Step 2 CK · Internal Medicine · Hematology/Oncology

Plasma Cell Disorders & Myeloma

Name: Plasma Cell Disorders & Myeloma
Creator: Veli Bakalov, MD

One clonal plasma cell, one M-spike, and the CRAB that names the damage

Hematology/Oncology·Hematologic Malignancies & Marrow Disorders·5 min read·9 high-yield points·Reviewed by Veli Bakalov, MD @HemeOncBuddy

Study materialsNo account needed

Card deckActive-recall cards · quick checks · quiz

High-yield

Active myeloma = ≥10% clonal marrow plasma cells (or plasmacytoma) plus a myeloma-defining event: CRAB (hyperCalcemia, Renal insufficiency, Anemia, Bone lytic lesions) or SLiM (≥60% plasma cells, free light chain ratio ≥100, >1 focal MRI lesion).
The M-spike is usually IgG: SPEP with immunofixation, serum free light chains, and UPEP for Bence Jones protein (the urine dipstick detects albumin, not light chains).
Clues: rouleaux, a high total protein–albumin gap, high ESR, low anion gap; recurrent encapsulated infections from functional hypogammaglobulinemia (infection is the leading cause of death).
Lesions are purely lytic and "punched-out" (RANKL-driven osteoclasts, no osteoblastic response), so the technetium bone scan is often falsely negative: use skeletal survey, low-dose whole-body CT, MRI, or PET-CT.
Myeloma kidney = light-chain cast nephropathy (light chains + Tamm-Horsfall protein); hydrate and avoid NSAIDs and IV contrast.
Myeloma hypercalcemia: aggressive IV isotonic saline first, then a bisphosphonate (zoledronic acid or pamidronate), plus calcitonin and glucocorticoids.
MGUS: M-protein <3 g/dL, <10% plasma cells, no CRAB, ~1%/yr progression → surveillance; smoldering: serum M-protein ≥3 g/dL (or urine ≥500 mg/24 h) or 10–60% plasma cells, no CRAB, ~10%/yr for the first 5 years.
AL amyloidosis: misfolded light chains → restrictive cardiomyopathy, nephrotic syndrome, neuropathy, macroglossia; Congo red apple-green birefringence.
Waldenström: monoclonal IgM (MYD88 L265P) causing hyperviscosity (blurred vision, bleeding, neurologic symptoms) → plasmapheresis; lymphadenopathy and hepatosplenomegaly but NO lytic lesions or hypercalcemia.

Overview: one clone, four kinds of damage

A clonal plasma cell tumor. Multiple myeloma is a malignant proliferation of a single plasma cell clone in the marrow that secretes a monoclonal immunoglobulin (M-protein). End-organ damage is captured by CRAB: hyperCalcemia, Renal insufficiency, Anemia, and Bone lytic lesions. Peak incidence is in older adults, and it is more common in Black patients. Typical presentations are back or bone pain, fatigue, recurrent infections, or an incidental finding of hypercalcemia, renal failure, or a high total protein.

Clonal plasma cellsMarrow infiltration crowds out erythropoiesis.
M-protein plus cytokines/RANKLLight chains injure tubules; osteoclasts are activated.
Organ injuryBone, kidney, marrow.
CRABHypercalcemia, renal failure, anemia, bone lesions.

How one clone causes CRAB

Laboratory diagnosis

Find the M-spike. The paraprotein is most often IgG (about 55%), then IgA; some clones make light chains only. Detect the spike on serum protein electrophoresis (SPEP) and confirm its type with immunofixation. Urine protein electrophoresis (UPEP) captures Bence Jones free light chains, and the serum free light chain assay (κ:λ ratio) adds sensitivity, especially for light-chain-only disease.

The urine dipstick detects albumin, not light chains, so Bence Jones proteinuria needs UPEP with immunofixation.

Supporting clues. Rouleaux (RBCs stacked like coins) on the smear, a large gap between total protein and albumin, and an elevated ESR all reflect the paraprotein. The anion gap is not elevated and is classically low, because cationic IgG offsets unmeasured anions. Functional hypogammaglobulinemia (normal immunoglobulins are suppressed despite a high total protein) causes recurrent infections with encapsulated organisms, and infection is the leading cause of death.

IMWG criteria for active myeloma: ≥10% clonal marrow plasma cells (or a plasmacytoma) plus a myeloma-defining event:

CRAB: calcium >11 mg/dL, creatinine >2 mg/dL (or clearance <40 mL/min), hemoglobin <10 g/dL, or ≥1 osteolytic lesion of 5 mm or more on CT, PET-CT, or radiographs.
SLiM biomarkers: Sixty percent or more clonal plasma cells, a serum free Light chain ratio ≥100, or more than one focal MRI lesion. These define myeloma even before overt organ damage.

