Multiple Myeloma Therapies What lies in the future?
Parameswaran Hari MD, MS Chief , Hematology Oncology Medical College of Wisconsin Conflict of Interest
Am a consultant or advisor and grant recipient from virtually every company that works in the Myeloma field
Framework for Newly Diagnosed MM—Patient Treatment Plan
Eligibility for Transplant: Co-morbidities PS Age Transplant Candidate Not Transplant Candidate Induction Therapy Induction therapy
Stem Cell Harvest Maintenance or extended therapy phase ASCT (early vs delayed)
Consolidation and/or Maintenance MAINTENANCE AFTER TRANSPLANT: A MUST!
CALGB
IFM 2005-02
REF:https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm542791.htm TRANSPLANT STUDIES IN MM (NOVEL ERA)
Study Author Year N ISS III High risk Follow-up Induction Conditioning SDT Maintenance cytogenetics (months) regimen (HDT +SDT)
LEN (till GIMEMA RV- Palumbo 2014 273 23.6% 28.8% 51.2 Rd Mel 200 x 2 MPR progression) MM –PI-209 TRANSPLANT for MM– Continues to remain standard vs. None
LEN + P vs. LEN RV-MM-EMN- Gay F 2015 256 29% 21.8% 52 Rd MEL 200 x 2 CRD (till 441 progression)
IFM/DFCI Attal M 2015 700 18% 12.8% 44 RVD MEL 200 RVD x 8 LEN x 1 year 2009
LEN till EMN02/HO95 Cavo M 2016 1192 21% 25% 26 CyBorD MEL 200 x 1 or 2 VMP x 4 progression MINIMAL RESIDUAL DISEASE AND TRANSPLANT
ARMS MRD negativity (%)
HDT (EARLY) 79%
SDT (DELAYED) 65%
Attal et al. NEJM 2017 Minimal Residual Disease: New Definitions for CR
12 S.S. Patient Newly diagnosed 1 x 10
Disease burden
CR 1 x 108
Stringent CR 1 x 104
Molecular/flow CR
Sequencing CR
True Cure? 0.0 FDA Approved MRD testing VACCINE POST TRANSPLANT(CTN 1401) TREATMENT MILESTONES IN MULTIPLE MYELOMA
Kenneth C. Anderson Clin Cancer Res 2016;22:5419-5427 11 Prehistory Myeloma
• Multiple myeloma has probably been present as a Four cases of possible multiple myeloma human disease for centuries. were found in Native American skeletons • There is evidence that multiple myeloma might date from 200 to 900AD. back to the time of the ancient Egyptians.
Xray and skull 25 yrold female Indian with lytic lesions. Estimated to be from 200 to 900 AD.
Anticancer Res.1999; Vol;19(5B):4273-7 Bull NY Acad Med. 1974; Vol 50. p 447-458. Clinical Trials ………………. MAKING MYELOMA History New Drugs – Are they Chemotherapy? CD38 ANTIBODIES TRANSPLANT INELGIBILBE- WHAT IS NEW?
CAN WE MOVE DARATUMUMAB UPFRONT?
