Plasma cell disorders

Summary

Plasma cell disorders (dyscrasias) are a group of diseases caused by clonal proliferation of plasma cells that secrete a single (monoclonal) immunoglobulin or light chain, called the M-protein (paraprotein).

The main entities to know are:

• MGUS — Monoclonal Gammopathy of Undetermined Significance (benign, premalignant).
• Smoldering multiple myeloma — intermediate, asymptomatic.
• Multiple myeloma (MM) — malignant; symptomatic with CRAB features.
• Waldenström macroglobulinemia (WM) — IgM-secreting lymphoplasmacytic lymphoma; causes hyperviscosity.
• Plasmacytoma — solitary plasma cell tumor (bone or extramedullary).
• AL amyloidosis — light chains deposit as amyloid in organs.

Multiple myeloma is the highest-yield. Suspect it in an older patient with bone pain, anemia, renal failure, and hypercalcemia.

Definition and Classification

A plasma cell is the final, antibody-producing form of a B-lymphocyte. In plasma cell disorders, a single clone expands and produces large amounts of one identical immunoglobulin — the monoclonal protein (M-spike).

These disorders sit on a spectrum from benign (MGUS) → premalignant (smoldering MM) → malignant (MM, WM, plasmacytoma) → deposition disease (AL amyloidosis).

Epidemiology

• Age: Almost always >40 years; median age at MM diagnosis ≈ 65–70 years.
• Sex: Male > Female.
• Race: African ancestry → 2× higher MM incidence.
• MGUS is common — present in ~3% of people over 50; most never progress.
• Multiple myeloma is the 2nd most common hematologic malignancy (after non-Hodgkin lymphoma) and the most common primary malignancy of bone.
• Risk factors: Older age, radiation exposure, obesity, family history, chronic immune stimulation.

Pathophysiology

A single malignant plasma cell clone proliferates in the bone marrow. The damage comes from two sources:

1. Direct marrow infiltration

• Plasma cells crowd out normal hematopoiesis → anemia, leukopenia, thrombocytopenia.
• Plasma cells secrete RANK-L and cytokines (IL-6, MIP-1α) that activate osteoclasts and inhibit osteoblasts → lytic bone lesions, bone pain, hypercalcemia, pathologic fractures.

2. Effects of the monoclonal protein (M-protein)

• Free light chains (Bence Jones protein) filter through glomeruli and precipitate in tubules with Tamm–Horsfall protein → cast nephropathy / myeloma kidney.
• Light chains may misfold into AL amyloid → cardiac, renal, nerve deposition.
• Large amounts of intact Ig (especially IgM in WM) → hyperviscosity syndrome.
• The clonal Ig is functionally useless → functional hypogammaglobulinemia → recurrent infections with encapsulated bacteria (S. pneumoniae, H. influenzae).
• M-protein coats RBCs → rouleaux formation on smear → ↑ ESR.

Most cases of MM are preceded by years of asymptomatic MGUS.

Clinical Features

The classic Multiple Myeloma patient is an older adult with back/bone pain + anemia + renal failure. Symptoms follow the CRAB framework:

• Bone pain (most common symptom, ~70%) — usually back, ribs, hips; worse with movement. May present as a pathologic fracture or vertebral compression.
• Anemia — fatigue, pallor, dyspnea.
• Hypercalcemia — "stones, bones, groans, psychiatric overtones": polyuria, constipation, confusion, nausea.
• Renal failure — foamy urine, edema, rising creatinine.
• Recurrent infections — sinopulmonary, urinary; encapsulated organisms.
• Neurologic — spinal cord compression (oncologic emergency), radiculopathy, peripheral neuropathy.

Waldenström macroglobulinemia presents differently — there are no lytic bone lesions and no hypercalcemia. Instead, expect:

• Hyperviscosity syndrome — headache, blurred vision, dizziness, mucosal bleeding (epistaxis, gum bleeding), "sausage-link" retinal veins.
• Lymphadenopathy and hepatosplenomegaly (because WM is a lymphoplasmacytic lymphoma).

AL amyloidosis presents with nephrotic syndrome, restrictive cardiomyopathy, hepatomegaly, macroglossia, periorbital purpura, and peripheral neuropathy.

Diagnosis — Laboratory Workup

The workup of a suspected plasma cell disorder follows a stepwise sequence:

1. Initial labs

• CBC — normocytic, normochromic anemia.
• Peripheral smear — rouleaux formation (RBCs stacked like coins).
• ↑ ESR (often very high), ↑ total protein with a narrow albumin–globulin gap (normal albumin, high globulin).
• ↑ Calcium, ↑ Creatinine, normal alkaline phosphatase (lytic, not blastic).

2. Detect the monoclonal protein

• Serum protein electrophoresis (SPEP) → tall, narrow M-spike in the γ-region.
• Urine protein electrophoresis (UPEP) → Bence Jones proteins (free light chains); missed by routine urine dipstick (which detects only albumin).
• Serum immunofixation → identifies the heavy chain (most commonly IgG, then IgA) and light chain (κ or λ).
• Serum free light chain (FLC) assay → abnormal κ/λ ratio.

