An Integrative Multiomics Approach to Multiple Myeloma

When practicing precision oncology for multiple myeloma, clinicians currently match specific DNA mutations to the optimal targeted therapy. However, it may be time to think about incorporating genome-wide RNA profiles to better guide therapy. A new trial published in JCO Precision Oncology found that a comprehensive RNA and DNA sequencing platform may benefit late-stage and drug-resistant multiple myeloma patients by determining which agents may work best for them.

The novel platform expands on traditional DNA-based approaches by using RNA sequencing to find targets for a broad swath of FDA-approved cancer drugs beyond those approved specifically for multiple myeloma. This approach was tested in a pilot precision medicine clinical trial with 64 patients with late-stage and drug-resistant multiple myeloma.

The study showed a comprehensive approach that includes RNA sequencing can provide more treatments for patients with advanced disease beyond the standard DNA analysis currently available. The researchers were able to generate treatment recommendations for 63 of 64 patients. Among these patients, 26 had the treatment implemented and 21 patients were assessable.

The investigators found that 11 patients received a drug that was based on RNA findings, 8 received a drug based on DNA, and 2 patients received a drug that was based on both RNA and DNA. Sixteen of the 21 evaluable patients had a clinical response, with a reduction of disease marker ≥ 25%. The overall clinical benefit rate was 76% and the overall response rate was 66%. 

“Our study demonstrated that tumor sequencing can help guide treatment decisions patients with relapsed/refractory multiple myeloma in a personalized manner. What was surprising was that the majority of patients who responded to the recommended treatment were treated based on their RNA expression, rather than on their DNA mutations,” said study investigator Alessandro Lagana, PhD, an assistant professor of genetics and genomic sciences at the Institute for Next Generation Healthcare and the Icahn Institute for Genomics and Multiscale Biology at the Icahn School of Medicine at Mount Sinai, New York.

Lagana said genome-wide RNA profiles had not been clinically assessed in MM until now and these findings suggest that RNA sequencing could play a larger role in precision oncology. The researchers theorized this could mark a paradigm shift, allowing treatment decisions based on the specific genomic alterations observed in a patient’s tumor instead of the tumor histology or tissue type.

“Our study demonstrates that RNA sequencing can provide further insights into the dynamics of the tumor’s biology beyond those provided by targeted DNA sequencing alone. Such technologies should be critically incorporated into routine cancer care and institutional infrastructures should evolve to enable this process,” Lagana told Cancer Network.

Henry Chi Hang Fung, MD, the vice chair of the department of hematology/oncology at Fox Chase Cancer Center, Philadelphia said these are exciting findings. He noted there is an urgent need to better identify agents that produce durable responses and RNA sequencing could be quite valuable. “It is an interesting area,” Fung said in an interview with Cancer Network.  “It is still incurable and there are a lot of patients who have been treated for years and keep relapsing. We need new approaches and something that has a durable response.”