PLASMA CELL DYSCRASIAS CLASSIFICATION Monoclonal gammopathy of uncertain

PLASMA CELL DYSCRASIAS CLASSIFICATION • Monoclonal gammopathy of uncertain significance (MGUS) Idiopathic q Associated with other diseases (autoimmune, infectious, non-heme cancer, etc) q • Plasma cell or lymphoid malignancy Waldenstrom's macroglobulinemia q Other lymphoproliferative disorders q Smoldering multiple myeloma q Multiple myeloma q

MOLECULAR PATHOGENESIS OF MYELOMA Lancet 2004; 363: 875

MULTIPLE MYELOMA Definition • • • Increased numbers of abnormal or immature plasma cells in the bone marrow, or localized plasmacytoma Monoclonal protein in blood or urine Ø Some patients are nonsecretors Lytic bone lesions Ø Not all patients have lytic bone disease

MULTIPLE MYELOMA EPIDEMIOLOGY • Incidence in US approx 3 cases/100, 000/yr • 98% of cases > 40 yrs old • Risk factors: genetic q radiation exposure q ? chemical exposure q

MULTIPLE MYELOMA Serum and urine protein electrophoresis Monoclonal Ig. G Serum Urine Free light chain

Multiple myeloma (Ig. G kappa) Ig. G 2080 Anemia, leukopenia Lytic bone lesions 10% marrow plasma cells

Multiple myeloma (Ig. A) Ig. A 1010 (nl 70 -140) Ig. G 165 (nl 695 -2190) Ig. M 14 (nl 60 -265) Anemia, thrombocytopenia 16% marrow plasma cells

MGUS Ifix: monoclonal Ig. G kappa No proteinuria Ig. A 234 (50 -540) Ig. G 1840 (600 -1600) Ig. M 85 (40 -250) Normal CBC

Waldenstrom macroglobulinemia with hyperviscosity syndrome Anemia, fatigue, retinopathy, bleeding disorder Ig. A 125 (70 -440) Ig. G 724 (695 -2190) Ig. M 5130 (60 -265) Serum viscosity 3. 6 Marrow: <5% plasmacytoid B-lymphocytes

Waldenstrom macroglobulinemia Mild fatigue Ig. M 8460, serum viscosity 2. 7 Hgb 12, WBC 3700, platelets 143, 000 Marrow: 50% plasmacytoid B-lymphocytes

Kappa light chain myeloma with cardiac amyloidosis Serum (hypogammaglobulinemia) Urine (kappa light chain) Always check the urine!

MULTIPLE MYELOMA – BONE MARROW ASPIRATE

MYELOMA CYTOGENETICS t(4; 14) del (13) Lancet 2004; 363: 875

MULTIPLE MYELOMA DIAGNOSIS • Monoclonal paraprotein q q Intact immunoglobulin in serum (SPEP) Light chains in serum or urine (IEP) • Marrow plasmacytosis (> 20% - may be patchy) • Lytic bone lesions • Plasmacytoma

MULTIPLE MYELOMA CLINICAL MANIFESTATIONS • Anemia progressing to pancytopenia • Bone pain/destruction • Hypercalcemia • Humoral immune defect • Local effects of plasmacytomas • Systemic effects of paraprotein

MONOCLONAL GAMMOPATHY COMPLICATIONS • Hyperviscosity (Ig. M >> Ig. A > Ig. G) • Renal dysfunction (light chains) Glomerular q Tubular Neuropathy Other organ damage (rare) Cryoglobulinemia (types I and II) Amyloidosis q • •

MULTIPLE MYELOMA Cast nephropathy

CRYOGLOBULINEMIA IN Ig. M GAMMOPATHY Brit J Haematol 2004; 124: 565

MULTIPLE MYELOMA Demographics Mayo Clin Proc 2003; 78: 21

MULTIPLE MYELOMA Presenting features (1027 pts) Mayo Clin Proc 2003; 78: 21 Bone pain 58% Fatigue 32% Weight loss 24% Paresthesias 5% Fever 0. 7% ECOG PS >2 10%

MULTIPLE MYELOMA Preexisting conditions and risk factors Mayo Clin Proc 2003; 78: 21 Cancer in 1 st degree relative 42% Myeloma in 1 st degree relative 2% Hx of plasma cell proliferative disorder 34%

MULTIPLE MYELOMA Pre-existing plasma cell disorders Mayo Clin Proc 2003; 78: 21

MULTIPLE MYELOMA Physical findings Mayo Clin Proc 2003; 78: 21 Palpable liver 4% Palpable spleen 1% Lymphadenopathy 1%

MULTIPLE MYELOMA Hematologic findings at presentation Mayo Clin Proc 2003; 78: 21 Hgb < 12 73% Hgb < 8 7% ESR > 20 84% ESR > 100 33% WBC < 4000 20% WBC < 2000 1% Plts < 100 K 5% Plts > 500 K 2%

MULTIPLE MYELOMA Laboratory findings Mayo Clin Proc 2003; 78: 21

MULTIPLE MYELOMA Serum and urine proteins Mayo Clin Proc 2003; 78: 21 Monoclonal band on SPEP in 82% 3% non-secretory at presentation

MULTIPLE MYELOMA Types of monoclonal proteins Mayo Clin Proc 2003; 78: 21

MULTIPLE MYELOMA Radiographic findings at presentation Mayo Clin Proc 2003; 78: 21

MULTIPLE MYELOMA Survival Mayo Clin Proc 2003; 78: 21

MULTIPLE MYELOMA Prognostic factors Mayo Clin Proc 2003; 78: 21 * * * Most important factors in multivariate analysis

*Adapted from Greipp et al, Blood 2003; 102: 190 a

Adverse cytogenetics in myeloma del 13 or del 13 q t(4; 14 del 17 p

MULTIPLE MYELOMA INDICATIONS FOR TREATMENT • Symptomatic disease • Bone destruction • Anemia • Organ dysfunction • Hypercalcemia • Increasing paraprotein microglobulin level or ß 2 -

TREATMENT MNEMONIC • Calcium increased • Renal dysfunction • Anemia • Bone lesions

MULTIPLE MYELOMA TREATMENT • Initial treatment: – Thalidomide or lenalidomide + dexamethasone – Bortezomib + lenalidomide + dexamethasone – Melphalan + prednisone + lenalidomide/thalidomide • Autologous SCT prolongs survival • Refractory disease: – High dose cyclophosphamide – Platinum-based regimen • Bisphonates as adjunctive Rx • Allogeneic transplant role?

Overall and progressionfree survival in multiple myeloma: standard chemotherapy vs highdose chemotherapy with stem cell rescue NEJM 2003; 348: 1875

Blood 2010; 116: 679 -686

N Engl J Med 1996; 334: 488 -93

Lancet 2004; 363: 875

How do thalidomide & related drugs work? Science 2014; 343: 256