INDUCTION TRANSPLANT CONSOLIDATION MAINTENANCE
STEM CELL Dara-VRD X 2 Dara +LEN Dara-VRD x4 TRANSPLANT
MMY2004 RANDOMZIED PHASE II TRIAL RANDOMIZE
VRD x4 STEM CELL TRANSPLANT VRD X2 LEN ALCYONE STUDY DESIGN
VMP × 9 cycles (n = 356)
Bortezomib: 1.3 mg/m2 SC Cycle 1: twice weekly Cycles 2-9: once weekly Melphalan: 9 mg/m2 PO on Days 1-4 Primary endpoint: Key eligibility criteria: Prednisone: 60 mg/m2 PO on Days 1-4 •PFS •Transplant- ineligible Secondary endpoints: NDMM Follow-up for •ECOG 0-2 PD and •ORR •Creatinine clearance survival •≥VGPR rate ≥40 mL/min D-VMP × 9 cycles (n = 350) D •≥CR rate • –5 No peripheral Cycles 10+ •MRD (NGS; 10 ) neuropathy grade ≥2 Daratumumab: 16 mg/kg IV •OS
1:1 Randomization (N (N 1:1 = 706)Randomization •Safety Cycle 1: once weekly 16 mg/kg IV Cycles 2-9: every 3 weeks + Every 4 weeks: Same VMP schedule until PD
Stratification factors Statistical analyses •ISS (I vs II vs III) • 360 PFS events: 85% power for • Cycles 1-9: 6-week cycles •Region (EU vs other) 8-month PFS improvementa • Cycles 10+: 4-week cycles •Age (<75 vs ≥75 years) • Interim analysis: ~216 PFS events
ECOG, Eastern Cooperative Oncology Group; ISS, International Staging System; EU, European Union; SC, subcutaneously; PO, orally; D, daratumumab; IV, intravenously; PD, progressive disease; PFS, progression-free survival; ORR, overall response rate; VGPR, very good partial response; CR, complete response; MRD, minimal residual disease; NGS, next-generation sequencing; OS, overall survival. a8-month PFS improvement over 21-month median PFS of VMP. EFFICACY:PFS
• Median (range) follow-up: 16.5 (0.1-28.1) months
12-month PFSa 18-month PFSa 100 87%
80 72%
76% D-VMP 60 Median: not reached
40 50% VMP Median: 18.1 months
% surviving without progression without % surviving 20 HR, 0.50 (95% CI, 0.38-0.65; P <0.0001) 0 0 3 6 9 12 15 18 21 24 27 Months No. at risk VMP 356 303 276 261 231 127 61 18 2 0 D-VMP 350 322 312 298 285 179 93 35 10 0
50% reduction in the risk of progression or death in patients receiving D-VMP
HR, hazard ratio; CI, confidence interval. aKaplan-Meier estimate. 21 QUIZ Walgreens Enema Syringe
Relapsed, Refractory Disease: New Agents CURREN TREAMENTS OPTIONS-- for relapse
• DARATUMAB-REVLIMID-DEXAMETHASONE • DARATUMUMAB-VELCADE-DEXAMETHASONE • DARATUMUMAB-POMALIDOMIDE-DEXAMETHASONE
• CARFILZOMOB-REVLIMID-DEXAMETAHSONE
• ELOTUZUMAB-REVLIMID-DEXAMETHASONE
• IXAZOMIB-REVLIMID-DEXAMETAHSONE Prevention Trials Phases of Clinical Trials Diagnostic Trials Screening Trials Quality of Life Trials • Phase I studies primarily concerned with assessing the drug's safety. How much can be safely given? • Phase II test for efficacy. How well does the drug work in this disease? • Phase III – How well does the new drug compare against standard treatment? Don’t wait for other people – Jump in Not all trials succeed …….. MAN – O - GRAM SELINEXOR
. Exportin 1 (XPO1) is the nuclear exporter for the majority of tumor suppressor proteins (TSPs), the glucocorticoid receptor (GR), and eIF4E-bound oncoprotein mRNAs
