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New Drug Approval: What Does the Arrival of XPOVIO (selinexor) Mean for Multiple Myeloma Patients?
Webinar – October 17, 2019
1
New Drug Approval: What
Does the Arrival of XPOVIO
(selinexor) Mean for Multiple
Myeloma Patients?
October 17, 2019
Tech Support
1-866-709-8255
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New Drug Approval: What Does the Arrival of XPOVIO (selinexor) Mean for Multiple Myeloma Patients?
Webinar – October 17, 2019
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Multiple Myeloma Research Foundation
Moderator
• Mary DeRome
Multiple Myeloma Research Foundation
Norwalk, Connecticut
www.themmrf.org
https://www.facebook.com/theMMRF
https://twitter.com/theMMRF
https://www.youtube.com/user/TheMMRF
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New Drug Approval: What Does the Arrival of XPOVIO (selinexor) Mean for Multiple Myeloma Patients?
Webinar – October 17, 2019
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Multiple Myeloma Research Foundation
Moderator
• Mary DeRome
Multiple Myeloma Research Foundation
Norwalk, Connecticut
www.themmrf.org
https://www.facebook.com/theMMRF
https://twitter.com/theMMRF
https://www.youtube.com/user/TheMMRF
Speakers
Ajai Chari, MD
Icahn School of Medicine at Mount Sinai
New York, New York
Paul G. Richardson, MD
Dana-Farber Cancer Institute
Boston, Massachusetts
Michael Walsh
Patient Advocate
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New Drug Approval: What Does the Arrival of XPOVIO (selinexor) Mean for Multiple Myeloma Patients?
Webinar – October 17, 2019
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Topics for Discussion
• Unmet needs for relapsing patients
• XPOVIO clinical data
• Patient management
• Future XPOVIO studies and use
• Patient perspective on XPOVIO
experience
Treatment Options for Relapsing
Patients
Paul G. Richardson, MD
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New Drug Approval: What Does the Arrival of XPOVIO (selinexor) Mean for Multiple Myeloma Patients?
Webinar – October 17, 2019
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Therapy for Relapsed/Refractory
Myeloma (RRMM): Numerous Choices
IMiDs
Proteasome
inhibitors
Chemotherapy
anthracyclines
Chemotherapy
alkylators Steroids
Novel
mechanisms
of action mAbs
Thalomid
(thalidomide)
Velcade
(bortezomib) Adriamycin Cytoxan
(cyclophosphamide)
Dexa- methasone
Farydak
(panobinostat)
Empliciti
(elotuzumab)
Revlimid
(lenalidomide)
Kyprolis
(carfilzomib)
Doxil (liposomal
doxorubicin) Bendamustine Prednisone Zolinza
(vorinostat)
Darzalex
(daratumumab)
Pomalyst
(pomalidomide)
Ninlaro
(ixazomib) Melphalan XPOVIO
(selinexor)
IMiD, immunomodulatory drug; HDAC, histone deacetylase; mAb, monoclonal antibody.
New formulations, new dosings, and new combinations
Despite Advances in Therapy, Multiple Myeloma Is Still
Considered Incurable; Almost All Patients Relapse
• Multiple myeloma is considered an
incurable, chronic disease
characterized by remissions and
relapses:
– Most patients experience multiple
relapses
– Some patients never respond, and
others stop responding to therapy
– Remission duration decreases with
each successive treatment regimen
– Patients with resistance to currently
available novel therapies have
particularly poor prognosis
18
13
7
5
0
5
10
15
20
1L 2L 3L 4L
Time to Progression,
mo Proportion Surviving
1.0
0.8
0.6
0.4
0.2
0.0
0 10 20 30 40 50
Months
Not triple-refractory (ie, double-refractory) (N=57)
Triple-refractory and
quad-refractory (N=148)
P Penta-refractory (N=70) =0.002
Line of Treatment
Harousseau JL et al. Blood. 2017;130:963; Sonneveld P et al. Haematologica. 2016;101:396; Rajkumar SV et al. Blood. 2011;117:4691-5;
Yong K et al. Br J Haematol. 2016;175:252; Gandhi UH et al. Leukemia. 2019;33:2266.
