Multiple Myeloma

What is multiple myeloma?

Plasma cells develop from B lymphocytes and produce antibodies (immunoglobulins) that fight infection. In myeloma, one plasma cell becomes cancerous and copies itself thousands of times. All the copies make the same useless antibody, called the M protein or paraprotein, or only part of it, called a light chain.

The word "multiple" refers to the many areas of bone marrow that are usually involved, in the spine, skull, pelvis, ribs and long bones.

From MGUS to myeloma

Almost all myeloma starts as MGUS (monoclonal gammopathy of undetermined significance), a symptomless state with a small amount of M protein found in about 3% of people over 50. MGUS turns into myeloma or a related disease at about 1% a year. An intermediate stage, smoldering myeloma, has more abnormal plasma cells but no organ damage.

Symptoms: the CRAB criteria

Doctors summarize the organ damage caused by myeloma as CRAB:

C: High calcium (hypercalcemia)

Bone breakdown releases calcium into the blood. High calcium causes thirst, frequent urination, constipation, nausea, tiredness and, when severe, confusion.

R: Renal (kidney) damage

Light chains clog the kidney tubules ("myeloma kidney"), and high calcium and dehydration add to the damage. Kidney problems may cause foamy urine, swelling or reduced urine, but are often found only on blood tests.

A: Anemia

Myeloma cells crowd out red cell production, causing anemia: tiredness, breathlessness and pale skin. It is present in most people at diagnosis.

B: Bone disease

Myeloma activates cells that dissolve bone and switches off those that rebuild it, creating punched-out holes (lytic lesions) and thinning. This causes:

• bone pain, most often in the back, ribs or hips, typically worse with movement
• fractures after minor injury, including vertebral collapse with loss of height
• spinal cord compression, a medical emergency

Other symptoms

• frequent infections, especially pneumonia and urinary infections, because normal antibodies are reduced
• numbness or tingling from nerve damage
• easy bruising or bleeding
• weight loss
• rarely, thick blood (hyperviscosity) causing headaches, blurred vision and nosebleeds
• swelling of the tongue, heart or kidney problems from amyloidosis, which affects some patients

Early myeloma can cause no symptoms and be discovered through a routine blood test showing high total protein, anemia or raised creatinine.

Risk factors

• age over 65, the main risk factor
• male sex
• Black ancestry
• MGUS
• a family history of myeloma or MGUS
• obesity
• exposure to high levels of radiation or certain chemicals, including some pesticides and Agent Orange in veterans

How multiple myeloma is diagnosed

• Blood tests: complete blood count, kidney function, calcium, albumin and beta-2 microglobulin.
• Serum protein electrophoresis (SPEP) and immunofixation: detect and identify the M protein.
• Serum free light chain test: measures kappa and lambda light chains. A ratio of 100 or more is a sign of active myeloma.
• 24-hour urine protein tests: look for light chains in urine (Bence Jones protein).
• Bone marrow biopsy: measures the percentage of plasma cells and tests their genetics (FISH), which classifies risk. Changes such as t(4;14), t(14;16) and del(17p) mean higher-risk disease.
• Imaging: whole-body low-dose CT, PET-CT or MRI. These are more sensitive than the older X-ray skeletal survey.

Myeloma is diagnosed as active when there are at least 10% clonal plasma cells and either CRAB features or certain markers of high risk, such as 60% or more plasma cells, a light chain ratio of 100 or more, or more than one focal lesion on MRI.

Staging

The Revised International Staging System (R-ISS) uses albumin, beta-2 microglobulin, LDH and high-risk genetics to group patients into stages I to III, which help predict outcome.

Multiple myeloma treatment

Treatment begins when myeloma is active. It usually combines 3 or 4 drugs from different classes.

Initial (induction) therapy

Common combinations include:

• a proteasome inhibitor (bortezomib or carfilzomib)
• an immunomodulatory drug (lenalidomide, pomalidomide or thalidomide)
• an anti-CD38 antibody (daratumumab or isatuximab)
• a steroid (dexamethasone)

Stem cell transplant

Fit patients, often up to about age 70 to 75, may have high-dose melphalan chemotherapy followed by an autologous stem cell transplant using their own previously collected stem cells. It deepens and lengthens remission.

Maintenance

Lower-dose treatment, often lenalidomide, continues after induction or transplant to keep the disease in remission.

Relapsed disease

Myeloma usually returns eventually. Options include switching drug classes, CAR T-cell therapy (such as idecabtagene vicleucel or ciltacabtagene autoleucel) and bispecific antibodies (such as teclistamab, elranatamab and talquetamab), which redirect the patient's T cells to myeloma cells.

Supportive care

• Bone protection: bisphosphonates or denosumab reduce fractures. Dental checks are needed first because of a rare risk of jaw bone damage.
• Radiation or surgery for painful bone lesions, fractures or spinal cord compression. Kyphoplasty can stabilize collapsed vertebrae.
• Kidney protection: plenty of fluids, treating high calcium and avoiding NSAIDs such as ibuprofen and contrast dye where possible.
• Infection prevention: vaccines (not live ones), antiviral tablets with some drugs, and sometimes antibody infusions (IVIG).
• Blood clot prevention: aspirin or a blood thinner with lenalidomide or thalidomide.
• Treatment of anemia and nerve pain.

Outlook and life expectancy

Survival has improved dramatically over the last two decades. The 5-year relative survival in the US is now around 60%, and many people live 10 years or more, especially standard-risk patients who respond well to treatment. Outlook depends on stage, genetic risk, age, kidney function and response to therapy. Deep remissions with no detectable disease (MRD negative) are linked to longer survival.

Frequently asked questions

What are the early signs of multiple myeloma?

Early signs are often vague: persistent back or rib pain, tiredness from anemia, frequent infections, thirst and constipation from high calcium, or abnormal kidney tests. Many cases are first suspected when a routine blood test shows high protein, anemia or a raised creatinine.

What are the CRAB criteria in myeloma?

CRAB stands for high Calcium, Renal (kidney) impairment, Anemia and Bone lesions. These are signs of organ damage caused by myeloma. Having one or more, along with abnormal plasma cells, defines active myeloma that needs treatment.

Is multiple myeloma curable?

For most people it is not considered curable, but it is very treatable. Combination drugs, stem cell transplant and newer immunotherapies can keep it under control for many years, and a small number of people have very long remissions with no detectable disease.

What does myeloma bone pain feel like?

It is usually a deep, aching pain in the lower back, ribs or hips that worsens with movement and may persist at night. Sudden severe pain can mean a fracture. Back pain with leg weakness or numbness needs emergency care because it can signal spinal cord compression.

What is the life expectancy with multiple myeloma?

Many people live 5 to 10 years or more after diagnosis with modern treatment, and the 5-year survival rate in the US is about 60%. Outlook varies widely with genetic risk, stage, age, kidney function and response to treatment.

Is multiple myeloma a type of leukemia?

No. Both are blood cancers that start in the bone marrow, but myeloma comes from plasma cells and mainly damages bones and kidneys, while leukemia arises from other white blood cell lines and mainly affects blood counts.