R4 Jae Joon Han

Introduction Smoldering multiple myeloma & Multiple myeloma Cannot be made by histopathologic exam. of the bone marrow Dependent on the presence or absence of a clinical findings that reflect end-organ damage. Needs to be differentiated from related plasma cell disorders Primary anyloidosis Waldonstrom’s macroglobulinemia Solitary plasmacytoma

Introduction Even with accurate diagnosis the outcome is variable Disease stage Key independent prognostic factors Vast amount of new translational and clinical research information has accumulated, new systems have been developed. Additionally, in the last year new uniform response criteria has been developed Eliminate the confusion that occurred with varying response criteria which had been used to assess response to therapy.

DIAGNOSTIC CRITERIA DDx. MGUS, SMM by presence of end-organ damage Osteolytic bone lesions and/or compression fractures Anemia : 70% Renal failure : 50% Hypercalcemia : 25%

DIAGNOSTIC CRITERIA M proteins Serum protein electrophoresis: 82% Serum immunofixation: 93% Up to 20% of patients lack heavy-chain expression are considered to have light-chain myeloma Urine PEP and Urine IFE: 97% Who are negative for M protein on serum and urine EP and IF Most (60%) will have evidence of clonal paraprotein on the Free light chain(FLC) assay Currently only 1-2% of patients will have no detectable M protein on any of these tests: non-secretory myeloma

STAGING Survival Survival depends of disease stage median survival: approximately 3-4years some patients can live longer than 10 years Survival depends of disease stage the Durie-Salmon staging system since 1975 A new international staging system (ISS)

staging Collaborative effort by investigators from 17 institutions worldwide and from data on 11,171 patients

Staging- two drawbacks of ISS Not useful unless the diagnosis of myeloma has already been made. The ISS has no role in MGUS or SMM, and cannot distinguish these two premalignant disorders from myeloma. Does not identify an adverse prognostic group that is at sufficiently high risk warrant a different therapeutic approach. A stronger risk-stratification model is needed for therapeutic purposes.

PROGNOSTIC FACTORS Age ISS stage Hemoglobin concentration Creatinine Calcium Albumin Immunoglobulin class subtype Extent of bone-marrow involvement Plasmablastic morphology Circulating plasma cells Lactate dehydrogenase C-reactive protein

Mayo risk stratification High-risk characteristic Percentage of newly diagnosed patients with the abnormality Conventional cytogenetics Deletion of chromosome 13 (monosomy) 14% Hypodiploidy ( <2n) 9% Either hypodiploidy or deletion 13 17% Fluorescent in-situ hybridization t(4;14) 15% t(14;16) 5% 17p- 10% Plasma-cell labeling index studies 6% Any one of the above high-risk abnormalities 25-30%

Plasma-cell labeling index Poor overall survival and progression-free survival Cut-off value of 1 or 2% At the Mayo clinic, a cut-off value of ≥ 3% has been defined as a high value for risk stratification Limitation: only a few labs in US are presently performing the test.

Translocation 4;14, 14;16 and deletion 17p– Deletion chromosome 13: 30-55% of patients Deletion 17p13.1: 10% p53 inactivation t(11;14)(q13;q32): 15-20% t(4;14)(p16.3;q32): 15% dysregulation of the FGFR3 and MMSET t(14;16)(q32;q23): 5% dysregulates the c-maf oncogene

Performance status The single most powerful predictor of outcome in myeloma Kyle and colleagues. 1027 newly diagnosed MM at Mayo Clinic Median survival 36 months vs. 11months – good vs. performance status 3-4 A greater adverse impact on outcome than any other single variable, including PCLI and ß 2-microglobulin

Risk stratification of myeloma

RESPONSE CRITERIA To monitor effectiveness of therapy To evaluate new drugs and interventions in clinical trials Chronic Leukemia-Myeloma Task Force Southwest Oncology group (SWOG) ECOG European Group for Blood and Bone Marrow Transplant /International Bone Marrow Transplant Registry /American Bone Marrow Transplant Registry (EBMT/IBMTR/ABMTR)

RESPONSE CRITERIA In 2006, the International Myeloma Working Group(IMWG) IMWG criteria is similar to the EMBT criteria with the following exceptions Addition of free-light-chain response and progression criteria Difference in definition of progression for patients in complete response Addition of very good partial response and stringent response categories Elimination of minor response category

Very good partial response (VGPR) Patients who had at least a VGPR with the first autologous stem- cell transplant do not benefit from a second transplant. Serum and urine M-component detectable by immunofixation but not on electrophoresis, or 90% reduction in serum M-component plus urine M-component <100 mg/24 h 50% reduction of serum M-protein and reduction in 24-h urinary M-protein by 90% or to <200 mg/24 h

Serum free-light-chain assay Monitor response to therapy in oligo- or non-secretory myeloma. κ/λ FLC ratio<0.26 monoclonal λ free light chain Ratio >1.65 monoclonal κ free light chain FLC levels vary considerably with changes in renal function and do not solely represent monoclonal elevations. Involved-uninvolved difference is considered in assessing response

SURVIVAL ESTIMATES Overall survival(OS) Progression-free survival(PFS) gold standard for comparing therapeutic strategies. Progression-free survival(PFS) can serve as a surrogate for OS in some settings Time from start of therapy to disease progression or death Event-free survival(EFS) Period from start of therapy to predefined events such as disease progression or relapse, death, or serious toxicity Time to progression(TTP) Start of therapy to disease progression, with deaths due to causes other than progression censored at that time-point.

SUMMARY Specific criteria have been developed for diagnosis and staging of multiple myeloma. Staging of myeloma should be done by the International Staging System. A risk-stratification model is recommended to define high-risk patients who can benefit from novel therapeutic strategies but do poorly with current transplant based therapy. The IMWG uniform response criteria should be used as the standard for response assessment in myeloma.