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 4 Therapeutic Strategies After First Relapse Following Initial Therapy Presented by Jesús F. San-Miguel, MD, PhD

3 Presenting Faculty Jesús F. San-Miguel, MD, PhD Director of Clinical and Transnational Medicine Clinica Universidad de Navarra Universidad de Navarra Pamplona, Spain Jesús F. San-Miguel, MD, PhD, has disclosed that he has received consulting fees from Amgen, Bristol- Myers Squibb, Celgene, Janssen, MSD, Novartis, Takeda, Sanofi-Aventis, and Roche.

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 4 A 60-year-old man was diagnosed with IgD lambda, stage II myeloma, and t(4;14) He received VTD for 3 cycles followed by ASCT and 2 years of lenalidomide maintenance He relapsed 18 months after discontinuing lenalidomide maintenance

6 How would you treat this patient? Expert Brian G.M. Durie, MD Philippe Moreau, MD Bruno Paiva, PhD Recommendation Treatment with a CD38 antibody combination until progression Rescue treatment followed by second ASCT or Treatment with a CD38 antibody combination until progression Treatment with a CD38 antibody combination until progression S. Vincent Rajkumar, MD Rescue treatment followed by second ASCT or Treatment with a CD38 antibody combination until progression Jesús F. San-Miguel, MD, PhD Rescue treatment followed by second ASCT or Treatment with a CD38 antibody combination until progression

7 Strategies at Relapse: How to Make the RIGHT CHOICE? Disease-related factors Type of relapse, cytogenetic risk, extramedullary disease Efficacy and toxicity of previous treatments Patient-related factors Age (Trx eligibility), comorbidities, frailty Further options

8 60-Year-Old Man Relapsing after VTD + ASCT + Len x 2y: How to Make the RIGHT CHOICE? Decisions based on the duration of the previous response Early relapse (< 1 year post ASCT) Overcome drug resistance Combination of non cross-resistant agents VTD (KRD)-PACE + Dara RIC-Allo Intermediate relapse (1-3 years post ASCT) Prolong survival until curative treatments are developed Sequential novel agent combinations: Dara + PomDex..KRD... Late relapse (> 3 years post ASCT) Aggressive relapse: Reinduction (KRD + Dara) + 2nd ASCT Biochemical relapse: Repeat the initial approach or same as above

9 Patient Case 5 A 72-year-old man was diagnosed with an IgA, stage I myeloma, and moderate renal insufficiency He was initially treated with a bortezomib-based VMP for 9 cycles and achieved VGPR that lasted for 2 years

10 How would you treat this patient at first relapse? Expert Brian G.M. Durie, MD Philippe Moreau, MD Bruno Paiva, PhD Recommendation Daratumumab/lenalidomide/dexamethasone Daratumumab/lenalidomide/dexamethasone Daratumumab/lenalidomide/dexamethasone S. Vincent Rajkumar, MD Daratumumab/lenalidomide/dexamethasone Jesús F. San-Miguel, MD, PhD Daratumumab/lenalidomide/dexamethasone

11 72y Man 1st/2nd Relapse Following Bortezomib Induction (VMP/VCD) Without lenalidomide maintenance: Lenalidomide/Dexamethasone until progression (PFS 15 m) but Triplets (with RD as backbone)* KRD (PFS 26.3 m) 1 IRD (PFS 20.6 m) 2 EloRD (PFS 19.4 m) 3 DaraRD (NR) 4 Economical constrains RD + Cyclophosphamide VTD ( if TFI > 12m) 1. Stewart AK, et al. NEJM 2015;372: Moreau P, et al. NEJM 2016;374: Lonial S, et al. NEJM 2015;373: Dimopoulos MA, et al. NEJM 2016;375:

12 Triplets with Len-Dex Combinations in Relapsed MM: Survival in Phase III Trials Carfilzomib ASPIRE trial (KRd vs Rd) 1 : CR: 31.8% vs 9.3% PFS: 26.3 vs 17.6 months (HR 0.69, P = ) 8.7 months OS: 48 vs 40 months 2 (HR 0.79, P =.01). 8 months Ixazomib TOURMALINE MM1 trial (IRd vs Rd) 3 : CR: 11.7% vs 6.6% PFS: 20.6 vs 14.7 months (HR 0.74, P = 0.01) 5.9 months IRd, ixazomib + lenalidomide + dexamethasone; KRd, carfilzomib +lenalidomide + dexamethasone. 1. Stewart AK, et al. N Engl J Med 2015;372: Stewart AK, et al. ASH Abstract Moreau P, et al. NEJM 2016;374:

