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