Plasma Cell Dyscrasias
Rahul Shah
Jennifer Marvin-Peek
Michael
Kaminski
Background
- Benign, pre-malignant, and malignant conditions with clonal proliferation of plasma cells or B cells that MAY produce monoclonal Igs detected in serum and/or urine
- Conditions include:
- Monoclonal gammopathy of undetermined significance (MGUS)
- Smoldering Multiple Myeloma (SMM)
- Multiple Myeloma (MM)
- Plasmacytoma
- Waldenstrom’s Macroglobulinemia (WM)
- Amyloidosis
- POEMS Syndrome
- NOTE MGUS, SMM, and MM represent a disease progression
- Complications either 2/2 malignant plasma cells or their Ig product
- Elevated protein gap (serum total protein – albumin > 4) often prompts work-up
- Symptoms reflect underlying organ disorder 2/2 malignant cells or Ig product
- Fatigue, weakness 2/2 anemia
- Bone pain 2/2 lytic lesions or malignant fractures
- Paresthesias, neuropathy 2/2 direct neuronal toxicity from Igs
- Visual disturbances 2/2 hyper-viscosity
- Fever, lymphadenopathy possibly 2/2 infection resulting from immunosuppression
Symptoms
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Signs
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- Fatigue, weakness, weight loss
- Bone pain
- Paresthesias, neuropathy, radiculopathy
- Visual disturbances (if hyperviscosity present)
- Lymphadenopathy (uncommon)
- Fever (uncommon)
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- 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
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Evaluation
- CBC w/ diff, peripheral blood smear, CMP (esp Creat, Ca, Alb)
- Serum Protein Electrophoresis (SPEP): detects and quantifies M-protein, ie monoclonal Ig from abnormal clonal B/plasma cell
- Serum Immunofixation (SIF): Identifies monoclonal vs polyclonal M protein and type (IgG/A/M/D/E, kappa/lambda), whether heavy or light chain only
- UPEP/UIF-detects Bence Jones protein/urine monoclonal kappa or lambda light chain
- Quantitative Igs: quantifies total IgG, IgM, IgA, IgD, IgE
- LDH and B2 microglobulin
- Consider UA: detects albumin, not light chains so will be negative in cast nephropathy (Bence-Jones proteinuria) but may be positive in AL amyloid with nephrotic syndrome
- Skeletal imaging to identify bone lesions: CT/PET-CT/MRI preferred over X rays
- BM Biopsy If CRAB criteria (Calcium>11, Renal Impairment/Cr>2, Anemia/Hb<10, Bone lesions on imaging), M-protein >1.5, non-IgG M-spike, or very abnormal FLC
- 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
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Free light chains (FLC)
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Urinalysis
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- 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
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- 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
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- 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
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MGUS
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SMM
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MM
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| % 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: Symptom check SPEP, FLC, CBC, BMP |
Usually monitoring, repeat SPEP, FLC, CBC, BMP Yearly skeletal survey |
Chemotherapy, plus SCT for eligible pts |
Monoclonal Gammopathy of Unknown Significance (MGUS)
- Pathophysiology: Asymptomatic, premalignant clonal neoplastic plasma cells in bone marrow with monoclonal Igs +/- abnormal free light chains
- NOTE: sometimes paraprotein can cause symptoms in skin, nerves, kidneys, ie monoclonal gammopathy of clinical significance
- Common, especially in elderly-prevalence >4% in 40+ year olds, >10% in 80+ year olds
- Subdivided into non-IgM MGUS which may progress into MM, IgM MGUS which may progress into WM, and light chain MGUS which may progress into light chain MM
- Risk of progression for non-IgM MGUS ~1%, higher if M-protein >1.5 g/dL and/or abnormal free light chain ratio
