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 2 Individualized Approaches to Treatment Selection for Induction Therapy Presented by S. Vincent Rajkumar, MD

3 Presenting Faculty S. Vincent Rajkumar, MD Edward W. and Betty Knight Scripps Professor of Medicine Mayo Clinic Rochester, Minnesota S. Vincent Rajkumar, MD, has no real or apparent conflicts of interest to report.

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 2 A 62-year-old male diagnosed with MM was referred to determine best option for initial therapy He has good performance status and no comorbidities A review of the baseline data shows: Hemoglobin 10.9 gm/dl, normal calcium and creatinine Serum monoclonal protein was 2.5 gm/dl, IgA kappa on immunofixation Urine protein immunofixation shows free kappa M protein 1100 mg/24 hours Serum free kappa level: 800 mg/l, serum free lambda level: 10 gm/l, with serum FLC ratio of 80 Low dose CT bone survey shows multiple lytic bone lesions Bone marrow biopsy shows 45% plasma cells, monoclonal kappa on flow cytometry FISH studies show trisomies involving chromosomes 3, 7, 9, and 11; no IgH translocations detected, and no del(17p) or gain 1q

6 How would you treat this patient? Expert Brian G.M. Durie, MD Philippe Moreau, MD Bruno Paiva, PhD Recommendation Bortezomib, lenalidomide, dexamethasone Bortezomib, lenalidomide, dexamethasone Bortezomib, lenalidomide, dexamethasone S. Vincent Rajkumar, MD Bortezomib, lenalidomide, dexamethasone Jesús F. San-Miguel, MD, PhD Bortezomib, lenalidomide, dexamethasone

7 How would you treat this patient if he were older than 75 years of age? Expert Brian G.M. Durie, MD Philippe Moreau, MD Bruno Paiva, PhD Recommendation Bortezomib, lenalidomide, dexamethasone (lite) Bortezomib, lenalidomide, dexamethasone Ixazomib, lenalidomide, dexamethasone S. Vincent Rajkumar, MD Bortezomib, lenalidomide, dexamethasone Jesús F. San-Miguel, MD, PhD Bortezomib, melphalan, prednisone

8 How would you treat this patient if he had del(17p)? Expert Brian G.M. Durie, MD Philippe Moreau, MD Bruno Paiva, PhD Recommendation Carfilzomib, lenalidomide, dexamethasone Bortezomib, lenalidomide, dexamethasone Bortezomib, lenalidomide, dexamethasone S. Vincent Rajkumar, MD Carfilzomib, lenalidomide, dexamethasone Jesús F. San-Miguel, MD, PhD Ixazomib, lenalidomide, dexamethasone

9 How would you treat this patient if he had high creatinine (acute renal failure)? Expert Brian G.M. Durie, MD Philippe Moreau, MD Bruno Paiva, PhD Recommendation Cyclophosphamide, bortezomib, dexamethasone Cyclophosphamide, bortezomib, dexamethasone Cyclophosphamide, bortezomib, dexamethasone S. Vincent Rajkumar, MD Cyclophosphamide, bortezomib, dexamethasone Jesús F. San-Miguel, MD, PhD Cyclophosphamide, bortezomib, dexamethasone

10 Myeloma Risk - Stratification msmart.org Standard-Risk Intermediate-Risk High-Risk Trisomies t(4;14) (FGFR3/MMSET) t(14;16) (C-MAF) t(11;14) (CCND1) Gain 1q t(14;20) (MAF-B) t(6;14) (CCND3) Del 17p (p53) Dispenzieri A, et al. Mayo Clin Proc 2007;82: Kumar SK, et al. Mayo Clin Proc 2009;84: Mikhael JR, et al. Mayo Clin Proc 2013;88:

11 Factors Influencing Treatment Choice in Myeloma Prognostic Determinant Standard Risk High Risk Host factors ECOG performance status 0-2 Normal renal function ECOG performance status 3 or 4 Renal failure (serum creatinine 2.0) Advanced age Tumor burden Durie-Salmon stage I, II Durie-Salmon stage III Tumor biology (disease aggressiveness) Hyperdiploidy t(11;14) t(6;14) t(4;14), t(14;16), t(14;20), 17p deletion High LDH High plasma cell proliferation rate High-risk signature on gene-expression profiling Rajkumar SV, et al. Blood 2011;118: Russell SJ, et al. Lancet Oncology 2011;12:

12 SWOG VRd vs Rd Eight 21-day cycles of VRd Randomization N = 525 Newly diagnosed MM Stratification: ISS (I, II, III) Intent to progression (yes/no) Bortezomib 1.3/mg 2 IV Days 1, 4, 8, and 11 Lenalidomide 25 mg/day PO Days 1-14 Dexamethasone 20 mg/day PO Days 1, 2, 4, 5, 8, 9, 11, 12 Six 28-day cycles of Rd Lenalidomide 25 mg/day PO Days 1-21 Dexamethasone 40 mg/day PO Days 1, 8, 15, 22 After induction, both arms received Rd maintenance until PD, toxicity, or withdrawal Durie BGM, et al. ASH Abstract 25.

