Monoclonal Antibody Triplets for First Relapse

Saad Z. Usmani, MD FACP Chief, Plasma Cell Disorders program Director, Clinical Research Department of Hematologic Oncology & Blood Disorders Clinical Professor of Medicine, UNC-CH School of Medicine Conflict of Interest

• Research funding: Amgen, BMS, Celgene, Janssen, Pharmacyclics, Prothena, Sanofi, Seattle Genetics, Takeda

• Consultancy: Abbvie, Amgen, BMS, Celgene, GSK, Janssen, Sanofi, Seattle Genetics, Takeda

• Speaking fees: Amgen, Celgene, Takeda, Janssen Disclosures

• This is not a debate between me and Sagar, because Sagar will likely win.

• This is a debate each of us have with ourselves when treating patients. Holy Grail of Cancer Medicine

Casey SC et al. Immunol Res. 2014 May; 58(0): 282–291. Cancer Cells: Evasion of Immune Response Suppression of dendritic cell & T-cell activation and proliferation (by cytokine production) Downregulation of MHC class I on the surface of cancer cells to prevent Ag presentation TGF-β, VEGF,

adenosine, PGE2 Dendritic cells

Upregulation of surface inhibitory ligands which mediate T-cell anergy / exhaustion (PD-1/PD-L1 pathway) T-cell

PD-L1

Tregs Recruitment of counterregulatory/ immunosuppressive cells (such as T- PD-L1 PD-L1 regs and MDSCs) MDSC Mature DC

TGF-β Efector T-cell CCL2, CXCL12

Image courtesy of Paula Rodríguez-Otero Mellman I et al. Nature, 2011;480:480-9. Excitement About Monoclonal Antibodies

Advantages Disadvantages

• Novel mechanism of action • Infusion reactions can limit − Additive or synergistic effects therapy in some with current anti-MM drugs • No biomarkers for response to • Generally well tolerated predict who may most benefit − Toxicity profile nonoverlapping • Few long-term survivors with approved anti-MM drugs • Can be combined with other • Cost: very expensive to produce immune therapies • May be ideally suited to eliminate MRD • May be beneficial in all patient groups (SMM, ND, RR, MRD) • Many targets possible − MM cell − Microenvironment − Immune signals mAb-Based Therapeutic Targeting of Tumor

Antibody-dependent Complement- Apoptosis/growth cellular cytotoxicity dependent arrest via targeting Antibody-delivery of Bispecific T-cell (ADCC) cytotoxicity (CDC) signaling pathways toxic payload (ADC) Engager (BiTE)

• 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) • Lucatumumab or Isatuximab (CD38) • GSK (BCMA) dacetuzumab (CD40) • SGN (CD48A)

Adapted from Tai YT, Anderson KC. Bone Marrow Res. 2011;2011:924058. Relapsed/Refractory Disease : Outcomes

100 • Despite the introduction of IMiDs and PIs, Kumar SK, et al. 2012. most patients relapse and outcomes are Usmani S, et al. 2016. poor in relapsed or refractory patients1 80

– Median OS of 9 months in patients 60 refractory to bortezomib and ≥1 IMiD1 40 Patients alive, % – Median OS of 8 months in patients with 20 relapsed or refractory MM who were double refractory or had relapsed after 0 ≥3 prior lines of therapy, including 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 2 pomalidomide and carfilzomib Time, months

MM, multiple myeloma; IMiD, immunomodulatory drug; PI, proteasome 1.Kumar SK, et al. Leukemia. 2012;26(1):149-157. inhibitor; OS, overall survival. 2.Usmani S, et al. Oncologist. 2016. doi:10.1634/theoncologist.2016-0104. Factors in Selecting Relapsed Therapy

Patient Disease Treatment Age Risk Status Previous therapy Performance status Cytogenetics – Depth Renal insufficiency del [17p], t(4;14), – Duration Poor marrow reserve t(14;16) Routh of administration Neuropathy Rapidity of relapse Single or combination Comorbidities – Rate of rise Cost – Cardiac disease – Organ damage Toxicity – Diabetes – Extramedullary – Myelosuppression disease – Neuropathy – Plasma cell leukemia – Thrombosis Risk of SPM

SPM: secondary primary malignancy. Treatment Approaches in Relapsed MM

1st Relapse Participate in clinical trials with novel agents

IMiD Based Regimen PI-based regimen Autologous Transplant

• No prior IMiD exposure • No prior Bortezomib exposure. • If transplant was not part of front line therapy. • Prior IMiD use with good • Prior Bortezomib use with good response and durable PFS. response and durable PFS. • If >18 months of PFS with transplant (no maintenance) • Prior Bortezomib refractoriness • Prior Len refractoriness or or intolerance. intolerance. • If >36 of PFS with transplant and maintenance • PI preference for translocation (4;14)

