The Future Treatment Landscape for Relapsed and Refractory Myeloma

New York—At the 2018 Lymphoma & Myeloma Congress, Kenneth C. Anderson, MD, Program Director, Jerome Lipper Multiple Myeloma Center and LeBow Institute for Myeloma Therapeutics, Dana-Farber Cancer Institute, Boston, MA, discussed the future of the treatment landscape for patients with relapsed and refractory myeloma.

“As you all know we have had, in myeloma, a number of advances with the proteasome inhibitors and in immunomodulatory drugs, HDAC inhibitor and antibodies, and new triplets, which are now used routinely and in patients with newly diagnosed and relapsed disease,” he told listeners.

Novel Strategies and Targets

Some of the newer strategies being used in the treatment of patients with multiple myeloma include administration of iMiD-based and immune therapies (eg, TP53-related proteins, CAR T-cells), and targeting of ubiquitin proteasome receptors, genomes, and epigenomes. These are areas in which Dr Anderson says we can make some progress.

Of note, he touched upon epigenetic therapy, which involves methylation and demethylation.

“In our opinion, one of the best demethylases in myeloma is KDM3A, and we and others are excited about it because if you inhibit KDM3A you restore methylation or suppress the transcription of certain genes including IRF4, which is a very important hallmark abnormality in myeloma,” Dr Anderson said.

As such, KDM3 inhibitors are likely going to be the first demethylases inhibited in myeloma.

He also spoke about the inhibition of protein arginine methyltransferase 5 (PRMT5), which is highly expressed in myeloma and associated with poor outcomes.

“There is an oral inhibitor of this particular PRMT5—the oral inhibitor is selective, potent, well-tolerated in animal models, and it shows efficacy in other tumors,” he told attendees.

EPZ015666, a first-in-class PRMT5 inhibitor, can be used to inhibit myeloma cell growth.

“We think it’s working by NF-kB signaling, that’s work in progress, but what’s neat is in our animal models the oral inhibitor is extremely well-tolerated and very selective,” Dr Anderson explained.

“We’re excited about these preclinical studies and have interest that this may actually translate from the bank to the bedside with one of the first epigenetic methyltransferase therapies,” he added.

Combination Therapies are the Future

In a prediction shared with attendees, Dr Anderson posited that combination therapies predicated and defined by clinical trials for use in specific subsets of patients through the use of biomarkers.

With triplet therapies demonstrating durable and deep responses in patients with newly diagnosed or relapsed myeloma, he also predicts that the future lies in the assessment of quadruplet therapies for this patient population.

Of note, Dr Anderson calculates that in the high-risk setting, combination maintenance therapies have the potential to overcome early relapses.

“Long-term disease-free survival and potential cure of multiple myeloma will require both achieving minimal residual disease negativity and the use of combined immune therapies to restore host immunity,” he said.—Hina Khaliq