Multiple Myeloma: A Complete Overview

What It Is

The Disease Spectrum

• MGUS (monoclonal gammopathy of undetermined significance): serum M protein <3 g/dL, clonal bone marrow plasma cells <10%, no myeloma-defining events. Progresses to myeloma at ~1%/year.
• Smoldering multiple myeloma: M protein ≥3 g/dL and/or 10-60% clonal bone marrow plasma cells, but no end-organ damage. Progression risk is much higher (~10%/year for the first 5 years).
• Symptomatic multiple myeloma: ≥10% clonal bone marrow plasma cells (or biopsy-proven plasmacytoma) PLUS at least one myeloma-defining event.

Diagnostic Criteria - "Myeloma-Defining Events"

• Calcium elevation (>11 mg/dL)
• Renal insufficiency (creatinine >2 mg/dL or CrCl <40 mL/min)
• Anemia (Hb <10 g/dL or >2 g/dL below normal)
• Bone lesions (one or more lytic lesions on imaging)
• Additional biomarkers of malignancy: clonal bone marrow plasma cells ≥60%, serum free light chain ratio ≥100, or >1 focal lesion on MRI

Pathophysiology

• Chromosomal translocations fusing the IgH locus (14q32) to oncogenes (cyclin D1/D3, MAF, FGFR3/MMSET); RAS mutations and MYC abnormalities drive progression from MGUS. Deletions of 17p and 1p, and amplification of 1q, are associated with adverse prognosis.
• IL-6, produced by bone marrow stromal cells, is the major growth factor supporting plasma cell proliferation.
• Bone destruction: myeloma cells upregulate RANKL on stromal cells/osteoblasts while reducing osteoprotegerin (OPG), activating osteoclasts; simultaneously, DKK1 and other factors suppress osteoblasts. This produces pure osteolytic lesions with hypercalcemia and pathologic fractures.
• Renal damage: light-chain (Bence Jones) cast nephropathy in the distal tubules ("myeloma kidney"), light chain deposition disease, AL amyloidosis (~10% of patients), hypercalcemia-induced injury, and Fanconi syndrome.
• Immune dysfunction: despite elevated total immunoglobulin, functional antibody production is suppressed, causing recurrent bacterial infections.

Wright-Giemsa stain of bone marrow aspirate showing increased plasma cells - Goldman-Cecil Medicine

Clinical Presentation

• Bone pain (back/chest most common) is present at diagnosis in >2/3 of patients; height loss from vertebral collapse
• Fatigue/weakness from anemia (present in ~75% at diagnosis, nearly universal eventually)
• Recurrent infections from functional hypogammaglobulinemia
• Renal insufficiency (~20% at diagnosis)
• Hypercalcemia (15-20% at diagnosis) - anorexia, nausea, polyuria, confusion
• Increased risk of deep vein thrombosis (compounded by immunomodulatory drug therapy)
• Radiculopathy/spinal cord compression from vertebral collapse

Workup

• Labs: CBC (normocytic anemia), serum protein electrophoresis + immunofixation, urine electrophoresis + immunofixation, serum free light chain assay, beta-2-microglobulin, albumin, LDH, calcium, creatinine. Combined serum/urine studies detect an M protein in ~97% of patients (IgG 52%, IgA 21%, light-chain only 16%). ~3% are "nonsecretory."
• Bone marrow biopsy/aspirate: clonal plasma cells, flow cytometry (CD38+/CD138+, CD19-/CD45-), FISH cytogenetics for risk stratification (t(4;14), t(14;16), t(11;14), del17p, 1q amplification)
• Imaging: low-dose whole-body CT or PET-CT are now preferred over plain films (conventional radiographs miss disease and are being phased out); MRI for spinal involvement/cord compromise

Staging (Revised International Staging System, R-ISS)

Treatment

Smoldering myeloma

Newly diagnosed, transplant-eligible (~50% of patients)

Newly diagnosed, transplant-ineligible

• VRd (bortezomib/lenalidomide/dexamethasone) for ~9 months then lenalidomide maintenance, or
• DRd (daratumumab/lenalidomide/dexamethasone) until progression
• As of January 2026, the FDA approved Darzalex Faspro (daratumumab/hyaluronidase) plus VRd specifically for transplant-ineligible newly diagnosed patients.

