Impact of Prior Therapies on The Safety and Efficacy of Once-Weekly Selinexor, Bortezomib, and Dexamethasone Compared with Twice- Weekly Bortezomib and Dexamethasone in Relapsed or Refractory Multiple Myeloma: Results from the BOSTON Study Maria V Mateos1, Sundar Jagannath2, Sosana Delimpasi3, Maryana Simonova4, Ivan Špička5, Ludĕk Pour6, Iryna Kriachok7, Maria Gavriatopoulou8, Meletios A. Dimopoulos9, Halyna Pylypenko10, Holger Auner11, Xavier Leleu12, Vadim Doronin13, Ganna Usenko14, Roman Hájek15, Reuben Benjamin16, Tuphan K Dolai17, Dinesh K Sinha18, Christopher Venner19, Mamta Garg20, Don A Stevens21, Hang Quach22, Philippe Moreau23, Moshe Levy24, Ashraf Z. Badros25, Larry A. Anderson26, Nizar J Bahlis27, Thierry Facon28, Michele Cavo29, Yi Chai30, Melina Arazy30, Jatin Shah30, Sharon Shacham30, Michael G Kauffman30, Paul G Richardson31, Sebastian Grosicki32 1Hospital Universitario de Salamanca, Salamanca, Spain; 2Icahn School of Medicine at Mount Sinai, New York City, NY; 3General hospital Evangelismos, Athens, Greece; 4Institute of Blood Pathology and Transfusion Medicine of NAMS of Ukraine, Lviv, Ukraine; 5Charles University and General Hospital in Prague, Czech Republic; 6University Hospital Brno, Brno, Czech Republic; 7National Cancer Institute, Kiev, Ukraine; 8Alexandra Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece; 9National and Kapodistrian University of Athens, Athens, Greece; 10Cherkassy Regional Oncological Center, Cherkassy, Ukraine; 11Imperial College London, London, UK; 12Department of Hematology, CHU la Miletrie and Inserm CIC 1402, Poitiers, France; 13City Clinical Hospital #40, Moscow, Russian Federation; 14City Clinical Hospital No.4 of Dnipro City Council, Dnipro, Ukraine; 15University Hospital Ostrava, Department of Hematooncology, Ostrava, Czech Republic; 16Kings College Hospital NHS Foundation Trust, London, UK; 17 Nil Ratan Sircar Medical College and Hospital, Kolkata, India; 18State Cancer Institute, Indira Gandhi Institute of Medical Sciences, Patna, India; 19Cross Cancer Institute, Edmonton, University of Alberta, Edmonton, Alberta, Canada; 20University Hospitals of Leicester NHS Trust, Leicester, UK; 21Norton Cancer Institute, St. Matthews Campus, Louisville, KY; 22University of Melbourne, St Vincent's Hospital, Melbourne, Victoria, Australia; 23University Hospital, Hotel-Dieu, Nantes, France; 24Baylor University Medical Center Dallas, TX; 25University of Maryland, Greenebaum Comprehensive Cancer Center, Baltimore, MD; 26Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX; 27University of Calgary, Charbonneau Cancer Research Institute, Calgary, AB; 28CHU Lille Service des Maladies du Sang F-59000, Lille, France; 29Seràgnoli Institute of Hematology, Bologna University School of Medicine, Bologna, Italy; 30 Karyopharm Therapeutics Inc, Newton, MA; 31Dana-Farber Cancer Institute, Boston, MA; 32Medical University of Silesia, Katowice, Poland; Conflict of Interest Disclosure

Research Support --

Consultant --

Honoraria Janssen, Celgene, Amgen, Takeda, Abbvie, GSK, Adaptive, Oncopeptides

Janssen, Celgene, Amgen, Takeda, Abbvie, GSK, Pfizer, Regeneron, Adaptive, Scientific Advisory Board Oncopeptides, Roche, Seattle Genetics

