Highlights from EHA Mieloma Multiplo Michele Cavo Istituto di Ematologia L. e A. Seràgnoli Alma Mater Studiorum Università degli studi di Bologna Firenze, 22-23 Settembre 27
Myeloma XI TE pathway 7 R : Induction Max. Induction 2 Maintenance CTD CRD KCRD response PD SD MR PR VGPR CR R : CVD No CVD ASCT R : Lenalidomide Observation This analysis compares toxicity and response to KCRD vs triplets pre and post - ASCT Patients were ineligible for the CVD randomisation if they had achieved a CR or VGPR to induction (went straight to ASCT if eligible or maintenance if not) or had PD or SD to induction (all primary refractory received CVD). Patients were ineligible for the maintenance randomisation if they failed to respond to lenalidomide as their induction IMiD or failed to respond to all trial induction treatment, had PD or had previous or concurrent active malignancies. Dose adjustments for renal impairment and following AEs were permitted.
Percentage of patients Response to initial induction Lenalidomide led to deeper responses than thalidomide 79.5% 9 8 7 5 4 3 52.8%.8% KCRD (n=52) VGPR CR w/o BM CR 2 CTD (n=2) CRD (n=2)
Percentage of patients Response to initial induction Quadruplet KCRD led to deeper responses than either triplet 9 8 79.5% 7 5 4 52.8%.8% VGPR CR w/o BM CR 3 2 CTD (n=2) CRD (n=2) KCRD (n=52)
Myeloma XI trial outline, TE pathway 3 Induction Maintenance R CTD n=2 CRD n=2 ASCT n=23 R Lenalidomide Observation Primary endpoints: PFS and OS for each randomisation Median follow up 3.3 months Patients with a suboptimal response to Induction (<VGPR) were eligible for Induction 2. Patients with PR/MR were randomised to CVD (cyclophosphamide, bortezomib and dexamethasone) or no further therapy prior to ASCT. Patients with NC/PD all received CVD. Patients were ineligible for the CVD randomisation if they had achieved a CR or VGPR to induction (went straight to ASCT) or had PD or SD to induction. Patients were ineligible for the maintenance randomisation if they failed to respond to lenalidomide as their induction IMiD or failed to respond to all trial induction treatment, had PD or had previous or concurrent active malignancies. Dose adjustments for renal impairment and following AEs were permitted.
2 4 PFS (%) 8 Maintenance randomisation Significant improvement in PFS from 28 to 5 months, HR.47 4 Len Median PFS [95%CI] Obs. (n=377) 28, [24, 32] Len. (n=45) 5, [44, Inf.) Obs HR:.47 95%CI [.37,.59] Logrank P <. Est. [95%CI] Obs. (%) Len. (%) 7. [ 7.5, 8.7] 53.5 [ 48., 59.7] 38.5 [ 32.5, 45.5] 22.2 [., 3.9]. [ 8.3, 27.3] 88.9 [ 85.8, 92.2] 7.5 [.5, 7.9] 3.3 [ 57., 9.5] 53.8 [ 4.7,.9] 49.5 [ 4.2, 59.4] 2 24 3 48 Time from maintenance randomisation (m) Number at risk Obs. 377 237 2 52 72 Len. 45 285 3 92 3 2 GH Jackson et al ASH 2 (abstract no. 43)
Maintenance randomisation Significant improvement in PFS from 28 to 5 months, HR.47 Subgroup Level No treat. Len. HR [ 95%CI ] P. (het) Gender Male n/n n/n.5 (.42,.74).24 3/235 9/294 Female 72/42 27/7.3 (.9,.47) Age <=5 years 49/3 9/34.47 (.3,.).9 >5 years 3/7 28/87.44 (.2,.74) ISS Stage I 2/37 37/49.42 (.28,.4).3322 Stage II 9/48 49/8.57 (.39,.82) Stage III 45/7 25/97.35 (.22,.58) t(4,4) Present 4/7 /29.44 (.9,.98).84 Absent 7/38 35/49.37 (.24,.55) del(7p) Present 8/9 9/7.4 (.4,.25).9872 Absent 7/4 37/.37 (.25,.55) q gain Present 2/44 24/9.4 (.2,.83).3 Absent 58/ 22/9.3 (.8,.5) Cytogenetic Risk SR 4/97 7/8.3 (.8,.55).855 HiR 23/4 3/.29 (.,.59) Overall UHiR 85/3778/45 /7 /2.47.3 (.37, (.4,.).92) Len Favours Favours Obs...2.5 HR.
