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Joan BladéUnidad de Amiloidosis y Mieloma
Servicio de HematologíaHospital Clínic de Barcelona
COMy Meeting, París, May 4th, 2018
Criteria for Disease Assessment
Response Evaluation
• EBMT, 1998- CR and progression
• IMWG Uniform Criteria 2006- sCR, VGPR
• IMWG updated, 2016- MRD (flow cytometry, NGS)- Imaging (PET/CT)
Bladé et al, 1998, Durie et al, 2006; Kumar et al, 2016
EBMT criteria for response, relapse and progression in MM
Response Category*
Criteria
CR • Negative IF (serum and urine)**•<5% bone marrow plasma cells•Disappearance of soft tissue plasmacytomas
PR • ≥50% serum M-protein • ≥90% urine M-protein or < 200 mg/24hrs• ≥50% soft tissue plasmacytomas
MR • 25-49% serum M-protein • 50-89% urine M-protein •25-49% soft tissue plasmacytomas
Stable disease • Not meeting criteria for MR nor PD
*All response categories must be maintained for at least 6 weeks** Excluding oligoclonal bands
EBMT, IBMTR, ABMTR Criteria for Definition of Response, Relapse and Progression in Patients With Multiple Myeloma
Treated by High-dose Therapy and Stem Cell Transplantation
Response Category Criteria
PD* • 25% and >5 g/L serum M-protein • 25% and >200 mg/24h urine M-protein • Bone marrow plasma cells >25% and absolute increase >10%• New lytic lesions, plasmacytomas or hypercalcaemia
Relapse from CR* •Paraprotein reappearance (IF or EP) (excluding oligoclonal reconstitution)• Bone marrow plasma cells > 5%• New lytic lesions, plasmacytomas or hypercalcaemia
*Confirmed on at least one repeated sample
EBMT, IBMTR, ABMTR Criteria for Definition of Response, Relapse and Progression in Patients With Multiple Myeloma
Treated by High-dose Therapy and Stem Cell Transplantation
International Uniform Response Criteria for Multiple Myeloma
Durie et al, Leukemia 2006; 20: 1467-1473
International Uniform Response Criteria for Multiple Myeloma (I)
Response Category*
Criteria
CR • Negative IF (serum and urine)•<5% bone marrow plasma cells•Disappearance of soft tissue plasmacytomas
sCR As above plus• Normal sFLC ratio• Absence of clonal plasma cells**
VGPR • ≥90% serum M-protein • Urine M-protein<100 mg/24h
PR • ≥50% serum M-protein • ≥90% urine M-protein or < 200 mg/24hrs• ≥50% soft tissue plasmacytomas
* All response categories require two consecutive measurements made at any time** A minimum of 3000 plasma cells analyzed by multiparametric flow cytometry (with 4 colors)
Durie et al, Leukemia 2006
IMWG definition of measurable disease and recommended measurements
Definitions of measurable disease
Response criteria to all categories of response except CR are aplicable only to patients who have “measurable” disease defined by at least one of the following measurements:
– Serum M-protein 10 g/L– Urine M-protein 200 mg/24h– Involved FLC level 100 mg/L plus an abnormal FLC ratio
Measurement of the M-protein– Serum M-protein: quantitated using densitometry on SPEP, unless than SPEP is unrelaible, which should be explicitly reported– Urine M-protein: quantitated using 24h-UPEP only– Patients with “measurable disease” should be followed monthly by both SPEP and UPEP for response assessment while on therapy
International Uniform Response Criteria for Multiple Myeloma (II)
Response Category* Criteria
Stable disease • Not meeting criteria for CR, VGPR, PR or PD
PD •25% and >5 g/L serum M-protein *• 25% and >200 mg/24h urine M-protein *• Difference between involved and uninvolved FLC levels must increase > 100 mg/L•Bone marrow plasma cells >25% and absolute increase >10%• New lytic lesions, plasmacytomas or hypercalcaemia
