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Published on: December 13, 2018
RNA-sequencing based first choice of treatment and determination of risk in multiple myeloma
Martina Emde-Rajaratnam1, Susanne Beck1,2, Vladimir Benes3
1Department of Hematology and Immunology, Myeloma Center Brussels & Labor für Myelomforschung, Vrije Universiteit Brussel (VUB), Jette, Belgium.
Background:
Immunotherapeutic targets in multiple myeloma (MM) have variable expression height and are partly expressed in subfractions of patients only. With increasing numbers of available compounds, strategies for appropriate choice of targets (combinations) are warranted. Simultaneously, risk assessment is advisable as patient's life expectancy varies between months and decades.
Methods:
We first assess feasibility of RNA-sequencing in a multicenter trial (GMMG-MM5, n=604 patients). Next, we use a clinical routine cohort of untreated symptomatic myeloma patients undergoing autologous stem cell transplantation (n=535, median follow-up (FU) 64 months) to perform RNA-sequencing, gene expression profiling (GEP), and iFISH by ten-probe panel on CD138-purified malignant plasma cells. We subsequently compare target expression to plasma cell precursors, MGUS (n=59), asymptomatic (n=142) and relapsed (n=69) myeloma patients, myeloma cell lines (n=26), and between longitudinal samples (MM vs. relapsed MM). Data are validated using the independent MMRF CoMMpass-cohort (n=767, FU 31 months).
Results:
RNA-sequencing is feasible in 90.8% of patients (GMMG-MM5). Actionable immune-oncological targets (n=19) can be divided in those expressed in all normal and >99% of MM-patients (CD38, SLAMF7, BCMA, GPRC5D, FCRH5, TACI, CD74, CD44, CD37, CD79B), those with expression loss in subfractions of MM-patients (BAFF-R [81.3%], CD19 [57.9%], CD20 [82.8%], CD22 [28.4%]), aberrantly expressed in MM (NY-ESO1/2 [12%], MUC1 [12.7%], CD30 [4.9%], mutated BRAF V600E/K [2.1%]), and resistance-conveying target-mutations e.g., against part but not all BCMA-directed treatments. Risk is assessable regarding proliferation, translated GEP- (UAMS70-, SKY92-, RS-score) and de novo (LfM-HRS) defined risk scores. LfM-HRS delineates three groups of 40%, 38%, and 22% of patients with 5-year and 12-year survival rates of 84% (49%), 67% (18%), and 32% (0%). R-ISS and RNA-sequencing identify partially overlapping patient populations, with R-ISS missing, e.g., 30% (22/72) of highly proliferative myeloma.
Conclusion:
RNA-sequencing based assessment of risk and targets for first choice treatment is possible in clinical routine.
Insights
RNA sequencing enables personalized treatment selection for multiple myeloma (MM) by assessing immune targets and patient risk. This approach guides optimal therapy choices and improves patient outcomes in clinical settings.
Area of Science:
- Oncology
- Immunotherapy
- Genomics
Background:
- Immunotherapeutic targets in multiple myeloma (MM) show variable expression, limiting treatment efficacy in some patients.
- Appropriate selection of targets and risk assessment are crucial due to varying patient prognoses.
Purpose of the Study:
- To assess the feasibility of RNA-sequencing for multiple myeloma (MM) patient stratification.
- To identify actionable immune targets and evaluate risk scores using gene expression profiling (GEP).
- To compare target expression across different stages of MM and validate findings in an independent cohort.
Main Methods:
- Feasibility assessment of RNA-sequencing in a multicenter trial (GMMG-MM5, n=604).
- RNA-sequencing, GEP, and iFISH performed on purified malignant plasma cells from a clinical cohort (n=535).
- Comparison of target expression with precursor cells, MGUS, asymptomatic, relapsed MM, and cell lines; validation in MMRF CoMMpass cohort (n=767).
Main Results:
- RNA-sequencing is feasible in 90.8% of patients.
- Identified 19 actionable immune targets with varying expression patterns in MM, including targets with expression loss or aberrant expression.
- Developed RNA-sequencing-based risk scores (e.g., LfM-HRS) that correlate with survival and identify high-risk patients missed by conventional staging (R-ISS).
Conclusions:
- RNA-sequencing is a feasible and valuable tool for routine clinical assessment in multiple myeloma.
- GEP-based risk stratification and target identification can guide personalized treatment strategies.
- This approach facilitates informed decisions for first-choice therapies in multiple myeloma.
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