1. R4 Jae Joon Han

2. 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

3. 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.

4. 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%

5. 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

6. 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)

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

8. 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.

9. 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

10. 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%

11. 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.

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

13. Performance status
The single most powerful predictor of outcome in myeloma
Kyle and colleagues 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

14. Risk stratification of myeloma

15. 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)

16. 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

17. 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

18. 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

19. 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.

20. 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.