safety and duration of clinical benefit.

Median follow-up was 10.1 months.

Researchers reported a 23% clinical benefit rate. This included two patients (5%) who achieved partial response and eight patients (19%) who achieved minimal response.

Median duration of clinical benefit was 8.3 months (range, 3-14.7) and median PFS was “striking” at 5.4 months, Richardson said. Twelve patients (28%) had stable disease after four or more treatment cycles.

Biomarker analyses are still ongoing.

Richardson and colleagues observed no clinically meaningful differences in tolerability between the four cohorts. Consequently, they pooled safety data for all 92 patients dosed in the study.

The safety profile of ibrutinib was consistent with what has been observed in CLL and Waldenstrom’s macroglobulinemia, and side effects generally were manageable, Richardson said.

The most common grade 3 to grade 4 hematologic adverse events were anemia (15%), thrombocytopenia (9%) and neutropenia (2%).

The most common grade 3 to grade 4 non-hematologic adverse events were pneumonia (7%), syncope (3%) and urinary tract infection (3%). Seven patients (8%) developed grade 1 to grade 2 peripheral sensory neuropathy.

Progressive disease was the most common reason for treatment discontinuation (56%). Nine percent of patients discontinued due to adverse events.

The observed activity and favorable safety profile of ibrutinib support further evaluation of the agent as part of combination treatment with other novel agents, Richardson said.

Two combination studies — one designed to assess ibrutinib plus carfilzomib and dexamethasone, and another designed to evaluate ibrutinib plus pomalidomide and dexamethasone — are under way.

“While it is important to recognize this was a single-arm phase 2 trial and we have to be very cautious when interpreting this information, for a 92-patient multicenter experience, I think this is an encouraging start,” Richardson said. – by Mark Leiser

Reference:

Richardson P, et al. Abstract O1. Presented at: Lymphoma & Myeloma 2015: An International Congress on Hematologic Malignancies; Oct. 22-24, 2015; New York.

Disclosure: Richardson reports research funding from and advisory roles with Celgene, Janssen and Millennium. Please see the abstract for a list of all other researchers’ relevant financial disclosures.