Getting Clear Answers to Complex Treatment Challenges in Multiple Myeloma: Case Discussions

Transcription

1 Getting Clear Answers to Complex Treatment Challenges in Multiple Myeloma: Case Discussions Friday, December 8, 2017 Atlanta, Georgia Friday Satellite Symposium preceding the 59th ASH Annual Meeting & Exposition. This activity is supported by educational grants from Amgen, Celgene Corporation, Janssen, Karyopharm, Takeda Oncology, and The Binding Site. Image: Copyright 2017 DNA Illustrations. All Rights Reserved

2 Discussion 1 Accurately Diagnosing MM: When Should Systemic Myeloma Treatment Be Initiated? Presented by Bruno Paiva, PhD

3 Presenting Faculty Bruno Paiva, PhD Department of Hematology and Immunology Flow Cytometry Core - CIMA LAB Diagnostics University of Navarra Pamplona, Spain Bruno Paiva, PhD, has disclosed that he has received consulting fees from Celgene, Janssen, Merck, Novartis, and Takeda, funds for contracted research from Celgene, EngMab and Sanofi, and fees for non-cme/ce services from Amgen, Celgene, Janssen, and Takeda.

4 Program Director Brian G.M. Durie, MD Co-Chair Myeloma Committee, SWOG Chairman, International Myeloma Foundation Specialist in Multiple Myeloma and Related Disorders Cedars-Sinai Outpatient Cancer Center Los Angeles, California Brian G.M. Durie, MD, has disclosed that he has received consulting fees from Celgene, Johnson & Johnson, Amgen, and Takeda.

5 Patient Case 1 A 52-yr-old asymptomatic male has elevated total serum protein (10.2 g/dl) with normal albumin during a routine analysis Labs show hemoglobin 14 g/dl and creatinine 0.8 mg/dl, with normal calcium levels and liver function IgG-Kappa M-protein was detected (3.5 g/dl) with hypogammaglobulinemia Serum kappa/lambda free light chain (sflc) ratio is 85 Skeletal survey, PET/CT, MRI show no lytic lesions, increased uptake, or focal lesions 12% plasma cell bone marrow infiltration, 97% are abnormal by flow FISH shows del(17p)

6 Would you consider this patient a candidate for treatment? Expert Brian G.M. Durie, MD Philippe Moreau, MD Bruno Paiva, PhD Recommendation Only on a clinical trial, because the patient has highrisk smoldering myeloma Only on a clinical trial, because the patient has highrisk smoldering myeloma Only on a clinical trial, because the patient has highrisk smoldering myeloma S. Vincent Rajkumar, MD Only on a clinical trial, because the patient has highrisk smoldering myeloma Jesús F. San-Miguel, MD, PhD Only on a clinical trial, because the patient has highrisk smoldering myeloma

7 Patient Case 1, Continued A 52-yr-old asymptomatic male has elevated total serum protein (10.2 g/dl) with normal albumin during a routine analysis Labs show hemoglobin 14 g/dl and creatinine 0.8 mg/dl, with normal calcium levels and liver function IgG-Kappa M-protein was detected (3.5 g/dl) with hypogammaglobulinemia Serum kappa/lambda free light chain (sflc) ratio is 85 Skeletal survey, PET/CT, MRI show no lytic lesions, increased uptake, or focal lesions 12% plasma cell bone marrow infiltration, 97% are abnormal by flow FISH shows del(17p) After 1 yr, his M-protein increases 15%, his sflc ratio increases up to 100, hemoglobin levels decrease by 1 g/dl, and bone marrow plasma cell infiltration increases up to 20% (100% clonality by flow)

8 Now, would you consider this patient a candidate for treatment? Expert Brian G.M. Durie, MD Philippe Moreau, MD Bruno Paiva, PhD Recommendation Yes, the patient has active myeloma Yes, the patient has active myeloma Yes, the patient has active myeloma S. Vincent Rajkumar, MD Yes, the patient has active myeloma Jesús F. San-Miguel, MD, PhD Yes, the patient has active myeloma

9 Accurately Diagnosing MM: When Should Systemic Myeloma Treatment Be Initiated? Bruno Paiva Hematology and Immunology Departments. Clinica Universidad de Navarra Flow Cytometry Core - CIMA LAB Diagnostics Universidad de Navarra EuroFlow Consortium Spanish Myeloma Group (GEM)

