Serum Free Light Chains should be the target of response evaluation in light chain myeloma rather than urines: results from the IFM 2009 trial

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1 Serum Free Light Chains should be the target of response evaluation in light chain myeloma rather than urines: results from the IFM 2009 trial Jill Corre*, Thomas Dejoie, Helene Caillon, Michel Attal*, Philippe Moreau, Nikhil Munshi and Hervé Avet-Loiseau* *Unit for Genomics in Myeloma, IUCT-Oncopole, Toulouse, France

2 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

3 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

4 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?

5 Serum Free Light Chains evaluation Polyclonal Ab evaluation (FreeLiteTM, TBS) : able to quantify Free Light Chains in serum (sflc) Bradwell AR, Carr-Smith HD, et al. Lancet. Feb 2003;361: 489 Freelite test could replace UPEP for monitoring LCMM (MRC Vth-VIIth trials, ) Sensitivity : 1,5mg/L (vs 30-50mg/L) Accuracy: 5% (vs > 15%) Dispenzieri A, Kyle R, et al. Leukemia. Feb 2008;23: 215 Not recommended to monitor myeloma patients, excepted for nonsecretory and oligo-secretory diseases Question : any place for Freelite test in LCMM response evaluation?

6 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

7 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

8 1) Aberrant results on urine assessment after 1 RVD Local evaluation after 1 RVD course LCMM IIMM with sflc Normal SPEP Normal UPEP - 52/84 (62%) 0/331 (0%) - Patients ncr* : 62% in LCMM vs 0% in IIMM SPEP : Serum protein Electrophoresis UPEP : Urine Protein Electrophoresis * ncr = VGPR with M protein only detectable on IF

9 2) Aberrant results on urine assessment after 3 RVD Central evaluation after 3 RVD courses LCMM IIMM with sflc Normal SPEP Normal UPEP - 88/112 (79%) 70/331 (21%) - Patients ncr* : 79% in LCMM vs 21% in IIMM * ncr = VGPR with M protein only detectable on IF

10 3) sflc evaluation of after 3 RVD Central evaluation after 3 RVD courses LCMM IIMM with sflc Normal SPEP Normal UPEP - 88/112 (79%) 70/331 (21%) - Normal iflc 58/112 (52%) 192/331 (58%) normal iflc = involved chain below the upper normal value (LC 19.4mg/L; LC 26.3mg/L)

11 4) Discrepancy between UPEP and sflc in LCMM Normal iflc 58 (52%) Abnormal iflc 54 (48%) Normal UPEP 88 (79%) 58 (52%) 30 (27%) median iflc = 95mg/L Abnormal UPEP 24 (21%) 0 24 (21%) median iflc = 306mg/L

12 5) Discrepancy between SPEP and sflc in IIMM Normal iflc 192 (58%) Abnormal iflc 139 (42%) Normal SPEP 70 (21%) 65 (19.6%) 5 (1.5%) Abnormal SPEP 261 (79%) 127 (38.4%) 134 (40.5%) Half-life IgA = 6 days ; IgG = 21 days; FLC = 2-4 hours; FLC = 3-6 hours

13 Conclusion Response evaluation based on urines is not reliable, notably because of the metabolism of FLC by the kidneys sflc assessment seems more reliable with response evaluation in LCMM statistically similar to that observed in classical MM (58% vs 52% normal iflc) Ongoing : - IFM2009 trial : response evaluation after consolidation - Correlation to patient s outcome

14 Many Thanks to my IFM Colleagues

15 Poster 3347 Dejoie et al. (IFM) Comparing the Performance of Serum Free Light Chain Measurements with Urine Electrophoresis and Immunofixation for Monitoring and Assessing Response to Therapy in Patients with Multiple Myeloma Poster 3427 Moustafa et al. (Mayo Clinic) Utility of Serum Free Light Chain Measurements in Multiple Myeloma Patients Not Achieving Complete Response Poster 2021 Fouquet et al. (IFM) Hevylite to Monitor Response to Therapy in Multiple Myeloma.

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17 IIMM : response to treatment 331/585 patients Response ncr : 70 (21,1%) VGPR : 120 (36,1%) PR : 141 (42,4%) 585 patients Response CR/nCR : 114 (19%) VGPR : 214 (37%) PR : 257 (44%)

18 Comparison with IIMM for sflc after 3 RVD courses Selection of IIMM with sflc 100 mg/l at diagnosis 331/585 patients Response iflc normal iflc abnormal ncr : 70 (21,1%) 65 (19.6%) 5 (1.5%) VGPR : 120 (36,1%) 98 (29.5%) 22 (6.6%) PR : 141 (42,4%) 29 (8.7%) 112 (33.7%) 193 (58%) 139 (42%)