Relapsed/refractory disease

• Immunomodulatory drugs: thalidomide, lenalidomide, pomalidomide (all carry VTE risk, need prophylaxis)
• Proteasome inhibitors: bortezomib, carfilzomib, ixazomib
• Monoclonal antibodies: daratumumab/isatuximab (anti-CD38), elotuzumab (anti-SLAMF7)
• Bispecific antibodies (target BCMA or GPRC5D): teclistamab, elranatamab, talquetamab - newer options; teclistamab + daratumumab combo was FDA-approved March 2026
• CAR-T cell therapy: idecabtagene vicleucel (ide-cel), ciltacabtagene autoleucel (cilta-cel) - target BCMA; main toxicities are cytokine release syndrome and neurotoxicity
• Other: venetoclax (only for t(11;14) subtype), selinexor, bendamustine, belantamab mafodotin (BCMA-ADC, re-approved with bortezomib/dex Oct 2025)

Managing Complications

• Hypercalcemia: hydration, steroids, bisphosphonates (zoledronic acid/pamidronate)
• Renal failure/cast nephropathy: aggressive hydration, treat underlying myeloma, plasmapheresis if severe light-chain burden, dialysis if needed
• Bone disease: zoledronic acid or pamidronate monthly (reduces fractures, may improve survival; watch for osteonecrosis of jaw with prolonged use), denosumab as alternative, kyphoplasty for vertebral fractures
• Infection prevention: pneumococcal/influenza/COVID vaccination, antiviral prophylaxis (acyclovir) with bortezomib, IVIG for recurrent severe infections

Prognosis

Variant/Related Entities

• Plasma cell leukemia: >5% circulating plasma cells or absolute count ≥500/μL; aggressive
• Solitary plasmacytoma of bone: localized disease without systemic myeloma-defining events
• AL amyloidosis: light-chain deposition as amyloid, occurring in ~10% of myeloma patients

Note on Recent Evidence

Pathophysiology

• Primary genetic event: chromosomal translocations fusing the immunoglobulin heavy chain (IgH) locus on chromosome 14q32 to oncogenes - most commonly cyclin D1 or cyclin D3, but also MAF and FGFR3/MMSET in other subtypes. This causes dysregulation of D-cyclins, driving increased plasma cell proliferation.
• Secondary events driving MGUS → myeloma progression: RAS mutations and MYC abnormalities are the two main drivers. Later in disease, deletions of chromosome 17p and 1p, and amplification of 1q, emerge and correlate with more aggressive, treatment-resistant disease. MYC translocations appear late and are associated with aggressive biology.
• Microenvironment: interleukin-6 (IL-6), secreted mainly by bone marrow stromal cells and macrophages, is the principal growth factor sustaining plasma cell proliferation. Angiogenesis and abnormal cytokine paracrine loops within the marrow niche further support tumor growth.

• Myeloma cells upregulate RANKL (receptor activator of NF-κB ligand) expression on osteoblasts and stromal cells, while simultaneously reducing osteoprotegerin (OPG), RANKL's decoy receptor.
• The resulting increase in the RANKL/OPG ratio drives osteoclast activation and bone resorption.
• Other osteoclast-activating factors include MIP-1α, SDF-1α, IL-3, IL-1β, and IL-6.
• Simultaneously, osteoblast differentiation is suppressed by IL-3, IL-7, and DKK1 (dickkopf-1), a Wnt-pathway inhibitor.
• Net effect: pure osteolytic lesions (no compensatory bone formation), leading to hypercalcemia, osteopenia, and pathologic fractures.

