Pocket Medicine

HEMATOLOGY-ONCOLOGY

PLASMA CELL DYSCRASIAS

MULTIPLE MYELOMA (MM)

Definition and epidemiology (NEJM 2011;364:1046)

•  Malignant neoplasm of plasma cells producing a monoclonal Ig = “M protein

•  ~21,700 new cases and ~10,710 deaths/y in U.S. (2012); median age at diagnosis 69 y

•  African American:Caucasian ratio 2:1

Clinical manifestations (CRAB criteria)

•  HyperCalcemia due to ↑ osteoclast activity

•  Renal disease: multiple mechanisms include toxic effect of filtered light chains → renal failure (cast nephropathy) or type II RTA; amyloidosis or light chain deposition disease → nephrotic syndrome; hypercalcemia, urate nephropathy, type I cryoglobulinemia

•  Anemia (normocytic) due to bone marrow involvement and autoimmune Ab

•  Bone pain due to ↑ osteoclast activity → lytic lesions, pathologic fx

•  Recurrent infxns due to relative hypogammaglob. (clonal plasma cells suppress nl Ig)

•  Neurologic: cord compression; POEMS (polyneuropathy, organomegaly, endocrinopathy, M protein, skin changes) syndrome

•  Hyperviscosity: usually when IgM >4 g/dL, IgG >5 g/dL, or IgA >7 g/dL

•  Coagulopathy: inhibition of or Ab against clotting factor; Ab-coated platelets

•  Amyloidosis (see “Amyloidosis”)

Diagnostic and staging evaluation

•  Symptomatic MM criteria (all 3 must be met)

1) M protein in serum or urine (no specific level required)

2) bone marrow clonal plasmacytosis (≥10%) or presence of a plasmacytoma

3) myeloma-related organ or tissue impairment (ROTI) = lytic bone lesions, Ca >11.5 g/dL, Cr >2 mg/dL, or Hb <10

•  Variants

smoldering MM: M protein >3 g/dL and/or plasmacytosis >10%, but asx & no ROTI risk of prog.: M protein concen., subtype & free light chain ratio (NEJM 2007;356:2582)

solitary bone plasmacytoma: 1 lytic lesion w/o M protein, plasmacytosis, or other ROTI

extramedullary (nonosseous) plasmacytoma: usually upper respiratory tract

plasma cell leukemia: plasma cell count >2000/µL in peripheral blood

nonsecretory MM (~2% of MM Pts): no M protein, but marrow plasmacytosis & ROTI

•  Ddx of M component: MM, MGUS (see below), CLL, lymphoma, cirrhosis, sarcoidosis, RA

•  Peripheral smear → rouleaux (see insert); ✓ Ca, alb, Cr; ↓ anion gap, ↑ globulin, ↑ ESR

•  Protein electrophoresis and immunofixation

serum protein electrophoresis (SPEP): quantitates M component;  in ~80% of Pts

urine protein electrophoresis (UPEP): detects the ~20% of Pts who secrete only light chains ( = Bence Jones proteins), which are filtered rapidly from the blood

immunofixation: shows component is monoclonal and identifies Ig type → IgG (50%), IgA (20%), IgD (2%), IgM (0.5%), light chain only (20%), nonsecretors (<5%)

serum-free light chain assay: important test for dx and follow-up of response to Rx

•  β2-microglobulin and LDH levels reflect tumor burden

•  BM bx cytogenetics: normal karyotype better than abnl. Standard risk = hyperdiploidy or t(11;14); high risk = hypodiploidy, del. 17p13 (~10% of Pts), t(4;14) & t(4;16)

•  Gene mutations include TP53NRASKRASBRAF & NK-kB pathway (Nature 2011;471:467)

• Skeletal survey (plain radiographs) to identify lytic bone lesions and areas at risk for pathologic fracture; bone scan is not useful for detecting lytic lesions

Treatment (NEJM 2011;364:1046; Am J Hematol 2012;87:79)

•  Not indicated for smoldering MM or asx stage I disease

•  Decisions generally dictated by risk stratification and transplant eligibility

•  Active agents include: bortezomib (V), dexamethasone (D), prednisone (P), lenalidomide (R), thalidomide (T), melphalan (M), cyclophosphamide (C), doxorubicin, carfilzomib (Cz)

•  Induction Rx regimens w/ best response rate incl. those w/ proteasome inhib (V, Cz) & immunomod (R), but many 2- or 3-drug options used based on comorbidities and risk. Proteasome inhib containing regimens incl. MPV, RVD, VCD & CzRD.