- Dx Criteria:
- Non-IgM MGUS: Serum monoclonal protein (IgG, IgA, IgD) <3 g/L, clonal BM plasma cells <10%, no CRAB SLiM
- IgM MGUS: Serum monoclonal protein (IgM) <3 g/L, clonal BM plasma cells <10%, no anemia, hyperviscocity, LAD, HSM
- Light Chain MGUS: + abnormal FLC ratio, increased level of involved free light chain, no monoclonal heavy chain, clonal BM plasma cells <10%, no CRAB SLiM
- Tx: No treatment. Risk stratify to determine monitoring strategy using 1. serum M protein level >1.5, 2. non-IgG MGUS, 3. abnormal FLC ratio (<0.26 OR >1.65). Also monitor for complications including fractures, infection, blood clots
- 0/3: repeat SPEP, FLC, CBC, CMP at 6M then Q2-3Y, +/- BMBx and imaging
- Everyone else: BMBx and low dose whole body CT at diagnosis; repeat SPEP, FLC, CBC, CMP at 6M then Q2-3
Smoldering Multiple Myeloma (SMM)
- Part of the continuum of MGUS > SMM > MM
- Approximately 10% risk of progression to MM per year
- Dx: M protein >3 g/dL and/or clonal plasma cells 10-60% on BMBx but no CRAB-SLiM
- Risk stratify: high risk if M protein >2 g/dL, FLCr >20, plasma cells>20%
- Tx: observe low-risk disease (repeat labs Q3-6M); high risk disease: maybe clinical trial vs monotherapy with daratumumab or lenalidomide vs lenalidomide plus dex
Multiple Myeloma (MM)
- Neoplastic proliferation of plasma cells that produce monoclonal Ig (“M protein”)
- S/Sxs from effects of plasma cells (bone pain, fractures, hypercalcemia, anemia) and/or Ig (renal impairment, paresthesias, protein gap, recurrent infection 2/2 hypogammaglobulinemia). Other Sxs nonspecific: generalized weakness, weight loss
Pathophysiology
- Progression from MGUS, SMM; post-germinal plasma cell has translocation event during class switching >> oncogene (Cyclin D1/3, FGFR-3,C-MAF) next to IgH (chromosome 14) or other mutation. Additional genetic alterations (MYC, RAS/MAPK activation, TP53 deletion) >> proliferative and survival >> MM
- Lytic Bone lesions/Hypercalcemia: MM cells activate osteoclasts 2/2 increased RANKL, cytokines, decreased OPG >> bone resorption and hypercalcemia. MM cells inhibit osteoblasts via cytokines, DKK1 >> net bone loss
- Kidney Impairment: Severe hypercalcemia >> arteriolar vasoconstriction. Proximal tubule resorption of light chains cytotoxic 2/2 accumulation within cells, causing proximal RTA. Light chain cast nephropathy from light chains filtered by glomerulus precipitate after binding uromodulin in thick ascending loop of Henle >> obstructing intratubular casts >> inflammation, rupture of tubules
- Anemia: bone marrow replaced by plasma cells. +/- CKD related low EPO, dilution (M protein increases plasma volume), folate/B12 deficiency, warm AIHA
Dx
- CMP (high creatinine, high calcium, paraprotein gap)
- CBC w/ diff (normocytic normochromic anemia); Smear (Rouleaux)
- SPEP (M protein >3), SIF (IgG, IgM, OR IgA; kappa or lambda)
- For risk stratification: UPEP/UIF; B2 microglobulin; high LDH o BMBx: IHC, flow cytometry, cytogenetics/FISH
- Imaging: cross sectional imaging preferred (low dose whole body CT wo contrast, whole body FDG-PET, whole body MRI), alternative is skeletal survey with X rays
- Criteria: BMBx: plasma cells >10% OR plasmacytoma AND 1+ CRAB-SLiM
- CRAB: Hypercalcemia >11, Renal Impairment/Creatinine >2, Anemia/Hb <10, Bone lytic lesions >5 mm on imaging (MRI, CT, X ray)
- SLiM (biomarkers): Sixty (>60% clonal plasma cells in BMBx), Light chain ratio (>100 or <0.01), MRI (more than 1 focal lesion >5 mm)
- Less common variations: non-secretory/oligo-secretory (~10%, Dx on imaging and biopsy), light chain only (~20%, Dx on SFLC and UPEP/UIF)
Tx
- Risk stratify patient: age, performance status, comorbidities, R-ISS; and risk stratify disease (high risk: del17p13, t(4:14), t(14:16), t(14:20), amp1q; LDH very high; plasma cell leukemia [5% circulating plasma cells]). Determine autoSCT eligibility. Note: regimens are attending and institution specific so may vary from those listed below.
