Multiple Myeloma

Multiple myeloma is a malignant plasma cell disorder characterized by clonal proliferation of plasma cells within the bone marrow, leading to the production of monoclonal immunoglobulin (M protein) or free light chains. The disease causes end-organ damage through bone destruction, bone marrow failure, renal impairment, hypercalcaemia, and immunodeficiency. Multiple myeloma is the second most common hematological malignancy and predominantly affects older adults. Early recognition and timely initiation of therapy improve symptom control, reduce complications, and prolong survival.

Epidemiology

Multiple myeloma accounts for approximately 10% of all hematological malignancies and about 1% of all cancers worldwide. The median age at diagnosis is approximately 65–70 years, with the disease being uncommon in individuals younger than 40 years. It occurs slightly more frequently in males than females and has a higher incidence among people of African ancestry. Most patients are diagnosed after developing symptomatic end-organ damage.

Risk factors

Risk factors for multiple myeloma include:

• Increasing age, particularly over 60 years

• Male sex

• African ancestry

• Monoclonal gammopathy of undetermined significance (MGUS)

• Smouldering multiple myeloma

• Family history of plasma cell disorders

• Exposure to ionizing radiation

• Occupational exposure to pesticides, petroleum products, and certain industrial chemicals

• Obesity

• Chronic immune stimulation

Pathophysiology

Multiple myeloma develops from malignant transformation of plasma cells, usually evolving from MGUS through smouldering multiple myeloma before becoming symptomatic disease. Clonal plasma cells accumulate in the bone marrow and produce excessive monoclonal immunoglobulin or free light chains.

The disease results in:

• Osteoclast activation with suppression of osteoblast activity, leading to osteolytic bone lesions and pathological fractures.

• Bone marrow infiltration causing anaemia, thrombocytopenia, and leukopenia.

• Light-chain deposition and hypercalcaemia contributing to renal impairment.

• Suppression of normal immunoglobulin production resulting in recurrent infections.

• Hyperviscosity syndrome in selected patients with markedly elevated monoclonal protein levels.

Clinical presentation

Patients commonly present with symptoms related to bone destruction, bone marrow failure, renal dysfunction, hypercalcaemia, or recurrent infections. The classic features are summarized by the CRAB criteria:

• C – Hypercalcaemia

• R – Renal impairment

• A – Anaemia

• B – Bone disease

Symptoms

• Bone pain, particularly involving the spine, ribs, pelvis, or long bones

• Generalized weakness and fatigue

• Symptoms of hypercalcaemia including thirst, constipation, nausea, vomiting, confusion, and polyuria

• Symptoms of renal impairment including reduced urine output and fluid overload

• Recurrent bacterial infections due to impaired antibody production

• Weight loss

• Bleeding tendencies

• Symptoms of hyperviscosity syndrome (rare), including headache, blurred vision, dizziness, and altered mental status

Clinical signs

• Pallor due to anaemia

• Bone tenderness

• Pathological fractures

• Reduced mobility

• Signs of dehydration

• Features of hypercalcaemia

• Evidence of renal impairment

• Signs of infection

• Bleeding manifestations such as petechiae or ecchymoses

• Neurological deficits in patients with spinal cord compression

Differential diagnosis

• Monoclonal gammopathy of undetermined significance (MGUS)

• Smouldering multiple myeloma

• Bone metastases from solid organ malignancies

• Waldenström macroglobulinaemia

• Primary amyloidosis

• Chronic kidney disease of other causes

• Osteoporosis with vertebral compression fractures

• Lymphoma involving bone marrow

• Plasma cell leukaemia

Diagnostic criteria

The diagnosis of multiple myeloma is based on evidence of clonal plasma cell proliferation together with myeloma-defining events.

Diagnosis is established by:

• Clonal bone marrow plasma cells ≥10% or biopsy-proven plasmacytoma.

AND one or more of the following:

• Hypercalcaemia attributable to multiple myeloma.

• Renal impairment attributable to multiple myeloma.

• Anaemia attributable to multiple myeloma.

• One or more osteolytic bone lesions.

Or the presence of validated myeloma-defining biomarkers according to the International Myeloma Working Group.

Disease staging should be performed using the Revised International Staging System (RISS) adopted by the International Myeloma Working Group.

Investigations

The following investigations should be performed:

• Full blood count (FBC)

• Renal function tests (RFT)

• Liver function tests (LFT)

• Serum electrolytes

• Peripheral blood smear

• Bone marrow aspiration and trephine biopsy

• Serum protein electrophoresis

• Urine examination for Bence Jones protein

• Skeletal survey using X-ray, CT scan, or MRI

• Serum β2-microglobulin

Management

Management aims to control disease progression, relieve symptoms, prevent complications, and improve quality of life.

