Hevylite : a New Serum Test for Assessing Patients with Multiple Myeloma

Transcription

1 Hevyite : a New Serum Test for Assessing Patients with Mutipe Myeoma Judith A. Finay, Ph.D. Director of Scientific Affairs The Binding Site, Inc. San Diego, CA X335 Some of the subject matter and data contained or addressed in the foowing presentation may invove off-abe or forward-ooking use of Freeite kits, Hevyite kits and other Binding Site products. As such, no off-abe use of Freeite, Hevyite or other Binding Site products can be supported by Binding Site Inc.

2 Why is Hevyite important? Not a patient m-proteins are easiy identified by SPE Hevyite can sometimes quantify sampes that SPE cannot New: Hevyite can measure the invoved (IgAk) and uninvoved (IgA) isotypes separatey

3 IgG, A and M assays measure IgXk and IgX isotypes together IgGk IgGL IgAk IgAL IgMk IgML Now they can be measured independenty with Hevyite

4 Hevyite antibodies (assays) recognize conformationa epitopes between heavy and ight chains Can distinguish: IgAκ v. IgAλ IgGκ v. IgGλ IgMκ v. IgMλ What is HevyLite?

5 Not a m-spikes are easiy identified by SPE (14 IgA patients) NHS β γ

6 HL IgAk/ assays can identify uncear SPE peaks n = 129 n=210 IgAλ (g/l) IgAκ (g/l) IgAκ MM IgAλ MM Norma sera Mirbahai et a. Presented at AACC 2011

7 Hevyite can sometimes quantify sampes that SPE cannot Isotype No. sampes not abe to be quantified by SPE/tota no. tested IgA 26/56 46 IgG 4/100 4 A sampes were abe to be quantified by Hevyite % Ludwig Leukemia 2013

8 Ony β2m and HLCR remain signif. Upon MV anaysis for PFS Bradwe Leukemia 2012

9 Nomencature IgAk MM patient Invoved HLC isotype: IgAk Uninvoved HLC isotype: IgA Immunosuppression can be in: Uninvoved HLC isotype: IgA Systemic immunogobuin suppression: IgG + IgM Both

10 Key driver: eevated monocona AND suppressed uninvoved HLC HLC inv./uninvo ratios Invoved HLC Uninvoved HLC Bue=more norma ratios Bue=ess invoved HLC Bue=ess suppressed uninvoved HLC Red=more abnorma ratios Red=more invoved HLC Red=more suppressed uninvoved HLC Cutpoint: ratio 0.01 or 200 Lower 2/3 vs upper 1/3 Lower 2/3 vs upper 1/3 Fig 2 b Fig 3 a Fig 3 b Red n = 116 Bue n = 209 Bradwe et a Leukemia 2013

11 Uninvoved HLC isotype suppression and systemic immunogobuin suppression

12 Hevyite chain ratio (HLCR) a hypothesis: HLCR Appears to be a unique, significant marker when monitoring MGUS, SMM and MM Hypothesis: Suppression of the uninvoved HLC isotype poycona proteins are a bioogicay important factor resuting from tumor-stroma interactions and/or microenvironment properties Not simpy crowding out in marrow by myeoma ces Evidence that supports this suppression seen in MGUS (<10% pasma ces) HLC isotype suppression has been reported as being prognostic for PFS and OS Systemic Ig suppression does not appear to be as strong

13 Frequenty Asked Question (FAQ) Q: Now that we have HL do we need FL? Answer: YES! Here s why...

14 sflc and HL are independent tumor markers n=164 IgGκ MM R 2 = Freeite κ sflc (mg/l) Hevyite IgGκ (g/l) IFM data courtesy of H. Avet-Loiseau

15 Immunogobuin and Free Light Chain Production by Pasma Ces Kappa Lambda

16 HLCR detects reapse 1st HL+FL supressed FL supressed HLR eev 1 st reap? h h h h h h h h h h h h IFE and HLC ratio norma at the same time HLC ratio became abnorma indicating reapse when IFE was sti norma IFE remained norma for further 5.5 months Laboratory reapse was confirmed by IFE Later cinica reapse was noted. Ludwig Leukemia 2013

17 Monitoring Jan 2008 Jan 2011 Eary indication of reapse? Poycona increase in IgA due to infection? Donato et a. Cin Chem. 2011;57(12):1645-8

18 IgAκ/IgAλ HLC ratio NEVER normaised Eary indication of reapse? Poycona increase in IgA due to infection? Donato et a. Cin Chem. 2011;57(12):1645-8

19 Summary: Importance of Hevyite Not a patient m-proteins are easiy identified by SPE Hevyite can sometimes quantify sampes that SPE cannot New: Hevyite can measure the invoved (IgAk) and uninvoved (IgA) isotypes separatey Cases: HL adds vaue not seen with other tests

20 Extra Sides

21 Free ight chain escape Keats et a 2012 Bood

22 The cone you present 1 Pt w/ high-risk t(4;14) with is not the cone (by acgh) that kis you Mayo Scottsdae Keats et a 2012 Bood

23 Free Light Chain Escape Prevaence: 2.5% (10/407 pts ) Patient Characteristics Stabe by intact Ig monitoring But deveoped severe organ dysfunction Median anti-mm cyces 6 sflc reiabe markers Kuhnemaund et. a. J Cancer Res Cin Onco 2009

24 Kuhnemund et a 2009 Tabe 1

25 Tabe 1. Freeite in IMWG Uniform Response Criteria in Myeoma CR scr VGPR PR SD PD Neg. s and uife <5% PC in bone marrow CR + Norma FLC ratio+ Absence of cona PCs by IHC or 2-4 coor Fow cytometry Carifications for CR and VGPR when ony measurabe disease is by sflc A decrease in >90% between invoved and uninvoved sflc eves is required If s and u m- protein not measurabe A decrease in >=50% between invoved and uninvoved sflc eves is required Don t meet criteria for other catagor -ies Patients w/o measurabe s and u m-prot Difference between invoved and uninvoved FLC eves must increase by >10 mg/dl Rajkumar Bood 2011

26 Immunogobuin Haf-Life Protein IgG IgA IgM Free Kappa Free Lambda Haf Life days 6 days 6 8 days 2 4 hours 3 6 hours

27 Mutipe Myeoma Diagnosis 1. >10% pasma ces in the bone marrow 2. Monocona protein in either serum or urine (or abnorma FLC ratio) 3. End Organ Damage (CRAB) Cacium eevation in the bood (hypercacemia) Rena Insufficiency (kidney damage) Anemia (bood disorder) Bone esions (bone damage)

28 Reductions in SPEP and ihlc in Patients with Quantifiabe SPEP 60% 40% y = x R² = % 0% -120% -100% -80% -60% -40% -20% 0% 20% 40% 60% % reduction in SPEP -20% -40% Series1 Linear (Series1) -60% -80% -100% -120% % reduction in invoved Hevyite Therefore IMWG guideines appy

29 ihlc (invoved Ig) uhlc (uninvoved Ig, isotype matched suppression) rhlc (Ig κ/ig λ ratio) dhlc (estimation of monocona Ig)

30 Reationship of SPE to qigs IgA IgG Murray et a. Cin Chem 2009;55(8):1523-9

31 Impact of SPE non-inearity on qigg SPE M-Ig = 44.9g/L A 30% reduction in M-Ig wi be missed using SPE due to dye saturation Tota IgG 66.7g/L