BENIGN MONOCLONAL GAMMOPATHY DOES EXIST frequency Percentage of

BENIGN MONOCLONAL GAMMOPATHY DOES EXIST? frequency Percentage of neoplastic transformation M. Boccadoro www. mieloma. it DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

BENIGN MONOCLONAL GAMMOPATHY M-COMPONENT ASYMPTOMATIC NO OSTEOLYTIC LESIONS DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

MONOCLONAL GAMMOPATHIES STABLE MDD PROGRESSIVE NN DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

Multistep cancerogenesis of myeloma Normal plasma cell Monoclonal gammopathy Myeloma Extramedullary myeloma Kariotipic instability Chromosome translocation Ig. H switch region K, N-ras, P 53 mutations DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

Incidence of Multiple Myeloma, macroglobulinemia, amyloidosis after recognition of M-component Kyle R. A. , Baillieres Clin Hematol, 1995 DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

BENIGN MONOCLONAL GAMMOPATHY OF UNDETERMINED SIGNIFICANCE MGUS DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

FREQUENCY OF MONOCLONAL GAMMOPATHIES Related to the sensitivity of the method DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

MONOCLONAL GAMMOPATHIES Detected by standard methods 1 -2 % normal population > 10 g/L Detected by sensitive methods ~ 10 % normal population < 5 g/L DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

OCCURRENCE OF MONOCLONAL GAMMOPATHIES IN A GENERAL HOSPITAL - Out-patients referred for routine laboratory tests - Ospedale Evangelico Valdese, Torino - Laboratorio analisi (Director: M. Saitta) - routine agarose electrophoresis (Hydrasis Ciampolini) - period: Genuary- May 1998 - 3013 serum samples analysed - 128 monoclonal gammopathies detected (4. 2%) DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

FREQUENCY OF MONOCLONAL GAMMOPATHY ACCORDING TO AGE % DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

DISTRIBUTION OF M-COMPONENT CONCENTRATION (g/L) Aguzzi et al, Eur J Haematol, 1992 DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

DISTRIBUTION OF M-COMPONENT CONCENTRATION (g/L) Ospedale Evangelico Valdese, Torino DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

MONOCLONAL GAMMOPATHY PROBABILITY OF TRANSFORMATION TO A MALIGNANT DISEASE • Evaluated in patient series: • Diagnosis 1960 s - 70 s • Standard electrophoresis • M-component at presentation >15 g/L DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

MONOCLONAL GAMMOPATHY PROBABILITY OF TRANSFORMATION FOR PATIENTS WITH M-component > 15 <30 g/L DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

MONOCLONAL GAMMOPATHY Neoplastic transformation is related to the M-component concentration Ig. G > 50 g/L require chemotherapy Ig. G > 30 g/L transformation within 1 year (Dimopoulos, 1993) Ig. G > 15 < 30 g/L 26% transformation after 10 years (Kyle, 1995) Ig. G<15 g/L 1. 3% transformation after 6 years (Baldini, 1996) DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

BENIGN MONOCLONAL GAMMOPATHY A pre-neoplastic disorder? - 5% frequency M-component - incidence of myeloma 2 -4/100. 000/year 1 out of 1. 000 -2000 M-component is transformed to myeloma every year DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

MONOCLONAL GAMMOPATHIES TRANSFORMATION TO MYELOMA Related to M-component level DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

~ 70% < 10 g/L ~ 4 -6% 10 -20 g/L 30 g/L BENIGN MONOCLONAL GAMMOPATHY OF UNDETERMINED SIGNIFICANCE MULTIPLE MYELOMA DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

BENIGN MONOCLONAL GAMMOPATHY DOES EXIST? PROBABLY YES PROSPECTIVE LARGE STUDIES ON PATIENTS WITH SMALL M-COMPONENTS ARE REQUIRED DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

MULTIPLE MYELOMA DIAGNOSTIC CRITERIA: ALL 3 REQUIRED 1 2 Monoclonal plasma cells in the bone marrow > 10% and/or presence of a biopsy-proven plasmacytoma 2 Monoclonal protein present in the serum and/or urine * 3 Myeloma-related organ dysfunction (1 or more) ** [C] Calcium elevation in the blood {S. Calcium >10. 5 mg/l or upper limit of normal} [R] Renal insufficiency {S. Creatinine > 2 mg/dl} [A] Anemia {Hemoglobin < 10 g/dl or 2 g < normal} [B] Lytic bone lesions or osteoporosis *** DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

