Myeloma multiple

01Definition and overview

Multiple myeloma is a malignant growth of one clone of plasma cells in the bone marrow. Plasma cells are the last stage of B-cell development and make antibodies; a myeloma clone makes a single immunoglobulin, whole or as free light chains alone, which forms a narrow band on electrophoresis: the paraprotein, also called the M protein. Free light chains that pass into the urine are Bence Jones protein. Myeloma belongs to a spectrum of plasma cell disorders:

Not every paraprotein is a plasma cell cancer. CLL and other B-cell lymphomas can make one, and HIV and autoimmune diseases can produce transient ones. A clone too small to be myeloma can still damage an organ through its protein, a monoclonal gammopathy of clinical significance, most often the kidney (of renal significance) or the nerves; POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, the M protein and skin changes) is a rare relative.

02Etiology and pathophysiology

Who gets it

• Age: a median of about 69 at diagnosis; only 2 per cent of patients are under 40.
• Sex and ancestry: more common in men, and about twice as common in Black people as in White people.
• A precursor: almost every myeloma is preceded by MGUS, found years earlier in stored blood. MGUS is present in about 3 per cent of people over 50, and more with age.
• Excess body fat modestly raises the risk; no other avoidable cause is firmly established.

How the clone forms

1. 1

   A long-lived plasma cell

   In a germinal centre, an activated B cell mutates and switches its antibody genes, then becomes a plasma cell that settles in the marrow. Myeloma cells carry these mutated, switched genes, so the clone arises at this late stage.
2. 2

   A first genetic event

   About half of clones gain extra copies of odd-numbered chromosomes (hyperdiploidy). Most of the others carry a translocation that puts an oncogene next to the immunoglobulin heavy-chain gene on chromosome 14: t(11;14) with cyclin D1, t(4;14) with FGFR3 and NSD2, t(14;16) with MAF, or t(14;20). These are present already in MGUS.
3. 3

   Progression

   Later events turn MGUS into myeloma: gain of 1q, loss of 1p or 17p (TP53), MYC rearrangement and RAS mutations. Several of them mark high-risk disease.
4. 4

   The marrow niche

   Stromal cells feed the clone with IL-6 and other growth signals, and the clone in turn reshapes bone, marrow and immunity around it.

How it does harm

About half of myelomas make IgG, a fifth IgA and a fifth light chains only; IgD, IgM and IgE myeloma are rare, and about 3 per cent are non-secretory.

03Clinical features

Many patients are found through a routine test: anaemia, a high ESR, a raised total protein or a raised creatinine. In a series of 1,027 patients at diagnosis:

had anaemia

73per centhad anaemia

had an abnormal skeletal X-ray

79per centhad an abnormal skeletal X-ray

had a creatinine of 177 µmol/L or more

19per centhad a creatinine of 177 µmol/L or more

had hypercalcaemia

13per centhad hypercalcaemia

• Bone pain in about 60 per cent, mostly in the back and ribs and worse on movement; pathological fractures, and vertebral collapse with loss of height.
• Fatigue and breathlessness from anaemia.
• Infections, chiefly pneumonia, urinary infections and shingles; about a quarter of patients have a serious infection within 3 months of diagnosis.
• Hypercalcaemia: thirst, polyuria, constipation, nausea, drowsiness and confusion.
• Acute kidney injury, in 20 to 30 per cent at diagnosis; frothy urine suggests amyloid with nephrotic syndrome.
• Bruising and bleeding, and hyperviscosity: headache, blurred vision, nosebleeds, confusion.
• Plasmacytomas in bone or soft tissue, which can compress the spinal cord or nerve roots.
• Amyloid: nephrotic syndrome, heart failure, neuropathy, carpal tunnel syndrome, an enlarged tongue, bruising around the eyes.

The emergencies

These four can cause permanent harm within hours to days, and treatment starts before the work-up is complete.

04Diagnosis and management

Tests

A urine dipstick does not detect light chains, so it cannot rule out Bence Jones proteinuria. A skeletal survey is used only when nothing else is available, because it misses many lesions, and an isotope bone scan is no use. When amyloid is suspected, a fat or organ biopsy stained with Congo red, echocardiography and NT-proBNP are added.

Diagnostic criteria

Myeloma needs clonal marrow plasma cells of 10 per cent or more, or a biopsy-proven plasmacytoma, and at least one myeloma-defining event, each caused by the plasma cell disorder:

The three SLiM biomarkers were added in 2014 because each carries a risk of organ damage of about 80 per cent within 2 years, which is too high to wait for. Hyperviscosity, infections, amyloidosis and neuropathy are not myeloma-defining events.

clonal marrow plasma cells, the threshold for myeloma

10per centclonal marrow plasma cells, the threshold for myeloma

plasma cells, myeloma even without CRAB

60per centplasma cells, myeloma even without CRAB

involved to uninvolved free light chains

100to 1involved to uninvolved free light chains

paraprotein, MGUS below and smouldering above

30g/Lparaprotein, MGUS below and smouldering above

Staging and risk

The International Staging System uses two blood tests: stage I is β2-microglobulin below 3.5 mg/L with albumin of 35 g/L or more, stage III is β2-microglobulin of 5.5 mg/L or more, and stage II is neither. The second revision, R2-ISS, adds points for ISS stage (II 1, III 1.5), deletion 17p (1), a high LDH (1), t(4;14) (1) and 1q gain (0.5):

The 2025 international definition of high-risk myeloma is any of: deletion 17p in more than 20 per cent of plasma cells or a TP53 mutation; t(4;14), t(14;16) or t(14;20) together with 1q gain or deletion 1p32; deletion 1p32 on both copies, or on one with 1q gain; or β2-microglobulin of 5.5 mg/L or more with a normal creatinine.

