What is multiple myeloma?
Multiple myeloma (also called myeloma) is the over-proliferation of abnormal plasma cells (which normally make antibodies) in the bone marrow (Figs 1&2).

Incidence of and risk factors for myeloma
The most recent data show that myeloma is the 19th most common cancer in the UK, with around 6300 new cases every year, accounting for 2% of cancer cases. It is usually diagnosed in people over 65 years old, with incidence rates highest in people aged 85–89 years.

Risk factors include increased age, being male, being overweight, being black, having a family history of the disease and having monoclonal gammopathy of undetermined significance (MGUS).

Symptoms

The main symptoms of myeloma are caused because the process takes place in the bone marrow (hence bone pain, especially in the back, hips and ribs as well as broken bones) along with the effects of anemia as not enough red blood cells are produced (hence fatigue, shortness of breath and weakness). Other symptoms can include lots of infections that don’t go away, and symptoms of increased blood calcium levels such as increased thirst and need to urinate, as well as, ultimately, kidney damage.

Figure 1. Hematopoiesis (Adobe Stock) Multipotent hematopoietic stem cells develop along different differentiation pathways into all the different types of blood cells. Myeloma is the over-proliferation of abnormal plasma cells.

How is myeloma usually diagnosed?

Initial tests involve blood and urine tests. The blood tests include a full blood count, liver and kidney function parameters and calcium levels. As the abnormal plasma cells produce aberrant immuno-globulins called paraproteins, blood tests are also done to test for levels of normal antibodies, serum protein electrophoresis to test for paraproteins and serum free light chain assay to detect levels of free kappa and lambda light chains in serum.

A urine sample may also be tested for free light chains, which when present in urine are called Bence Jones proteins, as well as checking kidney function.

If myeloma is suspected, further blood tests will test for beta 2 microglobulin (raised in myeloma) as well as immunofixation electrophoresis to show which type of immunoglobulin the myeloma is producing (IgA or IgG0.

A bone marrow biopsy will ascertain the percentage of abnormal plasma cells, which helps confirm the diagnosis and be used for other tests such as cytogenetics, immunophenotyping, or flow cytometry to assess chromosomal changes to provide further information about the type of melanoma and to help plan treatment.

Imaging (X-radiography, MRI an PET-CT scans) can be used to assess the extent and stage of the disease, monitor its progression and assess the effectiveness of treatment.

Treatment and survival

Myeloma cannot be cured but treatment can be very effective at managing the disease. Treatment usually involves multiple agents, previously with one from each of three groups of therapies (triplet therapy) but now more often one from each of four groups of therapies (quadruplet therapy), involving a monoclonal antibody, an immuno-modulatory agent, a proteasome inhibitor and a steroid. Autologous stem cell transplant can be used to give longer-lasting periods of remission. Additionally, in the USA, the FDA has approved CAR-T therapy, which also provides longer-lasting remission but requires a prolonged stay in hospital. Patients will usually eventually relapse as the result of disease evolution and the development of therapy resistance. In the USA and the UK the 5-year survival rate is around 54%, whereas the 10-year survival rate is approximately 40% (in the UK).

What factors affect prognosis?

Prognosis is very varied and depends on a number of factors, involving stage of disease at first diagnosis, the type of disease (whether it is high or low risk depending on the cytogenetics results) and age and physical fitness. Physical fitness or frailty is an important factor in prognosis because the patient has to be deemed strong enough to cope with some of the therapies, which are very intensive. Currently, fitness is determined by clinical frailty scores, such as the International Myeloma Working Group Frailty Index, which allocates patients into one of three levels: fit; intermediate fit; or frail. However, outcomes of therapy are still very variable. Two recent studies have sought to shed light on factors that are associated with prognosis [1,2].

Figure 2. Myeloma is caused by the overproliferation of abnormal plasma cells in the bone marrow, which then produce aberrant antibodies (Adobe Stock)

Immune signatures in new myeloma patients are associated with prognosis

Bruins et al. performed immunophenotyping of 89 newly diagnosed patients with myeloma to see if there were differences in the immune signatures between frail and intermediate-fit patients [1]. The composition of lymphoid and myeloid cells was comparable between the two patient groups apart from reduced naive CD4+ and CD8+ T-cells and increased effector memory CD4+ T-cells and CD56bright NK-cells in frail patients. Further analysis of 36 T-cell and NK-cell subsets revealed that 9 subsets showed a strong association with progression-free survival (PFS) and 5 with overall survival (OS). Four subsets of cells were linked to both PFS and OS; these were higher absolute counts of naive CD8+ T-cells, CD38+CD4+ T-cells, and CD56dimCD57+ NK-cells were linked with longer survival, and elevated EM CD8+ T-cell levels were linked to shorter survival. The results allowed the authors to develop two immune risk scores, one for PFS and one for OS.

Circulating tumour cells are a prognostic factor in myeloma

Garces et al. in their study analysed 540 newly diagnosed myeloma patients compared with baseline CTC data [2]. They characterized the genomic and transcriptomic features associate with CTC burden. They found that higher CTC levels were significantly associate with high-risk clinical features as well as being associated with genomic features that are linked to high-risk disease. Analysis of the transcriptome revealed that elevated CTCs were enriched in cell cycle and proliferation (PR) genes while presenting a reduced association with immune response. Hence, their findings showed that increased CTC levels are an indicator of aggressive myeloma.

Further study will hopefully allow the results of both of these studies to be incorporated into ris stratification and the development of personalized therapy plans for patients with newly diagnosed myeloma.

Reference
1. Bruins WSC, Smits F, Duetz C et al. Immune signatures in older patients with newly diagnosed multiple myeloma are associated with survival outcomes of first-line therapy irrespective of frailty levels. Hemasphere 2025;9(10):e70210 (https://doi.org/10.1002/hem3.70210).
2. Garces JJ, Diamond B, Sevcikova T et al. Elevated circulating tumor cells reflect high proliferation and genomic complexity in multiple myeloma. Hemasphere 2025;9(9):e70218 (https://doi.org/10.1002/hem3.70218).