Agarwal A, et al. Clin Lymph Myel Leuk. 2017;17(2):69-77. Lenalidomide/Dexamethasone-Based Therapy for Early Relapse

TOURMALINE-MM1: Rd± ixazomib for relapsed and relapsed/refractory multiple myeloma patients having received 1-3 prior lines of therapy. ELOQUENT-2: Rd± elotuzumab for relapsed and relapsed/refractory multiple myeloma patients having received 1-3 prior lines of therapy. ASPIRE: Rd± carfilzomib for relapsed and relapsed/refractory multiple myeloma patients having received 1-3 prior lines of therapy. POLLUX: Rd± daratumumab for relapsed and relapsed/refractory multiple myeloma patients having received ≥1 prior line of therapy.

TOURMALINE-MM1 ELOQUENT-2 ASPIRE POLLUX Treatment Arm RD IRD RD ERD RD KRD RD DRD ORR 71.5% 78.3%* 66% 79%* 66.7% 87.1%* 76.4% 92.9%* ≥ VGPR 39% 48%* 28% 33% 40.4% 69.9%* 44.2% 75.8%* Median PFS, mos 14.7 20.6* 14.9 19.4* 16.6 26.1* 1-yr 60.1% 1-yr 83.2%* PFS HR 0.74 0.70 0.66 0.37 Median OS, mos NR NR NR NR 40.4 48.3* 1-yr 86.6% 1-yr 92.1% *Statistically significant E=elotuzumab; I=ixazomib; K=carfilzomib; RD=lenalidomide-dexamethasone; mos=months; NR=not reported; ORR=overall response rate; OS=overall survival; PFS=progression-free survival; VGPR=very good partial response; yr=year

Lonial S, et al. N Engl J Med. 2015;373:621-631.; Dimopoulos MA, et al. N Engl J Med. 2016;375:1319-1331.; Stewart A, et al. N Engl J Med. 2014;372:142-152.; Moreau P, et al. N Engl J Med. 2016;374:1621-1634; Stewart A, et al. ASH 2017. Proteasome Inhibitor-Based Therapy for Early Relapse

PANORAMA-1: A phase III study of bortezomib-dexamethasone± panobinostat for relapsed and relapsed/refractory multiple myeloma patients having received 1-3 prior therapies. ENDEAVOR: A phase III study of bortezomib-dexamethasone vs carfilzomib-dexamethasone for relapsed and relapsed/refractory multiple myeloma patients having received 1-3 prior lines of therapy. CASTOR: A phase III study of bortezomib-dexamethasone± daratumumab for relapsed and relapsed/refractory multiple myeloma patients having received ≥1 prior line of therapy. PANORAMA-1 ENDEAVOR CASTOR Treatment Arm VD Pano-VD VD KD VD DVD Overall Response Rate 54.6% 60.7% 63% 77%* 63.2% 82.9%* ≥ VGPR 15.7% 27.6%* 29% 54% 29% 59.1%* Median Progression- All patients: 8.08 11.99* 9.4 18.7 7.2 Not yet Free Survival, mos ≥2 prior regimens + 12.5 reached* IMiD and bort: 4.7 PFS HR 0.63 0.53 0.39 Median OS, mos 30.39 33.64 40.0 47.6* NR NR *Statistically significant DVD=daratumumab-bortezomib-dexamethasone; KD=carfilzomib-dexamethasone; NR=not reported; Pano=panobinostat; VD=bortezomib-dexamethasone

San Miguel J, et al. Lancet Oncol. 2014;15:1195-1206.; Palumbo A, et al. N Engl J Med. 2016;375:754-766.; Dimopoulos M, et al. Lancet Oncol. 2016;17:27-38; Dimopoulos M, et al. Lancet Oncol. 2017;17:30578-8. Can We Choose Based on High Risk Disease Biology?

ASPIRE POLLUX ENDEAVOR Cytogenetic SR HR SR HR SR HR Risk Treatment RD KRD RD KRD RD DRD RD DRD VD KD VD KD Arm ORR (%) 73.5 91.2 59.6 79.2 ≥VGPR (%) 45.3 75.5 27 60.4 29.5 58.8 30.1 46.4 Median PFS, 19.5 29.6* 13.9 23.1 17.1 NR* 10.2 NR* 10.2 NR* 6.0 8.8* mos HR 0.66 HR 0.70 HR 0.30 HR 0.44 HR 0.439 HR 0.646 High risk: del(17p) (in ≥60% of PCs for ASPIRE), t(4;14), t(14;16) *Statistically significant

ELOQUENT-2: ERD vs RD. HR for PFS in del(17p): 0.65. HR for PFS in t(4;14): 0.44. TOURMALINE: IRD vs RD. Median PFS in high risk disease: 21.4 months (HR 0.54).