Initial management includes:

• Assess airway, breathing, and circulation in acutely ill patients.

• Identify and treat hypercalcaemia, renal impairment, severe anaemia, infection, spinal cord compression, or pathological fractures.

• Provide supportive care including hydration, blood transfusion, antibiotics, and analgesia when indicated.

• Confirm diagnosis and stage disease before initiating systemic therapy.

• Monitor treatment response, renal function, blood counts, and treatment-related adverse effects throughout follow-up.

Non-pharmacological treatment

• Adequate hydration.

• Nutritional support.

• Physiotherapy and rehabilitation to improve mobility.

• Prevention of falls and pathological fractures.

• Orthopaedic assessment for impending or established fractures.

• Radiotherapy for pain control of lytic lesions refractory to systemic therapy.

• Radiotherapy for spinal cord compression due to plasmacytoma.

• Primary radiotherapy for solitary plasmacytoma.

• Patient education regarding infection prevention and prompt reporting of new symptoms.

Pharmacological treatment

Supportive treatment with blood transfusion, antibiotics, hydration, and analgesia should be provided when indicated.

Bisphosphonate therapy:

• Zoledronic acid – 4 mg – IV – once monthly – for 2 years.

Recommended chemotherapy regimens include the following drugs in various combinations: Melphalan, Thalidomide, Lenalidomide, Bortezomib, Cyclophosphamide, Prednisolone and Dexamethasone.

Recommended regimens include:

• Thalidomide – 200 mg – PO – every 24 hours – for 28 days.

OR

• Lenalidomide – 25 mg – PO – every 24 hours – for 21 days.

AND

• Dexamethasone – 40 mg – PO – every 24 hours on days 1, 8, 15, and 22 – repeated every 4 weeks.

OR

• Bortezomib – 1.3 mg/m² – IV – every 24 hours on days 1, 8, 15, and 22 – repeated every 4 weeks.

AND

• Dexamethasone – 40 mg – PO – every 24 hours on days 1, 8, 15, and 22 – repeated every 4 weeks.

WITH/WITHOUT

• Cyclophosphamide – 300 mg/m² – PO – every 24 hours on days 1, 8, 15, and 22 – repeated every 4 weeks.

Management according to underlying cause

Hypercalcaemia

• Aggressive intravenous hydration.

• Initiate bisphosphonate therapy.

• Monitor serum calcium and renal function.

Renal impairment

• Optimize hydration.

• Avoid nephrotoxic medications.

• Prompt initiation of anti-myeloma therapy.

• Dialysis when indicated.

Bone disease

• Bisphosphonate therapy.

• Adequate analgesia.

• Radiotherapy for painful lesions refractory to systemic treatment.

• Orthopaedic intervention for pathological fractures or impending fractures.

Anaemia

• Blood transfusion when clinically indicated.

• Treat the underlying myeloma.

Infection

• Prompt initiation of appropriate antibiotics.

• Vaccination where appropriate according to local recommendations.

Spinal cord compression

• Urgent imaging.

• High-dose corticosteroids where indicated.

• Urgent radiotherapy and/or surgical decompression following specialist assessment.

Referral

Refer all patients with suspected or confirmed multiple myeloma to a specialist in haematology or oncology.

Urgent referral is indicated for patients with:

• Suspected spinal cord compression.

• Severe hypercalcaemia.

• Acute kidney injury.

• Pathological fractures.

• Hyperviscosity syndrome.

• Severe or recurrent infections.

• Rapidly progressive disease.

• Diagnostic uncertainty requiring specialist evaluation.

Complications

• Pathological fractures

• Spinal cord compression

• Hypercalcaemia

• Chronic kidney disease

• Acute kidney injury

• Severe anaemia

• Recurrent bacterial infections

• Hyperviscosity syndrome

• Amyloidosis

• Treatment-related complications

• Disease relapse

Prognosis

The prognosis depends on disease stage, cytogenetic abnormalities, renal function, response to therapy, and patient comorbidities. Modern combination therapies have significantly improved survival, although multiple myeloma remains an incurable disease for most patients. Early diagnosis, appropriate supportive care, and effective systemic treatment improve both survival and quality of life.

Prevention

There is no established method for preventing multiple myeloma. Early identification and monitoring of patients with MGUS or smouldering multiple myeloma may allow timely detection of disease progression. Preventive measures should also focus on reducing infection risk, maintaining bone health, preventing falls, and avoiding nephrotoxic agents.