Major Stockholder --

Employee, Speakers Bureau -- Selinexor: First-in-Class, Oral Selective Inhibitor of Nuclear Export1-7 Demonstrates synergistic activity in combination with bortezomib in vitro and in vivo

• Exportin 1 (XPO1) is overexpressed in MM and its levels correlate with poor prognosis and drug resistance • XPO1 Overexpression Causes: • Tumor suppressor protein (e.g., p53, IkB and FOXO) and glucocorticoid receptor inactivation and enhanced oncoprotein (e.g., c-Myc, Bcl-xL, cyclins) translation • Selinexor (S) is an oral selective XPO1 inhibitor that reactivates multiple TSPs and inhibits oncoprotein translation

• Selinexor synergizes with proteasome inhibitors (PIs): • In PI-sensitive cell lines and overcome resistance in PI resistant cell lines

1. Gupta A, et al. Therapeutic targeting of nuclear export inhibition in lung cancer. J Thorac Oncol. 2017;12(9):1446-1450. 2. Sun Q, et al. Inhibiting cancer cell hallmark features through nuclear export inhibition. Signal Transduct Target Ther. 2016;1:16010. 3. Gandhi UH, et al. Clinical implications of targeting XPO1-mediated nuclear export in multiple myeloma. Clin Lymphoma Myeloma Leuk. 2018;18(5):335-345. 4. Gravina GL, et al. Nucleo-cytoplasmic transport as a therapeutic target of cancer. J Hematol Oncol. 2014;7:85. 5. Turner, Oncotarget 2016, 6. Bahlis, Blood 2018, 7.Jakubowiak, BJH 2019 BOSTON Study Trial Design

BOSTON Trial: Phase 3, Global, Randomized, Open Label, Controlled Study in Patients with MM who had Received 1–3 Prior Therapies

Primary Endpoint: PFS Selinexor (oral) 100 mg Once Weekly Key Secondary Endpoints: SVd Weekly Bortezomib (SC) 1.3 mg/m2 Once Weekly 35-day cycles • ORR (Assessed by IRC) Dexamethasone (oral) 20 mg Twice Weekly • ≥VGPR • Grade ≥2 PN 2 Vd Bortezomib (SC) 1.3 mg/m Twice Weekly Secondary Endpoints: Twice Weekly Dexamethasone (oral) 20 mg QIW Vd Weekly* 35-Day cycles • 21-day cycles If IRC confirmed PD: crossover to SVd or Sd OS

Randomization 1:1 Randomization Cycles ≥9 Cycles 1-8 permitted • DoR • TTNT Planned 40% lower bortezomib and 25% lower dexamethasone dose PD or unacceptable toxicity PDunacceptable or • Safety with 37% fewer clinic visits in first 24 weeks in SVd vs. Vd arm

Stratifications: Prior PI therapies (Yes vs No); Number of prior anti-MM regimens (1 vs >1); R-ISS stage at study entry (Stage III vs Stage I/II) 5HT-3 prophylactic recommended in SVd arm

CR= complete response, DoR = duration of response, IMWG = International Myeloma Working Group, IRC = Independent Review Committee, OS = overall survival, PD = progressive disease, PFS = progression free survival, PR = partial response, PN = peripheral neuropathy, sCR = stringent complete response, TTNT = time to next therapy, VGPR = very good partial response. PFS defined as: Time from date of randomization until the first date of progressive disease, per IMWG response criteria, or death due to any cause, whichever occurred first, as assessed by IRC. ORR: Any response ≥PR (ie, PR, VGPR, CR, or sCR) based on the IRC’s response outcome assessments, according to IMWG response criteria (Kumar et al. Lancet oncology 2016). All changes in MM disease assessments were based on baseline MM disease assessments. *Vd weekly dosing and schedule for cycles≥ 9 as per SVd arm description. Overall Efficacy Results SVd vs. Vd

