Ibrutinib effective in relapsed MCL and CLL; however, responses often partial and resistance eventually develops.

Combining ibrutinib with secondary agents inhibiting targets within and outside B-cell receptor (BCR) pathway.

Inhibitors of targets within BCR pathway ineffective.

Substantial cytotoxicity seen with agents that target outside BCR pathway.

Notable robust and reproducible synergistic cytotoxicity when combining ibrutinib and proteasome inhibitors carfilzomib and bortezomib as well as BCL-2 inhibitor ABT-199.

Agents within BCR pathway did not display synergistic cytotoxicity with ibrutinib

Agents outside BCR pathway did synergize with ibrutinib, notably ABT-199, bortezomib, and carfilzomib in two MCL cell lines.

This effect appeared to be mediated via apoptosis.

Synergistic effect of ibrutinib + carfilzomib in MCL-SCID-hu mice demonstrated three-fold increased survival.

Combination of ibrutinib with either proteasome or BCL-2 inhibition looks promising as novel treatments for MCL and CLL.

Identification of synergistic cytotoxic interactions between inhibitors of apparently unrelated pathways looks promising.

Molecular mechanisms remain to be elucidated.

Further phase I/II studies planned.