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Risk Stratification and Targets in Multiple Myeloma: From Genomics to the Bedside
Aurore Perrot1, Jill Corre1, Hervé Avet-Loiseau1
1From the Hematology Department, University Hospital, Nancy, France; Myeloma Genomics Laboratory, University Hospital, Toulouse, France; and Myeloma Genomics Laboratory, University Hospital, Toulouse, France.
Abstract:
In the past 15 years, significant improvements in overall survival have been observed in multiple myeloma (MM), mainly due to the availability of novel drugs with variable mechanisms of action. However, these improvements do not benefit all patients, and some of them, defined as high risk, still display short survival. The most important risk factors are the genetic abnormalities present in the malignant plasma cells. The most important high-risk features are the del(17p), the del(1p32), the t(4;14), and 1q gains. Assessing these markers is mandatory at diagnosis and at least at first relapse, since it has been clearly shown that the lenalidomide-dexamethasone combination is not efficient in these high-risk patients. In contrast, a triplet combination adding a proteasome inhibitor or a monoclonal antibody to the lenalidomide-dexamethasone backbone clearly improves the survival. Another way to improve the outcome would be to specifically target genetic abnormalities with specific inhibitors. The sequencing of more than 1,000 MM exomes revealed again a huge heterogeneity. The most frequent mutations involve the KRAS and NRAS genes (20%-25% each). However, to date, no good RAS-inhibitors are clinically available, preventing targeted therapy. The only drugable target is the V600E BRAF mutation. Unfortunately, this specific mutation is present in only 3% of the patients. Finally, it has been recently reported a specific efficiency of the BCL2-inhibitor venetoclax in patients with the t(11;14) translocation, which is found in 20% of the patients.
Insights
High-risk multiple myeloma (MM) patients with specific genetic abnormalities have poor survival. Targeted therapies, like venetoclax for t(11;14) translocations, offer improved outcomes for these patients.
Area of Science:
- Hematology
- Oncology
- Genetics
Background:
- Multiple myeloma (MM) survival has improved due to novel drugs, but high-risk patients with genetic abnormalities still face poor prognoses.
- Key high-risk genetic features include del(17p), del(1p32), t(4;14), and 1q gains, necessitating mandatory assessment at diagnosis and relapse.
- Standard lenalidomide-dexamethasone therapy is less effective in high-risk MM patients, highlighting the need for alternative treatment strategies.
Purpose of the Study:
- To review the impact of genetic abnormalities on multiple myeloma prognosis and treatment efficacy.
- To explore the potential of targeted therapies for specific genetic alterations in MM.
- To discuss the current landscape and future directions for managing high-risk multiple myeloma.
Main Methods:
- Review of recent literature on multiple myeloma genetics, risk stratification, and therapeutic advancements.
- Analysis of clinical trial data and genetic sequencing studies in MM.
- Discussion of drug mechanisms and their efficacy in relation to specific genetic mutations.
Main Results:
- High-risk genetic features significantly correlate with shorter survival in MM patients.
- Triplet combinations (proteasome inhibitor or monoclonal antibody with lenalidomide-dexamethasone) improve survival in high-risk MM.
- While KRAS/NRAS mutations are common, effective inhibitors are lacking; BRAF V600E is rare but targetable.
- Venetoclax shows specific efficacy in MM patients with the t(11;14) translocation.
Conclusions:
- Accurate genetic profiling is crucial for personalized treatment of multiple myeloma.
- Targeted therapies, such as venetoclax for t(11;14), represent a promising strategy for improving outcomes in specific MM subgroups.
- Further research into novel targeted agents is needed to address the unmet needs in high-risk multiple myeloma.
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