PFS (%) 2 4 8 PFS (%) 2 4 8 PFS (%) 2 4 8 Maintenance randomisation Lenalidomide improved PFS irrespective of cytogenetic risk Standard risk High risk Ultra- high risk Len Median PFS [95%CI] Obs. (n=97) 28, [2, 48] Len. (n=8) NR, [5, Inf.) HR:.3 95%CI [.8,.55] Logrank P <. Len Median PFS [95%CI] Obs. (n=4) 24, [, 4] Len. (n=) 45, [45, Inf.) HR:.29 95%CI [.,.59] Logrank P = 4e-4 Len Median PFS [95%CI] Obs. (n=7) 7, [, Inf.] Len. (n=2) 9, [, 3] HR:.3 95%CI [.4,.92] Logrank P =.852 Obs Obs Obs Est. [95%CI] Obs. (%) 79. [ 7.7, 88.5] 55.2 [ 45., 7.] 45.4 [ 34.7, 59.3] 3.9 [ 8.5, 5.8] Est. [95%CI] Obs. (%) 3.5 [ 49.4, 8.5] 5.9 [ 37., 72.9] 25.4 [ 2., 53.8] 2.7 [ 3.7, 43.7] Est. [95%CI] Obs. (%) 4.2 [ 23.3, 72.7] 2.2 [ 8., 55.4]. [ 2., 57.2] 4.2 [ 23.3, 72.7] Len. (%) 97.2 [ 93.4,.] 8.2 [ 7., 92.] 7. [ 5., 88.8]. [ 52.8, 82.] Len. (%) 87.8 [ 79.7, 9.7] 78. [ 8., 9.9] 73. [ 59.5, 89.7] 48.7 [ 2.3,.] Len. (%) 5. [ 48., 88.] 3.7 [.3,.5] 8.4 [.8, 49.9] 5. [ 48., 88.] 2 24 3 48 72 Time from maintenance randomisation (m) Number at risk 9 34 Obs. 97 2 38 25 2 Len. 8 2 24 3 48 72 Time from maintenance randomisation (m) Number at risk 2 3 4 2 Obs. 4 44 2 3 Len. 2 24 3 48 72 Time from maintenance randomisation (m) Number at risk 7 2 Obs. 7 4 5 3 Len. 2 High risk (HiR) - presence of any one of t(4;4), t(4;), t(4;2), del(7p), or gain(q). Ultra-high risk (UHiR) - presence of more than one lesion. Standard risk (SR) - absence of any of the above lesions.
2 4 PFS (%) 8 Interaction between induction and maintenance The best outcomes are associated with lenalidomide maintenance induction and 8 Median PFS [95%CI] CTD/Obs (n=87) 4, [37, 5] CTD/Len (n=22) 58, [49, Inf.) CRD/Obs (n=9) 34, [32, 42] CRD/Len (n=23) NR, [5, Inf.) CRD - Len Logrank P <. 2 24 3 48 72 Time from randomisation (m) CTD/Obs = CTD induction, randomised to observation. CTD/Len = CTD induction, randomised to lenalidomidemaintenance. CRD/Obs = CRD induction, randomised to observation. CRD/Len = CRD induction, randomised to lenalidomidemaintenance.
