Plasma Cell Disorders

MGUS AND MULTIPLE MYELOMA (MM)

Patrick W. Burke

Hani Hassoun

Definition

Monoclonal gammopathy of undetermined significance (MGUS): Premalignancy w/clonal plasma cell (PC) proliferation. No e/o other B-cell disease. <10% monoclonal PCs in BM, <3 g/dL serum M-protein, & no MM-related organ dysfunction s/s.
Multiple myeloma (MM): Malignant neoplasm of clonal PC. Almost always in BM plus Ig or light chain production → M-protein in blood/urine. Arises from MGUS.
Plasma cell Leukemia: Rare variant of MM (2-4% of MM) w/↑ aggressive course. Leukemic phase of MM → either 1° or 2° (antecedent MM). ↓↓ OS.
Related organ or tissue impairment (ROTI): CRAB. C = ↑ Ca (>11.5 mg/dL); R = Renal insufficiency (Cr > 2 mg/dL); A = Anemia (Hb < 10 g/dL or 2 g/dL < nl); B = Bone disease (lytic lesion/pathologic fx/sev. osteopenia). Also consider recurrent infxn, ↑ viscosity, & amyloidosis.

MGUS

Myeloma

PC Leukemia

Smoldering Asymptomatic MM

Active (Sx) MM

Solitary Plasmacytoma

<10% BM Clonal PC

Serum M-Protein <3 g/dL

No ROTI

≥10% BM Clonal PC

AND/OR

Serum M-Protein ≥3 g/dL

BUT

No ROTI

Clonal PC

AND/OR

Serum M-Protein

≥1 ROTI

No BM Clonal PC

1 PC Lesion

No Other ROTI

PB PC > 2000/uL

PB PC > 20%

± ROTI

Epidemiology

MGUS: ↑ incidence w/age & in Western countries → 3% of adults >50 y.
- 7.5% in adults >85 y. ˜0.5-3% per y progress to MM.
MM: 1% all neoplasms. 13% of heme malignancies (2nd highest incidence in Western
- World. ˜5.6/100000/y). 2% of all CA death.
- U.S. 2012: ˜21700 new Dx. ˜10,710 death. ˜63000 total cases.
- Median age ˜65 y. Risk of Asymptomatic MM → Sx MM ˜10-20%/y.
- ↑ Incidence African-Americans, Afro-Caribbeans, & Pacific Islanders.
- Possible familial predisposition. Possible exposure risk (pesticides/herbicide).

Biology/Pathogenesis (N Engl J Med 2011;364:1046)

Progression: MGUS → Asymptomatic (Smoldering) MM → Sx MM → PC Leukemia
- Multistep progression of genetic & BM microenvironment changes.
- Genetic Abnl → MM PC altered expression of adhesion molecules/responses to microenvironment growth stimuli → ↑ cytokines/GF/cell cycle regulatory proteins/antiapoptotic proteins → ↑ growth, survival, migration, drug resistance.
MGUS: Asymptomatic proliferation of monoclonal PC from post-GCB.
- CG: 50% hyperdiploid (48-74 chromosomes); 50% nonhyperdiploid.
- Translocations at IgH switch region: Chromosome 14(q32.33) → IgH gene enhancers/promoter juxtaposed in proximity to oncogene locus.
- ↑ Prevalence IgH translocations w/↑ malignancy progression. MGUS → MM.
- Three common translocation partners: MAF → t(14;16)(q32.33;q23); MMSET→ t(4;14)(p16;q32.33) (deregulation of MMSET & FGFR3); CCND1 → t(11;14) (q13;q32.33).
- Molecular: ↑ expression of cyclins (D1, D2, & D3) & transcription factors.
MM: CG: Hyperdiploidy & nonhyperdiploid (hypodiploid, near tetraploid, & pseudohypodiploid) & IgH translocations seen.
- 2° translocations: MYC (8q24), MAFB (20q12), IRF4 (6p25) ↑ MM; rare MGUS.
- Del 18p, Del 17p13, Del 1p, amp 1q, Del 13 → only MM.
- Molecular: NRAS & KRAS activation; FGFR3 & TP53 Mt; inactivation CDKN2A & CDKN2C in MM.
- MM microenvironment: ↑ angiogenesis (↑ VEGF) + bone resorption (↓ Wnt signal → ↓ osteoblast action; ↑ RANK/MIP1α → ↑ osteoclast action).

Presentation

M-protein: 97%; anemia: 70% (CKD, chronic disease, BM infiltration); bone lytic lesion/osteopenia/pathologic fx: 80%; Renal impairment: 20-40% (M-Protein → tubular damage; dehydration; ↑ Ca; nephrotoxic meds).

Workup

Initial H&P, CBC, basic metabolic profile (BMP), LFTs, electrolytes (esp. serum Ca), SPEP, UPEP, quantitative Igs, urine immunofixation (UIF), serum immunofixation (SIF), serum free light chain assay (SFLC), 24-h urine protein quantification, β₂-microglobulin, albumin, BM aspirate & Bx (w/IHC, morphology, flow cytometry + CG w/karyotype + FISH), & x-ray skeletal survey. MRI or PET if bone sxs but negative skeletal survey.
Diff Dx: MGUS, MM, PC leukemia, lymphoplasmacytic lymphoma (LPL)/WM, NHL, 1° amyloidosis, heavy chain deposition disease, light chain deposition disease, cryoglobulinemia, idiopathic cold agglutinin disease.

Staging

Durie-Salmon (DS): MM “cell mass” c/w prognosis (response to CT & OS). 5 criteria (anemia, serum Ca, bone disease, M-protein, & serum Cr). Significantly c/w MM cell mass & prognosis. DS staging performed at Dx. 3 prognostic categories: Low (Stage 1), INT (Stage 2), & High (Stage 3).

Durie-Salmon MM Staging Criteria (Cancer 1975;36:842)
Stage 1	Stage 2	Stage 3
All criteria – Hb > 10 g/dL – Serum Ca nl (< 12 mg/dL) -X-ray: Nl bone structure or solitary bone plasmacytoma – ↓ M-Protein production rate – IgG < 5 g/dL – IgA < 3 g/dL – Urine light chain M-Component on electrophoresis < 4g/24 h	Meeting criteria neither for stages 1 or 3.	≥1 criterion – Hb < 8.5 g/dL – Serum Ca > 12 mg/dL – Adv lytic bone lesions – ↑ M-Protein production rate – IgG > 7 g/dL – IgA > 5 g/dL – Urine light chain M-Component on electrophoresis > 12 g/24 h
Subclassification A: Serum cr < 2 mg/dL B: Serum cr ≥ 2 mg/dL