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New Drug Approval: What Does the Arrival of XPOVIO (selinexor) Mean for Multiple Myeloma Patients?
Webinar – October 17, 2019
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Median Overall Survival for Patients
Progressing After Darzalex
Pick M et al. Eur J Haematol. 2018;100:494.
Patients with heavily-pretreated
MM, receiving salvage therapy
post-Darzalex
100
80
60
40
20
0
0 6 12 18 24
Months
Percent Survival
DARATUMUMAB REFRACTORY
N: 22
Median OS: 3.5 months
Unmet Needs for RRMM Patients
Multiple myeloma remains largely incurable despite novel therapies, with RRMM
representing an area of exquisite unmet medical need.
A growing number of patients are exposed to proteasome inhibitors, immunomodulatory
drugs, and have become refractory to monoclonal antibodies, including Darzalex
(daratumumab) and Empliciti (elotuzumab).
Eventually, patients develop penta-exposed and triple-class–refractory* myeloma and
have a dismal prognosis.
Response rate and PFS progressively diminish with each relapse.
Until now, there were no approved drugs with established clinical activity in triple-class–
refractory myeloma.
*Refractory to proteasome inhibitors, immunomodulatory drugs, and CD-38 targeting mAbs, such as
Darzalex
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New Drug Approval: What Does the Arrival of XPOVIO (selinexor) Mean for Multiple Myeloma Patients?
Webinar – October 17, 2019
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Clinical trials
Relapsing After Multiple Prior Treatments
What options to consider?
ASCT, autologous stem cell transplantation; SCT, stem cell transplantation; BiTE, bispecific T-cell engager.
Commercial/
investigational
agents
• XPOVIO-based therapy
• 4-5 novel drug
combinations
• Multi-agent chemotherapy
and ASCT
• Allogeneic SCT (under
protocol-directed
conditions)
Investigational
agents
• CAR T-cell therapy
(eg, bb2121)
• Bispecific
antibodies/BiTEs (eg,
anti-BCMA)
• Venetoclax (in select
patients)
• Next-generation novel
agents, with novel
mechanisms of action
• Target-based approach
• Marizomib
Next- generation
proteasome
inhibitors
• Isatuximab
• Belantamab
mafodotin
• Idasanutlin
• MOR03087
• TAK079
• TAK573
• BiTEs
Monoclonal
antibodies
•Vemurafenib
• Afuresertib
• Dinaciclib
•Ibrutinib
•Trametinib
• Dabrafenib
• Ruxolitinib
Kinase
inhibitors
• Ricolinostat
HDAC
inhibitors
• Venetoclax
• Melflufen
Novel MOA
• Immune
checkpoint
inhibitors
̶ Pembro- lizumab
̶ Nivolumab
• Immune cell
therapy
̶ CAR-T
Immuno- therapies
• Iberdomide
(CC-220)
• CC-480
New
IMiDs
Selected New Agents
Under Investigation in Myeloma
IMiD, immunomodulatory drug; HDAC, histone deacetylase inhibitor; MOA mechanism of action;
BiTE, bi-specific T-cell engager; CAR T, chimeric antigen receptor T cells
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New Drug Approval: What Does the Arrival of XPOVIO (selinexor) Mean for Multiple Myeloma Patients?
Webinar – October 17, 2019
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Novel Mechanisms of Action in RRMM:
Key New Directions
How does XPOVIO (selinexor) work?
Without XPOVIO With XPOVIO
XPO1 in MM
• Transports >200 proteins from the nucleus to cytoplasm
• Expression increased in MM vs normal PC/MGUS/SMM
• Correlates with shorter survival and increased bone disease
Tai YT et al. Leukemia 2014;28:155; Schmidt J et al. Leukemia 2013;27:2357.