Methods MM patients enrolled in the RV-MM-COOP-55 (EMN2/HO95 MM; NCT287) Newly diagnosed 5 years MRD assessement in patients achieving suspected CR before lenalidomide maintenance N: 7 N: 459 N: 499 4 VCD CTX + PBSC harvest R HDM-2 N: 5 R2 2 VRD N: 444 Lenalidomide maintenance 4 VMP No cons Pre Maint + +2 +8 +24 CR: complete response, N: number of patients ; V, bortezomib; C, cyclophosphamide; D, dexamethasone; CTX: cyclophosphamide 2-3g/mq, PBSC: peripheral stem cell collection, HDM: high dose melphalan 2mg/mq, R, lenalidomide; M, melphalan; P, prednisone; Cons: consolidation, Maint: maintenanc; Maint Maint Maint Maint EVERY MONTHS UNTIL CLINICAL RELAPSE Cavo M et al. ASH 2; Abstract 73. Sonneveld P. et al. ASH 2; Abstract 292
% of patients Results MRD status at pre-maintenance Sub-analysis on MRD positive patients at pre-maintenance who had a second MRD evaluation > year of Lenalidomide 24% 7% MRD positive Pre maintenance MRD positive MRD negative 8 4 2 44% 52% LEN maintenance -2 months
% of patients Results MRD status during maintenance Sub-analysis on MRD positive patients at pre-maintenance who had a second MRD evaluation > year of Lenalidomide 4% 8-24 months 8 44% -2 months MRD positive Pre maintenance 4 2 52% LEN maintenance MRD negative
Results Progression free Survival: Median Follow-Up from MRD enrollement of 33 Months. 3-yr PFS 77% Progression-free survival.75.5.25 N = 3 MRD negative MRD positive Median PFS NR 38 months 52%. Numbers at risk MRD Negative MRD Positive HR (95% CI) P value.33 (.2.53). 2 3 4 5 Months 239 222 92 3 53 3 77 8 52 33 4 4
Study Design Multicenter, randomized, open-label, active-controlled, phase 3 study Key eligibility criteria RRMM prior line of therapy Prior bortezomib exposure but not refractory R A N D O M I Z E : DVd (n = 25) Daratumumab ( mg/kg IV) Every week: Cycles -3 Every 3 weeks: Cycles 4-8 V:.3 mg/m 2 SC on Days, 4, 8, and of Cycles -8 d: 2 mg PO-IV on Days, 2, 4, 5, 8, 9,, and 2 of Cycles -8 Vd (n = 247) V:.3 mg/m 2 SC on Days, 4, 8, and of Cycles -8 d: 2 mg PO-IV on Days, 2, 4, 5, 8, 9,, and 2 of Cycles -8 D only Every 4 weeks: Cycles 9+ Obs only Primary endpoint PFS Secondary endpoints TTP OS ORR, VGPR, CR MRD Time to response Duration of response Exploratory Time to next therapy Stratification factors ISS (I, II, and III) Number of prior lines ( vs 2 or 3 vs >3) Prior bortezomib (no vs yes) Cycles -8: repeat every 2 days Cycles 9+: repeat every 28 days Premedication for the DVd treatment group consisted of dexamethasone 2 mg, acetaminophen, and an antihistamine MRD evaluation Assessed at suspected CR and at and 2 months following the first treatment dose for patients who maintain CR ISS, International Staging System; DVd, daratumumab, bortezomib, and dexamethasone; IV, intravenous; V, bortezomib; SC, subcutaneously; d, dexamethasone; PO, orally; Vd, bortezomib and dexamethasone; D, daratumumab; Obs, observation; PFS, progression-free survival; TTP, time to progression; OS, overall survival; ORR, overall response rate; VGPR, very good partial response; CR, complete response; MRD, minimal residual disease. 2
