Heme promotes venetoclax resistance in multiple myeloma through MEK-ERK signaling and purine biosynthesis.

We previously demonstrated that reduced intrinsic electron transport chain (ETC) activity predicts and promotes sensitivity to the BCL-2 antagonist, venetoclax (Ven) in multiple myeloma (MM). Heme, an iron-containing prosthetic group, and metabolite is fundamental to maintaining ETC activity. Interrogation of the CD2 subgroup of MM from the CoMMpass trial (NCT01454297), which can be used as a proxy for Ven-sensitive MM (VS MM), shows reduced expression of the conserved heme biosynthesis pathway gene signature.

Quadruplet therapy for newly diagnosed myeloma: comparative analysis of sequential cohorts with triplet therapy lenalidomide, bortezomib and dexamethasone (RVd) versus daratumamab with RVD (DRVd) in transplant-eligible patients.

Lenalidomide, bortezomib, and dexamethasone (RVd) have previously been established as standard-of-care induction therapy for newly diagnosed multiple myeloma (NDMM). More recently, randomized phase 3 data have demonstrated the benefit of the addition of daratumumab (Dara-RVd) to the RVd backbone in terms of improved both depth of response and long-term survival benefit as measured by progression-free survival (PFS). Our group has previously published on a historical cohort of 1000 NDMM patients uniformly treated with RVd induction with impressive both PFS and overall survival.

KDM6A regulates immune response genes in multiple myeloma.

The histone H3 at lysine 27 (H3K27) demethylase lysine demethylase 6A (KDM6A) is a tumor suppressor in multiple cancers, including multiple myeloma (MM). We created isogenic MM cells disrupted for KDM6A and tagged the endogenous protein to facilitate genome-wide studies. KDM6A binds genes associated with immune recognition and cytokine signaling.