13 Carfilzomib ASPIRE trial (KRd vs Rd): Overall survival Proportion surviving without progression KRd Rd Number of subjects at risk: KRd Rd HR (95% CI) = ( ) Death n (%) Median OS months HR for KRd vs Rd (95% CI) Months since randomization KRd (n = 396) 246 (62.1) 48.3 Rd (n = 396) 267 (67.4) ( ) 1-sided P = Stewart AK, et al. ASH Abstract 743. Stewart et al ASH 2017, Abstract 743

14 Carfilzomib-Len-Dex (KRd) in Relapsed MM Phase III ASPIRE Trial: Safety Profile Data KRd Rd Treatment discontinuation due to AE, % Grade 3 Anemia, % Neutropenia, % Thrombocytopenia, % Peripheral neuropathy, % Cardiac failure, % Ischemic heart disease, % Cardiovascular impact of CFZ in MM: Baseline elevated cardiac peptides and abnormal cardiac strain (60% at baseline) A rise in the NT-proBNP occurs immediately after Cfz based chemotherapy 5% of severe cardiac events attributable to cfz Stewart AK, et al. ASH Abstract 79, oral presentation. Stewart AK, et al. N Engl J Med 2015;372: Rosenthal AC, et al. ASH Abstract 4748, poster presentation.

15 Tourmaline-MM1: Ixazomib +/- RD: Safety Increased Rates with IRd Driven by Low-Grade Events IRd (N = 361), % Placebo-Rd (N = 359), % Preferred terms All-grade Grade 3-4 All-grade Grade 3-4 AEs overlapping with lenalidomide Diarrhea Nausea Rash* Upper respiratory tract infection 23 < 1 19 < 1 Thrombocytopenia AEs with proteasome inhibitors Peripheral neuropathy* Peripheral edema AEs with lenalidomide Thromboembolism* Neutropenia* *Represents multiple MedDRA preferred terms. Moreau P, et al. N Engl J Med 2016;374:

16 Monoclonal Antibodies in Multiple Myeloma Direct effects Alterations in intracellular signalling Inhibition of growth factor receptor function Inhibition of adhesion molecule function Activation of complement system Complement-dependent cytotoxicity (CDC) Activation of macrophages Antibody-dependent cell-mediated phagocytosis (ADCP) Activation of natural killer (NK) cells Antibody-dependent cellular cytotoxicity (ADCC) - Elotuzumab (Anti-SLAMF7) - Single Agent: 26% SD - Anti-CD38: Daratumumab * & Isatuximab - Single agent: 30-35% ORR Depletes CD38-expressing immunosuppressive regulatory cells (myeloid derived suppressor cells and regulatory T and B cells), which in turn promotes T-cell expansion and activation and increased T-cell clonality van de Donk NW et al. Blood 2016;127:681-95

17 Elotuzumab + Len/Dex (Eloquent-2): Extended PFS and OS ORR (ELd vs Ld): 79% vs 66% VGPR: 32.7% vs 27.9% Probability progression free year PFS 2-year PFS 3-year PFS PFS (months) No. of patients at risk: E-Ld Ld PFS 1 (19.4 vs 14.9 m) OS 2 (43.7 vs 39.6 m) % 57% % reduction in risk of disease progression or death PFS: 19.4 vs 14.9 HR 0.73 (95% CI 0.60, 0.89) P = % 27% % 18% E-Ld Ld Probability alive OS (months) 1. Lonial S, et al. N Engl J Med 2015;373: Dimopoulos MA, et al. Br J Haematol. 2017;178: No. of patients at risk: E-Ld Ld year OS 2-year OS 3-year OS 91% % % 69% OS: 43.7 vs 39.6 months HR 0.77 (95% CI ) P = % 53% E-Ld Ld 0 0

18 Elotuzumab + Len + Dex in RRMM Phase III Eloquent Trial: Results Treatment Grade 3 AEs, % ELd (n = 464) Ld (n = 465) Fatigue, % 9 8 Neutropenia, % Thrombocytopenia, % Anemia, % Infusion reactions, % 11% grade 1/2 1% grade 3 - Addition of elotuzumab did not increase the incidence of AE compared to Len/Dex alone. - 70% of infusion reactions occur with the first dose. - Only 2 patients discontinue the study due to an infusion reaction. Lonial S, ASCO Abstract Dimopoulos MA, ASH 2015 oral presentation 28. NA

