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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 (i.e., M-protein) that can be detected in serum and/or urine
  • Includes monoclonal gammopathy of undetermined significance (MGUS), smoldering myeloma (SMM), multiple myeloma (MM), Waldenström 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

Rouleaux formation on blood smear

Evaluation

  • 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 (call pathology to arrange, can typically be done same-day or next-day) 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

Monoclonal Gammopathy of Unknown Significance

(MGUS)

Smoldering Multiple Myeloma

(SMM)

Multiple Myeloma

(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 patients

Multiple Myeloma

Evaluation

  • 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)

Management

  • 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 patients
  • 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, 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

Lymphoplasmacytic Lymphoma/Waldenström Macroglobulinemia (IgM)

Presentation

  • 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

Evaluation

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

Management

  • Asymptomatic patients 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

Other Plasma Cell Dyscrasias

Light Chain (AL) Amyloidosis

  • Extracellular deposition of misfolded light chains (most commonly kidney & heart)
  • Features: nephrotic syndrome, restrictive CM, 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

POEMS Syndrome

  • 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

Castleman Disease

  • 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
Last update: 2022-06-25 02:05:01