13 100 S0777 Trial: VRd vs Rd Progression-Free Survival PFS (%) Events Median, mos (n/n) (95% CI) VRd 137/ (39-52) Rd 166/ (25-39) One sided P = (two-sided P = ) Median PFS 43 months with VRd Mos Since Registration Durie BG, et al. Lancet 2017;389:

14 S0777 Trial: VRd vs Rd Overall Survival Median OS 75 months with VRd OS (%) Deaths (n/n) Median, mos (95% CI) VRd 76/ (65-NR) Rd 100/ (56-NR) Two-sided P = Mos Since Registration Durie BG, et al. Lancet 2017;389:

15 Dara-VMP versus VMP in Newly Diagnosed MM (ALCYONE) Age 65 or otherwise ineligible for ASCT; 706 pts Response D-VMP, % VMP, % ORR scr CR VGPR PR VGPR CR MRD negative (10-5 ) Pts progression-free and alive (%) 12-month PFS 76% 87% HR: 0.05 (95% CI: ; P <.0001) 18-month PFS 50% 72% D-VMP Median PFS NR VMP Median PFS 18.1 mo After 9 cycles: Dara vs No Therapy PFS with VMP: VISTA 24 months; GEM months; ALCYONE 18.1 months Mateos MV et al. ASH LBA-4. Late Breaking Abstract.

16 Host Factors: Age, Frailty, Renal Failure

17 Age >75 SWOG S0777 Trial: VRd vs Rd PFS and OS age < 65, 65 75, > 75 years VRd was superior in age > 75 years vs Rd Median PFS: 39 vs 20 months Median OS: 63 vs 31 months (P <.05) Durie B, et al. Lancet 2017;389:

18 Frail, Multiple Comorbidities FIRST Trial: MPT vs Rd18 vs Rd Until Progression 100 Median PFS, Mos 100 Pts (%) Continuous Rd (n = 535) Rd18 (n = 541) MPT (n = 547) Pts (%) Continuous Rd (n = 535) Rd18 (n = 541) MPT (n = 547) 4-Yr OS, % No. at Risk Mos No. at Risk Mos Cont Rd Cont Rd Rd Rd MPT MPT Hazard ratio: Continuous Rd vs MPT: 0.72; P <.001 Continuous Rd vs Rd18: 0.70; P <.001 Hazard ratio: Continuous Rd vs MPT: 0.78; P =.02 Continuous Rd vs Rd18: 0.90; P =.31 Benboubker L et al. N Engl J Med 2014;371:

19 Acute Renal Failure: Cast Nephropathy Estimated Glomerular Filtration Rate Biopsy proven, or Presumptive (ARF with FLC > 200 mg/dl) VCD or VTD Plasma exchange and hemodialysis if needed Serum Free Light Chains Burnette BL, et al. N Engl J Med 2011; 364:

20 High-Risk Myeloma

21 A Phase I/II Trial of Carfilzomib/Lenalidomide/Dexamethasone With Lenalidomide Extension in Patients With Newly Diagnosed Multiple Myeloma (n = 53) Overall CR rate (n = 53): 42% (scr) MRD by Flow: Most negative Jakubowiak AJ, et al. Blood 2012;120:

22 Phase II trial of Carfilzomib-Lenalidomide-Dexamethasone With Lenalidomide Extension in Patients With Newly Diagnosed Multiple Myeloma (n = 45) Overall Progression-Free Survival Overall CR rate: 56%* MRD by NGS negative in ~2/3 of CR * VRd in IFM 2009: 48% Korde N, et al. JAMA Oncol. 2015;1(6): Attal M, et al. N Engl J Med. 2017;376:

23 msmart Off-Study Transplant Eligible msmart.org Standard-Risk Intermediate-Risk High-Risk t(11;14), t(6;14), Trisomies t(4;14) Del 17p, t(14;16), t(14;20) VRd VRd KRd Dispenzieri A, et al. Mayo Clin Proc 2007;82: Kumar S, et al. Mayo Clin Proc 2009;84: Mikhael J, et al. Mayo Clin Proc 2013;14:88:

24 CLARION: KMP vs VMP: Overall Survival At the data cutoff date for the primary analysis of PFS (Jul 15, 2016), the HR for OS was 1.21 In an updated evaluation of OS (Nov 4, 2016), the HR for OS was 1.08 Proportion Surviving Facon T. IMW Abstract OP Number at risk: KMP 478 VMP 477 KMP VMP Death n (%) Median OS months 107 (22.4) NE 95 (19.9) NE HR for KMP vs VMP (95% CI): 1.08 ( ) Mos KMP (n=478) Nominal 1-sided P = 0.71 Median follow-up time: 27.1 months for KMP and 26.3 months for VMP VMP (n=477) 42 0

25 Initial Treatment of Myeloma msmart.org Newly Diagnosed MM* Not Transplant Candidate Transplant Candidate VRd Rd (frail, multiple comorbidities) VRd x 4 cycles** Rajkumar SV * VCd if acute renal failure; VTd if Len not available **Consider KRd for high risk, transplant eligible patients

26 Active Drugs in Multiple Myeloma Old Drugs Older Drugs ( ) Recently Approved Drugs ( ) Future Treatment Options Alkylators Steroids Interferon Anthracyclines Bortezomib Thalidomide Lenalidomide Liposomal doxorubicin Carfilzomib Pomalidomide Panobinostat Ixazomib Daratumumab Elotuzumab Oprozomib Marizomib Isatuximab Filanesib LGH 447 Venetoclax Dinaciclib CAR-T Selinexor Rajkumar SV

27 Principles 1. Wait for OS improvements in Phase III trials 2. Consider cost, quality of life, convenience 3. Know when to break the rules

28 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