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This phase 1, dose-finding study investigated ibrutinib and carfilzomib ± dexamethasone in patients with relapsed or relapsed/refractory multiple myeloma (≥2 lines of therapy including bortezomib and an immunomodulatory agent). Of 43 patients enrolled, 74% were refractory to bortezomib and 23% had high-risk cytogenetics. No dose-limiting toxicities were observed. The recommended phase 2 dose was ibrutinib 840 mg and carfilzomib 36 mg/m2 with dexamethasone. The most common ≥ grade 3 (>10%) treatment-emergent adverse events were hypertension, anemia, pneumonia, fatigue, diarrhea, and thrombocytopenia. Overall response rate was 67% (very good partial response, 21%; stringent complete response, 2%), with an additional 9% minimal response. Median progression-free survival was 7.2 months and was not inferior in refractory nor high-risk patients. Median overall survival was not reached. Ibrutinib plus carfilzomib demonstrated encouraging responses with a manageable safety profile in this advanced population. [ABSTRACT FROM AUTHOR]

A phase 1 study with carfilzomib and vorinostat was conducted in 20 B-cell lymphoma patients. Vorinostat was given orally twice daily on days 1, 2, 3, 8, 9, 10, 15, 16, and 17 followed by carfilzomib (given as a 30-min infusion) on days 1, 2, 8, 9, 15, and 16. A treatment cycle was 28 days. Dose escalation initially followed a standard 3 + 3 design, but adapted a more conservative accrual rule following dose de-escalation. The maximum tolerated dose was 20 mg/m² carfilzomib and 100 mg vorinostat (twice daily). The dose-limiting toxicities were grade 3 pneumonitis, hyponatremia, and febrile neutropenia. One patient had a partial response and two patients had stable disease. Correlative studies showed a decrease in NF-κB activation and an increase in Bim levels in some patients, but these changes did not correlate with clinical response. [ABSTRACT FROM AUTHOR]

Mantle cell lymphoma (MCL) represents a subtype of non-Hodgkin''s lymphoma (NHL) which has a relatively poor prognosis compared to other forms of NHL. Despite multiple options for cytotoxic chemotherapy, attempts to prolong the survival of patients with this disease have not yet met with success. Consequently, the development of targeted approaches to therapy which minimize toxicities has potentially important implications for MCL. Proteasome inhibitors preferentially kill transformed cells through diverse mechanisms. The proteasome inhibitor bortezomib was initially approved for patients with relapsed or refractory multiple myeloma and now has been approved for relapsed or refractory MCL. The introduction of newer proteasome inhibitors with activity in bortezomib-resistant disease and reduced toxicity profiles may yield further benefits. Multiple ongoing studies are building on the known efficacy of proteasome inhibitors in MCL by evaluating combination regimens involving either cytotoxic or targeted therapies, with the ultimate goal of prolonging survival in this patient population. [Copyright &y& Elsevier]