Review of the recent publications from the French group of myeloma on urine vs serum FLC analysis in MM

Transcription

1 Review of the recent publications from the French group of myeloma on urine vs serum FLC analysis in MM

2 Multiple myeloma

3 Response evaluation Kumar Lancet Oncol 2016; 17: e328 46

4 Cumulative Proportion Surviving Pronostic value of response evaluation POURQUOI ÉVALUER LA MRD DANS LE MM? Le principal rationnel est la corrélation réponse/survie 1,0 0,9 0,8 OS RC vs TBRP RC vs RP TBRC vs RP p = 0,01 p < 10-6 p = 0,04 CR ncr PR PD Media ns EFS, months Media ns OS, months NR NR ,7 CR, n=278 0,6 0,5 ncr, n = 124 PR, n = 280 0,4 0,3 0,2 PD, n = 25 0, Months from diagnosis Lahuerta JJ, et al. J Clin Onc ol. 2008;26:

5 Recommandation IFM standard Considering standard IMWG criteria and no specific data about sflc evaluation sepp sif sflc UPEP uife Diagnosis X X If LCMM X X Follow up X If EPP normalized Confirm CR X X If LCMM If IF neg Follow uo for CR X X X relapse X If LCMM X If LCMM X If EPP normalized X X

6 Problematic clinical situation FLC only IgD/IgE Sometimes IgA Problems to obtain 24h urines no/oligo-secretants

7 Current IMWG criteria Evaluation of response in MM: measurement of the M-protein in serum and urine Partial Response (PR) : 50% reduction of serum M-protein 90% reduction of urine M-protein or to <200 mg/24h Very Good Partial Response (VGPR) : 90% reduction of serum M-protein reduction of urine M-protein to <100 mg/24h Complete Response (CR) : total clearance of M-protein in serum and urine + negative IFX <5% plasma cells in bone marrow Rajkumar SV, Harousseau JL, et al. Blood. May 2011;117: 4691 Durie BGM, Harousseau JL, et al. Leukemia. Sept 2006;20: 1467

8 Current IMWG criteria MM with only light chain (LCMM) : - based on the 24h urines collection - measurable disease defined by > 200 mg/24h Bence-Jones protein Partial Response (PR) : 50% reduction of serum M-protein 90% reduction of urine M-protein or to <200 mg/24h Very Good Partial Response (VGPR) : 90% reduction of serum M-protein reduction of urine M-protein to <100 mg/24h Complete Response (CR) : total clearance of M-protein in serum and urine + negative IFX <5% plasma cells in bone marrow

9 Pitfalls for LCMM response evaluation Pre-analytical : 24h urines collection - Rarely complete (+++ elderly patients) - Heavy to manage for patients and laboratory Analytical : quantification of M-component by urine protein electrophoresis (UPEP) is uneasy Metabolism of free light chains in the kidneys : may not reflect the response at the plasma cell level?

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11 IFM 2009 trial 700 pts < 66y, newly diagnosed MM from November 2010 to December 2012 (Exclusion criteria : serum creatinine >2.5 mg/dl or creatinine clearance <60mL/min) Arm A 3 RVD SC Collection 5 RVD 1y Lenalidomide maintenance Arm B 3 RVD SC Collection HD Melphalan / ASCT 2 RVD 1y Lenalidomide maintenance RVD: Lenalidomide Bortezomib Dexamethasone ; HD: High Dose; ASCT: Autologous Stem Cells Transplantation

12 IFM 2009 trial 700 pts < 66y, newly diagnosed MM from November 2010 to December 2012 (Exclusion criteria : serum creatinine >2.5 mg/dl or creatinine clearance <60mL/min) 115 LCMM Light Chain Myeloma (16,4%) 585 IIMM Intact Immunoglobulin Myeloma 331 IIMM with sflc 100 mg/l

13 Patients / material and methods Patients presented inclusion criteria for IFM 2009 trial Urine protein electrophoresis (UPEP) and urine immunofixation electrophoresis (uife; Sebia) were performed prospectively throughout the trial, using standard laboratory. sflc concentrations were measured using k sflc and l sflc Freelite assays (The Binding Site Group Ltd) on a BN II nephelometer (Siemens).

14 sflc are more sensitive Sensitivity of urine FLC and sflc measurements: Percentage of patients with positive UPEP and elevated serum iflc at baseline, and after 1 and 3 cycles of treatment (P and P,.001, respectively; Only 1 patient was recorded as being positive by UPEP but having a normal iflc concentration (after 1 cycle of treatment)

15 assessment made after 3 cycles of treatment curve separation was better for the serum measures and the difference between the populations reached significance (log-rank analysis), whereas it did not for the urine assessments. Similar results were obtained for prediction of OS only for the sflc ratio

16 after 3 treatment cycles For A C D patients with normal urine evaluation no patients with normal sflc ratio and a positive uife Separation according to positive/negative UPEP was not prognostic of PFS

17 Conclusion/proposition from the IFM Difficulties to obtain complete 24h urine evaluation SFLC are more sensitive at any time point High clinical correlation of sflc with prognosis (PFS and OS) There s now sufficient evidences to propose that sflc is the method of choice for response evaluation in LCMM patients Role for urine analysis: evaluation of proteinuria and renal function sepp sif sflc UPEP uife Diagnosis X X ou IT If LCMM X X Follow up X If EPP normalized Confirm CR X X If LCMM If IF neg Follow uo for CR X X X relapse X If LCMM X If LCMM X If EPP normalized X X

18 Why? One explanation might be that the renal threshold the sflc concentration above which significant amounts of FLC pass into the urine) is very variable, such that some patients, with relatively low FLC (tumor) production, may still have high urine FLC concentrations. Conversely, patients with very efficient renal metabolism could have undetectable concentrations of FLC in the urine despite high levels of FLC production.

19 What about Heavylite? antibodies against conjunction epitopes between the light and heavy chains enables the quantitation of specific pairs of heavy/light chains (IgGκ/IgGλ, IgAκ/IgAλ, and IgMκ/IgMλ) in the serum provides information on both the involved immunoglobulin (eg, IgGκ in an IgGκ patient) and the polyclonal non-involved pair (eg, IgGλ in an IgGκ patient). useful in patients with oligo-secretory disease and can overcome limitations associated with monitoring β-migrating monoclonal IgA by electrophoresis. associated with longer progression-free survival compared with normal ratios But not for MRD (NGS or NGF is superior)