XPO1
selinexor
selinexor
XPOVIO (selinexor)
• Inhibits XPO1 through reversible covalent modification
• Nuclear retention/activation of tumor suppressor
proteins and glucocorticoid receptor
• Reduction of oncoproteins through nuclear
retention of their mRNAs
XPOVIO Clinical Efficacy, Safety,
and Patient Management
Ajai Chari, MD
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New Drug Approval: What Does the Arrival of XPOVIO (selinexor) Mean for Multiple Myeloma Patients?
Webinar – October 17, 2019
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Nuclear Export Inhibitor:
XPOVIO (selinexor)
Drug Formulation Approval
XPOVIO
(selinexor) Twice a week tablet
• In combination with dexamethasone for
relapsed/refractory myeloma patients who
have received at least four prior therapies
and whose disease is refractory to at least
two proteasome inhibitors, at least two
immunomodulatory agents, and an anti- CD38 monoclonal antibody
XPOVIO is from a new class of drug,
selective inhibitor of nuclear export (SINE)
Selinexor is a new agent for myeloma patients who
have exhausted many of the existing therapies.
XPOVIO (selinexor) Clinical Study
Design That Led to Approval
Oral XPOVIO Dexamethasone 80
mg
20 + mg
XPOVIO/dexamethasone twice weekly (days 1 and 3) – 28 day cycle
MM, multiple myeloma; PI, proteasome inhibitor; IMiD, immunomodulatory drug; ANC, absolute neutrophil count
Primary end point
• Overall response rate (ORR)
Secondary end points
• Duration of response (DOR)
• Clinical benefit rate (CBR)
• Overall survival (OS)
• Progression-free survival (PFS)
• Safety
Patient population
• MM previously treated with
Velcade, Kyprolis, Revlimid,
Pomalyst, Darzalex, an
alkylator, and glucocorticoids
• Disease documented to be
refractory to ≥1 PI, ≥1 IMiD,
daratumumab, a glucocorticoid
and last line of therapy
Key inclusion and
exclusion criteria
• Creatinine clearance ≥20 mL/min
• ANC ≥1,000/mm3
• Platelets ≥75,000/mm3
(if bone marrow plasma cell
>50%; platelets >50,000/mm3)
• Hemoglobin ≥8.5 g/dL
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New Drug Approval: What Does the Arrival of XPOVIO (selinexor) Mean for Multiple Myeloma Patients?
Webinar – October 17, 2019
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Prior Treatments of Patients
Enrolled Onto XPOVIO Clinical Trial
A total of 123 patients were enrolled, however 1 patient did not meet eligibility criteria, thus was excluded from this analysis.
IMiD, immunomodulatory drug; PI, proteasome inhibitor
N=122
Median prior regimens (range) 7 (3–18)
Number of prior treatment regimens
≤6
7–8
≥9
50 (41%)
36 (30%)
36 (30%)
Prior treatments
Refractory to PI/IMiD/daratumumab/glucocorticoid
Refractory to carfilzomib/pomalidomide/daratumumab
Refractory to 2 PIs/2 IMiDs/daratumumab
Stem cell transplant
≥2 Transplants
Intensive combination chemotherapy (eg, DT-PACE)
Daratumumab in last prior regimen
Daratumumab in combination
CAR T-cell therapy
122 (100%)
117 (96%)
83 (68%)
102 (84%)
29 (28%)
32 (26%)
58 (48%)
86 (70%)
2 (2%)
Efficacy of Selinexor in Relapsed/Refractory
Myeloma: XPOVIO + Dexamethasone
IMiD, immunomodulatory drug; PI, proteasome inhibitor
1. STORM Trial. Chari A et al. N Engl J Med. 2019;381:727; 2. Gavriatopoulou M et al. Presented at the 17th International Myeloma Workshop;
September 12–15, 2019. Abstract FP-110; 3. Vogl DT et al. Presented at the 17th International Myeloma Workshop; September 12–15, 2019. Abstract FP-111.
