Initial Therapy For Transplant-Eligible Patients With Multiple Myeloma. Michele Cavo, MD University of Bologna Bologna, Italy

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1 Initial Therapy For Transplant-Eligible Patients With Multiple Myeloma Michele Cavo, MD University of Bologna Bologna, Italy

Treatment Paradigm for Autotransplant-Eligible Patients With Multiple Myeloma (MM) Treatment Phases Induction therapy Autograft 1 or 2 Consolidation Maintenance Goals: Maximize the rate and depth of

2 Treatment Paradigm for Autotransplant-Eligible Patients With Multiple Myeloma (MM) Treatment Phases Induction therapy Autograft 1 or 2 Consolidation Maintenance Goals: Maximize the rate and depth of response Minimize residual tumor cells beyond the level of MRD negativity Prevent or delay relapse Increase PFS and OS ultimately: Tailor treatment based on disease characteristics MRD, minimal residual disease; OS, overall survival; PFS, progression-free survival Cavo M, et al. Blood. 2011;117(23): Cavo M, et al. Blood. 2012;120(1):9-19. Kumar S, et al. Lancet Oncol. 2016;17(8):e328-e346.

3 PFS, % Induction Therapy: State of the Art Induction therapy VTD VCD VRD PAD ESMO Guidelines 2017: 3-drug VD-based combinations are the current standard of care for induction therapy. 4-6 courses of induction are recommended prior to peripheral blood stem cell collection Meta-Analysis of Bortezomib-Based Induction vs Non-Bortezomib Time, Months Moreau P, et al. Ann Oncol. 2017;28(suppl_4):iv52-iv61. Sonneveld P, et al. J Clin Oncol. 2013;31(26):

4 Regimens / Study Induction Therapy: State of the Art PAd vs VCD 34.3 vs 37.0 Prospective 1 P =.58 VTD vs VCD 66.3 vs 56.2 Prospective 2 P =.05 VTD vs VCD 64 vs 37 Case-matched 3 P<.001 Which is the best partner for a PI? Response Safety Profile VGPR % CR % SAEs % Grade 3/4 PN % 4.4 vs 8.4 P = vs 8.9 P = vs 6 P< vs 24 P = vs 2.9 P =.05 7 vs 2 P =.009 CR, complete response; PI, proteasome inhibitor; PN, peripheral neuropathy; SAE, serious adverse event; VGPR, very good partial response 1. Mai EK, et al. Leukemia. 2015;29(8): Moreau P, et al. Blood. 2016;127(21): Cavo M, et al. Leukemia. 2015;29(12):

Screening Follow-up VTD vs Dara-VTD Induction Therapy CASSIOPEIA Phase III Trial

2 years) R ASCT R Subjects with PR or better Arm B VTD + DARA 4x VTD + DARA 2x DARA q 8

2 years followed by observation until PD) Part 1 Part 2 ASCT, autologous stem cell

5 Screening Follow-up VTD vs Dara-VTD Induction Therapy CASSIOPEIA Phase III Trial Induction Consolidation Maintenance Arm A VTD 4x VTD 2x Observation until PD (max. 2 years) R ASCT R Subjects with PR or better Arm B VTD + DARA 4x VTD + DARA 2x DARA q 8 weeks until PD (max. 2 years followed by observation until PD) Part 1 Part 2 ASCT, autologous stem cell transplant; DARA, daratumumab; PD, progressive disease; PR, partial response National Institutes of Health. Accessed 5 June 2018.

6 VRD Induction Therapy (6 Cycles) Response Response, n (%) Overall Complete response 176 (39) scr 126 (28) CR 50 (11) VGPR 133 (29) PR 77 (17) MRD-negative* (n = 320) 35% Overall response 386 (85) Toxicity Grade 1 Grade 2 Grade 3 Grade 4 PN/neuropathic pain Neurologic Toxicity 91 (20%) 48 (10%) 14 (3%) 1 (<1%) Outcomes of VTD** Induction x 6 Cycles Complete response (%) 35 Grade 3 PN (%) 14 *NGF 3 x 10-6 *Bortezomib 1.3 mg/m 2 SC (days 1,4,8,11); lenalidomide 25 mg/day PO (days 1-21); dexamethasone 40 mg/day PO (days 1-4,9-12; 28-day cycles) **Bortezomib 1.3 mg/m 2 IV (days 1,4,8,11); talidomide 200 mg/day PO; dexamethasone 40 mg/day PO (days 1-4,9-12; 28-day cycles) Rosiñol L, et al. Blood. 2012;120(8): Rosiñol L, et al. Blood. 2017;130: Abstract 130.