3. Bone marrow biopsy

• Confirms diagnosis: ≥10% clonal plasma cells in marrow.
• Morphology: eccentric "clock-face" nucleus, abundant basophilic cytoplasm, perinuclear hof (pale Golgi zone).

Diagnosis — Imaging and Criteria

Imaging

• Preferred: whole-body low-dose CT, MRI, or PET-CT (more sensitive than plain films).
• Classic finding: "punched-out" lytic lesions, especially in the skull, spine, ribs, pelvis, and long bones.
• No osteoblastic activity → bone scan is typically NEGATIVE and alkaline phosphatase is normal. This distinguishes MM from metastatic bone disease.

Diagnostic criteria for Multiple Myeloma (IMWG)

Diagnosis requires both:

1. ≥10% clonal plasma cells in bone marrow (or biopsy-proven plasmacytoma), AND
2. One or more of the following:
   • CRAB features (hyperCalcemia, Renal insufficiency, Anemia, Bone lesions), OR
   • Myeloma-defining events (any one): bone marrow plasma cells ≥60%, serum free light chain ratio ≥100, or >1 focal lesion on MRI.

Differential Diagnosis

The three "monoclonal gammopathies" you must distinguish are MGUS, Multiple Myeloma, and Waldenström macroglobulinemia. Look carefully at the M-protein type and the presence/absence of CRAB and hyperviscosity.

Other look-alikes

• Metastatic bone disease (breast, prostate, lung): older patient with bone pain — but lesions are usually mixed or blastic, alkaline phosphatase is elevated, and bone scan is positive.
• Anemia of chronic disease / kidney disease: explains anemia and creatinine but no M-spike, no lytic lesions.
• Primary hyperparathyroidism: hypercalcemia, but PTH is high and there are no lytic lesions or M-protein.
• AL amyloidosis: may occur with or without MM; presents with restrictive cardiomyopathy, nephrotic syndrome, macroglossia.

Management

MGUS and Smoldering MM

• No treatment. Active surveillance with periodic SPEP and labs (every 6–12 months) to detect progression.

Multiple Myeloma

Treatment depends on whether the patient is a candidate for autologous stem cell transplant (ASCT).

• Induction chemotherapy — typically a triplet such as VRd: Velcade (bortezomib, a proteasome inhibitor) + Revlimid (lenalidomide, an immunomodulator) + dexamethasone. Anti-CD38 monoclonal antibodies (daratumumab) are increasingly used up-front.
• Autologous stem cell transplant (ASCT) — standard of care for fit patients <70 years.
• Maintenance therapy — lenalidomide.
• Supportive care:
  • Bisphosphonates (zoledronic acid, pamidronate) — for lytic lesions and hypercalcemia.
  • Radiation — for painful bone lesions, plasmacytomas, cord compression.
  • Hydration + loop diuretics — for hypercalcemia and renal protection.
  • Avoid nephrotoxins (NSAIDs, IV contrast); manage cast nephropathy.
  • Vaccinations (pneumococcal, influenza) for infection prevention.
  • VTE prophylaxis — lenalidomide ↑ thrombosis risk.

Waldenström macroglobulinemia

• Plasmapheresis — urgent for symptomatic hyperviscosity.
• Rituximab-based chemoimmunotherapy or BTK inhibitors (ibrutinib).

Solitary plasmacytoma

• Local radiotherapy is curative in many cases.

AL amyloidosis

• Same anti-plasma-cell regimens as MM (bortezomib-based ± daratumumab) to suppress the clone producing light chains.

Complications

• Hypercalcemia of malignancy — from osteoclast activation. Treat with IV fluids, calcitonin, bisphosphonates, and steroids.
• Renal failure (myeloma kidney) — caused by light-chain cast nephropathy, hypercalcemia, dehydration, NSAIDs, or AL amyloidosis. Hydrate, stop nephrotoxins, treat the underlying MM.
• Pathologic fractures and spinal cord compression — vertebral lytic lesions. Cord compression is an oncologic emergency: IV dexamethasone + emergent MRI + radiation/surgery.
• Recurrent infections — functional hypogammaglobulinemia → S. pneumoniae, H. influenzae, urinary infections. A leading cause of death in MM.
• Hyperviscosity syndrome — mostly with WM (IgM); treat with urgent plasmapheresis.
• AL amyloidosis — restrictive cardiomyopathy, nephrotic syndrome, macroglossia, periorbital purpura, peripheral neuropathy. Diagnose with biopsy showing apple-green birefringence on Congo red staining under polarized light.
• Venous thromboembolism (VTE) — increased risk from disease itself + lenalidomide. Use aspirin or LMWH prophylaxis.
• Anemia and cytopenias — marrow replacement; may need EPO and transfusion support.

Mnemonics

Key Points for Exams