Plasma Cell & Marrow Disorders

Multiple Myeloma: Pathogenesis and CRAB

Definition. Multiple myeloma is a malignant proliferation of monoclonal plasma cells in the marrow that secrete a single immunoglobulin, the M protein (usually IgG, then IgA). Peak age is 60 to 70, and it is more common and more aggressive in Black patients. It is the most common primary malignancy arising in bone in older adults.

CRAB. End-organ damage is summarized as hyperCalcemia, Renal insufficiency, Anemia, and Bone lytic lesions. These four features separate active myeloma from a benign paraprotein.

Bone disease. Myeloma cytokines (RANK-L, IL-6) drive osteoclasts with NO osteoblastic reaction; IL-6 is also the key myeloma growth factor. The result is purely lytic, punched-out lesions, pathologic fractures (vertebral collapse causes back pain), and hypercalcemia; the skull shows a raindrop or pepper-pot pattern. Because osteoblasts are quiet, a bone scan is often cold and alkaline phosphatase is typically normal, so image with a skeletal survey or MRI. Bisphosphonates reduce skeletal events.

Kidney and infection. Filtered free light chains are toxic to tubules and precipitate with Tamm-Horsfall protein into obstructing casts (myeloma cast nephropathy); hypercalcemia, AL amyloid, and light-chain deposition add further injury. Despite a high total immunoglobulin, functional antibody is low, so infection with encapsulated organisms (Streptococcus pneumoniae, Haemophilus influenzae) is the leading cause of death.

Laboratory Diagnosis and the Plasma Cell Spectrum

Protein studies. Serum protein electrophoresis (SPEP) shows a monoclonal M-spike, and immunofixation identifies its type. Urine contains Bence Jones proteins, free kappa or lambda light chains, which the dipstick MISSES because it detects albumin only; urine electrophoresis or serum free light chain assays find them.

Blood clues. Excess protein produces rouleaux (RBCs stacked like coins), a high ESR, and a high total protein. IgG is cationic, so the anion gap narrows; a low anion gap plus high protein is a classic myeloma clue.

Marrow and criteria. Diagnosis needs clonal marrow plasma cells of 10% or more (or a plasmacytoma), an M protein, and end-organ damage (CRAB) or a myeloma-defining biomarker: 60% or more plasma cells, an involved-to-uninvolved light-chain ratio of 100 or more, or 2 or more focal MRI lesions. Any of these triggers treatment. The marrow shows sheets of plasma cells with clock-face chromatin, fried-egg cytoplasm, and Russell bodies (cytoplasmic immunoglobulin inclusions).

Monoclonal vs polyclonal. The shape of the SPEP peak makes the call. A single narrow M-spike means one clone (myeloma, MGUS, Waldenström) and is neoplastic. A broad-based gamma elevation means many clones and is REACTIVE, seen in chronic infection, autoimmune disease, and liver disease.

MGUS. Monoclonal gammopathy of undetermined significance is the premalignant, asymptomatic stage and the most common plasma cell dyscrasia. It progresses to myeloma at about 1% per year, so patients are monitored, not treated. Smoldering myeloma sits between MGUS and active disease.

Waldenström Macroglobulinemia and AL Amyloidosis

Waldenström macroglobulinemia. A lymphoplasmacytic lymphoma secreting monoclonal IgM, typically carrying the MYD88 L265P mutation. Large pentameric IgM causes hyperviscosity syndrome: blurred vision, headache, dilated "sausage-link" retinal veins, mucosal bleeding such as epistaxis, and neurologic symptoms. As a lymphoma it may enlarge nodes, liver, and spleen, but there are NO lytic bone lesions. Plasmapheresis rapidly lowers viscosity.

AL (primary) amyloidosis. Free light chains from a plasma cell clone misfold into β-pleated sheet fibrils that stain with Congo red and show apple-green birefringence under polarized light. Deposits cause restrictive cardiomyopathy, nephrotic syndrome, macroglossia, and periorbital purpura. AL amyloidosis complicates myeloma and MGUS.

Marrow Failure: Myelodysplasia vs Aplastic Anemia

Myelodysplastic syndromes (MDS). Clonal stem-cell disorders with ineffective hematopoiesis: peripheral cytopenias despite a HYPERcellular marrow, with dysplasia, because abnormal precursors die before release. Findings include ringed sideroblasts (iron-laden mitochondria around the nucleus), pseudo-Pelger-Huët neutrophils (bilobed), and fewer than 20% blasts. MDS affects older adults or follows alkylating agents or radiation, and it can transform to AML. Isolated del(5q) responds to lenalidomide; hypomethylating agents (azacitidine) are used for higher-risk disease.

20% or more marrow blasts reclassifies MDS as acute myeloid leukemia.

Aplastic anemia. Pancytopenia from a HYPOcellular, fatty marrow with NO dysplasia and no splenomegaly; idiopathic cases usually reflect autoimmune T-cell destruction of stem cells. Causes include:

• Drugs: chloramphenicol, sulfonamides, carbamazepine, propylthiouracil, methimazole
• Toxins and radiation: benzene, ionizing radiation
• Viruses: hepatitis, EBV (parvovirus B19 instead causes pure red cell aplasia or transient aplastic crisis)
• Inherited: Fanconi anemia, a DNA-repair defect with short stature, thumb and radial anomalies, and café-au-lait spots
• Autoimmune or idiopathic

Treatment is stopping the offender, immunosuppression with antithymocyte globulin (ATG) plus cyclosporine, or stem-cell transplant.

Tumor Lysis Syndrome

Mechanism. Chemotherapy of bulky, fast-dividing tumors (Burkitt lymphoma, ALL, high-grade lymphoma) lyses cells within hours to days. Dying cells dump potassium, phosphate, and nucleic acids that are metabolized to uric acid, so all three run HIGH. Released phosphate binds calcium, so calcium falls LOW. Urate and calcium-phosphate crystals cause acute kidney injury; hyperkalemia risks arrhythmia, and hypocalcemia causes tetany or seizures.

Calcium is the one electrolyte that moves the wrong way: it falls while potassium, phosphate, and urate rise.