SVd Vd PFS, median 13.93 months 9.46 months Hazard Ratio; (p value) 0.70 (p=0.0075) ORR 76.6% 62.3% ≥VGPR 44.6% 32.4% DOR 20.3 months 12.9 months Methods We performed post-hoc analyses of the BOSTON study to determine efficacy and safety among patients treated with prior lenalidomide (Len) and based on number of prior regimens

SVd Arm (n=195) Vd Arm (n=207) SVd Len Treated SVd Len Naïve Vd Len Treated Vd Len Naïve Prior Lenalidomide 39% (n=77) 61% (n=118) 37% (n=77) 63% (n=130) Prior Number of Treatment SVd 1 Prior SVd ≥2 Priors Vd 1 Prior Vd ≥2 Priors Regimens 51% (n=99) 49% (n=96) 48% (n=99) 52% (n=108) Baseline Characteristics by Prior Len Treatment and Number of Prior Treatments

Len Categories SVd – Len Treated (n=77) SVd – Len Naïve (n=118) Vd – Len Treated (n=77) Vd – Len Naïve (n=130)

Median Age, Years (range) 65 (40, 87) 66 (45, 84) 66 (45, 85) 68 (38, 90)

Males, n (%) 53 (68.8) 62 (52.5) 40 (51.9) 75 (57.7) Females, n (%) 24 (31.2) 56 (47.5) 37 (48.1) 55 (42.3)

Number of Prior Regimens, n (%) 1 23 (29.9) 76 (64.4) 20 (26.0) 79 (60.8) 2 33 (42.9) 32 (21.7) 30 (39.0) 34 (26.2) 3 21 (27.3) 10 (8.5) 27 (35.1) 17 (13.1)

Prior Treatment Categories SVd – 1 Prior (n=99) SVd – ≥2 Priors (n=96) Vd – 1 Prior (n=99) Vd – ≥2 Priors (n=108)

Median Age, Years (range) 67 (45, 87) 65 (40, 84) 69 (44, 90) 65 (38, 85)

Males, n (%) 55 (55.6) 60 (62.5) 53 (53.5) 62 (57.4) Females, n (%) 44 (44.4) 36 (37.5) 46 (46.5) 46 (42.6)

Number of Prior Regimens, n (%) 1 99 (100.0) -- 99 (100.0) -- 2 -- 65 (67.7) -- 64 (59.3) 3 -- 31 (32.3) -- 44 (40.7) ≥Grade 3 Adverse Events, ≥5% Overall

SVd – Len SVd – 1 Vd – Len Vd – 1 SVd – Len SVd – ≥2 Vd – Len Vd – ≥2 AE Term Naïve Prior Naïve Prior Treated Priors Treated Priors (n=118) (n=99) (n=129) (n=98) (n=77) (n=96) (n=75) (n=106) Thrombocytopenia 40 (33.9) 39 (39.4) 17 (13.2) 17 (17.3) 37 (48.1) 38 (39.6) 18 (24.0) 18 (17.0) Anemia 15 (12.7) 10 (10.1) 15 (11.6) 11 (11.2) 16 (20.8) 21 (21.9) 6 (8.0) 10 (9.4) Pneumonia 13 (11.0) 9 (9.1) 15 (11.6) 10 (10.2) 9 (11.7) 13 (13.5) 7 (9.3) 12 (11.3) Fatigue 14 (11.9) 12 (12.1) 1 (0.8) 1 (1.0) 12 (15.6) 14 (14.6) 1 (1.3) 1 (0.9) Neuropathy Peripheral 7 (5.9) 6 (6.1) 13 (10.1) 9 (9.2) 2 (2.6) 3 (3.1) 5 (6.7) 9 (8.5) Asthenia 14 (11.9) 11 (11.1) 5 (3.9) 6 (6.1) 2 (2.6) 5 (5.2) 4 (5.3) 3 (2.8) Neutropenia 12 (10.2) 8 (8.1) 4 (3.1) 3 (3.1) 5 (6.5) 9 (9.4) 3 (4.0) 4 (3.8) Cataract 7 (5.9) 8 (8.1) 2 (1.6) 1 (1.0) 10 (13.0) 9 (9.4) 1 (1.3) 2 (1.9) Nausea 8 (6.8) 8 (8.1) -- -- 7 (9.1) 7 (7.3) -- -- Hypertension 4 (3.4) 5 (5.1) 3 (2.3) 3 (3.1) 4 (5.2) 3 (3.1) 3 (4.0) 3 (2.8) Diarrhea 5 (4.2) 5 (5.1) 1 (0.8) -- 7 (9.1) 7 (7.3) -- 1 (0.9) Hypokalemia 6 (5.1) 6 (6.1) 1 (0.8) 3 (3.1) 2 (2.6) 2 (2.1) 4 (5.3) 2 (1.9) Hypophosphatemia 5 (4.2) 4 (4.0) 1 (0.8) -- 5 (6.5) 6 (6.3) 2 (2.7) 3 (2.8)

