Once Weekly Selinexor, Bortezomib, and Dexamethasone Versus Twice Weekly Bortezomib and Dexamethasone in Relapsed or Refractory Multiple Myeloma: Age and Frailty Subgroup Analyses from the Phase 3 BOSTON Study

Holger W Auner1, Maria Gavriatopoulou2, Sosana Delimpasi3, Maryana Simonova4, Ivan Spicka5, Ludek Pour6, Meletios A. Dimopoulos7, Iryna Kriachok8, Halyna Pylypenko9, Xavier Leleu10, Vadim Doronin11, Ganna Usenko12, Roman Hajek13, Reuben Benjamin14, Tuphan Kanti Dolai15, Dinesh Kumar Sinha16, Christopher P Venner17, Mamta Garg18, Don Ambrose Stevens19, Hang Quach20 Sundar Jagannath21, Phillipe Moreau22, Moshe Levy23, Ashraf Badros24, Larry D. Anderson25, Nizar J. Bahlis26, Thierry Facon27, Maria Victoria Mateos28, Michele Cavo29, Anita A Joshi30, Yi Chai30, Melina Arazy30, Jatin Shah30, Sharon Shacham30, Michael G Kauffman30, Paul G. Richardson31, Sebastian Grosicki32 1Imperial College London, London, United Kingdom; 2Alexandra Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece; 3General Hospital Evangelismos, Athens, Greece; 4Institute of Blood Pathology & Transfusion Medicine of National Academy of Medical Sciences of Ukraine, Lviv, Ukraine; 5Charles University and General Hospital, Prague, Czech Republic; 6University Hospital Brno, Brno, Czech Republic; 7National and Kapodistrian University of Athens School of Medicine, Athens, Greece; 8National Cancer Institute Ukraine, Kiev, Ukraine; 9Department of Hematology, Cherkassy Regional Oncological Center, Cherkassy, Ukraine; 10Department of Hematology, CHU la Miletrie and Inserm CIC 1402, Poitiers, France; 11City Clinical Hospital #40, Moscow, Russian Federation; 12City Clinical Hospital No. 4 of Dnipro City Council, Dnipro, Ukraine; 13Department of Hemato-oncology, University Hospital Ostrava, University of Ostrava, Ostrava, Czech Republic; 14Kings College Hospital NHS Foundation Trust, London, United Kingdom; 15Nil Ratan Sircar Medical College and Hospital, Kolkata, India; 16State Cancer Institute, Indira Gandhi Institute of Medical Sciences, Patna, India; 17Cross Cancer Institute, University of Alberta, Edmonton, Alberta, Canada; 18University Hospitals of Leicester NHS Trust, Leicester, United Kingdom; 19Norton Cancer Institute, St. Matthews Campus, Louisville, KY; 20University of Melbourne, St. Vincent’s Hospital, Melbourne, Victoria, Australia; 21Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY; 22University Hospital, Hotel-Dieu, Nantes, France; 23Baylor University Medical Center, Dallas, Texas; 24University of Maryland, Greenebaum Comprehensive Cancer Center, Baltimore, MD; 25Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX; 26University of Calgary, Charbonneau Cancer Research Institute, Calgary, AB; 27CHU Lille Service des Maladies du Sang F-59000, Lille, France; 28Hospital Universitario de Salamanca, Salamanca, Spain; 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 Silesian, Katowice, Poland Conflict of Interest Disclosure

Research Support Amgen, Apollo

Consultant --

Honoraria --

Scientific Advisory Board Karyopharm, Amgen, Takeda

Major Stockholder --

Employee, Speakers Bureau Janssen Selinexor: First-in-Class, Oral Selective Inhibitor of Nuclear Export1-6 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 proteins (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 • The BOSTON Trial Velcade-dex ± S (SVd vs Vd): • Once weekly SVd significantly prolongs PFS (HR 0.70, p=0.0075) vs Vd, and was superior to Vd on ORR, TTNT, DoR • Older (≥65 years old) or Frail Patients with MM • Multiple comorbid conditions contribute to the complexity of patients and exacerbation of side effects • Simple, well tolerated regimens required 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 • Remains a challenging population to treat effectively 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. Chari NEJM 2019, 6. Gavriatopoulou IMW 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 Grosicki et al, The Lancet 2020;396(10262):1563-1573

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 <65 vs ≥65 years old or by Frailty score* (frail vs fit) Total Patients Enrolled SVd Arm (n=195) Vd Arm (n=207) SVd <65 years SVd ≥65 years Vd <65 years Vd ≥65 years Age Categories 44% (n=86) 56% (n=109) 36% (n=75) 64% (n=132) SVd Fit SVd Frail Vd Fit Vd Frail Frailty Categories 66% (n=129) 34% (n=66) 69% (n=143) 31% (n=64) *Frailty Score was assessed using baseline characteristics including: Age, Charlson Comorbidity Index, and Eastern Cooperative Oncology Group Performance Status (Facon et al. Leukemia 2019) Baseline and Disease Characteristics by Age Group and Frailty Category

