Results from a phase II, open-label, multicenter study have shown that patients with heavily pretreated multiple myeloma responded to ibrutinib combined with bortezomib (Velcade) and dexamethasone.
Results from a phase II, open-label, multicenter study have shown that patients with heavily pretreated multiple myeloma (MM) responded to ibrutinib (Imbruvica) combined with bortezomib (Velcade) and dexamethasone.
The authors, led by Roman Hajek, MD, PhD, of the University of Ostrava, Ostrava, Czech Republic, found that the median progression-free survival (PFS) was 8.5 months (95% Confidence Interval [CI], 6.210.8 months). The median overall survival (OS) was not reached. The overall response rate (ORR) was 57% (95% CI, 45–68%) and the median duration of response was 9.5 months (95% CI, 6.9–10.6 months).
Despite this clinical activity, investigators suspended study enrollment due to an initial increase of serious and fatal infections. Following a safety review and implementation of risk-minimization procedures, they planned to reopen enrollment. “However, efficacy assessments conducted at potential restart of enrollment indicated that the targeted PFS could not be reached with additional patient enrollment, and the study was terminated,” Hajek et al wrote recently in theEuropean Journal of Haematology.
PCYC-1139 enrolled adult MM patients with measurable disease who had received up to 3 previous lines of therapy. All patients had experienced progressive disease (PD) since the completion of their most recent treatment regimen. If bortezomib had been given previously, patients must not have been resistant to it. Enrolled patients had an ECOG performance status of 2 or better and sufficient hematological, hepatic, and renal function.
Patients’ prior proteasome inhibitor therapy use was scrutinized: They were excluded if they had previously been nonresponsive or refractory, or if they had progressed while on treatment. A history of plasma cell leukemia, primary amyloidosis, or POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin abnormalities) syndrome within 12 months prior to the first administration of the study treatment were also exclusion factors.
The study enrollment suspension occurred after 74 patients had initiated study treatment. Risk mitigation strategies included changing the dexamethasone dose so that it was effectively halved in the triple combination. The authors also strengthened their infection-prevention guidance and launched a safety review committee, which evaluated the rate of new infections every 6 weeks. Treatment of enrolled patients continued during the enrollment freeze with these new safeguards in place.
In addition to the PFS primary endpoint, the trial also considered several secondary endpoints. These included ORR, OS, PFS rate at landmark time intervals, duration of response, and time to progression. Safety and tolerability of the combined regimen were also secondary endpoints. The trial was powered to require approximately 125 patients to achieve 80% power at a one-sided 0.025 significance level to test the null hypothesis of median PFS ≤8 months versus ≥12 months under the alternative hypothesis, Hajek et al wrote.
In cycles 1 to 8, patients received oral ibrutinib of 840 mg once daily in combination with subcutaneous bortezomib 1.3 mg/m2on days 1, 4, 8, and 11. Initially, oral dexamethasone of 20 mg was given on days 1, 2, 4, 5, 8, 9, 11, and 12 of each 21-day cycle. The revised protocol limited the steroid to days 1, 4, 8, and 11.
Cycles 9 to 12 were expanded to 42 days, with dosing intervals for all three drugs adjusted accordingly. Bortezomib was discontinued for cycle 13 and later. For patients aged >75 years, the authors recommended adjusting the dexamethasone dose to 10 mg for cycles 1 to 12 and then 20 mg for any additional cycles. Treatment with ibrutinib plus dexamethasone continued until disease progression or unacceptable toxicity.
Of the 74 patients who received at least 1 dose of the study regimen, the median age was 67.5 years and nearly two-thirds (61%) were age 65 or older. Similarly, 61% of patients had received only 1 prior therapy, while 39% received 2 or 3 prior therapies. The most common prior therapies were dexamethasone (88%), bortezomib (81%), cyclophosphamide (65%), lenalidomide (39%), and melphalan (31%). The authors determined that 39% of the patients were refractory to their most recent therapy.
The median follow-up duration was 19.6 months (range, 0.224.6 months). The median duration of treatment for ibrutinib was 5.7 months (range, 0.1–23.7 months), 4.5 months for bortezomib (range, 0.0–12.6 months), and 5.6 months for dexamethasone (range, 0.1–20.1 months), Hajek et al reported.
Nearly three-quarters of the patient pool (73%) experienced grade 3/4 adverse events (AEs). AEs were fatal for 15% of patients. Serious AEs of any grade occurred in 47 patients (64%). Eleven patients (15%) developed pneumonia; 9 patients had grade 3 or 4 and 2 patients had grade 5 pneumonia.
Eighty percent of patients (n = 59) developed infections, including pneumonia, upper respiratory tract infections, bronchitis, conjunctivitis, nasopharyngitis, and urinary tract infection.
Hajek et al reported that fatal infections were reported as AEs in 8 patients (11%), with 4 fatal infections due to sepsis and 4 due to pneumonia.
About one-third of patients had a bleeding event of any grade (n = 23, 31%). Four patients developed major hemorrhage, including 1 fatality. Atrial fibrillation occurred in 7 patients (9%) and was grade 3/4 in 3 patients (4%).
PFS events had occurred in 55 patients (74%) at the median follow-up of 19.6 months. The median PFS was 8.5 months (95% CI, 6.210.8 months). Hajek et al estimated the PFS at 20 months to be 7%.
The ORR was 57% (95% CI, 4568). This included a single patient with a complete response (CR). Additionally, 13 patients had a “very good” partial response, and 28 others had a partial response. The median duration of response in these 42 patients was 9.5 months (95% CI, 6.9–10.6 months) and the median time to progression was 10.6 months (95% CI, 7.8–12.0 months). At the time of analysis, 27 patients (36%) had died and the median OS was not reached. Hajek et al estimated OS at 24 months to be 54%.
“While the incidence of infection of any grade in this study (80%) was similar to rates reported with ibrutinib in other haematological malignancies (6878%) over median follow-up durations of 9.4 to 33.4 months, the incidence of grade ≥3 infections (43%) was higher than rates previously reported with ibrutinib (7–29%),” Hajek et al wrote. “However, it should be noted that a higher dose of ibrutinib (840 mg once daily) was used in the current study compared with other haematological malignancies (420 mg or 560 mg once daily).”
Hajek et al also noted that, following the adoption of the improved safety protocol, there were no fatal infections among patients already enrolled in the study and a lower rate of serious infections. “Apart from infections, the safety profile was consistent with the known safety profiles of the individual study drugs,” they wrote.
Hajek R, Pour L, Ozcan M, et al. A Phase 2 Study of Ibrutinib in Combination with Bortezomib and Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma. Eur J Haematol. 2019 Dec 28. doi: 10.1111/ejh.13377. [Epub ahead of print]