Importancia del laboratorio en el seguimiento clínico de pacientes con mieloma múltiple

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1 Importancia del laboratorio en el seguimiento clínico de pacientes con mieloma múltiple Joan Bladé Unidad de Amiloidosis y Mieloma Servicio de Hematología Hospital Clínic de Barcelona Málaga, 16 de noviembre de 2017

2 Monoclonal Gammopathy of Undetermined Significance (MGUS) Diagnostic Criteria* Serum M protein size < 30 g/l Bone marrow plasma cells <10% No clinical manifestations or other laboratory abnormalities attributable to the monoclonal gammopathy The International Myeloma Working Group. Br J Haematol 2003

3 MGUS. Differential diagnosis MC (g/l) MGUS SMM MM <30 and 30 Present and/or BMPC (%) < * CRAB** / MDE*** No No Yes *Clonal **CRAB: Hypercalcemia, renal failure, anemia, lytic lesions, recurrent bacterial infections and/or extramedullary plasmacytomas ***MDE: >60% BMPC, serum FLC ratio 100, >1 focal lesion on the MRI Rajkumar et al, Lancel Oncol 2014

4 MGUS. Prevalence > 50 years 3% > 70 years 5.3% Kyle et al, N Engl J Med 2006;354:

5 Malignant Transformation of MGUS Actuarial probability: 1% per year (30% at 25 yrs) Actual probability (considering competing causes of death): 11% at 25 yrs

6 MGUS. Predictors of malignant transformation Tumor burden IgA isotype Aberrant phenotype (apc/bmpc 95%) Immunoparesis Pattern of MRI Abnormal FLC ratio Evolving type

7 MGUS. Predictors of malignant transformation Characteristic RR 95% CI p Evolving vs. non-evolving < IgA vs. others M-spike ( 15 g/l) Rosiñol et al, Mayo Clin Proc 2007

8 Evolving vs. Non-evolving MGUS 1,0 0,9 0,8 0,7 0,6 Evolving 0,5 0,4 Cumulative Proportion Surviving 0,3 0,2 0,1 0 Non-evolving months Rosiñol et al, Mayo Clin Proc 2007

9 MGUS. Risk-stratification model. Mayo Clinic HIGH RISK Risk at 20 years Abnormal FLC ratio, non-igg type MC 15g/L 58% LOW RISK Normal FLC ratio, IgG type MC <15 g/l 5% Rajkumar et al. Blood 2005; 106:

10 Mortality at 20 years of follow-up in 1384 pacients with MGUS Monoclonal gammopathy: 10% Unrelated cause: 72% Kyle et al, NEJM 2002; 346: 564-9

11 Smoldering Multiple Myeloma (Asymptomatic Myeloma) Diagnostic Criteria* Serum M protein size 3g/dL and/or urine light chain 1g/24 hours and/or bone marrow clonal plasma cells 10% No related organ tissue impairment (no end organ damage including bone lesions) or symptoms * The International Myeloma Working Group. Br J Haematol 2003; 121:

12 Evolving Smoldering Multiple Myeloma Rising M-protein Previously recognized MGUS Chromosomal losses, 1q gains Response to therapy ( 50%) Short time to symptomatic MM Rosiñol et al, Br J Haematol; 2003 Rosiñol et al, Br J Haematol; 2005

13 Evolving pattern as risk factor Median follow-up 6.8 years from the diagnosis of SMM Fernández de Larrea et al, IMW 2017

14 Monoclonal Gammopathies MM EVOLVING SMM NON EVOLVING MGUS NON EVOLVING Rosiñol et al. Br J Haematol 2003; 123: Rosiñol et al. Mayo Clin Proc 2007; 82:

15 Indicators of Increasing Disease and/or Endorgan Dysfunction MM-related (CRAB) HyperCalcemia (> 11.5 mg/dl) Renal failure ( serum creatinine by 2 mg/dl) Anemia ( Hb by > 2 g/dl or < 10 g/dl) Increase (> 50% and at least 1 cm) in size of existing Bone lesions or plasmacytomas Other: hyperviscosity, development of new soft tissue plasmacytomas or bone lesions *Rajkumar et al, Blood 2011; 117:

16 Ultra high-risk SMM = MM BMPC 60% Median TTP 7 months > 1 FOCAL LESION IN MRI Median TTP 13 months sflc RATIO Median TTP 15 months Rajkumar SV et al. NEJM, 2011 Hillengass J et al. JCO, 2010 Larsen JT et al. Leukemia, 2012 Risk of progression >80% at 2 years Rajkumar et al, Lancet Oncol 2014