Age Categories SVd – <65 years (n=86) SVd – ≥65 years (n=109) Vd – <65 years (n=75) Vd – ≥65 years (n=132)

Median Age, Years (range) 57 (40, 64) 71 (65, 87) 58 (38, 64) 71 (65, 90)

Males, n (%) 53 (61.6) 62 (56.9) 45 (60.0) 70 (53.0) Females, n (%) 33 (38.4) 47 (43.1) 30 (40.0) 62 (47.0)

Number of Prior Treatment Regimens, n (%) 1 43 (50.0) 56 (51.4) 29 (38.7) 70 (53.0) 2 28 (32.6) 37 (33.9) 26 (34.7) 38 (28.8) 3 15 (17.4) 16 (14.7) 20 (26.7) 24 (18.2)

Frailty Categories SVd – Fit (n=129) SVd – Frail (n=66) Vd – Fit (n=143) Vd – Frail (n=64)

Median Age, Years (range) 63 (40, 80) 71 (47, 87) 65 (38, 78) 76 (48, 90)

Males, n (%) 78 (60.5) 37 (56.1) 83 (58) 32 (50.0) Females, n (%) 51 (39.5) 29 (43.9) 60 (42) 32 (50.0)

Number of Prior Treatment Regimens, n (%) 1 64 (49.6) 35 (53.0) 71 (49.7) 28 (43.8) 2 43 (33.3) 22 (33.3) 42 (29.4) 22 (34.4) 3 22 (17.1) 9 (13.6) 30 (21.0) 14 (21.9) Related Adverse Events, All Grades, ≥10% Overall

SVd – <65 SVd – Fit Vd – <65 Vd – Fit SVd – ≥65 SVd – Frail Vd – ≥65 Vd – Frail AE Term (n=86) (n=129) (n=75) (n=142) (n=109) (n=66) (n=129) (n=62) Thrombocytopenia 47 (54.7) 78 (60.5) 18 (24.0) 33 (23.2) 63 (57.8) 32 (48.5) 29 (22.5) 14 (22.6) Neuropathy 27 (31.4) 45 (34.9) 35 (46.7) 62 (43.7) 34 (31.2) 16 (24.2) 58 (45.0) 31 (50.0) Peripheral Nausea 37 (43.0) 62 (48.1) 6 (8.0) 8 (5.6) 56 ( 51.4) 31 (47.0) 6 (4.7) 4 (6.5) Fatigue 26 (30.2) 49 (38.0) 8 (10.7) 14 (9.9) 43 (39.4) 20 (30.3) 11 (8.5) 5 (8.1) Decreased Appetite 27 (31.4) 44 (34.1) 6 (8.0) 7 (4.9) 36 (33.0) 19 (28.8) 1 (0.8) -- Diarrhea 21 (24.4) 25 (19.4) 10 (13.3) 19 (13.4) 16 (14.7) 12 (18.2) 19 (14.7) 10 (16.1) Anemia 18 (20.9) 30 (23.3) 6 (8.0) 12 (8.5) 25 (22.9) 13 (19.7) 11 (8.5) 5 (8.1) Insomnia 9 (10.5) 20 (15.5) 14 (18.7) 26 (18.3) 20 (18.3) 9 (13.6) 13 (10.1) 1 (1.6) Asthenia 17 (19.8) 20 (15.5) 5 (6.7) 7 (4.9) 21 (19.3) 18 (27.3) 6 (4.7) 4 (6.5) Weight Decreased 15 (17.4) 23 (17.8) 5 (6.7) 7 (4.9) 23 (21.1) 15 (22.7) 3 (2.3) 1 (1.6) Constipation 10 (11.6) 16 (12.4) 9 (12.0) 19 (13.4) 8 (7.3) 2 (3.0) 15 (11.6) 5 (8.1) Vomiting 18 (20.9) 22 (17.1) 1 (1.3) 4 (2.8) 16 (14.7) 12 (18.2) 4 (3.1) 1 (1.6) Cataract 21 (24.4) 29 (22.5) 2 (2.7) 3 (2.1) 11 (10.1) 3 (4.5) 2 (1.6) 1 (1.6)

• Similar to the overall population, the most common grade ≥3 AEs were thrombocytopenia, anemia, and fatigue. In the SVd arm, the incidence of AEs was comparable across subgroups except for a higher incidence of fatigue in ≥65 vs <65 (17% vs 8%) and pneumonia in the frail versus fit (19% vs 7%). There were more deaths in the ≥65 (30% [SVd 23%, Vd 36%]) and frail groups (35% [SVd 26%, Vd 44%]) compared with the <65 (23% [SVd 26%, Vd 20%]) and fit groups (24% [SVd 23%, Vd 24%]). SVd is Effective (PFS, ORR) in Patients <65 and ≥65 Years

PFSWith Nforumb e≥65r of Su bPatientsjects at Risk ORR

1.00 + Censored 100% sCR CR VGPR PR l a v i v r u AGE <65 AGE ≥65 S 0.75 e e r SVd – 21.0 months F n o i 80% 76.7% 76.1% s 0.50 s e r g o r 10.5% 9.2%

