Write a short note on multiple myeloma.

Definition

Multiple myeloma is a malignant clonal proliferation of plasma cells in the bone marrow, producing a monoclonal immunoglobulin (paraprotein or M-band) and causing end-organ damage. It accounts for about 1% of all malignancies and 10% of haematological cancers, with a median age at diagnosis of around 65 years.

Pathogenesis

Clonal plasma cells accumulate in the marrow and secrete a single immunoglobulin (IgG in 55%, IgA in 25%) or free light chains alone (light chain myeloma, 15%). The malignant cells:

• Secrete RANKL and inhibit osteoprotegerin, activating osteoclasts while suppressing osteoblasts → purely lytic bone lesions with hypercalcaemia and, characteristically, no osteoblastic reaction — which is why the bone scan is negative and skeletal survey or low-dose CT is required.
• Crowd out normal haemopoiesis → anaemia and cytopenias.
• Suppress normal immunoglobulin production (immune paresis) → recurrent infection, the leading cause of death.
• Produce free light chains that are filtered and precipitate in tubules → cast nephropathy and renal failure.

Myeloma is almost always preceded by monoclonal gammopathy of undetermined significance (MGUS), which progresses at about 1% per year.

Clinical Features — "crab"

Other features:

• Recurrent bacterial infections — pneumococcal and other encapsulated organisms, from immune paresis and neutropenia.
• Hyperviscosity syndrome — headache, blurred vision, confusion, mucosal bleeding, retinal vein engorgement (commoner with IgA and with very high paraprotein levels).
• Bleeding tendency — paraprotein interference with platelet function and coagulation factors.
• Amyloidosis (AL type) — macroglossia, nephrotic syndrome, cardiomyopathy, carpal tunnel syndrome, peripheral neuropathy, periorbital purpura.
• Peripheral neuropathy — from amyloid, the disease itself, or treatment (bortezomib, thalidomide).
• Extramedullary plasmacytoma and soft tissue masses.

Investigations

The diagnostic triad to demonstrate: a monoclonal protein, clonal marrow plasma cells, and end-organ damage.

• Serum and urine protein electrophoresis with immunofixation — demonstrates and types the M-band; Bence Jones protein (free light chains) in urine, which is not detected by standard urine dipstick — an important practical point.
• Serum free light chain assay with kappa:lambda ratio — essential, particularly in light-chain and non-secretory disease.
• Quantitative immunoglobulins — the paraprotein isotype is raised while the others are suppressed (immune paresis).
• Bone marrow aspiration and trephine biopsy — clonal plasma cells ≥ 10%, confirmed by immunohistochemistry or flow cytometry; cytogenetics by FISH for risk stratification (t(4;14), t(14;16) and del(17p) are high risk).
• CBC and smear: normocytic anaemia, rouleaux formation, and a markedly raised ESR.
• Biochemistry: calcium, renal function, albumin, LDH, uric acid, and beta-2 microglobulin (a key prognostic marker used in the Revised International Staging System with albumin, LDH and cytogenetics).
• Imaging: whole-body low-dose CT, MRI or PET-CT — these have replaced the traditional skeletal survey and detect lesions far earlier. MRI is essential where cord compression is suspected. A radionuclide bone scan is typically NEGATIVE because there is no osteoblastic response.

Diagnostic criteria (IMWG): clonal marrow plasma cells ≥ 10% (or biopsy-proven plasmacytoma) plus either CRAB features or a myeloma-defining biomarker — clonal plasma cells ≥ 60%, involved:uninvolved free light chain ratio ≥ 100, or more than one focal lesion on MRI.

Management

Myeloma remains incurable for most, but treatment has transformed survival from 2–3 years to often beyond 7–10 years.

1. Anti-myeloma therapy

• Induction with a triplet or quadruplet regimen combining a proteasome inhibitor (bortezomib, carfilzomib), an immunomodulatory drug (lenalidomide, thalidomide), a corticosteroid (dexamethasone), and increasingly an anti-CD38 monoclonal antibody (daratumumab).
• Autologous stem cell transplantation after induction for fit patients — still the standard of care in transplant-eligible disease, followed by lenalidomide maintenance.
• Relapsed and refractory disease: alternative combinations, CAR-T cell therapy (BCMA-directed), bispecific antibodies (teclistamab), and selinexor.
• Thalidomide is available and affordable in India and remains widely used, with attention to its teratogenicity, neuropathy and thrombotic risk.

2. Supportive care — as important as the chemotherapy

• Bone disease: bisphosphonates (zoledronic acid) or denosumab for all patients with bone disease — they reduce skeletal events and pain; dental assessment before starting because of osteonecrosis of the jaw. Radiotherapy for localised painful lesions and cord compression; vertebroplasty or kyphoplasty; orthopaedic fixation for impending fracture.
• Hypercalcaemia: aggressive intravenous hydration, bisphosphonates, corticosteroids (see the hypercalcaemia answer).
• Renal protection: maintain hydration, avoid NSAIDs and nephrotoxins, use contrast cautiously, treat hypercalcaemia and hyperuricaemia promptly, and start effective anti-myeloma therapy quickly — renal impairment is often reversible if treated early. Dialysis where required.
• Anaemia: transfusion, erythropoiesis-stimulating agents.
• Infection: prompt treatment, pneumococcal and influenza vaccination, consideration of prophylactic antibiotics and immunoglobulin replacement in recurrent infection; antiviral prophylaxis with bortezomib (herpes zoster reactivation).
• Thromboprophylaxis with immunomodulatory drugs — these substantially increase venous thromboembolism risk.
• Pain management using the WHO ladder; avoid NSAIDs because of renal risk.
• Plasmapheresis for symptomatic hyperviscosity.