•  If not transplant eligible: induction chemo ↑ survival, not curative; consider maint chemo

•  If transplant eligible: induction chemo (eg, RVD, VCD, RD, VTD; Lancet 2010;376:2075) then high-dose chemo + auto-HSCT. Not curative, but ↑ survival c/w chemo (NEJM 2009;360: 2645). Timing of HSCT (upfront vs. relapse) under study. Offer if <70 y w/ good perf. status & no prohibitive comorbidities. Maint Rx w/ R or V until progression or intolerance. Role of tandem auto-HSCT & allo-HSCT remains controversial (NEJM 2003;349:2495).

•  Local radiation for solitary or extramedullary plasmacytoma

•  Adjunctive Rx

bonebisphosphonates (JCO 2007;25:2464); XRT for sx bony lesions

renal: avoid NSAIDs & IV contrast; consider plasmapheresis for acute renal failure

hyperviscosity syndrome: plasmapheresis; infxns: consider IVIg for recurrent infections

•  Common toxicities of Rx: melphalan → myelosuppression; lenalidomide → low plts & thromboembolism; bortezomib → periph. neuropathy; steroids → hyperglycemia, infxn

MONOCLONAL GAMMOPATHY OF UNCERTAIN SIGNIFICANCE (MGUS)

Definition and epidemiology (NEJM 2006;355:2765)

•  M protein <3 g/dL, no urinary Bence Jones proteins, marrow plasmacytosis <10%, no ROTI

•  Prevalence ~3% in population >50 y of age, ~5% in population >70 y of age, and

7.5% in population >85 y of age (NEJM 2006;354:1362)

Management

•  ✓ CBC, Ca, Cr, SPEP, serum free light chains, UPEP w/ immunofixation (to exclude MM)

•  Close observation: repeat SPEP in 6 mo, then yearly thereafter if stable

Prognosis (NEJM 2002:346:564)

•  ~1%/y or ~25% lifetime risk → MM, WM, amyloidosis, or malign. lymphoproliferative dis.

•  Abnormal serum-free light chain ratio: ↑ risk of progression to MM (Blood 2005;105:812)

WALDENSTRÖM’S MACROGLOBULINEMIA (WM)

Definition (Blood 2009;114:2375)

•  B-cell neoplasm (lymphoplasmacytic lymphoma) that secretes monoclonal IgM

•  MYD88 (NF-кB pathway) L265P somatic mutation found in 91% of Pts w/ WM and could be used to distinguish WM from MM (NEJM 2012;367:826)

•  No evidence of bone lesions (IgM M component + lytic bone lesions = “IgM myeloma”)

Clinical manifestations

•  Fatigue from anemia is most common sx

•  Tumor infiltration: BM (cytopenias), hepatomegaly, splenomegaly, lymphadenopathy

•  Circulating monoclonal IgM

hyperviscosity syndrome (~15%)

neurologic: blurred vision (“sausage” retinal veins on funduscopy), HA, dizziness, Δ MS

cardiopulmonary: congestive heart failure, pulmonary infiltrates

type I cryoglobulinemia → Raynaud’s phenomenon

platelet dysfxn → mucosal bleeding

•  IgM deposition (skin, intestine, kidney); amyloidosis and glomerulopathy

•  Autoantibody activity of IgM

chronic AIHA (prominent rouleaux; 10% Coombs’  = AIHA)

peripheral neuropathy: may be due to IgM against myelin-associated glycoprotein

Diagnostic evaluation

•  SPEP + immunofixation with IgM >3 g/dL; 24-h urine for UPEP (only 20% have  UPEP)

•  Bone marrow biopsy: ↑ plasmacytoid lymphocytes; β2-microglobulin for prognostic eval

•  Relative serum viscosity: defined as ratio of viscosity of serum to H2O (nl ratio 1.8) hyperviscosity syndrome when relative serum viscosity >5–6

Treatment

•  Hyperviscosity: plasmapheresis

•  Symptoms (eg, progressive anemia): rituximab ± chemotherapy (eg, cyclophosphamide, chlorambucil, fludarabine, cladribine, bendamustine) or bortezomib

•  Thalidomide, alemtuzumab, everolimus, ibrutinib & auto-HSCT are investigational Rx