% surviving without progression Updated Efficacy: ITT P <. 8 4 2 No. at risk Vd 247 DVd 25 HR:.3 (95% CI,.24-.39; P <.) 3 9 2 8 2 24 27 3 82 2 29 98 74 39 38 Months 27 24 79 5 3 DVd Median:.7 mo Vd Median: 7. mo 8 ORR = 84% CR CR 9% ORR = 3% 29% a CR % Updated VGPR 2% a Primary Updated VGPR 29% Primary DVd (n = 24) Vd (n = 234) CR 9% Note: Primary analysis based on median follow-up of 7.4 months Duration of response: 8.9 months for DVd versus 7. months for Vd 9% reduction in risk of progression for DVd versus Vd 9.-month improvement in median PFS for DVd versus Vd Responses continue to deepen HR, hazard ratio; CI, confidence interval; PR, partial response; scr, stringent complete response.. Palumbo A, et al. N Engl J Med. 2;375(8):754-7. a P <. for DVd versus Vd. 2
% surviving without progression Updated Efficacy: Prior Line 8-month PFS a P =.4 8 4 2 No. at risk Vd 3 DVd 22 HR,.9 (95% CI,.2-.29; P <.) 3 9 2 8 2 24 27 3 9 9 9 4 43 99 22 89 Months 7 85 8 55 8% 2% Vd DVd Median: not reached 5 2 Median: 7.9 mo 4 ORR = 9% CR ORR = 74% 2% CR 4% b CR % Updated VGPR 7% b Primary Updated VGPR 42% Primary DVd (n = 9) Vd (n = 9) CR % Note: Primary analysis based on median follow-up of 7.4 months 8% reduction in risk of progression/death for DVd versus Vd Deeper responses with longer follow-up a Kaplan-Meier estimate. b P <. for DVd versus Vd.. Palumbo A, et al. N Engl J Med. 2;375(8):754-7. 22
% surviving without progression CASTOR: PFS by Cytogenetic Risk Status a 8 High risk DVd n = 44 Vd n = 5 4 DVd standard risk mpfs, mo.2 7.2 HR (95% CI) P value.45 (.25-.8).53 No. at risk Vd standard risk DVd standard risk Vd high risk DVd high risk 2 Vd standard risk 3 9 2 8 2 24 27 3 Months 35 23 5 44 32 38 79 23 34 44 83 3 2 25 74 4 2 3 2 2 5 3 Vd high risk 3 2 5 DVd high risk Standard risk mpfs, mo HR (95% CI) P value DVd n = 23 Vd n = 35 9. 7..2 (.8-.37) <. Adding DARA to standard of care prolongs PFS regardless of cytogenetic risk a ITT/biomarker-risk-evaluable analysis set: patients in the ITT population with both RNA and DNA results available. 23
POLLUX: Study Design Multicenter, randomized (:), open-label, active-controlled phase 3 study DRd (n = 28) RRMM Key eligibility criteria prior line of therapy Prior lenalidomide exposure, but not refractory Creatinine clearance 3 ml/min Stratification factors No. prior lines of therapy ISS stage at study entry R A N D O M I Z E : Daratumumab mg/kg IV Qw in Cycles -2, q2w in Cycles 3-, then q4w until PD R 25 mg PO Days -2 of each cycle until PD d 4 mg PO 