Phase II Study: Daratumumab-VRd vs VRd in NDMM Part 1: Safety Run-In (N = 16) Induction (Cycles 1-4) ASCT DARA: 16 md/kg weekly in cycles 1-4 and every 3 weeks in cycles 5-6

3 mg/m 2 SC D: 40 mg PO weekly Maintenance (Cycles 7-32) Consolidation (Cycles 5-6) DARA: 16 md/kg every 8 weeks for cycles 7-32 + R: 10 mg PO daily on days 1-21, then 15 mg

7 Phase II Study: Daratumumab-VRd vs VRd in NDMM Part 1: Safety Run-In (N = 16) Induction (Cycles 1-4) ASCT DARA: 16 md/kg weekly in cycles 1-4 and every 3 weeks in cycles R: 25 mg PO V: 1.3 mg/m 2 SC D: 40 mg PO weekly Maintenance (Cycles 7-32) Consolidation (Cycles 5-6) DARA: 16 md/kg every 8 weeks for cycles R: 10 mg PO daily on days 1-21, then 15 mg PO daily beginning cycle 10 (if no tolerability issues) D: 20 mg PO every 8 weeks Voorhees PM, et al. Blood. 2017;130: Abstract Safety Profile of Patients Treated During Cycles 1-4 N = 16 At least 1 treatment-emergent adverse event TEAE), n (%) 16 (100) Related to daratumumab 14 (88) Most common TEAEs (all grades) occurring in 20% of patients, n (%) Neutropenia 8 (50) Lymphopenia 7 (44) Thrombocytopenia 7 (44) Fatigue 6 (38) Edema peripheral 6 (38) Anemia 5 (31) Constipation 5 (31) Leukopenia 4 (25) Hypoalbuminemia 4 (25) Hypocalcemia 4 (25) Insomnia 4 (25) 2 patients had SAE considered related to daratumumab (gastroenteritis, pneumonitis) 5 patients had a grade 2 IRR

8 Screening VRD vs Elo-VRD Induction Therapy GMMG-HD6 Phase III Trial Induction Consolidation Maintenance VRD VRD Len/Dex VRD VRD + Elotuzumab Len/Dex + Elotuzumab R VRD + Elotuzumab ASCT VRD Len/Dex VRD + Elotuzumab VRD + Elotuzumab Len/Dex + Elotuzumab National Institutes of Health. Accessed 5 June 2018.

CR scr KRd, carfilzomib-lenalidomide-dexamethasone. R, lenalidomide. 1. Jakubowiak A, et al. Haematologica.

9 Patients, % Patients, % Patients, % Carfilzomib and IMiD-Based Induction Therapy KRd + ASCT Phase II (N = 73) 1 KRd + ASCT Phase II IFM (N = 46) 2 KTd + ASCT Phase II (N = 91) 3 Induction KRd x4 Induction KRd x4 Induction KTd x4 a b VGPR CR scr KRd, carfilzomib-lenalidomide-dexamethasone. R, lenalidomide. 1. Jakubowiak A, et al. Haematologica. 2016;101(S1): Abstract S Roussel M, et al. Blood. 2016;128: Abstract Sonneveld P, et al. Blood. 2015;125(3):

PBSC Mobilization Response, % KRd vs KCd Induction Therapy Four 28-Day Cycles Arm A: KCd Induction Carfilzomib* + cyclophosphamide + dexamethasone

005 Arm B: KRd Induction Carfilzomib* + lenalidomide + dexamethasone Arm C: KRd Induction Carfilzomib* + lenalidomide + dexamethasone *In the

