Study Design and Results
In the study, tumor genomic DNA and RNA were harvested from bone marrow aspirates and peripheral blood of 64 patients with relapsed/refractory MM. The median age at enrollment was 59 years, 39% of patients were women, and 67% harbored high-risk cytogenetic features. The median number of prior lines of therapy administered to each patient was 7 lines and 20% of patients had received at least 10 lines of treatment.
The researchers developed a software framework to define and execute data analysis workflows from the DNA and RNA sequencing results. Dr Laganà explained that “our platform consists of a software pipeline based on a modular plug-in architecture. Each module is either a third-party tool (eg, tools for mapping or mutation-calling) or a software developed in-house.”
The software processed raw DNA sequencing data and paired normal and tumor samples, then annotated and prioritized somatic mutations and CNAs to identify actionable mutations. Similarly, the software processed raw RNA data from tumor samples to identify outlier genes and pathway activation for drug repurposing. “The pipeline is fully automated, so the analysis starts from the raw sequencing data and produces a full report showing actionable alterations and the corresponding drug recommendations,” Dr Laganà said.
The analysis identified a mean of 527.5 mutations per patient, with 57% located within introns. The most common were missense mutations, followed by nonsense, splice site, and start codon mutations. Actionable mutations were identified in KRAS, TP53, NRAS, BRAF, ATM, and APC. An additional 31 actionable mutations were identified by CNA.
This approach resulted in treatment recommendations for 98% of patients in the study, and 42% of patients received at least 1 of the recommended agents as a result. Patients were treated with the recommended agent as a monotherapy or in combination with other agents.
The most common recommendations for drug treatment were trametinib for NRASor KRASmutations; venetoclax for high BCL2expression; and panobinostat for HDAC pathway activation or drug repurposing of vorinostat, as determined by RNA sequencing analysis. Dabrafenib was prescribed to a patient with both BRAFand RASmutations and etoposide was prescribed based on RNA-based drug repurposing information.
The clinical benefit rate was 76% and the overall response rate was 66%. Of the evaluable patients, a complete response was achieved by 5%, a very good partial response by 14%, and a partial response by 47%. The median duration of response was 131 days and 5 patients were expiring ongoing responses at study end.
Dr Fonseca said that a lot of research is ongoing to develop platforms that identify actionable mutations to guide treatment selection for individual patients, “but it is still mostly in the clinical trial and anecdotal arena.” He noted, however, that some patients with BRAFmutations have responded to BRAF inhibitors, “although they have been short lived, this is paving the way to think about BRAF inhibitors in combinations in the future and other trials are addressing this.”
Dr Laganà said that their platform is already being used by physicians at Mount Sinai in New York, New York for patients with MM. “Although more work still needs to be done, the precision medicine paradigm holds great promise for the treatment of cancer and represents a unique opportunity for accelerated development and application of novel therapeutic approaches,” he said.
- Lagana A, Beno I, Melnekoff D, et al. Precision medicine for relapsed multiple myeloma on the basis of an integrative multiomics approach[published online August 8, 2018]. JCO Precis Oncol. doi: 10.1200/PO.18.00019