Additional analyses showed clinical benefit with
XPOVIO regardless of patient age and renal function.2,3
1.6 2.3 1.7 1.2
4.9 4.7 6.9 4.8
19.7 22.1
25.9
19.3
13.1
14.0
10.3
12.0
0
5
10
15
20
25
30
35
40
45
50
All Patients
(N=122)
Prior Dara in Combo
(N=86)
Prior Dara in Last Line
(N=58)
2 PI, 2 IMiD, &
Dara Refractory
(N=83)
sCR VGPR PR MR
ORR 26.2%
ORR 29.1% ORR 34.5%
ORR 25.3%
Percent Response
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New Drug Approval: What Does the Arrival of XPOVIO (selinexor) Mean for Multiple Myeloma Patients?
Webinar – October 17, 2019
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M protein changes shown for all patients with increases, and for patients with decreases ≤20% (30 patients with decreases 0–19% not shown).
CR, complete response; FLC, immunoglobulin-free light chain; MR, minimal response; PD, progressive disease; PR, partial response; SD, stable disease;
VGPR, very good partial response
• The majority of evaluable patients (71%)
had reductions in M protein
• ≥SD: 78.7%
XPOVIO Effect on M Protein
Overall Survival of Patients on XPOVIO in STORM
Compared to Historical FHAD Patients (Database)
N=64
Median OS 10.4 months
N=36
Median OS 5.8 months
FHAD, Flatiron Health Analytic Database
STORM Trial. Chari A et al. N Engl J Med. 2019;381:727.
STORM Patients
Overall Survival
FHAD Patients
Overall Survival
0 4 8 12 16
0
25
50
75
100
Months
Percent Survival
0 4 8 12 16
0
25
50
75
100
Months
Percent Survival
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New Drug Approval: What Does the Arrival of XPOVIO (selinexor) Mean for Multiple Myeloma Patients?
Webinar – October 17, 2019
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Adverse Events That Emerged
During XPOVIO Treatment
Event (% of patients) Grade 3 Grade 4 Total
Low platelets 25 33 73
Low RBCs/hemoglobin 43 1 67
Low neutrophils 18 3 40
Low leukocytes 14 0 33
Low lymphocytes 8 3 16
STORM Trial. Chari A et al. N Engl J Med. 2019;381:727.
Event (% of patients) Grade 3 Grade 4 Total
Fatigue 25 0 73
Nausea 10 0 72
Decreased appetite 5 0 56
Decreased weight 1 0 50
Diarrhea 7 0 46
Vomiting 3 0 38
Low sodium 21 1 37
Upper respiratory tract infection 2 0 23
Constipation 2 0 22
Difficulty breathing 4 0 22
Hematologic Toxicities Non-Hematologic Toxicities
Supportive Care Strategies at Mt. Sinai
• Ritalin 5–10 mg OD as needed
Gastrointestinal
Fatigue
• Platelets ≤50K or less: initiate N-Plate 10 mcg/kg weekly
Cytopenias
• Weekly CMPs
• IV fluids as needed with .9NS
• NaCl tabs 1GM TID
Low sodium
(hyponatremia)
• Bring patient back
in D3 or 4 of 1st
week of treatment
to assess for AEs
and provide IV
hydration as
needed
Na
Sodium
22.990
• Antiemetic Protocol:
− Zofran
− Rolapitant
− Olanzapine
• Most patients need a combination
of all 3 above antiemetics.
Reassess need after C1
• Contact your doctor if nausea, vomiting,
or diarrhea occur or persist
• Emend is avoided
− May potentiate the
activity with dex and
lead to hyperglycemia
• Avoid Megace (4 pts
developed clots)
• Maintain fluid intake
• Stay hydrated and active
• Report signs of bleeding right away
• Report signs of fatigue or shortness of breath
Patients Doctors
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New Drug Approval: What Does the Arrival of XPOVIO (selinexor) Mean for Multiple Myeloma Patients?