19 % surviving without progression Daratumumab-Len-Dex (DRd) vs Len-Dex (Rd) in Relapsed MM Phase III POLLUX trial ORR: 93% vs 76% CR: 51% vs 21% Median follow-up of 25.4 months PFS (ITT) HR, 0.41 (95% CI, ; P < ) 24-month PFS 68% 41% Months DRd (n = 286) Median not reached Rd (n = 283) Median 17.5 mo Dimopoulos MA, et al. NEJM 2016;375: Bahlis NZ, et al. Poster presentation at ASCO Abstract MRD-negative rate (%) MRD 6 DRd 13 DRd Rd DRd Rd DRd Rd Rd

20 Daratumumab-Len-Dex (DRd) vs Len-Dex (Rd) in Relapsed MM Phase III POLLUX trial Dara-Rd All AEs Grade 3/4 AEs All AEs Grade 3/4 AEs Neutropenia 59% 52% 43% 37% Diarrhea 43% 5% 25% 3% Upper respiratory tract infection 32% 1% 21% 1% Fatigue 35% 6% 28% 3% Anemia 31% 12% 35% 20% Constipation 29% 1% 25% 1% Thrombocytopenia 27% 13% 27% 14% Infections 28% 23% Treatment discontinuation due to AEs 7% 8% DRd was associated with a manageable safety profile consistent with the known safety profile of D and Rd. Dimopoulos MA, et al. NEJM 2016;375: Rd

21 72y Man 1st /2nd Relapse Following Bortezomib Induction (VMP/VCD) Without lenalidomide maintenance: Lenalidomide/Dexamethasone until progression (PFS 15 m) but Triplets (with RD as backbone)* KRD (PFS 26.3 m) 1 IRD (PFS 20.6 m) 2 EloRD (PFS 19.4 m) 3 DaraRD (NR) 4 Economical constrains RD + Cyclophosphamide VTD ( if TFI > 12m) 1. Stewart AK, et al. NEJM 2015;372: Moreau P, et al. NEJM 2016;374: Lonial S, et al. NEJM 2015;373: Dimopoulos MA, et al. NEJM 2016;375:

22 Lenalidomide-Cyclophosphamide-Prednisone Phase I/II trial in LEN-REFRACTORY Patients Phase I: define MTD (n = 21)...Expansion Phase: ORR, CBR, PFS, & OS (n = 61) Lenalidomide 25 mg Days Cyclo 50 mg/day + Predn 20 mg/day (28-day cycle) Patient population: > 1 prior line + lenalidomide refractory Median nº prior lines: 3 (1 10), 66% Bort-refractory ORR 67%; VGPR 23%; CR 5% (1 scr) Median PFS: 12.1 m Median OS: 29.0 m Median FUP: 24.5 m Nijhof I, et al. Blood 2016;128: Nijhof I, et al. Blood 2016;128(19):

23 72-Yr-Old Man 1 st /2 nd Relapse Following VRD Induction Pomalidomide (4 mg x D1-21) + Cyclophosphamide (300 mg per wk) + Dexamethasone (2 pulses 40 mg) in 28 day cycle in relapsing patients treated with IFM2009/DFCI trial protocol: VRD (induction & consolidation) followed by 1-Yr len maintenance (arm A) or ASCT after induction (arm B) N = 90 patients: ORR 91% (2% CR, 32% VGPR) after 4 cycles Garderet, et al. ASH Abstr 837. Pomalidomide + Dex..Addition of Cyclophosphamide 500 mg D1, 15 (iv) if < PR on Cycle 3 in patients with R/R MM after 2 prior tx lines including bortezomib and lenalidomide N = 60 patients..36 pts refractory (16 PD, 15 SD, 5 MR): 13 (32%) achieved at least PR, with median PFS from start of cyclophosphamide of 5 months Weisel K, et al. ASH Abstr 1849.

24 Patient Case 6 A 82-year-old woman was diagnosed with an IgGk, stage III myeloma, and deletion p53 in 20% of PC She achieved a VGPR with lenalidomide/dexamethasone On month 24 of continuous treatment, she developed rapid disease progression

25 How would you treat this patient now? Expert Brian G.M. Durie, MD Philippe Moreau, MD Bruno Paiva, PhD Recommendation Daratumumab/bortezomib/dexamethasone Daratumumab/bortezomib/dexamethasone Daratumumab/bortezomib/dexamethasone S. Vincent Rajkumar, MD Daratumumab/bortezomib/dexamethasone Jesús F. San-Miguel, MD, PhD Daratumumab/bortezomib/dexamethasone