• AEs of ≥Grade 3 were more commonly reported in the SVd treatment arm than in the Vd arm, LEN treated (83% SVd, 57% Vd), LEN-naïve (76% SVd, 55% Vd), 1 prior line (77% SVd, 56% Vd), 2-3 prior lines (81% SVd, 56% Vd), and were mostly managed with dose modification and/or supportive treatment. Grade ≥2 peripheral neuropathy occurred less frequently across all SVd subgroups compared with Vd: LEN treated (21% SVd, 37% Vd, p=0.0166); LEN-naïve (21% SVd, 33% Vd, p=0.0252), 1 prior line (21% SVd, 33% Vd, p=0.0501); 2-3 prior lines (21% SVd, 36% Vd, p=0.0107). SVd is Effective (PFS, ORR) in Patients with or without Prior Len Treatment

PFS for Len Treated Patients ORR With Number of Subjects at Risk 100% 1.00 HR – 0.63 + Censored sCR CR VGPR PR l a v

i (p=0.017) v r u 0.75 82.2% S

e 80% e SVd – 9.5 months r

F 11.0% n

o Vd – 7.2 months i 67.5% s 0.50 67.7% s e r 9.3% g o 7.8%

r 8.5% P

f 60% o 0.25 3.9% 53.2% 3.8% y t i l i 2.6% b a b 5.2% o 29.7% r 0.00 P 24.7% 23.1% 40% 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 19.5% Time (Months) Treatment Group: SVd Arm Vd Arm 20% SVd Arm 77 73 68 57 47 39 35 26 25 23 20 17 16 15 13 12 10 7 7 7 5 5 2 1 1 0 31.2% 32.2% 32.3% Vd Arm 77 66 59 50 42 37 32 30 27 25 18 16 13 12 12 8 7 6 3 3 1 1 0 26.0%

PFS forWi thLen Num bNaïveer of Sub jPatientsects at Risk 0%

l 1.00 a + Censored SVd Len Vd Len SVd Len Naïve Vd Len Naïve v i v r

u HR – 0.66

S Treated (n=77)Treated (n=77) (n=118) (n=130)

e (p=0.015)

e 0.75 r F

SVd – 16.6 months n o i • PFS was significantly prolonged in both Len groups with SVd compared s Vd – 10.6 months s

e 0.50 r g o

r to Vd. In Len treated patients, PFS was 9.5 vs 7.2 months (HR, 0.63; 95% P f o 0.25 y CI, 0.41-0.97; p=0.017) and in Len naïve, PFS was 16.6 vs 10.6 months t i l i b a b (HR, 0.66; 95% CI, 0.45-0.96; p=0.015) o r 0.00 P