Webinar – October 17, 2019
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Selinexor and Backbone Treatments of MM
Patients (STOMP): Phase 1 Preliminary Results
STOMP Patient Characteristics SVd SPd SRd SDd SKd
Lines of therapy
≥1
Not V
refractory
≥2
including
PI and IMID
≥1
Not R25
refractory
≥3
including
PI and IMID
Patients enrolled 42 34 19 21 21
Median age, years 64 61 68 68 64
Median time diagnosis to treatment, years 5 6 4 5 4.5
Median prior regimens 3 4 1 4 4
Overall response rate 84% 50%* NR 74% 63%
ORR in backbone refractory 43% 38% NR N/A 67%
Progression-free survival 9.2 mos 10.3 mos NR NR 3.7 mos
PFS in backbone refractory 6.1 mos 4.8 mos NR N/A NR
*N=30 evaluable
Lonial S et al. NCCN 2018; Bahils et al 2018; Chen et al 2018; Jakubowiak et al ASH 2016; Gasparetto C et al Blood. 2018;132: Abstract 599;
White D et al. Presented at the 17th International Myeloma Workshop; September 12–15, 2019. Abstract OAB-083.
Summary
Due to aggressiveness of the disease and short half-life of drug, STORM treatment
begins with high doses of XPOVIO in an effort to obtain rapid disease control.
The XPOVIO clinical trial (STORM) included the largest, most heavily treated
patient population with MM in a prospective clinical trial to date.
XPOVIO plus dex treatment achieved an overall response rate of 26.2% in penta- exposed and triple class refractory MM.
Patient counseling, optimal supportive care, dose holds/modification associated with
less drug discontinuation due to AEs and increased RR, PFS, OS.
Accelerated approval demonstrates activity of XPOVIO/dex without additional anti- myeloma agents; however, given genomic complexity of RRMM, combination
strategies use only weekly XPOVIO and will likely be primary use.
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New Drug Approval: What Does the Arrival of XPOVIO (selinexor) Mean for Multiple Myeloma Patients?
Webinar – October 17, 2019
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Patient Perspective
Michael Walsh
• 59 years old
• Singer, actor, pianist
• Owner of home
recording studio in
Manhattan
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New Drug Approval: What Does the Arrival of XPOVIO (selinexor) Mean for Multiple Myeloma Patients?
Webinar – October 17, 2019
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Cancer Journey
• Diagnosed with lamda light chain multiple
myeloma on November 8th, 2013
• Treated with at least 11 lines of therapy including
3 bone marrow transplants
• Participated in 5 clinical trials that failed
• In 2017, from September to the end of the year,
spent 55 days in-patient trying to get my cancer
under control
XPOVIO (selinexor)
• In January, 2018 I took part in a clinical trial of
selinexor
• After just a few weeks taking selinexor, my light
chains dropped significantly from over 12,000
mg/l to under 800
• Took it again in May of 2019; light chains
numbers dropped from 19,000 to 300
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New Drug Approval: What Does the Arrival of XPOVIO (selinexor) Mean for Multiple Myeloma Patients?
Webinar – October 17, 2019
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Getting Hydration
Questions & Answers
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New Drug Approval: What Does the Arrival of XPOVIO (selinexor) Mean for Multiple Myeloma Patients?
Webinar – October 17, 2019
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New Drug Approval: What Does the Arrival of XPOVIO (selinexor) Mean for Multiple Myeloma Patients?
Webinar – October 17, 2019
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Upcoming MMRF Webinar
For more information or to register, visit
theMMRF.org/PatientEd
Title Date Time
Maintenance Therapy November 2019 1:00 PM ET
American Society of Hematology (ASH)
2019 Meeting Highlights December 18, 2019 1:00 PM ET
MMRF Patient Summits
Saturday, November 2, 2019
Philadelphia, Pennsylvania
• Adam Cohen, MD—Co-Chair
University of Pennsylvania
• Edward Stadtmauer, MD—Co-Chair
University of Pennsylvania
Saturday, November 9, 2019
Toronto, Ontario, Canada
• Donna Reece, MD—Co-Chair
Princess Margaret Cancer Centre
• Suzanne Trudel, MD—Co-Chair
Princess Margaret Cancer Centre
For more information
or to register, visit
theMMRF.org/Patient