Mapping the Proteogenomic Landscape of Multiple Myeloma: Implications for Targeted Therapy

Researchers have now mapped the proteogenomic landscape of multiple myeloma (MM), enhancing clinical understanding of the molecular characteristics and genetic alterations underlying the disease. The study authors highlight protein-level molecular changes specific to MM, as well as new potential target proteins that can be used to identify risk profiles in patients with MM and offer high-risk patients improved treatment options.

The proteomic mapping of MM enabled researchers to identify a risk profile based on the levels of different proteins that may predict more aggressive disease. Image Credit: © kamonrat - stock.adobe.com

MM is the second most common hematological malignancy that originates from malignant plasma cells within the bone marrow, resulting in the overproduction of abnormal cells. This causes brittle bones, renal insufficiency, immune function suppression, and organ dysfunction. There is no cure for MM, but continued research and development of advanced therapies offer many patients optimal health outcomes. However, high-risk patients with aggressive disease or mutations often face relapse, treatment resistance, and significantly poorer outcomes.^1,2

Standard-of-care treatment for MM typically involves immunomodulatory agents, proteasome inhibitors, or chemotherapy, followed by autologous stem cell transplantation. However, the efficacy and success of these treatments is often hindered by the high tendency for patients to relapse and develop drug resistances. Evolving treatments, such as GPRC5D-targeted chimeric antigen receptor (CAR) T-cell therapy, target specific proteins that are highly expressed on malignant cells. Targeted therapies offer patients with MM more precise treatments that optimize their overall responses while decreasing likelihood of adverse effects, such as cytokine release syndrome (CRS) or neurotoxicity.^1,2

The success of CAR T-cell therapies in targeting novel proteins, such as B-cell maturation antigen (BCMA), CD38, and GPRC5D, has changed the treatment landscape of MM, emphasizing the association between proteins and proliferation of malignant cells.2 In a study, published by Nature, the researchers aimed to identify and understand the proteome of MM, which offers insights into the underlying molecular mechanisms of MM, as well as the disease pathology.

To understand the genetic changes happening at the protein level in MM, the researchers analyzed plasma cells from 138 patients with MM, comparing NDMM (n=114), monoclonal gammopathy of unknown significance (MGUS; n=7), and plasma cell leukemia (PCL; n=17). To determine the primary and secondary chromosomal alterations, they used fluorescence in situ hybridization (FISH), RNA sequencing, and copy number alterations (CNAs) to map the proteomic landscape of NDMM, investigate the impact of amplification of the long arm of chromosome 1 (1q), identify the unique protein signatures in MGUS and PCL, and discover potential new therapeutic targets.^3,4

The researchers identified protein signatures specific to MM, which offer deeper insights into the underlying mechanism of the disease. RNA sequencing data revealed significant discrepancies between RNA and protein levels in malignant cells, which may point to intricate post-transcriptional regulatory mechanisms driving protein expression. Additionally, there were stronger correlations amongst proteins that regulate B cell differentiation, a key determinant of malignant cell proliferation and survival.³

Assessments into the significance of 1q gain demonstrated a substantial number of upregulated proteins (147 out of 237, 62%), including known oncogenic drivers such as ANP32E, BCL9, and MCL1. The study authors also identified several additional upregulated proteins involved in proteasomal degradation, proteostasis, and protein folding pathways, of which UBE2Q1 was a significant focus. They found that UBE2Q1 had strong associations with adverse overall survival (OS) and progression-free survival, as well as an increased expression correlated with shorter OS. Further, when overexpressed, UBE2Q1 results in the deregulation of proteins, suggesting that gene amplification in UBE2Q1 influences the levels of other critical proteins.³

Proteomic analysis of MGUS demonstrated little differentiation of proteins when compared with malignant NDMM cells. However, despite genetic similarities between MGUS and PCL, the proteomic profile of PCL revealed upregulations in proteins associated with metastasis and aggressive disease. PCL also exhibited lower levels of CD38, indicating treatments such as monoclonal antibodies, antibody-drug conjugates, and immunomodulatory drugs may be less effective treatments for patients.³

The proteomic mapping of MM enabled researchers to identify a risk profile based on the levels of different proteins that may predict more aggressive disease. Based on this profile, high risk patients had a median survival (MS) without cancer progression of about 1 year, median scores were associated with a 2.5 MS, and low risk patients had MS of over 7 years. The risk score progressively increased from MGUS, to NDMM, to PCL.^3,4

The researchers identified several proteins that were highly expressed in MM cells, suggesting the significance of their role in disease progression, and their potential as new therapeutic targets for patients. Based on genetic data, they discovered that POU2AF1, which regulates B cell development, and IRS1, a signaling pathway that promotes cell growth, are essential for the proliferation of malignant MM cells.³

The findings underscore the importance of understanding the proteogenomic environment of MM for creating targeted therapies that are tailored to each patient, potentially improving treatment response rates and overall outcomes for high-risk patients. Ongoing research aims to pinpoint the most promising therapeutic targets among these overexpressed proteins, paving the way for expanded treatment options that could significantly enhance outcomes for high-risk or treatment-resistant patients with MM.

REFERENCES

1. Quadruple therapies including immunotherapy agents show benefit in multiple myeloma. Pharmacy Times. May 31, 2024. Accessed July 3, 2024. https://www.pharmacytimes.com/view/quadruple-therapies-including-immunotherapy-agents-show-benefit-in-multiple-myeloma

2. The evolving treatment landscape of multiple myeloma: gprc5d-targeted car t-cell therapy. Pharmacy Times. July 2, 2024. Accessed July 3, 2024. https://www.pharmacytimes.com/view/the-evolving-treatment-landscape-of-multiple-myeloma-gprc5d-targeted-car-t-cell-therapy

3. Ramberger E, Sapozhnikova V, Ng Y.L.D., et al. The proteogenomic landscape of multiple myeloma reveals insights into disease biology and therapeutic opportunities. Nat Cancer. June 28, 2024. doi:10.1038/s43018-024-00784-3

4. Analyses identify proteins tied to multiple myeloma disease course. Myeloma Research News. July 2, 2024. Accessed July 3, 2024. https://myelomaresearchnews.com/news/analyses-identify-proteins-tied-multiple-myeloma-disease-course/