Myeloma: Are We on the Brink of a Cure?

Transcription

1 Myeloma: Are We on the Brink of a Cure? Survival in Myeloma IFM DFCI; 2015 Proportion Surviving Follow up from diagnosis (years) Kumar S. Blood 2008;111: ; Kumar S. Leukemia (2014) 28,

2 New Definitions n MM is characterized by: n Excessive numbers of abnormal plasma cells in the bone marrow u u u Overproduction of intact monoclonal immunoglobulins (IgG, IgA, IgD) or free antibody light chains concomitant drop in other immunoglobulins CRAB Criteria u HyperCalcemia u Renal u Anemia u Bone Lesions Myeloma Reproduced with permission from the Multiple Myeloma Research Foundation Web site. Available at: Kufe. Cancer Medicine. 6th ed. 2003:

3 Characteristics of Active Multiple Myeloma and Its Precursors Kyle R et al. N Engl J Med 2007;356: Smoldering Multiple Myeloma Probability of Progression (%) Smoldering MM MGUS Mimics MGUS 27% more will convert in remaining 15 yrs ~ 2% per yr 51% will convert in first 5 yrs ~ 10% per yr Yrs Since Diagnosis Kyle RA, et al. N Engl J Med. 2007;356: Greipp PR, et al. J Clin Oncol. 2005;23:

4 Biomarkers to Predict Risk of Progression n FLC ratio 100 predicts risk (P <.0001) n Clonal plasma cells in BM predicts risk (P <.001) BM plasma cells 60% % Progression to MM FLC ratio Median TTP: FLC ratio < mos Median TTP: mos Mos to Progression 72 % Progression to Symptomatic Myeloma BM plasma cells < 60% HR: 13.7; P < Mos to Progression Larsen JT, et al. Leukemia. 2013;27: Kastritis E, et al. Leukemia. 2013;27: Updated IMWG Criteria for Diagnosis of Multiple Myeloma MGUS Smoldering Myeloma Multiple Myeloma M protein < 3 g/dl Clonal plasma cells in BM < 10% No myeloma defining events M protein 3 g/dl (serum) or 500 mg/24 hrs (urine) Clonal plasma cells in BM 10% to 60% No myeloma defining events Underlying plasma cell proliferative disorder AND 1 or more myeloma defining events 1 CRAB* feature Clonal plasma cells in BM 60% Serum free light chain ratio 100 > 1 MRI focal lesion *C: Calcium elevation (> 11 mg/dl or > 1 mg/dl higher than ULN) R: Renal insufficiency (creatinine clearance < 40 ml/min or serum creatinine > 2 mg/dl) A: Anemia (Hb < 10 g/dl or 2 g/dl < normal) B: Bone disease ( 1 lytic lesions on skeletal radiography, CT, or PET-CT, MRI) Rajkumar SV, et al. Lancet Oncol. 2014;15:e538-e548. 4

5 Measurement of the Disease n Measurement of protein u Immunoelectropheresis (IEP) or Immunofixation (IF or IFE) u Serum Protein Electropheresis (SPEP) with M-spike (M-protein) u Quantitative immunoglobulins (IgG. IgA. IgD, IgM) u Free light chain analysis replacing urine studies, including Bence-Jones and 24 hour total protein umrd Flow or NGS Measurements of Response n IMWG Criteria u SD = <25% reduction u MR = 25% - 49% reduction u PR = 50 % or greater reduction u VGPR = 90% reduction in protein spike (includes ncr) u ncr = pos IEP u CR = neg IEP u scr = nml free lite and absence of clonal cells in BM umrd neg CR u Progression = 25% increase u CR + ncr +VGPR + PR= > PR = ORR 5

6 Close but No Cigar PR (CBNCPR) Imaging 6

7 Bortezomib +/- Dex: Confirmation of Remission: PET Scan Plasmacytomas Pretreatment After 4 Cycles Jagannath et al. ASH 2004; Abstract 333 Imaging n Either upet/low dose whole body CT umri of spine and pelvis unew: Combined WB PET/MRI n Must be used uto confirm scr and MRD neg CR uto confirm smoldering myeloma 7

