The evolution to hepta-refractory myeloma involves sequential loss of CD38, BCMA and GPRC5D

Area of Science:

• Oncology
• Genetics
• Immunotherapy

Background:

• Hepta-refractory multiple myeloma (MM) represents a novel, ultra-refractory end-stage disease.
• Patients are resistant to CD38 antibodies, immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), and BCMA- and GPRC5D-directed immunotherapies.
• This population faces extremely poor prognoses with limited salvage therapy options.

Purpose of the Study:

• To characterize the genomic landscape and clinical outcomes of hepta-refractory MM.
• To investigate mechanisms of therapeutic resistance, including antigen loss.
• To identify potential predictive markers for treatment response.

Main Methods:

• Multi-center cohort study of 37 hepta-refractory MM patients.
• Whole genome sequencing (WGS) to identify genomic alterations.
• Immunohistochemistry (IHC) to assess protein expression (e.g., BCMA).

Main Results:

• Median overall survival was 12.8 months; progression-free survival was short across salvage therapies.
• Frequent biallelic tumor suppressor gene events (e.g., TP53) were observed.
• Genomic alterations linked to resistance against various therapies were common (IMiD 71%, BCMA 41%, GPRC5D 35%, CD38 12%).
• Concurrent loss of BCMA (TNFRSF17) and GPRC5D occurred in nearly one-third of patients.
• WGS revealed complex evolutionary trajectories and distinct TNFRSF17/GPRC5D variants within patients.
• IHC confirmed BCMA loss due to genomic events and other mechanisms.
• BCMA status predicted benefit from BCMA re-treatment.

Conclusions:

• Hepta-refractory MM is characterized by significant genomic complexity and antigen loss.
• These factors contribute to profound therapeutic resistance and poor outcomes.
• Integrated genomic and IHC testing is crucial for diagnosing and managing this population, guiding the development of novel therapies.