. Selinexor is a first-in-class XPO1 inhibitor that induces nuclear retention and activation of TSPs and the GR in the presence of steroids and suppresses oncoprotein expression SELINEXOR: EFFICACY
ORR CBR VGPR PR MR Category N (%) (%) (%) (%) (%)
Overall 78 16 (21%) 26 (33%) 4 (5%) 12 (15%) 10 (13%)
Quad 48 10 (21%) 14 (29%) 2 (4%) 8 (17%) 4 (8%) Refractory
Penta 30 6 (20%) 12 (40%) 2 (7%) 4 (13%) 6 (20%) Refractory
6 Doses / 51 10 (20%) 15 (29%) 3 (6%) 7 (14%) 5 (10%) Month
8 Doses / 27 6 (22%) 11 (41%) 1 (4%) 5 (19%) 5 (19%) Month
Vogl DT, et al. Blood. 2016;128:491. VENETOCLAX
• Venetoclax induces cell death in multiple myeloma (MM) cell lines and primary samples, particularly those positive for the translocation t(11;14), which correlates with higher ratios of 1,2 BCL2 to MCL1 and BCL2 to BCL2L1 (BCL-XL) mRNA
1. Touzeau C, et al. Leukemia. 2014;28(1):210-212. 2. Punnoose E, et al. Mol Cancer Ther. 2016;15(5):1132-1144. VENETOCLAX: EFFICACY
5 0 T im e to P ro g re s s io n D u ra tio n o f O v e ra ll R e s p o n s e sC R C R V G P R P R 1 0 0 A ll P a tie n ts 1 0 0 A ll P a tie n ts O R R 4 0 % t(1 1 ;1 4 ) t(1 1 ;1 4 )
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P 1 0 8% 0 2 4 6 8 1 0 1 2 1 4 1 6 1 8 2 0 2 2 2 4 0 2 4 6 8 1 0 1 2 1 4 1 6 1 8 2 0 2 2 2 4 O R R 6 % 1 3 % M o n th s s in c e firs t d o s e M o n th s s in c e fir s t re s p o n s e 3% 6% 3% N o . a t ris k 6 6 3 3 2 7 2 0 1 6 9 3 1 1 1 1 1 1 4 1 4 1 3 1 3 9 3 2 1 1 1 1 0 N o . a t ris k 3 0 2 0 1 9 1 7 1 3 7 2 1 1 1 1 1 1 2 1 2 1 1 1 1 8 3 2 1 1 1 1 A ll P a t ie n t s t( 1 1 ; 1 4 ) n o n - t ( 1 1 ; 1 4 ) N o . a t ris k 3 6 1 3 8 3 3 2 1 2 2 2 2 1 N = 6 6 n = 3 0 n = 3 6
Kumar S, et al. Blood. 2016;128:488. BCMA – THE NEW TARGET BCMA expressed on normal and malignant plasma cells • Promotes MM cell survival
BCMA-targeted therapies, including CAR T cells, show pre-clinical and early clinical activity in myeloma
Penn/Novartis CART-BCMA cells • Autologous T cell product • Human anti-BCMAscFv • CD3ζ /41BB stimulatory domains • Lentiviral vector • CD3/CD28 bead-stimulated manufacturing
Tai et al, Blood 2014; Carpenter et al, Clin Can Res 2013; Tai et al, Blood 2016; Ali et al, Blood 2016; Cohen et al, ASH 2016, #1147; Lin et al, EHA 2017; Fan et al ASCO 2017, #LBA3001; Singh R et al. submitted 2017 Pagel, J JAMA Oncol 2017 BCMA CAR-T
Ali SA, et al. Blood. 2016;128:1688-1700. 37 TUMOR RESPONSE
6 • *15 U 17/18 (94%) ORR, 10/18 (56%) 14 CR at active doses
11 • 9/10 evaluable patients MRD 800 x 10 x 800 negative *12 † *21 • Durable ongoing responses over *18 6 1 year *16 *13 PD • Responses continue to improve *10 U as late as month 15 (VGPR to CR) 450 x 10 x 450 7 PD *9 • Median PFS not reached in active 8 dose cohorts – 4 patients progressed 19 PD – Median follow up 40 weeks 6 *20 17 PD 4 † CR/sCR VGPR PR
150 x 10 x 150 *6 U 5 Stable PD MRD- Disease