Risk stratification. Marrow biopsy with cytogenetics confirms and risk-stratifies (del(17p) and t(4;14) are high risk); β2-microglobulin and albumin define the International Staging System.

End-organ damage and its management

Bone. Myeloma causes purely osteolytic "punched-out" lesions (skull, spine, long bones), pathologic fractures, and hypercalcemia via RANKL-driven osteoclast activation with no osteoblastic response. Because there is no bone formation, a technetium bone scan is often falsely negative; image with a skeletal survey, low-dose whole-body CT, MRI, or PET-CT. Back pain with leg weakness raises concern for cord compression from vertebral collapse or a plasmacytoma.

Osteoblastic (blastic) bone metastases suggest prostate cancer, not myeloma.

Kidney. Renal failure is most often light-chain cast nephropathy ("myeloma kidney"): filtered free light chains precipitate with Tamm-Horsfall protein in the tubules. Hypercalcemia, hyperuricemia, and AL amyloidosis contribute. Hydrate, treat hypercalcemia, avoid nephrotoxins, NSAIDs, and IV contrast, and treat the underlying clone.

Hypercalcemia is osteolytic. Give aggressive IV isotonic saline first, then a bisphosphonate (zoledronic acid or pamidronate), which also reduces skeletal events; add calcitonin for rapid control and glucocorticoids, which are directly antimyeloma. Monitor renal function when dosing bisphosphonates.

Anemia and infection. The anemia is typically normocytic, from marrow replacement and renal disease. Vaccinate and treat infections aggressively.

The plasma cell spectrum: MGUS to active myeloma

MGUS vs smoldering vs active myeloma

Feature	MGUS	Smoldering myeloma	Active myeloma
Serum M-protein	<3 g/dL	≥3 g/dL (or urine ≥500 mg/24 h), or	Any
Clonal marrow plasma cells	<10%	10–60%	≥10% (or plasmacytoma)
CRAB or SLiM event	None	None	Present
Progression	~1% per year, indefinitely	~10% per year for the first 5 years	Already active
Management	Surveillance: periodic SPEP and labs	Close monitoring or clinical trials	Treat

Smoldering myeloma needs either criterion (serum M-protein ≥3 g/dL or urine M-protein ≥500 mg/24 h, or 10–60% plasma cells) without a myeloma-defining event.

MGUS is common in the elderly; with no end-organ damage, it is watched, not treated. Smoldering (asymptomatic) myeloma sits between MGUS and active disease: a higher tumor burden but still no CRAB or SLiM-defining event.

Related disorders: AL amyloidosis and Waldenström

AL (primary) amyloidosis. Clonal plasma cells make immunoglobulin light chains that misfold into β-pleated fibrils and deposit in the heart (restrictive cardiomyopathy), kidney (nephrotic syndrome), nerves (neuropathy, carpal tunnel), and tongue (macroglossia); periorbital purpura is another clue. Diagnose with tissue, often an abdominal fat pad aspirate, showing Congo red apple-green birefringence, plus serum free light chains. Suspect it when a plasma cell disorder meets these organ patterns.

Waldenström macroglobulinemia is a lymphoplasmacytic lymphoma secreting monoclonal IgM (MYD88 L265P mutation). The large pentameric IgM causes hyperviscosity (blurred vision, bleeding such as epistaxis, headache and other neurologic symptoms), treated urgently with plasmapheresis.

Myeloma vs Waldenström

Feature	Multiple myeloma	Waldenström
Paraprotein	IgG or IgA (or light chain only)	IgM (pentamer)
Bone	Lytic lesions, hypercalcemia	No lytic lesions or hypercalcemia
Signature complication	Renal failure (cast nephropathy)	Hyperviscosity → plasmapheresis
Nodes and organs	Usually no adenopathy	Lymphadenopathy, hepatosplenomegaly

Treatment of active myeloma

Triplets, then transplant. Active myeloma is treated with combinations such as a proteasome inhibitor (bortezomib), an immunomodulator (lenalidomide), and dexamethasone, increasingly with an anti-CD38 antibody (daratumumab), often followed by autologous stem cell transplant in eligible patients. It is treatable but generally not curable. Know the signature toxicities:

Bortezomib: peripheral neuropathy and herpes zoster reactivation (acyclovir prophylaxis).
Lenalidomide and thalidomide: venous thromboembolism (thromboprophylaxis) and teratogenicity.
Bisphosphonates: osteonecrosis of the jaw; adjust for renal function.