Plasma Cell Dyscrasias¶

Rahul Shah, Jennifer Marvin-Peek

Background¶

A heterogenous group of benign, premalignant, and malignant conditions characterized by clonal proliferation of plasma cells
Results in over-production of monoclonal immunoglobulins or polypeptides (e.g. M-protein) that can be detected in serum and/or urine
Includes monoclonal gammopathy of undetermined significance (MGUS), smoldering myeloma (SMM), multiple myeloma (MM), Waldenstrom’s macroglobulinemia (WM), extra-medullary plasmacytoma, AL amyloidosis, POEMS syndrome
Spectrum of MGUS, SMM, and MM represents natural progression of same disease process
Complications: increased infectious risk, cytopenias, renal failure, hyperviscosity syndrome, malignant hypercalcemia, pain crisis from bony disease
Elevated gamma/protein gap (serum total protein minus albumin >4) often prompts work-up for an underlying plasma cell dyscrasia (high specificity but low sensitivity)

Symptoms	Signs
Fatigue, weakness, weight loss Bone pain Paresthesias, neuropathy, radiculopathy Visual disturbances(if hyperviscosity present) Lymphadenopathy (uncommon) Fever (uncommon)	Anemia (Hgb <10) Renal insufficiency (Cr > 2) Hypercalcemia (Ca > 11.5) Elevated protein gap (Total protein - Alb > 4) Osteolytic bone lesions (typically central) Unexplained heavy proteinuria Rouleux formation on blood smear

CBC w/ diff, peripheral blood smear, CMP (for Ca, Cr, albumin), LDH, CRP, urinalysis
SPEP with immunofixation, UPEP (24-hour urine) with immunofixation, serum free light chains (FLC)
Quantitative immunoglobulins (IgA, IgM, IgG, IgD, IgE)
If Hgb <10, Cr >2, Ca >11.5, M-protein >1.5, non-IgG M-spike, abnormal FLC ratio:
- Bone marrow biopsy + cytogenetics
- β2-microglobulin, serum viscosity (in WM)
- Skeletal imaging to identify bone lesions: skeletal survey (x-ray) often done initially, then more sensitive CT/PET-CT/MRI if biopsy shows SMM/MM
- If considering amyloidosis: abdominal wall fat pad biopsy with Congo red staining typically sufficient vs. direct biopsy of amyloid-involved tissue

Additional Tips for Lab Interpretation
SPEP/UPEP	Free light chains (FLC)	Urinalysis
Initial screening test to look and quantify M-protein Serum immunofixation determines clonality (e.g. mono or polyclonal) Monoclonal spike >1.5 is indicative of underlying dyscrasia Polyclonal spike suggests infectious, inflammatory, or reactive etiology	Ratio of kappa/lambda >3 highly suggestive of plasma cell dyscrasia or amyloidosis Ratio 1.65 to 3 can be due to infectious process or renal insufficiency Helpful in pts that only produce Bence-Jones protein (FLC w/o heavy chain) which isn’t seen on SPEP	Detects albumin, not light chains In myeloma cast nephropathy, dipstick will be negative since proteinuria is from FLC (i.e. Bence-Jones proteinuria) In AL amyloid, dipstick will be positive 2/2 albumin loss from nephrotic syndrome

	MGUS	SMM	MM
% Plasma Cells in BM	<10%	10-60%	≥ 10% (typically >30%)
Monoclonal Protein	IgG, IgA, IgM: 1.5 -3	IgG or IgA >3	IgG or IgA >3
Laboratory studies	Normal Hgb, Ca, Cr	Normal Hgb, Ca, Cr	↓Hgb, ↑Ca, ↑Cr
Symptoms	None	None	Lytic bone lesions, fatigue
Prognosis	1% / year progression to MM	10% / year progression to MM	R-ISS staging (see below)
Monitoring and/or Treatment	Monitoring only Yearly: Symptom check SPEP, FLC, CBC, BMP	Monitoring only In 2-3 months, repeat SPEP, FLC, CBC, BMP Yearly skeletal survey	Chemotherapy, plus SCT for eligible pts