- Transplant eligible: Induction with bortezomib (proteosome inhibitor), lenalidomide (immunomodulator), dexamethasone (VRd) +/- daratumumab (anti- CD38), followed by autoSCT. Maintenance therapy with lenalidomide +/- bortezomib if high risk cytogenetics. Induction with CyBorD if renal failure at diagnosis.
- Transplant ineligible: Patient specific, maybe induction with reduced intensity bortezomib, lenalidomide, and dexamethasone (VRD-lite) or lenalidomide, dexamethasone and daratumumab (DRd) with lenalidomide maintenance HEMATOLOGY-ONCOLOGY 239
- Relapsed/refractory disease: if good response to initial treatment could repeat proteasome inhibitor, lenalidomide, dara regimen +/- auto SCT; if not: clinical trials, BCMA CAR-T, BCMA/CD3 Bispecific Ab, venetoclax (only if t(11:14))
- Supportive Care:
- aggressive pain management including possible RT
- bisphosphonates or denosumab to protect bones, surg fix if fracture/impending
- DVT PPX when on immunomodulatory agent like lenalidomide: ASA vs DOAC vs LMWH based on bleeding risk, comorbidities
- VZV PPX when on proteosome inhibitors, PJP PPX if on prolonged steroids
Plasmacytoma
- Collection of monoclonal plasma cells that form a mass, may be seen in connection with MM or may be solitary
- Solitary plasmacytomas subdivided into solitary bone plasmacytoma (SBP) and solitary extramedullary plasmacytoma (SEP)
- Seen in ~7% of MM patients at diagnosis by PET/CT or as purple, subQ masses
- Dx: workup as per MM (CMP, CBC, SPEP/IFE, UPEP/IFE, Igs, BMBx and aspirate, FDG PET/CT vs MRI) plus biopsy of lesion
- Criteria for Solitary Plasmacytoma: biopsy proven tumor of clonal plasma cells, BMBx with no clonal plasma cell population (<10%), no CRAB criteria, no lytic lesions on imaging
- Tx: Solitary: radiation, possibly surgical resection of SEP if anatomy permits; monitor for MM
Waldenstrom Macroglobulinemia (WM)/ Lymphoplasmacytic Lymphoma
- WM = lymphoplasmacytic lymphoma in bone marrow (pathologic finding) + IgM monoclonal gammopathy in blood
Pathophysiology
- Post-germinal center IgM memory B cell undergoes malignant transformation, MYD88 L265P mutation common. Produces massive monoclonal IgM
- Serum: massive IgM increases serum viscosity, slowing blood flow in capillaries >> hyper-viscosity syndrome: blurry vision, retinal hemorrhage, papilledema, headache, dizziness, AMS, TIA, bleeding diathesis, epistaxis
- RBCs: B cell infiltration of bone marrow>>low RBC, WBC, plt production with anemia, thrombocytopenia/bleeding, and neutropenia/immunosuppression; IgM against RBC antigen>>Combs-positive autoimmune hemolytic anemia
- Lymph Nodes/Liver/Spleen: B cell infiltration>>LAD, HSM
- Blood Vessels: IgM precipitate in capillaries at cold temp>>cryoglobulinemia, Raynaud’s, acral cyanosis, tissue necrosis
- Kidneys: IgM deposits into glomerular basement membrane, B cells may infiltrate, may also have glomerulonephritis from cryoglobulinemia
- Peripheral nerves: IgM against myelin-associated glycoprotein>>distal, symmetric, sensorimotor neuropathy
- General: B symptoms, weight loss, fatigue
Dx
- CMP (paraprotein gap), CBC (anemia), smear (rouleaux), BMBx (lymphoid, plasmacytoid cells with intranuclear vacuoles containing IgM, molecular studies for MYD88), SPEP/IFE (monoclonal IgM), Igs (IgM very high, other immunoglobulins may be low), Serum viscosity (Sxs unlikely 2/2 hyperviscosity if viscosity <4 CP, likely symptomatic if >6), SFLC, high LDH, high B2-microglobulin; CT CAP (HSM, LAD; should not be lytic bone lesions); maybe EMG
- Criteria:
- IgM monoclonal gammopathy in serum
- BMBx >10% lymphocytes with plasmacytoid differentiation
