Multiple Myeloma and Other Plasma Cell Disorders

Summary of Plasma Cell Development

Plasma cell dyscrasias

distinguished by the presence of a monoclonal immunoglobulin in the serum or urine. This protein is known as the "M" component (Monoclonal) or "paraprotein", and is composed of 2 heavy chains of the same class (IgG, A, M, D, or E), and 2 light chains of the same class (k or l ).

Detection of M proteins – M spikes are 75% MGUS, 11% Multiple myeloma, 6% amyloidosis, and 2% Waldenstöm’s.

serum (or urine) protein electrophoresis/SPEP or UPEP:

Immunofixation electrophoresis (IFE) – defines the monoclonal protein, more sensitive than SPEP, can detect m-proteins "hidden" in polyclonal bands on SPEP.

Quantitative immunoglobins – assess for depression of other Ig’s (ß Ig’s is an effect of IL-1 and TNF from the monoclonal cells), not as accurate as SPEP, expensive.

Multiple Myeloma

a plasma cell disorder which is associated with a neoplastic proliferation monoclonal immunoglobulin producing cells, promoted by IL-6. IgG most common but others are possible.

Presentation: depends on the degree of infiltration and the type as well as amount of paraproteinemia.

Skeletal involvement – bone pain (68%), discrete lytic lesions on x-ray, diffuse osteoporosis

multiple myeloma cells produce IL-6, which acts by autocrine (signals self to make more IL-6) and paracrine (signals bone marrow stroma to produce IL-1 and TNF). IL-6, IL-1, and TNF all act to Ý bone reabsorption and ß osteoblast activity.

Bone marrow dysfunction – anemia (66%), thrombocytopenia, and neutropenia

Renal insufficiency – myeloma cast nephropathy, light chain deposition (rare) and amyloidosis

Hypercalcemia- due to IL-1

Neuropathy – carpal tunnel (from amyloidosis), POEMS, spinal cord compression

Infection- suppression of normal immunoglobulin synthesis, also ß CD4+ T cells

Hyperviscosity – rare but can occur with high IgG₃ or IgA levels (IgM is seen in Waldenström’s Macroglobulinemia)

Other symptoms: fatigue (anemia), back pain (fractures), Ý ESR, dehydration (nephrogenic DI)

Diagnosis: (need at least one major and one minor or three minor)

major criteria

plasmacytoma of tissue biopsy
bone marrow plasmacytosis with > 30% plasma cells
monoclonal globulin spike on serum electrophoresis

minor criteria

bone marrow plasmacytosis with 10-30% plasma cells
monoclonal spike less than required level
lytic bone lesions
suppression of other immunoglobulins

Prognosis – 7 months untreated, 3 years with treatment. All patients will relapse with standard treatment.

Staging – 4 most important factors: 1) b -2 microglobulin (less is better), 2) age (younger is better), 3) cytogenetics (deletion of chrom. 13 is bad), and 4) Plasma cell labeling index (what % are going into S phase, is less better)

Treatment – steroids (Prednisone) plus alkylating agents (Cyclophosphamide). BMT may prolong survival but does not cure. Supportive treatments include Epo, for anemia, antibiotic prophylaxis, and plasmaphoresis for acute renal failure.

Newer treatments: Thalidomide (an anti-angiogenic) mechanism unclear, IL-6 receptor antagonists, and meds to inhibit pathways of drug resistance.

Monoclonal Gammopathy of Undetermined Significance (MGUS)

the most common clonal disorder of immunoglobulins. M-protein spike in serum or urine without any signs or symptoms. 1% of population, 3% of folks > 70 y/o. 25% progress to malignancy (2/3rds of which is multiple myeloma) but it takes ~10 years (old, they die of other stuff)

	MGUS	Multiple Myeloma
Osteolytic bone lesions	absent	present
Marrow plasma cells	<10%	>12%
Hemoglobin	>12 gm%	<12 gm%
Serum calcium	normal	elevated in 30%
Serum creatinine	normal	may be elevated
M-protein	unchanged over time	progressive increase
Polyclonal immunoglobulins	normal	reduced

Waldenström’s Macroglobinemia

a malignant clone of cells that falls between a mature B-cell and a plasma cell (plasmacytoid lumphocyte). Proliferation of cells is accompanied by the production of a monoclonal IgM. The accumulation of the IgM paraprotein results in high blood viscosity, the major morbidity in this disorder.

Symptoms – Fatigue, weakness, cold insensitivity, hepatosplenomegaly, lymphadenopathy (unlike multiple myeloma) and Hyperviscosity symptoms (bleeding, neurological distrubances, "sausage" retinal veins, hypervolemiaÞ CHF)

Prognosis – 4-5 year survival, No cure

Treatment – Plasma electrophoresis is very effective for hyperviscosity syndrome, alkalating agents and Prednisone.

Amyloidosis

Primaryamyloidosis (AL type): clonal proliferation of plasma cells can lead to accumulation of amyloid. Usually light chains.

Secondary amyloidosis (AA type): amyloid accumulation in the setting of certain infections or inflammatory conditions.

Symptoms: macroglossia, Nephrotic syndrome, CHF (restrictive cardiomyopathy), malabsorption, peripheral or autonomic neuropathy, Carpal tunnel syndrome, and dermatologic signs.

Prognosis – 2 years, less if there’s cardiac involvement, no cure

Diagnosis – biopsy reveals apple-green birefringence on Congo-red stain using polarized light.

Treatment – Melphalan and Prednisone may modestly improve survival but do not cure.