* All response categories require two consecutive measurements made at any time
Durie et al, Leukemia 2006
Suggested Modifications of the International Uniform Response Criteria for Multiple Myeloma (Consensus panel, IMW 2009 and 2011)
Response Category Criteria
MR(relapsed/refractory myeloma)
25-49% serum M-protein 50-89% urine M-protein 25-49% soft tissue plasmacytomas
Immunophenotypic CR Stringent CR plusAbsence of phenotypically aberrantplasma cells*
Molecular CR Stringent CR plus Negative ASO-PCR**
* Minimum of 1 million total BM cells analyzed by MFC with ≥4 colors**Sensitivity 10-5
Suggested Modifications of the International Uniform Response Criteria for Multiple Myeloma (Kyle & Rajkumar, Leukemia 2009)
Response Category*
Criteria
Relapse from CR*
Paraprotein reappearance (IF or EP) (excluding oligoclonalreconstitution) >5 g/L serum M-protein >200 mg/24h urine M-protein Bone marrow plasma cells > 5% New lytic lesions, plasmacytomas or hypercalcaemia
PD 10 g/L are sufficient to define relapse if starting M-component is 50 g/L
Response to Treatment
Fernández de Larrea et al. Leukemia 2013
Multiple Myeloma Workup
1. Complete blood count and differential; peripheral blood smear
2. Chemistry screen, including creatinine, calcium, LDH, beta2-microglobulin
3. Serum protein electrophoresis and immunofixation
3. Serum immunoglobulins (nephelometric quantification)
4. Measurement of serum free light chain (FLC)
5. 24-hour urine collection for electrophoresis and immunofixation
6. Bone marrow aspirate: morphology, immunophenotype and cytogenetics by FISH (13q, t(11;14); t(4;14); t(14;16); 17p)
7. Radiologic skeletal survey
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10. CT and/or MRI if clinically needed
11. PET/CT in patients with suspected extramedullary disease
Monitoring of Patients under Active Therapy
Induction and/or Maintenance
Before every cycle
CBC, chemistry including serum EP and 24-hours protein urine excretion with EP
If EP negative serum and urine IF and, if negative, bone marrow aspirate in order to confirm CR
Follow-up in Patients with Multiple Myeloma Off-TherapyAfter conventional therapy:(patients with stable response)
First year: every 2 months Beyond first year: every 3
months Beyond 5 years: every 4 months
After HDT/SCT:
First 6 months: every 2 months Two first years: every 3 months From 2 to 5 years: every 4
months Beyond 5 years: every 6 months
Patients with asymptomatic relapse or PD*
After conventional therapy: every 2 months
After HDT/SCT: every 3 months
* Unless abrupt PD
Lab work-up during follow-up off therapy
1. Complete blood count and chemistry
2. Serum total protein and EF
3. 24-hours urine protein measurement with EF
4. Serum and urine immunofixation and serum FLC every 2 visits only in patients in CR
5. Bone marrow aspirate and/or imaging techniques only when clinically indicated
Bone marrow: unexplained cytopenias (medullary progression, MDS)
Imaging: bone or extramedullary progression
Oligoclonal Bands
1. Monoclonal protein ≠ original
2. In patients in CR (ASCT, novel therapies)
3. Faint small bands in the gamma region, usually non-quantifiable
4. More frequent: IgG-k, IgG-, IgM (k or ), k or light chains, rarely IgA
5. Frequently multiple and fluctuating
6. Never show a significant increase
7. Tipically persistent all along the CR duration and their disappearance usually precedes relapse
Response Evaluation
• EBMT, 1998- CR and progression
• IMWG Uniform Criteria 2006- sCR, VGPR
• IMWG updated, 2016- MRD (flow cytometry, NGS)- Imaging (PET/CT)
Bladé et al, 1998, Durie et al, 2006; Kumar et al, 2016