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 Time (Months) • The ORR significantly improved with SVd in Len treated (67.5% vs Treatment Group: SVd Arm Vd Arm 53.2%; p=0.035) and Len naïve (82.2% vs 67.7%, p=0.004). The ≥VGPR SVd Arm 118 114 107 95 88 78 71 63 54 53 49 47 41 36 32 29 25 20 19 15 14 9 7 6 5 4 2 1 0 Vd Arm 130 121 116 102 96 90 79 70 63 56 48 43 43 41 37 34 28 20 17 13 9 7 5 4 3 3 2 1 0 rate was also higher in SVd compared to Vd. SVd is Effective (PFS, ORR) in Patients with 1 Prior or ≥2 Prior Treatments

PFSW iforth Nu 1m bPriorer of Su bTreatmentjects at Risk ORR 100% 1.00 + Censored l sCR CR VGPR PR a HR – 0.63 v i v r (p=0.015) u S

0.75 80.8% e e SVd – 16.6 months r 80% F

n Vd – 10.6 months 71.9% o i 15.2% s s 0.50 65.7% 4.2% e r 1.0% g o r 6.1% 59.3% P f 60% 13.1% o 0.25 5.1% 6.5% y t i l i 3.7%

b 31.3% a b o 18.2% r 0.00 P 40% 24.2% 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 25.0% Time (Months)

Treatment Group: SVd Arm Vd Arm 20% 36.4% 35.4% SVd Arm 99 93 86 79 71 64 59 49 43 41 37 36 34 32 28 26 23 17 16 15 14 10 7 5 5 3 1 0 28.3% 24.1% Vd Arm 99 90 85 73 71 65 59 52 45 40 38 32 31 31 28 22 19 14 12 10 8 7 5 4 3 3 2 1 0 0% PFSW iforth Nu ≥2mbe rPrior of Subj eTreatmentscts at Risk l

a SVd 1 Prior Vd 1 Prior SVd ≥2 Priors Vd ≥2 Priors v i 1.00 v

r + Censored u (n=99) (n=99) (n=96) (n=108) S HR – 0.69 e e (p=0.029) r 0.75 F

n SVd – 11.7 months o i • PFS was significantly prolonged in both prior treatment groups with s s Vd – 9.4 months e r 0.50 g

o SVd compared to Vd. In patients with 1 prior, PFS was 16.6 vs 10.6 r P f o months (HR, 0.63; 95% CI, 0.41-0.96; p=0.015) and ≥2 priors, PFS y 0.25 t i l i b a was 11.7 vs 9.4 months (HR, 0.69; 95% CI, 0.48-1.01; p=0.029) b o r 0.00 P

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 Time (Months) • The ORR significantly improved with SVd in patients with 1 prior Treatment Group: SVd Arm Vd Arm (80.8% vs 65.7%; p=0.008) and ≥2 priors (71.9% vs 59.3%, p=0.029). SVd Arm 96 94 89 73 64 53 47 40 36 35 32 28 23 19 17 15 12 10 10 7 5 4 2 2 1 1 1 1 0 Vd Arm 108 97 90 79 67 62 52 48 45 41 28 27 25 22 21 20 16 12 8 6 2 1 0 The ≥VGPR rate was also higher in SVd compared to Vd. Conclusions

• Regardless of prior lenalidomide, the combination of SVd was active with a PFS HR of 0.63 among patients with prior lenalidomide treatment who received SVd compared to Vd

• Regardless of prior treatment, SVd treatment led to significantly improved ORR and PFS with the highest PFS of 16.6 months in first relapse

• Regardless of prior treatments SVd was associated with significantly reduced rates of ≥ grade 2 peripheral neuropathy (PN) compared with Vd

• AEs of ≥Grade 3 were more commonly reported in the SVd treatment arm than in the Vd arm, but most non- PN AEs were reversable and treatable; major organ toxicities were not common

Once weekly SVd is effective and a convenient treatment option for patients with previously treated MM, including those who have been treated with Lenalidomide