Diagnosis requires clonal bone marrow plasma cells ≥10% or bony/extramedullary plasmacytoma AND one or more end-organ event (CRAB criteria) or biomarker of myeloma
CRAB criteria
- Hypercalcemia, renal impairment, anemia, bone osteolytic lesions
Biomarkers of multiple myeloma
- Clonal bone marrow plasma cells ≥ 60%
- Serum FLC ratio ≥ 100 or ≤ 0.01
- >1 focal lesion ≥ 5mm on MRI
- >Skeletal imaging: whole-body PET-CT or CT preferred, MRI, bone survey (x-ray)

First-line induction therapy typically is RVd: immunomodulatory agent (lenalidomide [Revlimid]), proteasome inhibitor (bortezomib [Velcade]) and dexamethasone
Consolidation therapy includes autologous SCT for transplant eligible pts
Maintenance therapy is often given indefinitely, typically lenalidomide or bortezomib
Relapsed disease is often treated with anti-CD38 monoclonal Ab (daratumumab) with a steroid and either immunomodulatory drug or proteosome inhibitor; CAR-T also recently approved for relapsed MM
Supportive Care
- VTE prophylaxis with DOAC or LMWH if on an immunomodulatory agent with 2 VTE risk factors; if only 0-1 VTE risk factors à aspirin
- EPO and G-CSF for treatment-related anemia and neutropenia
- Bisphosphonate (ideally zoledronic acid) to reduce risk of fractures; analgesia ± radiotherapy for bone pain and palliation
- (Val)acyclovir if on bortezomib for VZV prophylaxis

Hyperviscosity syndrome: blurred vision, dizziness, diplopia, hypoxia, ataxia, vertigo, stroke, coma
Peripheral neuropathy
Retinal changes: dilated veins, hemorrhages, papilledema
Cryoglobulinemia: large IgM complexes precipitate out in the cold, causing Raynaud's, urticaria, purpura, acral cyanosis, tissue necrosis

Requires: IgM monoclonal gammopathy on SPEP, BM biopsy with ≥10% lymphocytes with plasmacytoid differentiation (late stage B-cell differentiation), and MYD88 mutation
CBC, coagulation studies, cryoglobulins, IgM, β2-microglobulin
Serum viscosity: If <4 symptoms are rare, If >6 typically symptomatic.

Asymptomatic pts managed with close observation
Symptomatic hyperviscosity is treated with plasmapheresis
Induction: may include bendamustine ± rituximab if IgM level is <4000 (rituximab can temporarily ↑ IgM and ↑ risk of hyperviscosity syndrome)
Monitor response with: IgM levels, monoclonal IgM on SPEP

Extracellular deposition of misfolded light chains (most commonly kidney and heart)
- Features: nephrotic syndrome, restrictive cardiomyopathy, peripheral neuropathy, HSM, macroglossia, easy bruising/bleeding, dysautonomia/orthostasis
Diagnosis
- Need ALL 4: amyloid related systemic syndrome, positive congo red staining on any tissue, evidence that amyloid is light chain related, evidence of monoclonal plasma cell disorder

Cause unknown, possibly chronic overproduction of pro-inflammatory cytokines such as VEGF
Features: Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal protein (usually λ light chain), Skin changes
Diagnosis:
- Mandatory criteria: peripheral neuropathy, monoclonal plasma cell disorder
- Major criteria (need ⅓): osteosclerotic lesions, VEGF, Castleman disease
- Minor criteria (need ⅙): organomegaly, volume overload, endocrinopathy, skin changes, papilledema, thrombocytosis or polycythemia

Angiofollicular lymph node hyperplasia
Antibodies to HHV-8 implicated in >50% of cases
Features: lymphadenopathy, fever, night sweats, fatigue, fluid accumulation, violaceous lymph node biopsy w/characteristic hematopathology papules