17 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) hour urine collection for electrophoresis and immunofixation 6. Bone marrow aspirate: morphology, immunophenotype and cytogenetics by FISH (t(11;14); t(4;14); t(14;16); 17p) 7. Radiologic skeletal survey CT and/or MRI if clinically needed 11. PET/CT in patients with suspected extramedullary disease

18 EBMT criteria for response, relapse and progression in MM

19 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* CR PR MR Stable disease Criteria Negative IF (serum and urine)** <5% bone marrow plasma cells Disappearance of soft tissue plasmacytomas 50% serum M-protein 90% urine M-protein or < 200 mg/24hrs 50% soft tissue plasmacytomas 25-49% serum M-protein 50-89% urine M-protein 25-49% soft tissue plasmacytomas Not meeting criteria for MR nor PD *All response categories must be maintained for at least 6 weeks ** Excluding oligoclonal bands

20 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 PD* Relapse from CR* Criteria 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 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

21 International Uniform Response Criteria for Multiple Myeloma Durie et al, Leukemia 2006; 20:

22 International Uniform Response Criteria for Multiple Myeloma (I) Response Category* CR scr VGPR Criteria Negative IF (serum and urine) <5% bone marrow plasma cells Disappearance of soft tissue plasmacytomas As above plus Normal sflc ratio Absence of clonal plasma cells** 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

23 International Uniform Response Criteria for Multiple Myeloma (II) Response Category* Stable disease Criteria 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

24 Progression-free survival (%) Overall survival (%) Patients attaining CR experience prolonged PFS and OS but CR vs ncr: P =.001 ncr vs PR: P =.025 PR vs <PR: P =.061 CR vs ncr: P =.141 ncr vs PR: P =.002 PR vs <PR: P =.006 P <.001 P <.001 Time from response assessment (months) Time from response assessment (months) CR (n=542) median PFS: 45 months ncr (n=242) median PFS: 33 months PR (n=507) median PFS: 25 months <PR (110) median PFS: 16 months GEM2000, GEM2005MENOS65, GEM2005MAS65, GEM2010MAS65 (n=1401) CR (n=542) median OS: 96 months ncr (n=242) median OS: 81 months PR (n=507) median OS: 64 months <PR (110) median OS: 37 months Lahuerta JJ, et al. manuscript under review

25 Progression-free survival (%) Overall survival (%) The true value of CR relies in the MRD status, and CR w/o MRD is no better than PR MRD- vs CR: P <.001 CR vs ncr: P =.127 MRD- vs CR: P <.001 CR vs ncr: P =.657 P <.001 P <.001 Time from response assessment (months) MRD- (n=316) median PFS: 58 months CR (n=128) median PFS: 24 months ncr (n=96) median PFS: 21 months PR (n=199) median PFS: 26 months <PR (38) median PFS: 9 months GEM2000, GEM2005MENOS65, GEM2005MAS65, GEM2010MAS65 (n=777) Time from response assessment (months) MRD- (n=316) median OS: 145 months CR (n=128) median OS: 59 months ncr (n=96) median OS: 63 months PR (n=199) median OS: 59 months <PR (38) median OS: 32 months Lahuerta JJ, et al. manuscript under review

26 Reliable and widely available techniques to monitor MRD Flow cytometry ASO-PCR / ddpcr Next-gen sequencing Cellular PET/CT Imaging

27 International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma Sustained MRD-negative: MRD negativity in the marrow (NGF or NGS, or both) and by imaging, confirmed minimum of 1 year apart. Flow MRD-negative: Absence of phenotypically aberrant clonal plasma cells by NGF on bone marrow aspirates using the EuroFlow standard operation procedure for MRD detection in multiple myeloma (or validated equivalent method) with a minimum sensitivity of 1 in 10⁵ nucleated cells or higher. Sequencing MRD-negative: Absence of clonal plasma cells by NGS on bone marrow aspirate in which presence of a clone is defined as less than two identical sequencing reads obtained after DNA sequencing of bone marrow aspirates using the LymphoSIGHT platform (or validated equivalent method) with a minimum sensitivity of 1 in 10⁵ nucleated cells or higher. Imaging MRD-negative: MRD negativity as defined by NGF or NGS plus disappearance of every area of increased tracer uptake found at baseline or a preceding PET/CT or decrease to less mediastinal blood pool SUV or decrease to less than that of surrounding normal tissue. Kumar et al. Lancet Oncology 2016