8 Why are we Failing In 25% of Patients? High Risk Disease Short Remission Posttransplant in High Risk Despite High Response Rates 4 cycles of CyborD induction and high-dose melphalan del17 or t(4;14) all others %Alive and Progression Free Del 17 t(4;14) All others Time (months) 8

9 Staging Changes 9

10 Beyond ISS: Cytogenetics and FISH n Good risk u normal cytogenetics u hyperdiploidy u t(11;14) n Poor risk u t(4;14) u t(14;16) u t(14;20) u del 17p (by FISH) u del 13 (by metaphase cytogenetics) u 1q21 overexpression u hypodiploidy (by metaphase cytogenetics) International Staging System (ISS) n Stage I (OS 62 months) u B2M < 3.5 mg/l u Albumin >/= 3.5 n Stage II (45 months) u B2M < 3.5 u Albumin <3.5 g/dl t or u B2M >/= n Stage III (29 months) u B2M > 5.5 n 10,000 patients Patients treated through

11 Revised ISS Palumbo JCO 2015 (A) Overall survival (OS) in patients with multiple myeloma stratified by revised International Staging System (R-ISS) algorithm. Revised ISS Antonio Palumbo et al. JCO, by American Society of Clinical Oncology 11

12 Evidence that CR Matters 12

13 The Iceberg CR vs ncr / VGPR / PR vs Less Prognostic effect of CR patients vs those in ncr or VGPR or PR vs patients with SD or PD after HDT/ASCT PFS P = years years OS P = CR (n=63) ncr (n = 66) + VGPR (n = 54) + PR (n = 114) SD (n = 12) + PD (n = 14) Martinez-Lopez J, et al. Blood. 2011;118:

14 IFMDFCI 2009 MRD Evolution of Myeloma Therapy 14

15 Patient Case: 39 y.o. female with months of severe back pain, right leg pain, and lower extremity weakness. Subsequently she developed clavicular fractures and spine and lower extremity deformities. Admitted to her local hospital, April 15, 1844 Solly, Med Chirur Trans London 1844 Treatment wine arrow-root a mutton chop a pint of porter daily an infusion of orange peel a rhubarb pill when necessary opiates 15

16 Conclusion earthy matter of the bone is absorbed and thrown out by the kidneys Myeloma Therapy ( ) CP

17 Myeloma Therapy ( ) n Steroids n Alkylators ucyclophosphamide (Cytoxan) umelphalan (low dose) n OS = 2 years Myeloma Therapy ( ) n VAD (Vincristine, adriamycin, decadron) n Autologous PSC-T(peripheral stem cell transplant) (use of high dose melphalan) n +/- Allogeneic PSC-T n +/- Interferon n OS = 3-4 years for good risk, lower stages = 2 years for everyone else 17

18 Myeloma Therapy ( ) nthalidomide nbortezomib (Velcade) (5/2003) nlenalidomide (Revlimid) (12/27/05) npegylated liposomal doxorubicin (Doxil) (2007) (in combo with bortezomib) ncontinued auto PSC-T nbegan combinations with new agents and old urvd ucybord Myeloma Therapy ( ) n Carfilzomib (Kyprolis) (7/20/12) n Pomalidomide (Pomalyst) (2/8/13) n Role of Maintenance Therapy defined n Develop combinations for induction followed by transplantation n OS = 8-10 years for standard risk 18

19 Myeloma Therapy ( ) n Panobinostat (Farydak) (2/23/15) n Daratumumab (Darzalex) (11/16/15) n Ixazomib (Ninlaro) (11/20/15) n Elotuzumab (Empliciti) (11/30/15) n Concept of post transplant consolidation n Adding in newer agents (Carfilzomib) to induction n Doublets and triplets for High Risk maintenance n Use of Minimal Residual Disease testing n Further confirmation of the role of auto PSC-T Decisions at Diagnosis n Does this patient need treatment at all? Smoldering? u Use of PET/CT u Studies of Revlimid, Daratumumab, Elotuzumab and other agents in smoldering n Transplant candidate vs not (Melphalan issue) u Not necessarily still true t Nobody (except in Europe) uses frontline melphalan t There are combinations that work for both groups t We now have Plerixafor 19