Novel combinations improve but do not overcome high risk cytogenetics Novel triplets should be used in high risk disease

Avet-Loiseau et al. Blood 2016;128:1174-80. Usmani et al. ASH 2016. Chng et al. Leukemia 2017 [Epub ahead of print] Proportion of MRD-negative Patients at 10–4, 10–5, and 10–6 Thresholds

POLLUX CASTOR *** *** *** *** ** * 35 3.6X 4.4X 4.8X 35 5.1X 4.3X 5.5X 31.8

30 30

24.8 25 25

20 20 18.3

15 15 11.9

MRD negative, % 10.4 MRD negative, % 10 8.8 10 5.7 4.4 5 5 3.6 2.5 2.4 0.8 0 0 DRd Rd DRd Rd DRd Rd DVdVdDVdVdDVdVd Sensitivity 10-410–4 10-510–5 10-610–6 10-410–4 10-510–5 10 10-6–6 threshold

. Daratumumab in combination with standard of care significantly improved

MRD‐negative rates at all thresholds *** P <0.0001. ** P <0.005. * P <0.05. P values calculated using likelihood-ratio chi-square test. Avet-LoiseauH, et al. ASH 2016 (Abstract 246), oral presentation. 14 MRD at 10–5 by Cytogenetic Risk by NGS

POLLUX CASTOR ** *** ** ** 35 35 30 30 30 a a 25 25

20 18 20 14 15 15 12 10 10 10 per risk group, % per risk per risk group, % per risk MRD-negative patients MRD-negative patients 5 5 2 0 0 0 0 High risk Standard risk High risk Standard risk n = 28 n = 37 n = 133 n = 113 n = 44 n = 51 n = 123 n = 135

DRd (17% high riskb) Rd (25% high riskb) DVd (26% high riskb) Vd (27% high riskb) . No high‐risk MRD‐negative patients have progressed or converted to MRD positive – High risk = any of t(4;14), t(14;16), del17p – Standard risk = conclusive absence of all 3 markers In high‐risk patients, MRD‐negative status was achieved only in those treated with daratumumab‐containing regimens

P values calculated using likelihood-ratio chi-square test. aPercentage of patients within a given risk group and treatment arm. bPercentage of patients within a given treatment *** P <0.0001. arm, within the biomarker-evaluable population. Avet-LoiseauH, et al. ASH 2016 (Abstract 246), oral presentation. ** P <0.005. 15 PFS According to MRD Status at 10–5

POLLUX CASTOR Vd MRD– 100 100 – Rd MRD– DVd MRD DRd MRD– 80 80

DRd MRD+ 60 60 DVd MRD+

40 40 Rd MRD+

20 20

+ Patients progression and alive (%) free Patients progression and alive (%) free Vd MRD 0 0 0 3 6 9 12 1518 2124 27 0 3 6 9 12 15 1821 24 Months Months Patients at risk Patients at risk Rd MRD negative 16 16 16 15 15 12 10 0 0 0 Vd MRD negative 6 6 6 5 3 2 0 0 0 DRd MRD negative 71 71 71 70 66 57 28 6 0 0 DVd MRD negative 26 26 26 26 15 7 1 0 0 Rd MRD positive 267 233 190 166 144 120 38 5 0 0 Vd MRD positive 241 176 123 68 20 7 0 0 0 DRd MRD positive 215 195 178 167 161 137 54 9 1 0 DVd MRD positive 225 189 172 134 76 26 4 1 0 . Lower risk of progression in MRD‐negative patients . PFS benefit in MRD‐positive patients who received daratumumab‐containing regimens versus standard of care Avet-LoiseauH, et al. ASH 2016 (Abstract 246), oral presentation. 16 Treatment Approaches in Relapsed MM

1st Relapse Participate in clinical trials with novel agents

IMiD Based Regimen PI-based regimen Autologous Transplant

Fast or Slow, Fast or Slow, Aggressive Biochemical Aggressive Biochemical Relapse Relapse Relapse Relapse

Dara-Rd Elo-Rd or or Dara-Vd Kd KRd Ixa-Rd (prefer for t4;14) (prefer for t4;14)

Agarwal A, et al. Clin Lymph Myel Leuk. 2017;17(2):69-77. Summary • One size does not fit all in the long-term management of multiple myeloma.

• Weigh disease biology, disease burden and host factors to decide best next line of therapy.

• Monoclonal mAb based triplets have demonstrable superior depth of response (including achieving MRD negativity) compared to doublets in both standard and high risk MM.

• Other Phase III trials in the relapse setting (Pom-Vd vs. Vd, Kd-Dara vs. Kd, Dara-Pom-Dex vs. Pom-Dex) will make next year’s debate more interesting. Questions

Presented by: Saad Z. Usmani, MD FACP, @szusmani