Plasma Cell Dyscrasias

Plasma Cell Dyscrasias – Jennifer Marvin-Peek

Background

  • A heterogenous group of benign, premalignant, and malignant conditions characterized by clonal proliferation of plasma cells
  • Results in production of monoclonal immunoglobulins or polypeptides (i.e. monoclonal proteins, or M-protein) 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, Castleman’s disease
  • Complications: Increased infectious risk, renal failure, hyperviscosity syndrome, malignant hypercalcemia, pain crisis from bony disease

 

 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

 

Evaluation

  • CBC w/ diff, BMP (for Ca, Cr)
  • SPEP with immunofixation, UPEP (24 hour urine) with immunofixation, urinalysis, 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, peripheral blood smear review
    • LDH, albumin, CRP, β2-microglobulin, serum viscosity
    • Skeletal survey

Additional Tips for Lab Interpretation

SPEP/UPEP

Free light chains (FLC)

Urinalysis

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

 

-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, get negative dipstick 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:
    • One of:
      • Clonal bone marrow plasma cells >10%
    • Biopsy proven extramedullary plasmacytoma (tumor of plasma cells)AND ≥1 myeloma-defining event:
      • One or more of the CRAB criteria
      • Clonal bone marrow plasma cells ≥ 60%
      • Serum FLC ratio ≥ 100 or ≤0.01
      • >1 focal lesion larger than 5mm on MRI
 

Management

  • Active disease: induction includes a proteasome inhibitor (bortezomib or carfilzomib)
  • Consolidation therapy includes SCT for eligible patients <65-70 years old
  • Maintenance therapy is often given indefinitely, typically lenalidomide and/or bortezomib
  • VTE prophylaxis if on an immunomodulatory agent with 2 VTE risk factors
    • If only 0-1 VTE risk factors aspirin
  • Supportive Care: EPO for anemia, analgesia ± radiotherapy for bone pain, vaccinations
  • Bisphosphonate (ideally zoledronic acid)
  • (Val)Acyclovir ppx if on bortezomib

 

Additional Information

  • Prognosis
    • Revised Multiple Myeloma International Staging System (R-ISS) (available on MD Calc)
      • Serum β2-microglobulin (indicator of plasma cell turnover)
      • Serum albumin
      • Serum LDH
    • Cytogenetic markers from biopsy

 

Lymphoplasmacytic Lymphoma Waldenstrom’s Macroglobulinemia (IgM)

Presentation

  • Hyper-viscosity syndrome: blurred vision, dizziness, diplopia, 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% plasma cells, and MYD88 mutation detected
  • CBC, coagulation studies, cryoglobulins, IgM, β2-microglobulin
  • Serum viscosity (If <4 symptoms are rare, If >6 typically symptomatic)

 

Management

  • Only treated if symptomatic
  • If Hyper-viscosity syndrome treatment in Plasma Exchange
  • 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
    • Hepatomegaly
    • Macroglossia
    • Easy bruising/bleeding
    • 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

  • 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 1/3)
      • Osteosclerotic lesions, VEGF, Castleman disease
    • ​​​​​​​Minor Criteria (need 1/6)
      • ​​​​​​​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
  • Skin findings: violaceous Lymph node biopsy w/characteristic hematopathology papules