Multiple myeloma

doi:10.1016/S0140-6736(21)00135-5

The Lancet

Volume 397, Issue 10272, 30 January–5 February 2021, Pages 410-427

https://doi.org/10.1016/S0140-6736(21)00135-5 Get rights and content

Summary

Multiple myeloma is the second most common haematological malignancy in high-income countries, and typically starts as asymptomatic precursor conditions—either monoclonal gammopathy of undetermined significance or smouldering multiple myeloma—in which initiating genetic abnormalities, such as hyperdiploidy and translocations involving the immunoglobulin heavy chain, are already present. The introduction of immunomodulatory drugs, proteasome inhibitors, and CD38-targeting antibodies has extended survival, but ultimately the majority of patients will die from their disease, and some from treatment-related complications. Disease progression and subsequent relapses are characterised by subclonal evolution and increasingly resistant disease. Patients with multiple myeloma usually have hypercalcaemia, renal failure, anaemia, or osteolytic bone lesions—and a detailed diagnostic investigation is needed to differentiate between symptomatic multiple myeloma that requires treatment, and precursor states. Risk stratification using both patient-specific (eg, performance status) and disease-specific (eg, presence of high-risk cytogenetic abnormalities) is important for prognosis and to define the best treatment strategy. Current research strategies include the use of minimal residual disease assays to guide therapy, refining immunotherapeutic approaches, and intercepting disease early in smouldering multiple myeloma.

Introduction

In multiple myeloma research, there is increased focus on understanding disease evolution from precursor conditions, use of minimal residual disease for prognosis, and continued fast-paced development of new therapies. Such therapies include both next-generation agents of known classes of antimyeloma drugs, and agents with new mechanisms of action, particularly new immunotherapies. Supportive care measures are of key importance in multiple myeloma management, and need to keep pace with both unfamiliar toxicities from new treatments and survivorship challenges from extending survival without cure. In this Seminar, we provide a practical approach to understanding these latest developments and their implications for how clinicians manage this challenging malignancy in the real world.

Section snippets

Epidemiology, risk factors, and clinical course

Multiple myeloma is a blood cancer of monoclonal plasma cells that accumulate in the bone marrow and produce M-protein (also known as monoclonal immunoglobulin or paraprotein). Multiple myeloma is complicated by organ dysfunction: hypercalcaemia, renal insufficiency, anaemia, and bone destruction (known as the CRAB criteria). Multiple myeloma accounts for 1% of neoplastic diseases, and is the second most common haematological malignancy in high-income countries, with an incidence of 4·5–6 per

Pathogenesis, genomics, and the marrow microenvironment

The initiating event driving malignant development is either the acquisition of hyperdiploidy or a translocation involving the immunoglobulin heavy chain gene locus.⁸ Such clonal events can occur in almost all cells, and are present in the precursor conditions monoclonal gammopathy of undetermined significance (MGUS) and smouldering multiple myeloma. Aetiological translocations mean oncogenes are controlled by the strong immunoglobulin heavy chain gene enhancer; the t(4;14) translocation

Symptoms, diagnostic investigation, and prognostic models

Patients are sometimes identified on the basis of an M-protein on routine blood testing, although most patients have signs and symptoms of organ damage (eg, bone pain and fractures, infections, anaemia, renal failure, and hyperviscosity). A detailed diagnostic investigation of patients with MGUS or smouldering multiple myeloma is needed to differentiate between multiple myeloma and asymptomatic precursor conditions, using clinical, biochemical, and radiological criteria (table 1).29, 30

Disease monitoring including assesment of minimal residual disease

Response to therapy is determined by measuring M-protein in serum and urine, combined with bone marrow assessment of plasma cells (appendix p 5). Minimal residual disease assessment of bone marrow is generally only done in the context of clinical trials, but evidence from current trials supports its use in the near future to help direct treatment choice. Cross-sectional imaging is repeated during follow-up if clinically indicated—eg, as part of response assessment in extra-osseous tumours, in

MGUS and smouldering multiple myeloma: management and risk models

There is good evidence that multiple myeloma is always preceded by the precursor conditions MGUS or smouldering multiple myeloma.⁴⁹ These precursors are characterised by the absence of signs or symptoms related to multiple myeloma or other lymphoproliferative diseases. Only 5–7% of patients with MGUS, and around 50% of patients with smouldering myeloma, will develop multiple myeloma within 5 years of diagnosis.50, 51 Careful assessment of disease bulk and organ function, using the same

Treatment of myeloma

Proteasome inhibitors and immunomodulatory drugs are the current mainstay of myeloma therapy and in clinical trials are usually the standard of care to which newer drugs are added. Steroids, in the form of dexamethasone or prednisolone, are invariably included. The fourth class of drug, which is becoming a key component of relapse and first-line therapies, is CD38-targeting antibodies (appendix pp 6–7). The main drugs used, together with their licensed indications and main toxicities, are

Solitary plasmacytoma

Solitary plasmacytomas usually arise in marrow-bearing bone (ribs, vertebrae, pelvis, femurs) with or without extraosseus extension.¹¹⁶ Solitary extramedullary plasmacytomas have no bone involvement, and occur most commonly in the head and neck, gastrointestinal tract, and lungs. Diagnosis is made on the basis of tissue evidence of monoclonal plasma cell infiltrate; it is important to exclude the presence of occult multiple myeloma, hence investigations should include bone marrow examination,

Supportive care

Patients with myeloma have a considerable disease and treatment burden, causing morbidity and mortality. Disease complications (eg, infections, bone disease, and gastrointestinal upsets), lead to treatment delays or discontinuation, reducing disease-free survival for patients who suffer with such complications.121, 122, 123, 124 Infections, cardiovascular disease, and renal failure are major causes of early death in multiple myeloma.125, 126 Before the introduction of novel drugs, around 10% of

New agents and future therapies

New therapies with novel mechanisms of action are still needed for patients with disease that is refractory to all available approved drugs, and for patients with high-risk disease. Improved understanding of molecular abnormalities related to disease initiation and progression, and of how tumour cells interact with the protective microenvironment, enabled the development of new drugs, including interventions based on biomarkers for personalised therapeutic treatment of specific molecular

Managing myeloma in the real world

Rapid pharmacological and technological developments have markedly improved patient survival, albeit with increasing treatment costs and clear global differences in the availability and reimbursement of the newer drugs because of economic constraints.¹ Clinical trial data can help to advance clinical practice and product licensing, but need to be supplemented with real world evidence to provide greater clarity about benefit, toxicity and tolerability, treatment duration, and long-term effects.

Search strategy and selection criteria

We searched PubMed on Feb 1, 2020, and the websites for the major conferences of the American Society of Hematology, the American Society of Clinical Oncology, and the European Haematology Association, on Feb 10, 2020, using the search terms “myeloma”, “multiple myeloma”, “MGUS”, “monoclonal gammopathy of undetermined significance”, “smoldering multiple myeloma”, and “primary plasma cell leukemia”. We searched for papers and abstracts published in English, without restriction on the earliest

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