• Light-chain cast nephropathy ("myeloma kidney"): free light chains (Bence Jones protein) precipitate with Tamm-Horsfall protein to form large, waxy, laminated casts obstructing the distal tubules and collecting ducts. Severity correlates directly with the quantity of urinary free light chain.
• Hypercalcemia: from bone resorption, causes nephrogenic diabetes insipidus, dehydration, and vasoconstriction, worsening renal perfusion.
• AL amyloidosis: light chains misfold and deposit as amyloid in the glomeruli/interstitium, occurring in ~10% of myeloma patients, producing nephrotic-range proteinuria.
• Light chain deposition disease: non-amyloid, linear deposition of light chains in glomerular/tubular basement membranes.
• Acquired Fanconi syndrome: proximal tubular dysfunction from light chain toxicity, causing glycosuria, phosphaturia, aminoaciduria.
• Contributing factors: dehydration, hyperuricemia, and increased susceptibility to pyelonephritis (from hypogammaglobulinemia).

Complications and Their Management

• Lytic lesions, osteopenia, pathologic fractures (vertebrae, skull, ribs, pelvis, proximal humerus/femur most common sites); vertebral collapse can cause height loss and radiculopathy or cord compression.
• Management: zoledronic acid or pamidronate monthly (reduce fracture risk, bone pain, cord compression risk; may improve survival). After 1-2 years, dosing interval can be extended to reduce osteonecrosis of the jaw risk. Denosumab is an alternative. Kyphoplasty for vertebral fractures. Radiation therapy for localized, refractory painful lesions or cord compression.

• Present in 15-20% at diagnosis; presents with anorexia, nausea, vomiting, polyuria, polydipsia, constipation, weakness, confusion, stupor.
• Management: aggressive hydration, corticosteroids, bisphosphonates (zoledronic acid/pamidronate) - corrects hypercalcemia in nearly all patients.

• Present in ~20% at diagnosis (creatinine >2 mg/dL); most often from light-chain cast nephropathy and/or hypercalcemia.
• Management: aggressive IV hydration + furosemide to maintain high urine flow if not oliguric; allopurinol if hyperuricemic; plasmapheresis (daily x5 days) if cast nephropathy suspected with very high free light chains (>150 mg/dL); hemodialysis if symptomatic azotemia; rapid initiation of anti-myeloma therapy (e.g., bortezomib-based regimens) is critical since reducing the light-chain burden is the definitive treatment.

• Due to functional hypogammaglobulinemia, neutropenia (from marrow infiltration/chemo), and immunosuppressive therapy.
• Management: prompt antibiotic therapy for bacterial infections; prophylactic trimethoprim-sulfamethoxazole with high-dose steroids; acyclovir prophylaxis with bortezomib (reactivation of herpes zoster); IVIG for recurrent severe infections with hypogammaglobulinemia; pneumococcal, influenza, and COVID vaccination for all patients.

• Normocytic, normochromic; present in ~75% at diagnosis, eventually in nearly all patients. From marrow infiltration and disease burden.
• Management: treat underlying myeloma; erythropoietin for anemia persisting despite treatment.

• Radiculopathy (most common - thoracic/lumbosacral, from vertebral collapse or nerve compression)
• Spinal cord compression (up to 10% of patients) - from vertebral collapse or extramedullary plasmacytoma; presents with severe back pain, leg weakness/paresthesia, bowel/bladder dysfunction - treated with dexamethasone and/or urgent radiation, surgical decompression if deficits progress
• Peripheral neuropathy - uncommon from myeloma itself, usually from associated amyloidosis (or treatment-related, e.g., bortezomib/thalidomide)

• Less common than in Waldenström macroglobulinemia but can occur with high M protein burden.

• Increased baseline risk of DVT/PE, compounded by immunomodulatory drugs (lenalidomide, thalidomide, pomalidomide) - requires routine antithrombotic prophylaxis during treatment.

• A subset develop an acute terminal phase: rapid tumor growth, pancytopenia, subcutaneous soft-tissue plasmacytomas, paradoxically decreased M protein, fever - survival limited to months.
• Related aggressive variant: plasma cell leukemia (>5% circulating plasma cells or absolute count ≥500/μL in peripheral blood).
• Goldman-Cecil Medicine International Edition, p. 1976-1982
• Robbins & Kumar Basic Pathology, p. 2869-2883