28 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

29 Follow-up in Patients with Multiple Myeloma Off-Therapy After conventional therapy: (patients with stable response) After HDT/SCT: First year: every 2 months Beyond first year: every 3 months Beyond 5 years: every 4 months 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

30 Patients with asymptomatic relapse or PD* After conventional therapy: every 2 months After HDT/SCT: every 3 months * Unless abrupt PD

31 Lab work-up during follow-up off therapy 1. Complete blood count and chemistry 2. Serum total protein and EF 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

32 Serum Free Light Chains exposed surface hidden surface Kappa exposed surface hinge region heavy chain light chain carbohydrate Bradwell. Serum free Light Chain Analysis Lambda Previously hidden surface and antibody target Constant domain Variable domain

33 Serum Free Light Chains SPE sensitivity Normal sera κ LCMM l FLC (mg/l) 100 λ LCMM 10 Renal impairment 1 0,1 IFE sensitivity 0, k FLC (mg/l) Bradwell. Serum free Light Chain Analysis Kappa Lambda

34 Serum FLC measurements FLC value, normal range: Kappa: mg/l Lambda: mg/l Involved (iflc) and uninvolved FLC (uflc) FLC ratio: kappa / lambda FLC value Normal range: FLC-diff = dflc = iflc uflc Measurable for response if dflc mg/l

35 Free light chains measurement: When indicated in monoclonal gammopathies? Diagnosis Monoclonal gammopathies Oligosecretory MM AL amyloidosis Response Prognosis

36 MGUS Monoclonal gammopathies Plasma cell Kappa CLL Lambda CLL Only immunoglobulins Bence Jones Non secretor AL Amyloidosis LCDD Multiple myeloma

37 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

38 Monoclonal (amyloidogenic) LIGHT CHAINS 75% l; 25% k Small bone marrow PLASMA CELL clone AL Amyloidosis proteotoxicity Misfolded free LC Extracellular deposition and structural damage Amyloid fibrils Merlini & Stone, Blood. 2006

39 Monoclonal Gammopathy M protein by electrophoresis (moderate size): 50% M protein by immunofixation: 90-95% Isotype: 32% IgG 24% Bence-Jones 10% IgA, 5% IgM 1% IgD Light chain isotype: LAMBDA (75%) Bone marrow plasma cell infiltration: 5-10% (>20% in about ¼ patients) No CRAB

40 Serum and/or urine M protein Normal

41 Diagnostic investigations: Diagnostic performance of quantitative ĸ and λ FLC assays in clinical practice Katzmann et al. Clin Chem 2005

42 Diagnostic investigations: Serum and Urine In the diagnostic evaluation of AL amyloidosis serum FLC and serum and urine immunofixation are complementary

43 What is in the urine? Selective proteinuria Light chains predominate MM cast nephropathy Gamma Albumin Non-selective proteinuria Or albumin predominance Glomerular or tubular pathology: AL amyloidosis MIDD Other MIg-related or -unrelated condition Dimopoulos MA, et al. J Clin Oncol 2016 MIDD, monoclonal Ig deposition disease; MIg, monoclonal immunoglobulin

44 Revised Prognostic Staging System (I) Kumar et al, JCO 2012 (Mayo Clinic) N: 810 newly AL Prognostic factors for OS FLC-diff 180 mg/l ctnt ng/ml NT-proBNP 1800 pg/ml

45 Revised Prognostic Staging System (II) Median OS: - I: 94 mos. - II: 40 mos. - III: 14 mos. - IV: 5.8 mos.

46 Hem Response (HR) Evaluation Gertz et al, 2005 Palladini et al, 2012 CR Negative serum and urinary immunofixation Normal FLC ratio BMPC <5% acr = BM needed? PR If serum M protein >5 g/l 50% If urinary M protein > 100 mg/day 50% If iflc > 100 mg/l 50% SD VGPR dflc* <40 mg/l PR dflc* decrease >50% No CR, PR or progression SD No response * Baseline dflc must be 50 mg/l

47 Serum FLC and oligoclonal bands Median value 0.87 [CI 95% ] versus 2.55 [CI 95% ] (p=0.011) Fernández de Larrea et al, Blood 2009

48 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-l, IgM (k or l), k or l 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

49 Conclusions Initial and sequential studies in serum, urine and/or bone marrow (+/- imaging) are essential to monitor all patients with multiple myeloma. Importance of response criteria for standardization both in clinical trials and in daily clinical practice. Progression / relapse criteria are crucial for follow up and retreatment

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