NEW YORK (FRONTLINE MEDICAL NEWS) – Three “Achilles heels” of multiple myeloma offer exciting promise for additional advances that will begin to see therapeutic payoffs within the next year, according to Kenneth C. Anderson, MD.

The three targets – excess protein production, immune suppression, and genomic abnormalities – can be addressed by focusing on protein degradation, restoring anti–multiple myeloma immunity, and targeting and overcoming genomic abnormalities, respectively, Dr. Anderson of Dana-Farber Cancer Institute in Boston said at Imedex: Lymphoma & Myeloma, an international congress on hematologic malignancies.

“In terms of protein degradation, we can block upstream of the proteasome now with what’s called a deubiquitylating agent (DUB),” he said, explaining that protein needs to be labeled with ubiquitin to be targeted for degradation, and the label has to be taken off by a DUB.

“So if you block those so-called DUBs, you block this same pathway upstream of the proteasome,” he said.

One DUB inhibitor (P5091) was shown in a preclinical trial to overcome bortezomib resistance in multiple myeloma, as was another novel, more user-friendly agent (b-AP15) that blocks USP14/UCHL5 and can be active with immunomodulatory drugs. A clinical trial of b-AP15 is ongoing, Dr. Anderson said.

In contrast to the conventional approach of inhibiting proteins and signaling pathways needed for the survival of the cancer cells, a new technology called “degronimids” turns on the cereblon gene and delivers protein-degrading machinery to targeted proteins. Cereblon, a protein-degrading enzyme that forms part of the ubiquitin E3 ligase complex, tags proteins in the cell for destruction, he noted.

As for immune suppression, he said, the selective plasma cell antigen BCMA (B-cell maturation antigen) is “probably a better target than either CD38 or SLAMF7,” and has already been targeted with an auristatin immunotoxin that induced strong anti–multiple myeloma effects.

“Excitingly, there is this concept of BCMA-BiTEs (B-cell maturation antigen–bispecific T-cell engagers) where we have one linkage of BCMA to the myeloma cell and CD3 attracting a local immune response,” he said.

Other promising new approaches with respect to immune suppression involve checkpoint inhibitors, histone deacetylase (HDAC) inhibitors, and chimeric antigen receptor (CAR) T-cells, he added.

Genomic abnormalities represent another potential vulnerability, and venetoclax (Venclexta) could prove to be the first precision medicine for multiple myeloma, he suggested.

In myeloma, “we are trying to treat the abnormality, but what about treating the genetic consequences of this abnormality,” he said, adding that clinical trials that target the consequences of genomic heterogeneity or instability are on the horizon.

Dr. Anderson reported serving as a consultant for, or receiving other financial support from Acetylon, Bristol-Myers Squibb, C4 Therapeutics, Celgene, Gilead, Millennium, and OncoPep.


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