Here we report that in MM cells, increased expression as well as activation of cyclin T and CDK9 play critical functional roles in Mcl-1 maintenance, including in the setting of bortezomib resistance, and that targeting components of the P-TEFb pathway pharmacologically or genetically potently down-regulate Mcl-1 expression and promote cell death, particularly in the presence of proteasome inhibitors or BH3-mimetics. Here, CCNT1 is linked to Miyoshi myopathy.