20 Frontline Therapy for Patients Ineligible for Transplant Melphalan OK Improving Response Rates with Combination Therapies 20

21 KRd (? Improvement over RVd?) Jakubowiak, 2015 Stem Cell Transplantation Is there still a role? 21

22 The Debate ASCT: Up-Front or at Relapse DFCI/IFM 2009 Trial Len-Bz-Dex 3 Stem collection ASCT Len-Bz-Dex 2 Len 12m (IFM) Len until relapse (US) Len-Bz-Dex 3 Stem collection Len-Bz-Dex 5 Len 12m (IFM) Len until relpase (US) ASCT at relapse NCI Clinical Trial Identifier NCT IFM/DFCI HDT no HDT Patients (%) P<0.001 Transplant improved PFS N at risk HDT no HDT Months of follow-up

23 Further Evidence for Role of Auto ASCT KRd (? Improvement over RVd?) Jakubowiak,

24 KRd + ASCT Zimmerman, 2016 Maintenance Therapy (continuation therapy) 24

25 CALGB : Time to Progression ASCT: autologous stem cell transplant; CALGB: Cancer and Leukemia Group B; HR: hazard ratio; LEN: lenalidomide; N/A: not applicable; PBO: placebo; TTP: time to progression. McCarthy PL. N Engl J Med. 2012;366: CALGB : Overall Survival ASCT: autologous stem cell transplant; CALGB: Cancer and Leukemia Group B; HR: hazard ratio; LEN: lenalidomide; N/A: not applicable; OS: overall survival; PBO: placebo. McCarthy PL. N Engl J Med. 2012;366:

26 n IFM : Progression-Free Survival LEN maintenance significantly prolonged median PFS vs. placebo u PFS improvement observed across all stratified patient subgroups (β 2 -M, del(13q), VGPR post-asct) ASCT: autologous stem cell transplant; β2-m: β2-microglobulin; del: deletion; HR: hazard ratio; IFM: Intergroupe Francophone du Myélome; LEN: lenalidomide; PBO: placebo; PFS: progression-free survival; VGPR: very good partial response. Attal M. N Engl J Med. 2012;366: n IFM : Overall Survival With a median follow-up of 45 months, no differences in OS have been observed across treatment arms u 4 year OS (post-randomization): 73% (LEN) vs. 75% (placebo) IFM: Intergroupe Francophone du Myélome; LEN: lenalidomide; N/A: not applicable; OS: overall survival; PBO: placebo. Attal M. N Engl J Med. 2012;366:

27 Lenalidomide Maintenance After High- Dose Melphalan and Autologous Stem Cell Transplant in Multiple Myeloma: A Meta- Analysis of Overall Survival Michel Attal, 1 Antonio Palumbo, 2 Sarah A. Holstein, 3 Valérie Lauwers-Cances, 1 Maria Teresa Petrucci, 4 Paul Richardson, 5 Cyrille Hulin, 6 Patrizia Tosi, 7 Kenneth C. Anderson, 5 Denis Caillot, 8 Valeria Magarotto, 9 Philippe Moreau, 10 Gerald Marit, 11 Zhinuan Yu, 12 Philip L. McCarthy 13 1 Institut Universitaire du Cancer, Toulouse-Oncopole, France; 2 The Myeloma Unit, Department of Hematology, University of Turin, Turin, Italy; 3 Roswell Park Cancer Institute, Buffalo, NY; 4 University La Sapienza, Rome, Italy; 5 Dana-Farber Cancer Institute, Boston, MA; 6 Bordeaux Hospital University Center (CHU), Bordeaux, France; 7 Seràgnoli Institute of Hematology and Medical Oncology, Bologna University, Bologna, Italy; 8 Dijon University Hospital Center, Dijon, France; 9 University of Torino, Torino, Italy; 10 University Hospital Hôtel-Dieu, Nantes, France; 11 Centre Hospitalier Universitaire, Bordeaux, France; 12 Celgene Corporation, Summit, NJ; 13 Blood and Marrow Transplant Program, Roswell Park Cancer Institute, Buffalo, NY Overall Survival: Hazard Ratios HR (95% CI) C A L G B ( n = ) 0.56 ( ) I F M ( n = ) 0.91 ( ) G I M E M A ( n = ) 0.66 ( ) Pooled (N = 1209) ( ) H R Favors LEN Favors control The size of the box is related to the size of the individual study. The confidence interval is a function of the overall sample size. HR, hazard ratio. 27