10 PBSC Mobilization Response, % KRd vs KCd Induction Therapy Four 28-Day Cycles Arm A: KCd Induction Carfilzomib* + cyclophosphamide + dexamethasone (n = 159) Preliminary Efficacy P =.01 P =.005 Arm B: KRd Induction Carfilzomib* + lenalidomide + dexamethasone Arm C: KRd Induction Carfilzomib* + lenalidomide + dexamethasone *In the current analysis patients randomized to arms B and C were pooled together (n = 318) PBSC, peripheral blood stem cell; ncr, near CR; scr, stringent CR Gay FM, et al. J Clin Oncol. 2017;35((Suppl 4): Abstract Gay F, et al. Blood. 2017;130:Abstract 4541.

11 PFS, Probability PFS Patients, % Upfront ASCT: State of the Art Autograft 1 or 2 ESMO Guidelines 2017: High-dose therapy (HDT) with autologous stem cell transplantation (ASCT) is the standard treatment in fit patients EMN02/HO95 Phase III Study: VMP vs ASCT IFM 2009 Phase III Study: RVD vs ASCT Median follow-up: 37.8 months Median follow-up: 43.5 months Cavo M, et al. Blood. 2017;130: Abstract 397. Attal M, et al. N Engl J Med. 2017;376(14):

12 OS, Probability OS Patients, % Upfront ASCT: State of the Art Autograft 1 or 2 Though, no OS benefit with auto-transplant was seen in both studies. The follow-up is still too short to justify any delay of autotransplant at the time of relapse EMN02/HO95 Phase III Study: VMP vs ASCT IFM 2009 Phase III Study: RVD vs ASCT HR: 1.00 (95% CI, ), P =.981 HR: 1.16 (95% CI, ), P =.87 HR (95% CI: 1.16 ( ); P = 0.87 Cavo M, et al. Blood. 2017;130: Abstract 397. Attal M, et al. N Engl J Med. 2017;376(14):

13 EMN02/HO95 MM Phase III Trial: Study Design VCD induction x 3-4 cycles + PBSC collection R1 VMP x 4 cycles Bortezomib 1.3 mg/m 2 d 1,4,8,11,22,25,29,32/42 Melphalan 9 mg/m 2 d 1-4/42 Prednisone 60 mg/m 2 d 1-4/42 (497 patients) Melphalan (HDM) 200 mg/m 2 x 1-2 courses* + single or double ASCT (695 patients) R2 VRD consolidation x 2 cycles No consolidation Maintenance lenalidomide Stratification according to center and ISS disease stage (I vs II vs III) Randomization to VMP or HDM was 1:1 in centers with a fixed single ASCT policy Randomization to VMP or HDM-1 or HDM-2 was 1:1:1 in centers with a double ASCT policy Cavo M, et al. Blood. 2017;130: Abstract 401

14 EMN02/HO95 Trial: Randomization patients were eligible for R1 Single ASCT policy Randomization 1:1 Double ASCT policy Randomization 1:1:1 VMP (294 patients) VMP (203 patients) ASCT-1 (280 patients) ASCT-1 (208 patients) ASCT-2 (207 patients) Cavo M, et al. Blood. 2017;130: Abstract 401

15 PFS By Randomization and Cytogenetic Risk ASCT-1 vs ASCT-2 ASCT-1 vs ASCT-2 by High Risk ASCT-2 by Standard or High Risk HR: 0.71 (95% CI, ), P =.040 HR: 0.42 (95% CI, ), P =.014 HR: 0.79 (95% CI, ), P =.483 Cavo M, et al. Blood. 2017;130: Abstract 401

16 OS probability OS By Randomization and Cytogenetic Risk All Patients By High-Risk Cytogenetics % (77.3% ; 93.2%) % (63.6% ; 83.4%) 0.25 HR: 0.51 (95% CI, ), P = ASCT-1 ASCT-2 HR: 0.52 HR: 0.52 (95% (95% CI, CI, ), ), P P=0.042 = Months Number at risk EHA 2018 Oral Presentation, Friday, June 15, ; Abstract S105 (Tacchetti P, et al) Months Cavo M, et al. Blood. 2017;130: Abstract 401

