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