28 Overall Survival: Median Follow-Up of 80 Months There is a 26% reduction in risk of death, representing an estimated 2.5-year increase in median survival a yr OS Survival Probability Patients Overall Survival, mos at risk a Median for lenalidomide treatment arm was extrapolated to be 116 months based on median of the control arm and HR (median, 86 months; HR = 0.74). HR, hazard ratio; NE, not estimable; OS, overall survival. N = 1209 LENALIDOMIDE CONTROL Median OS (95% CI), mos HR (95% CI) P value NE (NE-NE) 0.74 ( ) ( ) 62% 50% New Drugs/New Studies 28

29 ASPIRE Rd vs KRd Aspire: Carfilzomib-Rd vs Rd PFS (1-3 Prior Lines) Progression-free Survival. Stewart AK, et al. N Engl J Med. 2015;372(2):

30 ENDEAVOR K x2 d vs Vd Endeavor: Kd vs Vd PFS (1-3 Prior Lines) Disease progression or death n (%) Median PFS mo HR for Kd vs. Vd (95% CI) Kd (n=464) 171 (37) ( ) 1-sided P< Vd (n=465) 243 (52) 9.4 Proportion Surviving without Progression Kd Vd No. at Risk Kd Vd Months since Randomization Median follow-up: 11.2 months CI, confidence interval; HR, hazard ratio; ITT, intent-to-treat; PFS, progression-free survival

31 Proportion Surviving without Progression Endeavor PFS and ORR by Prior Bortezomib Exposure No prior bortezomib Prior bortezomib Kd Vd Proportion Surviving without Progression Kd Vd Months since Randomization Months since Randomization Median PFS, mo ORR, % (95% CI) Kd (n=214) Vd (n=213) NE (78 88) 1-sided P-value 65 (59 < ) Median PFS, mo ORR, % (95% CI) Kd (n=250) Vd (n=252) (65 77) CI, confidence interval; NE, not estimable; ORR, overall response rate; PFS, progression-free survival. 60 (54 66) 1-sided P-value Panorama 1 Bortezomib/dex +/- Panobinostat 31

32 PANORAMA - 1 Progression-free survival Probability (%) PAN-BTZ-Dex Pbo-BTZ-Dex Events PAN-BTZ-Dex 207/387 Pbo-BTZ-Dex 260/381 Median PFS (95% CI) months HR (95% CI) 12.0 (10.3, 12.9) (7.6, 9.2) ( ) Number of patients at risk Months PAN-BTZ-Dex Pbo-BTZ-Dex P value <.0001 Primary endpoint was met (P <.0001), with clinically relevant increase in median PFS of 3.9 months for PAN-BTZ-Dex arm ELOQUENT-2 Rd vs ERd 32

33 ELOQUENT-2: Ld vs Eld PFS (1-3 Prior Lines) Co-primary endpoint: ORR Richardson PG et al. Presented at: ASH 2015 (abstr 28). Lonial SG et al. N Engl J Med. 2015;373(7): E-Ld Ld % % CI 74,83 60,71 Median (95% CI) PFS: E-Ld 19.4 ( ) months Ld 14.9 ( ) months Hazard ratio: 0.70 (95% CI: 0.57 to 0.85 P=0.0004) TOURMALINE MM-1 Rd vs IRd 33