The drugs

First-line treatment

Treatment starts when myeloma is diagnosed, and its intensity follows fitness rather than age alone; a transplant is usually offered to fit patients up to about 70.

1. 1

   Induction

   Several cycles (4 in the main daratumumab trial) of a quadruplet: daratumumab or isatuximab with bortezomib, lenalidomide and dexamethasone. Stem cells are collected after 3 to 4 cycles.
2. 2

   Autologous transplant

   High-dose melphalan, 200 mg/m² (less in kidney failure), then the patient's own stem cells are returned. It deepens and lengthens the response but does not cure.
3. 3

   Consolidation

   A few more cycles of the quadruplet.
4. 4

   Maintenance

   Lenalidomide 10 mg daily until progression, or lenalidomide with daratumumab.

In a trial of 709 patients aged up to 70, daratumumab added to this sequence left 84 per cent free of progression at 4 years, against 68 per cent (PERSEUS). Patients who cannot have a transplant but are fit, up to about 80, receive the same quadruplet without the transplant: in a trial of 446 such patients, isatuximab added to bortezomib, lenalidomide and dexamethasone left 63 per cent free of progression at 5 years, against 45 per cent (IMROZ). Daratumumab with the same three drugs cut the risk of progression or death by 43 per cent in 395 patients who were not having a transplant or were deferring it (CEPHEUS). Older or frail patients receive daratumumab with lenalidomide and dexamethasone until progression, with the dexamethasone reduced or stopped after the first months.

Smouldering myeloma

Smouldering myeloma is watched, with tests every few months at first. High risk is commonly judged by the 20-2-20 rule: two or more of marrow plasma cells above 20 per cent, a paraprotein above 20 g/L and a free light chain ratio above 20, with a median of 29 months to myeloma. Daratumumab for up to 3 years is now licensed in the EU for high-risk smouldering myeloma: in a trial of 390 patients, 63 per cent were free of progression to myeloma at 5 years, against 41 per cent with monitoring, with fewer deaths (AQUILA).

Relapse

Myeloma relapses in almost everyone, either as a rising paraprotein or light chains or with new organ damage. The choice depends on which drugs the disease is refractory to (lenalidomide and anti-CD38 above all), on fitness and on earlier side effects. Early relapses use drugs the myeloma has not failed, such as an anti-CD38 antibody with carfilzomib or pomalidomide; when it is refractory to lenalidomide, CAR T cells can be given from the first relapse. Later relapses, after an immunomodulatory drug, a proteasome inhibitor and an anti-CD38 antibody (triple-class exposed), are treated with bispecific antibodies or CAR T cells. EU licences:

Other plasma cell disorders

• MGUS: no treatment. Low-risk MGUS (IgG, below 15 g/L, normal free light chain ratio) is rechecked at 6 months and then every 2 to 3 years; higher-risk MGUS after 6 months and then yearly, for life. Bone pain, tiredness, frothy urine or numbness bring the patient back early.
• Solitary plasmacytoma: PET-CT or whole-body MRI and a marrow first, to exclude myeloma; then radiotherapy to the lesion, and follow-up for progression.
• AL amyloidosis: suspected with nephrotic syndrome, heart failure with thick ventricular walls, neuropathy, carpal tunnel syndrome, an enlarged tongue or bruising around the eyes. A fat or organ biopsy shows apple-green birefringence with Congo red, and the amyloid is typed. Daratumumab with cyclophosphamide, bortezomib and dexamethasone is the first treatment, licensed in the EU.
• Waldenström macroglobulinaemia: an IgM paraprotein with lymphoplasmacytic cells in the marrow, about 9 in 10 with the MYD88 L265P mutation. It is treated when it causes symptoms (anaemia, hyperviscosity, bulky disease, neuropathy), with rituximab-based chemoimmunotherapy or a BTK inhibitor, and plasma exchange for hyperviscosity.

05Epidemiology

There were about 188,000 new cases and 121,000 deaths from myeloma worldwide in 2022, about 50,000 of the cases in Europe, and numbers are expected to rise by about 70 per cent by 2045 as populations age. In Europe the incidence is 4.5 to 6 per 100,000 a year, 1 to 1.8 per cent of all cancers; it is the second commonest haematological cancer. Rates are highest in North America and Australia and New Zealand, and lower in Asia. The median age at diagnosis is about 69, men are affected more than women, and Black people about twice as often as White people. MGUS is far commoner: about 3 per cent of people over 50.

06Prognosis

Myeloma remains incurable for most patients: each remission tends to be shorter than the last as resistant clones emerge. Yet survival has changed beyond recognition, from a median of 33 months in patients diagnosed between 1985 and 1998 to a 5-year relative survival of about 64 per cent in the United States today, and in trials of quadruplets most patients are still free of progression after 4 to 5 years.

• Worse outcomes come with a high R2-ISS stage or high-risk genetics, plasma cell leukaemia, disease outside the bone, a high LDH, kidney failure that does not recover, frailty, and failure to reach undetectable residual disease.
• Smouldering myeloma progresses at about 10 per cent a year for the first 5 years, 3 per cent a year for the next 5 and 1 to 2 per cent a year after that.
• AL amyloidosis is judged by the heart: advanced cardiac involvement carries most of the early deaths.

During and after treatment, the paraprotein or free light chains, blood count, creatinine and calcium are checked every 1 to 3 months. New back pain, weakness in the legs, confusion or a fall in urine output in a patient with myeloma needs to be seen the same day.