STaMINA Phase III Study of Single vs Double ASCT Autograft 1 or 2 The STaMINA study was designed to randomize patients after induction to receive high-dose intensification therapy with Mel-200 and

17 STaMINA Phase III Study of Single vs Double ASCT Autograft 1 or 2 The STaMINA study was designed to randomize patients after induction to receive high-dose intensification therapy with Mel-200 and ASCT followed by either lenalidomide maintenance, or VRD consolidation (4 cycles) + lenalidomide maintenance, or a second ASCT + lenalidomide maintenance PFS (ITT Analysis) PFS (High-Risk Patients) Median follow-up 38 months Stadtmauer E, et al. Blood. 2016;128; Abstract LBA1.

Consolidation Therapy: State of The Art Consolidation is not yet a standard clinical practice EMN02/HO95 Phase III Study of VRD Consolidation vs No Consolidation PFS by R2 STaMINA Phase III Study of

18 Consolidation Therapy: State of The Art Consolidation is not yet a standard clinical practice EMN02/HO95 Phase III Study of VRD Consolidation vs No Consolidation PFS by R2 STaMINA Phase III Study of VRD Consolidation vs No Consolidation PFS (ITT analysis) Median follow-up 25 months EHA 2018 Oral Presentation, Friday, June 15, ; Abstract S108 (Sonneveld P, et al) Sonneveld P, et al. Blood. 2016;128: Abstract 242. Stadtmauer E, et al. Blood. 2016;128; Abstract LBA1. Median follow-up 38 months

Maintenance Therapy With Lenalidomide ESMO Guidelines 2017: Lenalidomide maintenance is EMA-approved for the treatment of adult patients with

19 Maintenance Therapy With Lenalidomide ESMO Guidelines 2017: Lenalidomide maintenance is EMA-approved for the treatment of adult patients with newly-diagnosed MM who have undergone ASCT 0.75 ( ).001 Median follow-up 80 months McCarthy PL, et al. J Clin Oncol. 2017;35(29):

Lenalidomide Maintenance After ASCT: OS Subgroup Analysis a Number of patients. b Cytogenetic data were available only for the IFM and GIMEMA studies.

20 Lenalidomide Maintenance After ASCT: OS Subgroup Analysis a Number of patients. b Cytogenetic data were available only for the IFM and GIMEMA studies. c CrCl post-asct data were available only for the CALGB and IFM studies. CrCl, creatinine clearance; ISS, International Staging System McCarthy PL, et al. J Clin Oncol. 2017;35(29): Attal M, et al. J Clin Oncol. 2016;34(suppl):Abstract 8001.

0001 HR: 0.69; 95% CI [0.52-0.93] Log-rank P =.0130 Jackson GH, et al. Blood.

21 MYELOMA XI Maintenance With Lenalidomide Transplant Eligible Pathway: PFS Transplant Eligible Pathway: OS HR: 0.48; 95% CI [ ] Log-rank P<.0001 HR: 0.69; 95% CI [ ] Log-rank P =.0130 Jackson GH, et al. Blood. 2016;128: Abstract Jackson GH, et al. J Clin Oncol. 35(Suppl 4): Abstract 8009.

22 OS (%) OS (%) Transplant Eligible Pathway Lenalidomide improved OS irrespective of cytogenetic risk t(4;14) and/or del(17p) absent: HR 0.54 t(4;14) and/or del(17p) present: HR 0.51 Obs Len Median OS [95%CI] Obs. (n=165) NR Len. (n=209) NR Obs Len Median OS [95%CI] Obs. (n=36) 30, [24, Inf.) Len. (n=62) 50, [46, Inf.) HR: %CI [0.26, 1.01] Logrank P = HR: %CI [0.30, 0.98] Logrank P = Est. [95%CI] Est. [95%CI] Obs. (%) 97.5 [ 95.2, 100.0] 88.6 [ 83.4, 94.1] 81.0 [ 74.3, 88.3] 77.2 [ 69.7, 85.5] 73.3 [ 64.7, 83.1] Obs. (%) 78.1 [ 65.0, 93.9] 67.1 [ 52.2, 86.4] 42.4 [ 26.2, 68.7] 42.4 [ 26.2, 68.7] 31.8 [ 15.1, 66.9] Len. (%) 98.0 [ 96.2, 100.0] 96.8 [ 94.3, 99.4] 93.7 [ 89.5, 98.1] 82.5 [ 74.2, 91.7] 75.0 [ 64.4, 87.5] Len. (%) 91.5 [ 84.6, 98.9] 80.6 [ 70.4, 92.4] 69.0 [ 56.1, 84.8] 59.7 [ 44.7, 79.7] 49.7 [ 33.9, 73.0] Time from maintenance randomisation (m) Number at risk Obs Len Time from maintenance randomisation (m) Number at risk Obs Len Jackson GH, et al. Blood. 2017;130: Abstract 436.

