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

In this double-blind, Phase 2 study, 220 patients with relapsed/refractory multiple myeloma were randomly assigned 1:1:1 to receive placebo (N�=�72), tabalumab 100�mg (N�=�74), or tabalumab 300�mg (N�=�74), each in combination with dexamethasone 20�mg and subcutaneous bortezomib 1�3�mg/m2 on a 21-day cycle. No significant intergroup differences were observed among primary (median progression-free survival [mPFS]) or secondary efficacy outcomes. The mPFS was 6�6, 7�5 and 7�6�months for the tabalumab 100, 300�mg and placebo groups, respectively (tabalumab 100�mg vs. placebo Hazard ratio (HR) [95% confidence interval (CI)]�=�1�13 [0�80–1�59], P�=�0�480; tabalumab 300�mg vs. placebo HR [95% CI]�=�1�03 [0�72–1�45], P�=�0�884). The most commonly-reported treatment-emergent adverse events were thrombocytopenia (37%), fatigue (37%), diarrhoea (35%) and constipation (32%). Across treatments, patients with low baseline BAFF (also termed TNFSF13B) expression (n�=�162) had significantly longer mPFS than those with high BAFF expression (n�=�55), using the 75th percentile cut-off point (mPFS [95% CI]�=�8�3 [7�0–9�3] months vs. 5�8 [3�7–6�6] months; HR [95% CI]�=�1�59 [1�11–2�29], P�=�0�015). Although generally well tolerated, PFS was not improved during treatment with tabalumab compared to placebo. A higher dose of 300�mg tabalumab did not improve efficacy compared to the 100�mg dose. Nonetheless, BAFF appears to have some prognostic value in patients with multiple myeloma. � 2016 John Wiley & Sons Lt

Common gene variants within 3'-untranslated regions as modulators of multiple myeloma risk and survival

Contains fulltext : 232394.pdf (Publisher’s version ) (Closed access)We evaluated the association between germline genetic variants located within the 3'-untranlsated region (polymorphic 3'UTR, ie, p3UTR) of candidate genes involved in multiple myeloma (MM). We performed a case-control study within the International Multiple Myeloma rESEarch (IMMEnSE) consortium, consisting of 3056 MM patients and 1960 controls recruited from eight countries. We selected p3UTR of six genes known to act in different pathways relevant in MM pathogenesis, namely KRAS (rs12587 and rs7973623), VEGFA (rs10434), SPP1 (rs1126772), IRF4 (rs12211228) and IL10 (rs3024496). We found that IL10-rs3024496 was associated with increased risk of developing MM and with a worse overall survival of MM patients. The variant allele was assayed in a vector expressing eGFP chimerized with the IL10 3'-UTR and it was found functionally active following transfection in human myeloma cells. In this experiment, the A-allele caused a lower expression of the reporter gene and this was also in agreement with the in vivo expression of mRNA measured in whole blood as reported in the GTEx portal. Overall, these data are suggestive of an effect of the IL10-rs3024496 SNP on the regulation of IL10 mRNA expression and it could have clinical implications for better characterization of MM patients in terms of prognosis