4 mg weekly until PD Rd (n = 283) R 25 mg PO Days -2 of each cycle until PD d 4 mg PO 4 mg weekly until PD Cycles: 28 days Primary endpoint PFS Secondary endpoints TTP OS ORR, VGPR, CR MRD Time to response Duration of response Statistical analyses Primary analysis: ~77 PFS events Prior lenalidomide Pre-medication for the DRd treatment group consisted of dexamethasone 2 mg a, acetaminophen, and an antihistamine a On daratumumab dosing days, dexamethasone was administered 2 mg premed on Day and 2 mg on Day 2. RRMM, relapsed and/or refractory multiple myeloma; ISS, international staging system; DRd, daratumumab/lenalidomide/dexamethasone; IV, intravenous; qw, once weekly; q2w, every 2 weeks; q4w, every 4 weeks; PD, progressive disease; R, lenalidomide; PO, oral; d, dexamethasone; Rd, lenalidomide/dexamethasone; PFS, progression-free survival; TTP, time to progression; OS, overall survival; ORR, overall response rate; VGPR, very good partial response; CR, complete response; MRD, minimal residual disease. 24
% surviving without progression Overall response rate, % Updated Efficacy 8 8-month PFS* 7% Median: not reached DRd 9 8 ORR = 93% 23 P <. ORR = 7% 4 2 HR:.37 (95% CI,.28-.5; P <.) 49% Median: 7.5 months 3 9 2 8 2 24 27 Rd 7 5 4 3 2 CR: 4% a 8 CR: 2% 2 23 VGPR: 78% a 25 32 32 DRd (n = 28) Rd (n = 27) VGPR: 45% scr CR VGPR PR No. at risk Months Rd DRd 283 28 249 2 2 249 8 237 9 227 32 94 48 82 5 Median follow-up: 7.3 (range, -24.5) months Responses continue to deepen in the DRd group with longer follow-up Note: PFS: ITT population; ORR: response-evaluable population. * Kaplan-Meier estimate; a P <. for DRd vs Rd. 25
% surviving without progression POLLUX: PFS by Cytogenetic Risk Status a 8 High risk DRd n = 28 Rd n = 37 DRd standard risk mpfs, mo 22..2 DRd high risk HR (95% CI).53 (.25-.3) 4 Rd standard risk Rd high risk P value.92 2 Standard risk DRd n = 33 Rd n = 3 Patients at risk Rd standard risk DRd standard risk Rd high risk DRd high risk 3 9 2 8 2 24 27 3 33 Months 3 33 37 28 4 28 32 22 92 2 2 2 77 8 9 72 9 3 8 5 2 3 47 99 4 3 7 3 9 4 4 2 2 mpfs, mo HR (95% CI) P value NR 8.5.3 (.2-.47) <. Adding DARA to Rd prolongs PFS regardless of cytogenetic risk mpfs, median PFS; NR, not reached. a ITT/biomarker-risk-evaluable analysis set: patients in the ITT population with both RNA and DNA results available. 2
MRD negative, % Proportion of MRD-negative Patients at 4, 5, and Thresholds MRD negative, % 35 32 *** 3.X POLLUX *** 4.2X *** 4.X 35 *** 4.5X CASTOR ** 5.X * 4.X 3 25 25 3 25 2 2 8 5 9 2 3 4 5 4 5-4 -5 - Sensitivity threshold DRd Rd 5 *** P <. ** P <.5 * P <.5 4-4 -5 - Sensitivity threshold Daratumumab in combination with standard of care significantly improved MRD-negative rates at all thresholds DVd 2 Vd 4 P values calculated using likelihood-ratio chi-square test.