6 *3 PD † Deceased U Unconfirmed MRD+ *2 PD † † response 1 PD † High Tumor Burden (>50% Bone Marrow Involvement)
50 10 x 50 * 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 Patient 12 died of cardiopulmonary arrest Weeks on Study Patient 4 died of MDS following discontinuation 38 SELECT TREATMENT EMERGENT TOXICITIES • No dose-limiting toxicities (DLTs) observed in Dose Escalation Patients dose escalation (N = 21)1 • Cytopenias mostly related to Cy/Flu lymphodepletion Overall Grade 3 or higher Preferred Term – Recovery to Grade < 3 cytopenias by n (%) n (%) Month 2 following infusion: • ANC ≥ 1000/mm3 – 70% of patients Cytokine release syndrome 15 (71) 2 (10) • PLT ≥ 75/mm3 – 75% of patients Neurotoxicity2 5 (24) 0 • 5 deaths Neutropenia 18 (86) 18 (86) – 3 due to disease progression at 50 × 106 dose Thrombocytopenia 11 (52) 9 (43) – 2 in patients treated at active doses in CR Anemia 14 (67) 12 (57) at the time of death (cardiac arrest, MDS following discontinuation) • 1Data cut-off of October 2, 2017 14 patients experienced 1 or more SAEs 2Neurotoxicity includes the preferred terms: depressed level of consciousness, confusional state, bradyphrenia, somnolence – CRS* Grade 1-2 that required hospitalization per protocol (N=4) – Pyrexia (N=2)
*CRS uniformly graded according to Lee et al., Blood 2014;124:188-195 COMPARISON OF BCMA TARGETED CAR-T CELLS Anti-BCMA CAR (1) Bb2121 (2) LCAR-B38M (3) CART-BCMA (4)
Group/Company NCI Bluebird/Celgene/NCI Nanjing Legend Biotech Novartis/UPenn
Binder/co-stimulatory Murine/CD3 & CD28 Murine/CD3 & 41-BB Murine/CD3 & 41-BB Fully human/CD3 & 41-BB signaling
Transfection Gamma-retroviral Lentiviral Lentiviral Lentiviral
Trial ID NCT02215967 NCT02658929 NCT03090659 NCT02546167
BCMA expression Yes Yes Yes No required?
Median prior lines of 7 7 3 9 therapy Reported Efficacy 1 CR (relapsed), 7 PRs 10 CRs, 6 VGPRs, 1 PR 15 CRs and 13 PRs in 35 2 CRs, 3 VGPRs, 6 PRs in 24 in 16 patients in 18 patients patients patients
Safety Data Substantial but 1 death, Transient CRS 1 death – progressive reversible cardiopulmonary arrest disease/candidemia (unrelated)
1. Ali S et al, Blood 2016 2. Berdeja J et al, ASH 2017 3. Wanghong Zao et al, ASCO 2017 4. Cohen A, et al. ASH 2017 TARGETING BCMA: GSK2857916
AD C ADC GSK2857916 Fc BCMA Receptor C - is a humanized Lysosome BCMA Effecto - afucosylated IgG1 anti-BCMA r Cell BCMA antibody conjugated to a microtubule BCMA GSK2857916 disrupting agent MMAF via a stable, x Fc region of – Target specific protease resistant maleimidocaproyl Malignant the Antibody – Enhanced ADCC Plasma linker Cell – Stable in Linker circulation
– MMAF (non cell Cell death Drug permeable, highly potent auristatin
1. ADC mechanism 2. ADCC mechanism 3. Immunogenic cell death 4. BCMA receptor signalling inhibition
Tai YT, et al. Blood. 2014;123(20):3128-3138. 41 DREAMM-1 RESPONSE
ORR = 60% (21/35; 95% CI: 42.1%, 76.1%) •1 sCR, 2 CR, 15 VGPR, 3 PR
*
Trudel et al. ASH 2017 42 RESPONSE contd..