10 MGUS to Myeloma: A Continuum TUMOR Inter- and intraclonal heterogeneity Normal? Polyclonal Pre-MGUS MGUS SMM Myeloma Genomic instability Secondary events Sub-clonal evolution?? Big bang? Clonal evolution MICROENVIRONMENT Immune cells Bone cells Niche-derived signals Others Growth restricting signals Growth permissive signals Dhodapkar MV. Blood. 2016;128:

11 Risk of Progression Is Not the Same for All Smoldering Myeloma Patients Probability of Progression (%) Smoldering MM MGUS Yrs Since Diagnosis Kyle R, et al. N Engl J Med. 2007;356:

12 Smoldering Multiple Myeloma Ultra-high-risk SMM (15%): 40% per yr risk of MM 60% BMPC FLCr 100 > 1 MRI focal lesions High-Risk SMM (25%): 25% per yr risk of MM Standard-Risk SMM (60%): 5% per yr risk of MM

13 IMWG Updated Criteria for the Diagnosis of Multiple Myeloma MGUS SMM MM < 10% BMPC AND < 3 g/dl M protein AND No MDE 10% to 60% BMPC OR 3 g/dl serum M protein OR 500 mg/24 hr urine M protein AND No MDE No MDE PCPD, AND 1 or more MDE o CRAB o 60% BMPC o 100 FLC ratio o > 1 MRI focal lesion MDE MDE, myeloma-defining events Rajkumar SV, et al. Lancet Oncol. 2014;15:e538-e548.

14 60% Plasma Cells in Bone Marrow - Myeloma Defining Event - Biomarker validated in three independent series 1-3 BMPC < 60% (N = 634) BMPC 60% (n = 21); median TTP: 7 months 1. Rajkumar SV, et al. N Engl J Med. 2011;365: Kastritis E, et al. Leukemia. 2013;27: Waxman AJ, et al. J Leukemia. 2015;29:

15 Free-Light Chain (FLC) Ratio Myeloma Defining Event - Biomarker validated in three independent series 1-3 FLC ratio 100 or 1/100; median TTP: 13 months FLC ratio < 100 or > 1/100; median TTP: 75 months 1. Larsen JT, et al. Leukemia. 2013;27: Kastritis E, et al. Leukemia. 2013;27: Waxman AJ, et al. J Leukemia. 2015;29:

16 > 1 Focal Lesion by MRI - Myeloma Defining Event - Biomarker validated in two independent series 1, focal lesion > 1 focal lesion Progression-Free Survival Log-rank P<.001 Median TTP: NR Median TTP: 13 mos Mos Since MRI Treatment 1. Hillengass J, et al. J Clin Oncol. 2010;28: Kastritis E, et al. Leukemia. 2013;27:

17 Smoldering Multiple Myeloma Before 2014 After 2014 SR 60% U-HR 15% HR 25% HR 15% SR 85%

18 Biomarkers Currently Used to Identify Patients with High-Risk Smoldering MM (50% Risk at 2y) High-risk model Mayo Clinic PETHEMA 10% BMPC infiltration 3 g/dl of serum M-protein sflc ratio between <0.125 or >8 95% of aberrant PCs by MFC Immunoparesis Risk of progression to active MM 1.9-year median TTP 1.9-year median TTP Heidelberg T-mass (Mayo) high + t(4;14), del17p, or þ1q 3-year TTP, 55% SWOG Penn Japanese Czech and Heidelberg Barcelona Mayo Clinic evolving model Danish Serum M-protein 2 g/dl Involved FLC >25 mg/dl GEP risk score > % clonal BMPC infiltration sflc ratio 50 Albumin 3.5 mg/dl Beta 2-macroglobulin 2.5 mg/l M-protein increment rate >1 mg/dl/d Immunoparesis Serum M-protein 2.3 g/dl Involved/uninvolved sflc >30 Evolving pattern Serum M-protein 3 g/dl Immunoparesis em-protein ehemoglobin 20% PCs Serum M-protein 3 g/dl Immunoparesis 2-year TTP, 71% 2-year TTP, 81% 2-year TTP, 67.5% 2-year TTP, 81% 2-year TTP, 80% 1-year median TTP 2-year TTP, 50%