- Those meeting criteria for WM but lack the symptoms/signs such as hyperviscosity, anemia, LAD, HSM have SMOLDERING WM
Tx
- Asymptomatic/no end organ damage: observation q4-6M, higher risk of progression if IgM>4500, B2-micro>4, Alb<3.5, BMBx lymphoplasmacytic population >70%. IF Sx of hyper-viscosity or end organ damage (cytopenias, neuropathy): 1st plasmapheresis to lower IgM then bendamustine+ritux (if fit pt) vs BTKi (if unfit)
Other Plasma Cell Dyscrasias
Light Chain (AL) Amyloidosis
- Pathophysiology: Monoclonal plasma cell population >> Ig with light chains that deposit as beta pleated sheets in tissues >> end organ damage
- Kidneys: GBM deposition >> proteinuria up to nephrotic range
- Heart: Inter-myocyte deposition esp. in septum >> restrictive cardiomyopathy with systolic or diastolic dysfunction
- Nerves: peripheral nerve sheath deposition >> small fiber neuropathy (numbness + paresthesias), autonomic dysfunction, maybe carpal tunnel from compression
- Blood vessels: Vessel walls deposition >> fragility with easy bruisability/purpura
- Liver, spleen, tongue: HSM, macroglossia 2/2 infiltration
- Dx: All 4 necessary: 1. amyloid-related systemic syndrome 2. + Congo red tissue biopsy (usually fat pad + BMBx) 3. amyloid is light chain (mass spec or immunoelectron microscopy) 4. monoclonal plasma cell disorder (SPEP/IFIX, SFLC, UPEP/IFIX)
- Organ involvement: CMP, coags, UPCR/UACR, trop, NT-proBNP, EKG, TTE, EMG
- Tx: Daratumumab + cyclophosphamide + bortezomib + dexamethasone (Dara-CyBorD); maybe auto SCT if candidate
POEMS Syndrome
- “POEMS PEST”: Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal plasma cell disorder, Skin changes, Papilledema, Extravascular volume overload, Sclerotic bone lesions, Thrombocytosis
- Pathophysiology: cause unknown, likely associated with chronic overproduction of inflammatory cytokines (IL-1, IL-6, TNF-a, etc) and VEGF
- Dx: CBC (high Hb, plts), CMP, SPEP/IFIX, UPEP/IFIX; VEGF; BMBx; glucose/A1c; hormones: AM cortisol, TSH, prolactin, T, E, other hormones; CT skeletal survey; dilated fundoscopic exam
- Mandatory (both): peripheral neuropathy, monoclonal plasma cell disorder
- Major (need 1/3): osteosclerotic lesions, elevated VEGF, Castleman Disease
- Minor (need 1/6): organomegaly, volume overload, endocrinopathy, skin changes, papilledema, thrombocytosis, polycythemia
- Tx: depends on disease burden, maybe localized radiation if bony disease is limited; for disseminated disease chemotherapy (some combo of dara, lenalidomide, bortezomib, dex) +/- autoSCT; treatment of volume overload, endocrine deficiency, DVT ppx
Castleman Disease
- Angiofollicular lymph node hyperplasia, subdivided into Unicentric (LNs in single region) and Multicentric (multiple LN regions), also subdivided by HHV-8 association
- Pathophysiology: For HHV-8 associated: uncontrolled HHV-8 causes inflammatory cytokine release (mostly IL-6); Pathophysiology of HHV-8 negative CD poorly understood
- Features: LAD, HSM, fever, night sweats, fatigue, fluid accumulation, cytopenias, violaceous papules, lymph node biopsy w/characteristic pathology
- Dx: different criteria for unicentric, multicentric, but big picture you have 1. imaging evidence of LAD 2. path signs of inflammatory reaction (+/-HHV-8) 3. Clinical signs of massive inflammation (fevers, night sweats, HSM) or HHV-8 (violaceous papules) and 4. lab evidence of inflammation and organ dysfunction (high ESR/CRP, cytopenias, AKI, hypoalbuminemia) AFTER RULING OUT other Dxs (autoimmune, malignancy)
- Tx: if associated with POEMS, treat the POEMS; if not: Unicentric: maybe resection, observation, or ritux; Multicentric: maybe ritux +/- chemo; ART if HIV