sCR CR VGPR PR NE ORR* % % % % % % Part 2 3 6 43 9 9 60 (N=35) (n = 21) Prior daratumumab 7 0 21 14 14 43 (N=14) (n = 6) Refractory to both IMiD and 3 6 42 6 10 58 PI (n = 18) (N=31) Refractory to IMiD, PI and 8 0 25 8 17 42 prior daratumumab (n = 5) (N=12) Progression-free Survival and duration of response
Number of subjects 35 Number of subjects 21 Progressed or died 15 (43%) Progressed or died 4 (19%) Censored, f/u ended 3 (9%) Censored, f/u ended 0 Censored, f/u ongoing 17 (49%) Censored, f/u ongoing 17 (81%)
Progression-free survival (months) Duration of response (months) Q1 (95% CI) 2.3 (0.7, 6.8) Q1 (95% CI) 6.7 (1.6, -) Median (95% CI) 7.9 (3.1, -) Median (95% CI) N/A (6.7, -) Q3 (95% CI) N/A Q3 (95% CI) N/A
43 mAb-Based Therapeutic Targeting of Tumor
Antibody-dependent Complement- Apoptosis/growth cellular cytotoxicity Antibody-delivery of Bispecific Monoclonal dependent arrest via targeting toxic payload (ADC) Antibodies (ADCC) cytotoxicity (CDC) signaling pathways
• Elotuzumab (SLAMF7) • Daratumumab, • Siltuximab (IL-6) • Brentuximab (CD30) • BCMA • Daratumumab, Isatuximab, MOR202, • BHQ880 (DKK1) • huN901-DM1 (CD56) • SLAMF7 Isatuximab, MOR202, TAK-079 (CD38) • RAP-011 (activin A) • nBT062-maytansinoid • CD123 TAK079 (CD38) • Daratumumab/ (CD138) • CD38 • Lucatumumab or Isatuximab (CD38) • GSK (BCMA) dacetuzumab (CD40) • SGN (CD48A)
Adapted from Tai YT, Anderson KC. Bone Marrow Res. 2011;2011:924058. Bispecific Monoclonal Antibodies (BiTE, Duobodies, etc.)
2 BCMA BiTe 1 CD38 BiTe at MCW
• BCMA • CD38 • SLAMF7
Frankel SR et.al 2013 Current Opinion in Chemical Biology Anti CD 74 Ab Drug Conjugate
OPEN AT MCW
Embry, M et al. Blood 2017 130:4420 Antibody-coupled T cell receptor (ACTR) in Myeloma
ACTR SEA-BCMA OPEN AT MCW
Kudo K et. al Cancer Res 2014 Jan; 74(1):93-103, Cheema et al Cancer Res 2017 BCMA – APRIL – TACI AXIS April Antibody in MM
OPEN AT MCW
Tai et al, Blood 2016 IMMUNE APPROACHES SUMMARY
Neri P et al. CCR 2016 Beyond Single Hypothesis Testing: Master Protocols
Functional high-risk patients
Profiling for alterations (NCT02884102)
No detectable actionable RAF/RAS IDH CCND1 PI3K/AKT FGFR3 t(11;14) alterations mutations activating activating activating activating mutations alteration alterations alterations
Backbone Backbone MAPKi IDHi CDKi AKTi FGFRi BCLi regimen + regimen immune checkpoint inhibitor MAPKi + IDHi + CDKi + AKTi + FGFRi + BCLi + backbone backbone backbone backbone backbone backbone regimen regimen regimen regimen regime regimen Multiple Myeloma Precision Medicine Trials RISK ASSESSMENT TOOLS Sources of Information and what to do with them?
https://www.myeloma.org/understanding/online-information-resources CONCLUSIONS • Significant progress made in myeloma treatment armamentarium
• Disease relapse inevitable --- BUT…
• Great potential with newer therapies (immune and non-immune approaches)
• Goal– deep and lasting remissions; potential cure NEW AGENT TRIALS AT MEDICAL COLLEGE OF WISCONSIN
• Vaccine (MM-DC fusion) • PROMISS • Oprozomib • Anti cd 74 • Anti-April Aduro • BCMA BITE – short acting / long acting • Tak 079 anti CD38 • GSK 2857916 • Car-T: 4 trials (UNM, JUNO, bb21, and Jansen) AND CLINICAL TRIALS QUESTIONS?