34 TOURMALINE MM-1: Rd vs IRD PFS (1-3 Prior Lines) 1.0 Median follow-up:~15 months Probability of progression-free survival Median PFS: IRd: 20.6 months Placebo-Rd: 14.7 months Time from randomization (months) A non-inferential PFS analysis was conducted at a median follow up of 23 months with 372 PFS events Hazard ratio of PFS was 0.82 (95% confidence interval [0.67, 1.0]) for IRd vs Rd Estimated median PFS was 20 months in IRd and 15.9 months in Rd Log-rank test p=0.012 Hazard ratio (95% CI): (0.587, 0.939) Number of events: IRd 129; placebo-rd 157 Moreau P. et al., Presented at ASH 2015 (abstr 727). Pom/cy/dex 34

35 Pom/Cy/dex vs Pom/dex Baz, Martin, et.al. Blood, 3/1/16 Daratumumab Anti CD 38 35

36 Castor: Vd vs Dara Vd Pollux: Rd vs Dara Rd 36

37 Minimal Residual Disease (MRD) Flow Next Generation Sequencing Measurement of MRD n Black Swan (Spanish) Flow u 8-12 color n Clonoseq (Adaptive) u NGS n Characteristics u 10 5 u u No need for ID specimen Must do it on fresh specimen n Characteristics u 10 6 u u Requires ID specimen 8 % failure to identify clone 37

38 Time to progression for patients achieving conventional complete remission (CR), according to minimal residual disease (MRD) status as determined by deep sequencing. Martinez-Lopez J et al. Blood 2014;123: Further Evidence 38

39 IFMDFCI 2009 MRD 39

40 Potential Use of MRD in Making Treatment Decisions CG No High Risk Features, CTN Trial, scr 40

41 KR No High Risk Features, scr JF No High Risk Features, IFM/DFCI Trial, scr 41

42 HL No High Risk Features, scr prior to ASCT DL No High Risk Features, scr on Maintenance Diagnosis ASCT RVd Revlimid Velcade Maintenance Myeloma molecules per 1M leukocytes Bone marrow /11 0 9/ / / / / /15 Date (Month/Year) 42

43 CP del 17 p, scr prior to ASCT Diagnosis 17p deleted, renal failure, dialysis ASCT Myeloma molecules per 1M leukocytes Bone marrow CyBorD x /14 0 4/ / / / / Date (Month/Year) That s All Folks 43

44 Multiple Myeloma (MM) n Approximately 30,330 new cases in n 95,874 currently with MM u Accounts for 1% of all malignancies and about 10% of hematological cancers u Accounts for 2% of deaths from all cancers and 20% of deaths from hematological cancers n Slightly more common in men than women n Incidence in African Americans is about twice that of whites n Median age at diagnosis is 66 years u Age <50 years: 10% u Age <40 years: 2% American Cancer Society. Cancer Facts and Figures Atlanta, GA: American Cancer Society; 2007; Kufe. Cancer Medicine. 6th ed. 2003:2219; Clinical and laboratory manifestations of MM. UpToDate Web site. Available at: topic.do?topickey=plasma/2083&type=a&selectedtitle=2~80. Accessed January 2, Pre-existing MGUS (Monoclonal Gammopathy of Undetermined Significance) 44

45 PLCO Study Landgren, et.al. n 100% of patients with samples 2 years prior had MGUS n 82.4% with samples 8 years prior had MGUS n 97.1% of all patients had MGUS from 2 to 8 or more years prior Walter Reed Study Weiss et.al. n Samples available for 30/90 n Median number of samples available 3.5 (1-14) n PPCD detected in 27/30 u +SPEP and/or IFE 21 u + sflc 6 n First detected u sflc alone 6 u IFE alone 1 u SPEP + IFE 5 u IFE + sflc 1 u All three 14 45

46 UAMS: Total Therapy 4 and 5 Overall Survival 100% 80% 60% P < LOW RISK 30/235 40% 20% HIGH RISK 18/40 0% Years From Start of Protocol Therapy 4 Event-free Survival 100% CR Duration 100% 80% 60% 40% 20% P < HIGH RISK 22/40 LOW RISK 38/235 80% 60% 40% 20% HIGH RISK 15/32 P < Bodes well for cure! LOW RISK 18/189 0% Years From Start of Protocol Therapy 0% Years from Date of First CR or near CR Usmani SZ et al. ASCO Abstract