New horizons in our understanding of precursor multiple myeloma and early interception.

Abstract

Multiple myeloma is an incurable plasma cell malignancy that evolves over decades through the selection and malignant transformation of monoclonal plasma cells.

The evolution from precursor states to symptomatic disease is characterized by an increasing complexity of genomic alterations within the plasma cells and a remodelling of the microenvironment towards an immunosuppressive state.

Notably, in patients with advanced disease, similar mechanisms of tumour escape and immune dysfunction mediate resistance to modern T cell-based therapies, such as T cell-engaging bispecific antibodies and chimeric antigen receptor (CAR)-T cells.

Thus, an increasing number of clinical trials are assessing the efficiency and safety of these therapies in individuals with newly diagnosed multiple myeloma and high-risk smoldering multiple myeloma.

In this Review, we summarize the current knowledge about tumour intrinsic and extrinsic processes underlying progression from precursor states to symptomatic myeloma and discuss the rationale for early interception including the use of T cell-redirecting therapies.

COI Statement

Competing interests: I.M.G. received honoraria from Celgene, Bristol-Myers-Squibb, Takeda, Amgen, Janssen and Vor Biopharma; had consultancy/advisory roles with Bristol-Myers-Squibb, Novartis, Amgen, Takeda, Celgene, Cellectar, Sanofi, Janssen, Pfizer, Menarini Silicon Biosystems, Oncopeptides, The Binding Site, GSK, AbbVie, Adaptive and 10X Genomics; has received speaker fees from Vor Biopharma and Veeva Systems, Inc.; is a co-founder and equity holder in PreDICTA Biosciences; and her spouse is the CMO and equity holder of Disc Medicine. None of these interests are related to the financing of this Review. D.M.C.d.S., R.T., L.B. and J.-B.A. declare no competing interests.

References:

Howlander, N. et al. SEER Cancer Statistics Review, 1975–2013, National Cancer Institute, Bethesda, MD. http://seer.cancer.gov/csr/1975_2013/ based on November 2015 SEER data submission, posted to the SEER web site, April 2016 (2016).
Rajkumar, S. V. et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 15, e538–e548 (2014).
Kyle, R. A. et al. Long-term follow-up of monoclonal gammopathy of undetermined significance. N. Engl. J. Med. 378, 241–249 (2018).
Landgren, O. et al. Monoclonal gammopathy of undetermined significance (MGUS) consistently precedes multiple myeloma: a prospective study. Blood 113, 5412–5417 (2009).
Kyle, R. A. et al. Prevalence of monoclonal gammopathy of undetermined significance. N. Engl. J. Med. 354, 1362–1369 (2006). This study describes a long-term median follow-up of over 34 years for patients with MGUS, establishing a progression risk of 1% per year.

Article info

Journal issue:

Volume: 24
Issue: 12

Doi:

10.1038/s41568-024-00755-x

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New horizons in our understanding of precursor multiple myeloma and early interception.

Abstract

Multiple myeloma is an incurable plasma cell malignancy that evolves over decades through the selection and malignant transformation of monoclonal plasma cells.

COI Statement

References:

Howlander, N. et al. SEER Cancer Statistics Review, 1975–2013, National Cancer Institute, Bethesda, MD. http://seer.cancer.gov/csr/1975_2013/ based on November 2015 SEER data submission, posted to the SEER web site, April 2016 (2016).
Rajkumar, S. V. et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 15, e538–e548 (2014).
Kyle, R. A. et al. Long-term follow-up of monoclonal gammopathy of undetermined significance. N. Engl. J. Med. 378, 241–249 (2018).
Landgren, O. et al. Monoclonal gammopathy of undetermined significance (MGUS) consistently precedes multiple myeloma: a prospective study. Blood 113, 5412–5417 (2009).
Kyle, R. A. et al. Prevalence of monoclonal gammopathy of undetermined significance. N. Engl. J. Med. 354, 1362–1369 (2006). This study describes a long-term median follow-up of over 34 years for patients with MGUS, establishing a progression risk of 1% per year.