23 Maintenance With Bortezomib Lack of phase studies comparing bortezomib vs no bortezomib/placebo Study Details* n Treatment PFS OS HOVON 65 MM / GMMG-HD4 1 Median follow-up: 91.4 months (Overall trial) PAD x 3 HDM bortezomib every 2 weeks for 2 years VAD x 3 HDM Thalidomide daily for 2 years 34 months 28 months; P = % 45%; P =.22 RMST 8 years: 4.8 months; P =.04 PETHEMA/GEM 2 Median follow-up: 58.6 months (From maintenance start) *Bortezomib administered at 1.3 mg/m 2 IV in both studies TV (thal daily, 1 cycle bortezomib every 3 m) for 3 years Thal (daily for 3 years) Interferon- 2b (3 x week for 3 years) 50.6 months 40.3 months 32.5 months; P =.03 Not significantly diffferent between arms 1. Sonneveld P, et al. Blood. 2015;126: Abstract Rosiñol L, et al. Leukemia. 2017;31(9):

24 Current And Future Treatment Algorithm For Transplant-Eligible Patients With MM Until 2017 Ongoing/Planned Induction: 3-drug bort-based tx VTD VCD VRD PAD HDM (200 mg/m 2 ) + ASCT x 1 or 2 Consolidation: 3-drug bort-based tx Induction 3-drug vs 4-drug mab-based tx VTD vs Dara-VTD VRD vs Elo-VRD VTD vs Dara-VCD VRD vs Dara-VRD VRD vs KRD KRD vs Dara-KRD HDM (200 mg/m 2 ) + ASCT x 1 or 2 Consolidation: 3-drug vs 4-drug mab-based tx Maintenance: IMiD-based Maintenance: IMiDs vs PI-lMiDs vs mab-imids vs mab-pis Cavo M, personal communication. Clinicaltrials.gov identifiers: NCT ; NCT ; NCT ; NCT

25 Improvements in Front-Line Therapy for ASCT-Eligible Patients With MM NOVEL AGENTS Induction therapy Autograft 1 or 2 Consolidation Maintenance New drug combinations Cavo M, personal communication. Future Cure myeloma? Trial design with genomic and MRD as treatment drivers

26 Summary Induction therapy followed by ASCT is the standard treatment in fit, newly-diagnosed patients with MM Three-drug combinations including bortezomib and dexamethasone are the current standard of care for induction These triplets might be replaced in the near future by four-drug combinations including a mab combined with a PI and an IMiD Double ASCT improves outcomes, especially in patients with unfavorable cytogenetic abnormalities PFS benefit with consolidation therapy confirmed in the second interim analysis of EMN02/HO95 phase III study Lenalidomide maintenance is EMA-approved for the treatment of patients with newlydiagnosed MM who have undergone ASCT Some patient populations may benefit from alternative maintenance regimens Different treatment strategies for transplant-eligible patients with MM possibly guided by genomics and MRD Cavo M, personal communication.

Induction Therapy in Transplant Eligible MM 2 December Tontanai Numbenjapon, M.D.

Induction Therapy in Transplant Eligible MM 2 December 2017 Tontanai Numbenjapon, M.D. What we need from induction therapy in NDMM Depth of response: MRD-negative, scr, CR Longest response Acceptable toxicity