26 82-Year-Old Woman First or Second Relapse Following continuous Lenalidomide Dexa (Lenalidomide refractory)* Bortezomib-Dex (PFS: 9.4 m) Carfilzomib-Dex (PFS: 18.7 m) 1 Triplets based on bortezomib: EloVD (PFS: 9.7 m) 2 DaraVd (60.7% 12-m PFS) 3 PanobinostatVd (PFS: 12 m) 4 Economical Constrains VMP/VCD (16 m; 83% at 1 Yr) 5,6 * If she was on len maintenance : the previous mentioned triplets (VTD, KRD) could be considered 1. Dimopoulos MA, et al. Lancet Oncol. 2016;17: Jakubowiak A, et al. Blood. 2016;127: Palumbo A, et al. N Engl J Med. 2016;375: San Miguel JF, et al. Lancet Oncol 2014;15: Reece DE, et al. JCO 2008;26: Reece DE, et al. Clin Lymphoma Myeloma Leuk. 2016;16:

27 Carfilzomib-Dex vs Bortezomib-Dex in RMM Phase III ENDEAVOR Trial: PFS and OS Data Primary Endpoint: PFS 1 Secondary Endpoint: OS 2 Proportion Surviving Without Progression Kd Vd Kd Vd Events, n Median PFS, mo HR (95% CI) 0.53 ( ) P < Months Since Randomization Proportion Surviving Kd Vd Death n (%) Median OS months HR for Kd vs Vd (95% CI) Kd (n = 464) Months Since Randomization Vd (n = 465) 189 (40.7) 209 (44.9) ( ) 1-sided P = ORR (Kd vs Vd): 77% vs 63%. CR: 13% vs 6% Median DOR (Kd vs Vd): 21.3 vs 10.4 months 1. Dimopoulos MA, et al. Lancet Oncol. 2016;17: Dimopoulos MA, et al. Lancet Oncol. 2017;18:

28 Dara-Vd vs Vd in Relapsed MM (Castor) Updated efficacy % surviving without progression Median follow-up of 19.4 months 100 ITT month PFS a 48% HR: % (95% CI, ; P <0.0001) Months DVd (n = 251) Median 16.7 mo Vd (n = 247) Median 7.1 mo SOC, standard of care. a Kaplan-Meier estimates; exploratory analyses based on 1-year update: clinical cut-off date of January 11, ORR, % CR 29% ORR = 84% 9% 20% 35% 22% P < CR 10% VGPR 62% ORR = 63% 3% 7% 19% 34% DVd (n = 240) Vd (n = 234) VGPR 29% scr CR VGPR PR 1. Lentzsch S et al. Poster presentation at ASCO Abstract 8036.

29 Daratumumab- Carfilzomib- Dexamethasone 85 Patients : all exposed to PI & IMIDs and 60% refractory to Len Dara: 16 mg/k C1-2/w, C3-6/2w, C7./4w; K: C1D1: 20 mg/m 2 and C1D8: 70; weekly D1,8,15 Dex: 40 mg/w ORR: 84%; PFS at 12-m: 74 % Lonial S, ASH 2017 Abstract 1869

30 PANORAMA 1: Panobinostat + Bort + Dex vs Bort + Dex ORR PanoBD vs PcboBD: 60.7% vs 54.6% CR: 27.6% vs 15.7% PFS Probability, % Median PFS(m) PAN-BTZ-Dex Pbo-BTZ-Dex PFS PAN-BTZ-Dex Pbo-BTZ-Dex 12 ( ) 8.1 ( ) HR (95% CI) 0.63 ( ) Number of patients at risk Months PAN-BTZ-Dex Pbo-BTZ-Dex No benefit in OS PFS Probability, % Subgroup Analysis by Prior Treatment: PFS Prior BTZ + IMiDs w/ 2 Prior Lines Median PFS(m) PAN-BTZ-Dex (n/n = 44/73) Pbo-BTZ-Dex (n/n = 54/74) PAN-BTZ-Dex Months Number of Patients at Risk PAN-BTZ-Dex Pbo-BTZ-Dex Pbo-BTZ-Dex 12.5 ( ) 4.7 ( ) HR (95% CI) 0.47 ( ) San Miguel JF et al. Lancet Oncol. 2014;15(11):

31 82-Year-Old Woman First or Second Relapse Following continuous Lenalidomide Dexa (Lenalidomide refractory)* Bortezomib-Dex (PFS: 9.4 m) Carfilzomib-Dex (PFS: 18.7 m) 1 Triplets based on bortezomib: EloVD (PFS: 9.7 m) 2 DaraVd (60.7% 12-m PFS) 3 PanobinostatVd (PFS: 12 m) 4 Economical Constrains VMP/VCD (16 m; 83% at 1 Yr) 5,6 * If she was on len maintenance : the previous mentioned triplets (VTD, KRD) could be considered 1. Dimopoulos MA, et al. Lancet Oncol. 2016;17: Jakubowiak A, et al. Blood. 2016;127: Palumbo A, et al. N Engl J Med. 2016;375: San Miguel JF, et al. Lancet Oncol 2014;15: Reece DE, et al. JCO 2008;26: Reece DE, et al. Clin Lymphoma Myeloma Leuk. 2016;16:

32 82-Year-Old Woman: First Relapse or Primary Refractory VCD (/21d x 8 cycles) vs KCD (/28d x 6): Btz 1.3 mg biweekly, K 20/36 mg; cyclo 550 mg/w, Dex: 40 mg/w Patients: 99 vs 201 in first relapse or refractory ORR 68% vs 84% ( VGPR: 32 vs 40%) PN ( 8,6 vs 0,7%) Cardiac ( 1,4 vs 4%) Kwee Young, et al. ASH Abstr 835. VCD (/35d x 9 cycles) vs LCD (/28d x 9): Btz 1.3 mg/w L: 25 mg; cyclo 550 mg D 1,8, Dex: 40 mg/w Patients: 77 vs 77 in first relapse ORR 68% vs 84% (VGPR: 16% vs 20%); PFS: 16 vs 20 m ; OS: 31 vs 36 m Motefusco, et al. ASH Abstr 836.

33 What Are the Factors Influencing Our Decisions? Age Type of relapse Number/Types of prior lines of therapy Cytogenetic abnormalities

34 Would Advanced Age Modify Our Strategy? Impact of AGE PFS HR (95% CI) POLLUX (DRd vs Rd) 1 ASPIRE (KRd vs Rd) 2 ELOQUENT (ERd vs Rd) 3 TOURMALINE (IRd vs Rd) 4 ENDEAVOR (Kd vs Vd) 5 CASTOR (DVd vs Vd) 6 < 65y 65 y < 65y 65 y < 65y 65 y < 65y y < 75y 75 y < 65y 65 y 0.4 ( ) 0.4 ( ) 0.60 ( ) 0.74 ( ) 0.75 ( ) 0.65 ( ) ( ) 0.35 ( ) Favors novel-agent 1. Dimopoulos MA, et al. NEJM 2016;375: Stewart AK, et al. N Engl J Med 2015;372: Lonial S et al, NEJM 2015 Aug 13;373(7): Moreau P et al. N Engl J Med. 2016;374: Dimopoulos MA, et al. Lancet Oncology 2016; 17: Palumbo A et al, NEJM 2016; 6. Moreau P, ASH 2015 abst

35 What Are the Factors Influencing Our Decisions?: Prior Lines of Therapy HR (95% CI) POLLUX (DRd vs Rd) 1 ASPIRE (KRd vs Rd) 2 ELOQUENT (ERd vs Rd) 3 TOURMALINE (IRd vs Rd) 4 ENDEAVOR (Kd vs Vd) 5 CASTOR (DVd vs Vd) 6 1 line 2 lines 1 line 2 lines 1 line 2 lines 1 line 2 lines 1 line 2 lines 1 line 2 lines ( ) 0.69 ( ) 0.79 ( ) 0.68 ( ) ( ) 0.6 ( ) Favors novel-agent 1. Dimopoulos MA, et al. NEJM 2016;375: Stewart AK, et al. N Engl J Med 2015;372: Lonial S et al, NEJM 2015 Aug 13;373(7): Moreau P et al. N Engl J Med. 2016;374: Dimopoulos MA, et al. Lancet Oncology 2016; 17: Palumbo A et al, NEJM 2016; 6. Moreau P, ASH 2015 abst

36 What Are the Factors Influencing Our Decisions?: Cytogenetic Abnormalities POLLUX (DRd vs Rd) 4 ASPIRE (KRd vs Rd) 1 TOURMALINE (IRd vs Rd) 6 ENDEAVOR (Kd vs Vd) 2 CASTOR (DVd vs Vd) 5 SR HR SR HR SR HR SR HR SR HR HR (95% CI) 0.30 ( ) 0.44 ( ) 0.66 ( ) 0.70 ( ) ( ) 0.64 ( ) 0.29 ( ) 0.53 ( ) Favors novel-agent 1 1. Dimopoulos MA, et al. NEJM 2016;375: Stewart AK, et al. N Engl J Med 2015;372: Lonial S et al, NEJM 2015 Aug 13;373(7): Moreau P et al. N Engl J Med. 2016;374: Dimopoulos MA, et al. Lancet Oncology 2016; 17: Palumbo A et al, NEJM 2016; 6. Moreau P, ASH 2015 abst 727.

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