19 Biomarkers Currently Used to Identify Patients with High-Risk Smoldering MM (50% Risk at 2y) Biomarker M protein concentration 1,2 BJ proteinuria 3,4 M protein type 1,3 Immune paresis 1-3 Serum FLC ratio 5 Evolving M protein 6,7 BMPCs on microscope 1 Phenotyping of BMPCs 2,8 Circulating tumor cells 9,10 Cytogenetics 11,12 Gene expression profiling 13,14 MRI 15 PET/CT 16,17 1. Kyle RA. N Engl J Med 2007; 356: Pérez-Persona E. Blood. 2007;110: Kyle RA. Lancet Haematol. 2014;1(1):e28-e36 4. Gonzalez V. Leukemia. 2016;30(10): Dispenzieri A. Blood. 2008;111(2): Rosiñol L. Mayo Clin Proc. 2007;82(4): Proteins Cells Dissemination Partial overall regarding myeloma biology Complementary information on patients outcome 7. Ravi P. Blood Cancer J. 2016;6(7):e Dhodapkar MV. Blood. 2014;123(1): Paiva B. Leukemia. 2013;27(10): Khan R. Haematologica. 2015;100(9): Bianchi G. Leukemia. 2013;27(3): Merz M. Leukemia. 2014;28(9): Gonsalves WI. Leukemia. 2017;31(1): Neben K. J Clin Oncol. 2013;31(34): Siontis B. Blood Cancer J. 2015;5:e Zamagni E, et al. Leukemia. 2016;30(2): Rajkumar SV. Leukemia. 2013;27(8):

20 Biomarkers Currently Used to Identify Patients with High-Risk Smoldering MM (50% Risk at 2y) Biomarker Interpretation Standardization Automation M protein concentration 1,2 Semi-informatic No (total proteins, yes) Yes BJ proteinuria 3,4 Visual No Yes M protein type 1,3 Visual No Yes Immune paresis 1-3 Informatic Yes Yes Serum FLC ratio 5 Informatic No Yes Evolving M protein 6,7 Semi-informatic No (total proteins, yes) Yes BMPCs on microscope 1 Visual No No Phenotyping of BMPCs 2,8 Visual No No Circulating tumor cells 9,10 Visual No No Cytogenetics 11,12 Visual No No Gene expression profiling 13,14 Bioinformatic No Yes MRI 15 Visual No No PET/CT 16,17 Visual No No 1. Kyle RA. N Engl J Med 2007; 356: Pérez-Persona E. Blood. 2007;110: Kyle RA. Lancet Haematol. 2014;1(1):e28-e36 4. Gonzalez V. Leukemia. 2016;30(10): Dispenzieri A. Blood. 2008;111(2): Rosiñol L. Mayo Clin Proc. 2007;82(4): Ravi P. Blood Cancer J. 2016;6(7):e Dhodapkar MV. Blood. 2014;123(1): Paiva B. Leukemia. 2013;27(10): Khan R. Haematologica. 2015;100(9): Bianchi G. Leukemia. 2013;27(3): Merz M. Leukemia. 2014;28(9): Gonsalves WI. Leukemia. 2017;31(1): Neben K. J Clin Oncol. 2013;31(34): Siontis B. Blood Cancer J. 2015;5:e Zamagni E, et al. Leukemia. 2016;30(2): Rajkumar SV. Leukemia. 2013;27(8):

21 Biomarkers Currently Used to Identify Patients with High-Risk Smoldering MM (50% Risk at 2y) Risk-stratification Invasive BMPCs on microscope 1, Phenotyping of BMPCs 2,8, Cytogenetics 11,12, Gene expression profiling 13,14 Risk-stratification Recalibration of risk Recalibration of risk Minimally invasive M protein concentration 1,2, BJ proteinuria 3,4, M protein type 1,3, Immune paresis 1-3, Serum FLC ratio 5, Evolving M protein 6,7, Circulating tumor cells 9,10, MRI 15, PET/CT 16,17 1. Kyle RA. N Engl J Med 2007; 356: Pérez-Persona E. Blood. 2007;110: Kyle RA. Lancet Haematol. 2014;1(1):e28-e36 4. Gonzalez V. Leukemia. 2016;30(10): Dispenzieri A. Blood. 2008;111(2): Rosiñol L. Mayo Clin Proc. 2007;82(4): Ravi P. Blood Cancer J. 2016;6(7):e Dhodapkar MV,. Blood. 2014;123(1): Paiva B. Leukemia. 2013;27(10): Khan R. Haematologica. 2015;100(9): Bianchi G. Leukemia. 2013;27(3): Merz M. Leukemia. 2014;28(9): Gonsalves WI. Leukemia. 2017;31(1): Neben K. J Clin Oncol. 2013;31(34): Siontis B. Blood Cancer J. 2015;5:e Zamagni E, et al. Leukemia. 2016;30(2): Rajkumar SV. Leukemia. 2013;27(8):