Patients progression free and alive (%) Rd MRD DRd MRD Patients progression free and alive (%) PFS According to MRD Status at 5 POLLUX CASTOR Vd MRD DVd MRD 8 8 DRd MRD + DVd MRD + 4 Rd MRD + 4 2 2 Vd MRD + 3 9 2 8 2 24 27 3 9 2 8 2 24 Patients at risk Rd MRD negative DRd MRD negative Rd MRD positive DRd MRD positive 7 27 2 7 233 95 7 9 78 7 7 44 Months 2 57 2 37 28 38 54 5 9 Patients at risk Vd MRD negative DVd MRD negative Vd MRD positive DVd MRD positive 2 24 225 2 7 89 2 23 72 5 2 8 34 Months 3 2 7 2 7 7 2 4 Lower risk of progression in MRD-negative patients PFS benefit in MRD-positive patients who received daratumumab-containing regimens versus standard of care
MRD-negative patients POLLUX: MRD in Patients of High Cytogenetic Risk Status ( 5 ) % surviving without progression 35 3 MRD-negative rates PFS P =.9 DRd MRD negative 8 per risk group, % a 25 2 5 2 4 2 DRd MRD positive Rd MRD positive DRd n = 28 High risk Rd n = 37 No. at risk Rd MRD negative DRd MRD negative Rd MRD positive DRd MRD positive 3 9 2 8 2 24 27 3 33 Months 37 22 32 2 8 3 3 2 3 8 7 4 4 2 In POLLUX, high-risk patients treated with DARA who were MRD negative remained progression free a Percentage of patients within a given risk group and treatment arm. 29
MRD-negative patients CASTOR: MRD in Patients of High Cytogenetic Risk Status ( 5 ) % surviving without progression MRD-negative rates P =.8 PFS DVd MRD negative 4 4 8 per risk group, % a 2 8 4 4 2 DVd MRD positive 2 DVd n = 44 High risk Vd n = 5 No. at risk Vd MRD negative DVd MRD negative Vd MRD positive DVd MRD positive 3 9 2 8 2 24 27 5 38 32 32 23 28 3 2 Months 4 2 4 3 8 Vd MRD positive 2 In CASTOR, high-risk patients treated with DARA who were MRD negative remained progression free a Percentage of patients within a given risk group and treatment arm. 3
Background Anti-apoptotic proteins BCL-2 and MCL- promote multiple myeloma (MM) cell survival Venetoclax is a selective, orally available small molecule BCL-2 inhibitor and bortezomib can indirectly inhibit MCL- 2 When combined, venetoclax can enhance the activity of bortezomib in MM cell lines and xenograft models 2. Roberts AW et al. N Eng J Med 2; 374:3-22 2. Punnoose E et al. Mol Cancer Ther 2;(5):32-44 3
Dosing and Enrollment Patients received 5 2 mg venetoclax per designated dose escalation cohorts Cycles 8 Designated Cohort Dose Cycles 9 Designated Cohort Dose Cycles 2+ Days 35 at Monotherapy Day 2 4 5 8 9 2 8 22 Dexamethasone and bortezomib (.3 mg/m 2 SC) Dexamethasone (2 mg, PO) Dosing cycle 2 days for cycles 8 and 35 days for cycles 9+ Enrollment by Dose Cohort Dose (mg) 5 2 3 4 5 8 2 Total DE SE Total DE + SE n 3 5 7 7 5 3 3 9 54 2 DE, dose escalation cohorts; SE, safety expansion cohort (8 mg) As of 9Aug2 32
Objective Responses in All Patients and Those Non- Refractory and Refractory to PIs and IMiDs Percentage of patients ORR=92% 8% ORR=82% ORR=7% 22% 4% % 5% 27% ORR=57% 7% 23% 38% ORR=32% 4% 4% 27% 9% 24% 24% 25% 4% 3% All patients (N=) Non-refractory (n=37) Refractory (n=28) Non-refractory (n=22) Refractory (n=42) Prior proteasome inhibitors (PIs) Prior immunomodulatory drugs (IMiDs) As of 9Aug2 33
P e r c e n ta g e o f P a tie n ts BCL2 Gene Expression and Clinical Response s C R /C R V G P R P R T im e to P r o g r e s s io n O R R 9 4 % B C L 2 H ig h 8 33% 7 5 B C L 2 L o w O R R 5 9 % 7% 5 4 33% % 2 5 2 28% 37% 2 4 8 2 4 8 2 2 2 2 4 2 2 8 3 B C L 2 H ig h ( n = 8 ) B C L 2 L o w ( n = 2 7 ) M o n th s s in c e firs t d o s e P a tie n ts a t ris k 8 8 4 9 5 3 3 3 2 2 2 2 P a tie n ts a t ris k 2 7 2 2 8 8 4 2 2 2 2 2 2 2 2 BCL2 quantitation using ddpcr performed on CD38-selected bone marrow mononuclear cells collected at baseline. BATTing was used to estimate a threshold of BCL2 to provide optimum selection of patients likely to have a response. As of 9Aug2 34