P Vd – 9.4 months f o 64.4%

0.25 y t i 5.5% l i b 9.3% 58.7% 6.8% a 60% b HR – 0.55 o r 0.00 P 5.3% 3.8% 5.3% 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 28.4% Time (Months) 26.7% 20.5% 40% Treatment Group: SVd Arm Vd Arm 24.0% SVd Arm 109 103 95 83 73 62 56 48 40 39 35 31 27 25 21 20 17 13 13 12 10 8 6 6 6 4 2 1 0 Vd Arm 132 121 111 98 87 79 71 63 56 49 42 36 35 32 30 27 25 18 13 12 6 4 3 2 1 1 0 20% PFSWith Nforumb e

S 0.75 0% e e r F

n SVd – 12.2 months SVd <65 (n=86) Vd <65 (n=75) SVd ≥65 (n=109) Vd ≥65 (n=132) o i s 0.50 s e r g o r P f Vd – 9.4 months • PFS was prolonged in both age groups with SVd compared to Vd. In ≥65, o

0.25 y t i l i b PFS was 21.0 vs 9.4 months (HR, 0.55; 95% CI, 0.37-0.83; p=0.002) and in a b o r 0.00 HR – 0.75 P <65, PFS was 12.2 vs 9.4 months (HR, 0.74; 95% CI, 0.41-1.10; p=0.07). 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)

Treatment Group: SVd Arm Vd Arm • The ORR significantly improved with SVd in those ≥65 (76.1% vs 64.4%; SVd Arm 86 84 80 69 62 55 50 41 39 37 34 33 30 26 24 21 18 14 13 10 9 6 3 1 0 p=0.0243) and <65 (76.7% vs 58.7%, p=0.0071). The ≥VGPR rate was also Vd Arm 75 66 64 54 51 48 40 37 34 32 24 23 21 21 19 15 10 8 7 4 4 4 2 2 2 2 2 1 0 higher in SVd compared to Vd. SVd is Effective (PFS, ORR) in Frail and Fit Patients

WPFSith N forumbe Frailr of Sub Patientsjects at Risk ORR l a 100% v 1.00 i

v + Censored r u sCR CR VGPR PR S e e r 0.75 F 79.8% n o

i 80% s SVd – 13.9 months s 10.1% e r 0.50 g 69.7% o r P

8.5% f 62.9% 9.1% o

60.9% y 0.25 60% 5.6% t i 4.5% l Vd – 9.4 months i 7.8% b 4.9% a

b 3.1% o r 0.00 HR – 0.69 P 30.2% 22.7% 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 40% 23.1% 18.8% Time (Months)

Treatment Group: SVd Arm Vd Arm

SVd Arm 66 62 54 46 39 31 28 23 19 18 14 13 11 11 10 8 6 2 2 1 1 1 0 20% 33.3% Vd Arm 64 59 57 48 40 34 30 27 24 23 21 20 20 18 17 15 11 10 8 8 4 2 2 1 0 31.0% 29.4% 31.3%

0% WPFSith N uformbe rFit of S Patientsubjects at Ri sk 1.00 SVd Fit Vd Fit (n=143) SVd Frail Vd Frail l + Censored a v i v

r (n=129) (n=66) (n=64) u S

e 0.75 e r F

n SVd – 13.2 months o i s s 0.50 • The PFS benefit of SVd was sustained and comparable in the frail e r g o r

P pts: 13.9 vs 9.4 months (HR, 0.69; 95% CI, 0.40-1.17; p=0.08); and f o 0.25 Vd – 9.4 months y t i l

i in the fit pts: 13.2 vs 9.4 months (HR, 0.66; 95% CI, 0.47-0.93; b a

b HR – 0.69 o r 0.00 p=0.008). 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 were higher with SVd in frail (69.7% vs 60.9%; p=0.1479) Treatment Group: SVd Arm Vd Arm and fit patients (79.8% vs 62.9%, p=0.001). The ≥VGPR rate was SVd Arm 129 125 121 106 96 86 78 66 60 58 55 51 46 40 35 33 29 25 24 21 18 13 9 7 6 4 2 1 0 Vd Arm 143 128 118 104 98 93 81 73 66 58 45 39 36 35 32 27 24 16 12 8 6 6 3 3 3 3 2 1 0 also higher in SVd compared to Vd. Conclusions

• Both elderly and frail patients benefit from SVd compared to Vd • Activity of SVd was preserved in patients ≥65 with a mPFS of 21 months and HR of 0.55 • SVd had similar PFS benefit in Fit vs Frail pts (13.2 vs 13.9 months with SVd) • Once weekly SVd led to prolonged PFS, improved response rates and lower rates of PN regardless of age and frailty score compared to standard twice weekly Vd • Non-PN AEs were higher with in SVd than Vd therapy, but most of the AEs were reversible and treatable

Once weekly. SVd is an effective and safe treatment option for patients with previously treated MM, including those who are ≥65 years old or frail