Phase 1 Study of Tabalumab, a Human Anti-B-Cell Activating Factor Antibody, and Bortezomib in Patients with Relapsed/Refractory Multiple Myeloma

Abstract

Purpose: Tabalumab, a human mAb that neutralizes B-cellactivating factor (BAFF), demonstrated antitumor activity in xenograft models of multiple myeloma. Here we report on a phase I study of relapsed/refractory multiple myeloma patients in which the primary objective was to identify a tolerable and potentially efficacious dose of tabalumab when combined with bortezomib.Experimental Design: Forty-eight patients were enrolled; 20 to the dose-escalation cohort, and 28 to cohort expansion in which a dose of 100 mg of tabalumab was evaluated. All patients had received either prior bortezomib or an immunomodulatory drug; the median number of prior therapies was 3. Bortezomib was administered intravenously on days 1, 4, 8, and 11 of a 21-day schedule. Tabalumab was given every 21 days for 3 cycles, then every 42 days thereafter. Results:The most common grade 3/4 toxicities included thrombocytopenia, neutropenia, pneumonia, and peripheral sensory neuropathy. There were no dose-limiting toxicities, and the maximum tolerated dose was not reached. Pharmacokinetic data suggested serum exposure increased in a greater than doseproportional manner up to a dose of 100 mg. Out of 46 evaluable patients, 20 had confirmed responses. The median time to progression (9 patients censored) was 4.8 months, and the median response duration (4 patients censored) was 7.2 months.Conclusions: A dose of 100 mg tabalumab in combination with bortezomib was well tolerated and active and is currently under further investigation.

Phase 2 study of tabalumab, a human anti‐B‐cell activating factor antibody, with bortezomib and dexamethasone in patients with previously treated multiple myeloma

“…We found that patients with low baseline BAFF expression (75th percentile cut‐off point) had significantly longer PFS compared to patients with high baseline BAFF expression, independent of treatment. Our results are consistent with those from the previous Phase 1 tabalumab study in previously‐treated multiple myeloma patients, which reported that none of the 9 patients who had baseline BAFF levels >1500 pg/ml had a best overall response of PR or better, whereas 19 of the 37 patients with baseline BAFF <1500 pg/ml had a response (Raje et al , ). Our results are also consistent with reports of significantly shorter survival among newly diagnosed, treatment‐naïve multiple myeloma patients who had BAFF values that were higher than the median of all multiple myeloma patients (Fragioudaki et al , ; Lemancewicz et al , ).…”

“…The Phase 2 study described in this report was undertaken to compare 100 mg and 300 mg doses of tabalumab combined with dexamethasone and bortezomib to dexamethasone and bortezomib in patients with relapsed or refractory multiple myeloma. This study was initiated following our previous Phase 1 study of tabalumab plus bortezomib in relapsed or refractory multiple myeloma, which showed favourable efficacy and safety results and provided preliminary evidence of a potential relationship between response and baseline BAFF levels (Raje et al , ). We hypothesized that a 300 mg dose of tabalumab might be necessary to provide an adequate level of target neutralization in patients with higher BAFF levels, thereby maximizing the probability of achieving the best possible treatment effect in this patient population.…”

“…On the basis of preclinical data showing that BAFF neutralization decreased osteoclast numbers (Neri et al , ) and that bortezomib demonstrated potent activity against multiple myeloma and also increased osteoblast number and function (Mukherjee et al , ), a Phase 1 trial combining tabalumab and bortezomib was conducted and found the combination to be well‐tolerated and active in the relapsed/refractory multiple myeloma setting (Raje et al , ). Interestingly, at 100 mg tabalumab, the lowest dose thought to provide full saturation of the target, non‐response was observed among all multiple myeloma patients with very high baseline BAFF levels (>1500 pg/ml).…”

Changes in uninvolved immunoglobulins during induction therapy for newly diagnosed multiple myeloma

“… 16 In addition, in vitro studies have shown that monoclonal antibodies directed against BCMA or APRIL augment the cytotoxicity of lenalidomide and dexamethasone against MM cells, 19 , 20 and such combinations are being investigated in Phase 1 trials. 21 Taken together, these mechanisms could explain our findings that RD, VD and especially VRD produced the largest rises in uninvolved Ig and greatest humoral responses, as lenalidomide and bortezomib may inhibit pathways that lead to immunoparesis in MM.…”

Genetically engineered T cells for cancer immunotherapy

“…Two BCMA CAR-T cell products (bb2121 and LCAR-B38M) were subject to clinical trials for the treatment of MM. The data from the bb2121 phase I dose-escalation trial showed that the CR rate reached 71% among the 21 patients treated 106 . LCAR-B38M treatment in 57 recruited patients produced an ORR of 88% and a CR of 74% 107 .…”