22 Rd vs Observation in Patients with High-Risk SMM (QuiRedex): Long-Term Follow-Up* * Median follow-up for surviving patients was 75 months (IQR 67 85) Mateos MV, et al. Lancet Oncol. 2016;17:

23 Clinical Outcomes in Patients with High-Risk SMM After 8 Cycles of KRd and 2 Years of Lenalidomide Maintenance PFS OS Survival Probability Survival Probability Censored Censored Biochemical PFS, months Pts at risk, n OS, months Pts at risk, n Median potential follow-up was 43.3 months. Mailankody S, et al. Blood Advances. 2017;1:

24 Clinical trials being presented at EHA & ASH 2017 Monotherapy Combination therapy Siltuximab (Brighton. Abst 3155) Pembrolizumab (Manasanch. Abst 3089) Daratumumab (Hofmeister. Abst 510) Elotuzumab-Rd (Ghobrial. Abst S779) CESAR (KRd) (Mateos. Abst 402) Design Patients Treatment TEAEs (N) Randomized, doubleblind, placebo-controlled Phase II trial 74 high-risk (including ultra-hr) Until disease progression Infections (N=5) and renal/urinary disorders (N=1) Pilot study 12 intermediate & highrisk (including ultra-hr) 8 cycles (24 cycles if MR at Cycle 8) G2 elevation in LFT (N=2), G3 myalgia (N=1), and G3 acute kidney injury (N=2); there were no G4/5 Open-label Phase II trial; 3 treatment arms 123 intermediate & highrisk (excluding ultra-hr) 20 cycles (2 arms) or 1 cycle (1 arm) Hematologic were < 10% & G3/4 infection 5% in all arms. IRR occurred in 56%, 37%, and 55% of pts (but G3 < 3%) Phase II double-arm 50 high-risk (excluding ultra-hr) Until disease progression CR (%) NR 1/12 (8%) 1/122 (0.8%) 2/31 (7%) G3 hypophosphatemia (30%), neutropenia (14%), infection (12%), anemia (2%), pulmonary embolism (2%), rash (4%), and diarrhea (2%). G4 thrombocytopenia (2%), neutropenia (2%) and one instance of cholecystitis (2%) Phase II single-arm 90 high-risk SMM < 70y (including ultra-hr) KRd x 6, HDT/ASCT, KRd x 2, Rd for 2y G3/4 infections (N=9),skin rash (N=7), neutropenia (N=4) and thrombocytopenia (N=2) during induction 20/43 (46%) after induction Outcome 84.5% PFS at 1-Yr NR 89-98% PFS at 1-Yr 100% PFS at 1-Yr 98% PFS at 1-Yr

25 Disease Control vs Curative Strategy for High-Risk Smoldering Multiple Myeloma CESAR ASCENT Induction 6 cycles of KRd KRd + DARA x 4 cycles MRD MRD ASCT (melphalan 200) Consolidation (2 cycles of KRd) MRD at CR MEL 200 ASCT KRd + DARA x 4 cycles KRd + DARA x 4 cycles MRD Maintenance (Len-dex for 2yrs) KR DARA x 1 year MRD The depth of response improved along with the duration of treatment, achieving up to 85% of CR in patients who completed induction, ASCT, and consolidation, with an acceptable safety profile. Mateos, et al. ASH Abstract 402. Sunday, Dec 10 at 9:30 AM-11:00 AM NCT

26 Summary Better understanding of myeloma biology and development of sensitive biomarkers have contributed to accurately diagnosing myeloma o Initiate treatment in the presence of CRAB and/or MDE Goals by initiating treatment earlier: o Prevent development of CRAB (MDE) o Prevent transformation to malignant states that remain mostly incurable (eg: R-ISS-3) Disease control (eg, monotherapy) Disease eradication (eg, intensive combination therapy) IMWG guidelines to standardize biomarkers (invasive and minimally invasive) to identify patients with high-risk SMM candidates to be enrolled in clinical trials

27 Go Online for More CCO Coverage of Myeloma! On-demand Webcast of this event at myeloma.org Capsule Summaries of all the key data for ASH 2017 Additional CME-certified slideset on myeloma with expert faculty commentary Online treatment decision aid with recommendations from 5 experts for your individual patients with myeloma ashsymposium2017.myeloma.org clinicaloptions.com/oncology clinicaloptions.com/myelomatool