MGUS: Monoclonal Gammopathy of Undetermined Significance DIAGNOSTIC CRITERIA: ALL 3 REQUIRED 1. Serum Monoclonal protein and/or urine monoclonal protein 2. level < 30 g/L 3. 2. Monoclonal bone marrow plasma cells < 10% 3. Normal serum calcium, hemoglobin level and serum creatinine. No bone lesions on full skeletal x-ray survey and/or other imaging if performed. No clinical or laboratory features of amyloidosis or light chain depostion disease. DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

Prevalence of MGUS in Reported Studies Kyle R et al. N Engl J Med 2006; 354: 1362 -1369

Prevalence of MGUS According to Age Group and Sex among Residents of Olmsted County, Minnesota Kyle R et al. N Engl J Med 2006; 354: 1362 -1369

Prevalence of MGUS According to Age Kyle R et al. N Engl J Med 2006; 354: 1362 -1369

The New England Journal of Medicine DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

Cut-Off Levels for a Prognostic Score, Drawn From the Best Fitting Covariates and Their Relative Hazards 0 1 2 3 Serum monoclonal component, g/d. L < 0. 7 -1. 399 1. 4 -2. 099 2. 1 Hemoglobin, g/d. L 15 13 -14. 99 11 -12. 99 < 11 Female — — Male Covariate Sex NOTE. Low risk: 0 -2; intermediate risk: 3 -5; high risk: 6 -9. DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

Low risk (serum M protein <15 g/d. Lm Ig. G subtype, normal FCL ratio) Absolute risk of transformation at 20 yrs % 5 Absolute risk of transformation at 20 yrs accounting for death as a compiting risk, % 2 DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

Fracture risk in patients with monoclonal gammopathy of undetermined significance. Henrik Gregersen, Paw Jensen, Mette Gislum, Birgit Jørgensen, Henrik Toft Sørensen and Mette Nørgaard Br J Haematol. 2006 Oct; 135(1): 62 -7 DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

Table I. Mean ± SD values of anthropometric, biochemical and densitometric parameters in patients affected by MGUS considered as a whole group and subdivided on the basis of the presence of vertebral osteoporotic fractures. Total (n = 65) MGUS Fx (n = 34) MGUS NFx (n = 31) Age (years) 61· 3 ± 5· 8 62· 8 ± 6· 1 59· 7 ± 5· 0* Height (m) 1· 60 ± 0· 05 1· 59 ± 0· 04 1· 60 ± 0· 06 Weight (kg) 70· 7 ± 11· 8 69· 6 ± 11· 8 72· 0 ± 11· 9 BMI (kg/m 2) 27· 7 ± 4· 6 27· 6 ± 5· 0 27· 9 ± 4· 2 Years since diagnosis 7· 4 ± 6· 0 8· 8 ± 7· 1 5· 8 ± 4· 1* Hb (g/dl) 12· 9 ± 1· 0 12· 9 ± 0· 9 12· 9 ± 1· 1 Cr (μmol/l) 73· 4 ± 11· 5 73· 4 ± 12· 4 74· 2 ± 17· 7 Cr. Cl (ml/min 1· 73 m 2) 80· 5 ± 18· 2 77· 1 ± 17· 7 84· 3 ± 18· 3 BMD L 1–L 4 (g/cm 2) 0· 880 ± 0· 15 0· 811 ± 0· 14 0· 956 ± 0· 12*** T-score L 1–L 4 − 1· 52 ± 1· 34 − 2· 1 ± 1· 3 − 0· 84 ± 1· 04*** BMD neck (g/cm 2) 0· 702 ± 0· 10 0· 660 ± 0· 09 0· 747 ± 0· 10*** T-score neck − 1· 38 ± 0· 93 − 1· 75 ± 0· 80 − 0· 99 ± 0· 90*** BMD total (g/cm 2) 0· 834 ± 0· 12 0· 788 ± 0· 11 0· 884 ± 0· 11*** T-score total − 0· 89 ± 0· 99 − 1· 26 ± 0· 91 − 0· 45 ± 0· 91*** *P ≤ 0· 05; ***P ≤ 0· 001 compared with MGUS Fx. British Journal of Haematology 134 (5), 485 -490.

TRANSFORMATION FROM BENIGN TO PRE-NEOPLASTIC DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY

BENIGN MONOCLONAL GAMMOPATHY DOES EXIST? PROBABLY YES - M component < 0. 5 g/L - NO CRAB - Normal Free Light Chain DIVISIONE UNIVERSITARIA DI EMATOLOGIA AZIENDA OSPEDALIERA SAN GIOVANNI TORINO, ITALY