Advances in Myeloma Treatments: What Patients & Caregivers Need to Know by International Myeloma Foundation

Thank you to our sponsors!

IMF Patient and Family Webinar Agenda

*times listed in US Eastern Time Zone

10:00 – 10:05 AM 10:05 – 10:25 AM

Welcome Announcements with Dr. Brian G.M. Durie Myeloma 101 Dr. Brian G.M. Durie

10:25 – 10:50 AM

Life Is A Canvas, You Are The Artist: Side Effects & Symptom Management

Teresa Miceli RN, BSN, OCN 10:50 – 11:10 AM

Addresses in Myeloma Treatments: Looking Beyond 2021 Dr. Brian G.M. Durie

11:10 – 11:20 AM

Panel Discussion

11:20 – 11:30 AM

BREAK

IMF Patient and Family Webinar Agenda

*times listed in US Eastern Time Zone

11:30 – 12:00 PM

Immune Therapies: Treatments That Work With Our Own Immune Systems Dr. Adam Cohen

12:00 – 12:20 PM

How to Find What You Need to Know Robin Tuohy, IMF Vice President, Support Groups

12:20 – 12:50PM

When Myeloma Comes Back: Approaches to Relapse Dr. Rafat Abonour

12:50 – 1:00 PM

Summary Panel Discussion Webinar Survey & Closing Remarks 3

IMF Patient and Family Webinar

Myeloma 101 and COVID-19 updates Brian G.M. Durie, MD Cedars-Sinai Outpatient Cancer Center Los Angeles, CA 4

Global cases of COVID-19 reported

Data from the CDC and WHO. The data includes cases as of October 25, 2021. https://covid.cdc.gov/covid-data-tracker/#global-counts-rates and https://covid19.who.int/

Overall U.S. COVID-19 Data Tracker Trends in Number of COVID-19 Cases and Deaths in the US Reported to CDC

Overall US COVID-19 Vaccine | Deliveries and Administration; Maps, charts, and data provided by CDC https://covid.cdc.gov/covid-data-tracker/#vaccinations and https://covid.cdc.gov/covid-data-tracker/#datatracker-home

Delta Variant: Infections and Spread

CDC -- Delta Variant: What We Know About the Science https://www.cdc.gov/coronavirus/2019-ncov/variants/delta-variant.html

Vaccination for Myeloma Patients YES is good!!! Checking antibody levels becoming more important Additional vaccine dose strongly recommended 4th dose (booster) under review Please note: Antibody tests for COVID-19 are available through healthcare professionals and laboratories. Check with your healthcare professional to see if they offer antibody tests and whether you should get one. https://www.cdc.gov/coronavirus/2019-ncov/testing/serology-overview.html

Which vaccine?  Pfizer/ Moderna – Excellent!

 J&J – not live!/ single shot only  Blood clot risk  AstraZeneca – 79%76% efficacy

(slightly reduced)  Blood clot risk

100% reduction of hospitalizations and deaths

Important to know Airborne transmission dominant Variants a serious challenge Beware asymptomatic spread Watch out for young people! Still avoid travel Indoor space a severe problem 10

Risks of Air Travel    

Significant Beware the food service time (maybe skip) Boarding/ disembarking a concern One infected individual can infect plane

 Still considered as essential only!

Masks – still required! So: use best masks possible – BROAD AirPro Mask  AirPro Mask is a Powered Air-Purifying Respirator system. It includes a KN95 mask and a filtration unit with a 3-speed fan, HEPA H13 filter, and chargeable lithium battery.

CDC: Your Guide to Masks https://www.cdc.gov/coronavirus/2019-ncov/prevent-getting-sick/about-face-coverings.html

What Can You Do Once You’re Vaccinated?

New York Times – March 30, 2021 https://www.nytimes.com/interactive/2021/03/30/opinion/coronavirus-vaccine-risks.html

When you’ve been fully vaccinated

CDC: When You’ve Been Fully Vaccinated - How to Protect Yourself and Others https://www.cdc.gov/coronavirus/2019-ncov/vaccines/fully-vaccinated.html

Patient Guidance Question: Can I go for a walk?

• Yes Question: Can I go to the dentist?

• Yes, with care 15

 

   

Common Issues Pandemic fatigue/ stress Not feeling resilient Healthcare team not coordinated Not prepared for Zoom or appointments Need electronic help! Contacts with unknown COVID-19 status 16

Pandemic Fatigue  Real for everyone!

 Important to reach out to family and friends  Try to de-stress

 Shedd Aquarium – Penguins  Work on resilience  Living Well with Myeloma: Building Your

Resilience During Challenging Times (IMF video)  Resilience Builder Tool (link on IMF website)

Who is eligible for a COVID-19 Vaccine Booster Shot?

CDC: Who Is Eligible for a COVID-19 Vaccine Booster Shot? https://www.cdc.gov/coronavirus/2019-ncov/vaccines/booster-shot.html

18 18

Vaccination Boosters and Antibody Levels

Current questions

COVID-19 vaccination in patients with multiple myeloma: a consensus of the European Myeloma Network

COVID-19 vaccination in patients with multiple myeloma: a consensus of the EMN https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(21)00278-7/fulltext

20 20

What does the future hold?

 Vaccination essential.

 Masks required.  Caution in indoor spaces.

Other IMF Resources: Ask Dr. Durie Videos

COVID-19 FAQ #35: What should myeloma patients know about antibody testing and booster shots?

COVID-19 FAQ #34: How can myeloma patients protect themselves

https://www.myeloma.org/videos/covid-19-faq-35-shouldmyeloma-patients-know-about-antibody-testing-booster-shots

https://www.myeloma.org/videos/covid-19-faq-34-how-canmyeloma-patients-protect-themselves-against-delta-variant

against the Delta variant?

Support Group Virtual Meetings

Over 90 support groups are now holding monthly virtual GoToMeetings through the IMF

Support Group Virtual Meetings

Over 90 support groups are now holding monthly virtual GoToMeetings through the IMF

We will get through this together! Myeloma has no borders

“Do Remember They Can’t Cancel the Spring” – David Hockney

Support messages in the sky above Los Angeles An apricot tree grows in Turkey

IMF Patient and Family Webinar

Teresa Miceli RN, BSN, OCN Mayo Clinic Rochester, MN

Life Is A Canvas, You Are The Artist: Side Effects & Symptom Management 26

Patient Family Seminar, October 30, 2021

LIFE IS A CANVAS, YOU ARE THE ARTIST Name Teresa Miceli, RN BSN OCN Institution Mayo Clinic-Rochester, MN

Patient Education Slides 2021

OBJECTIVES FRAMING YOUR CARE

Know your care team, Shared Decision Making & Reliable Resources

COLOR WHEEL OF TREATMENT

Myeloma and treatment side effects & symptom management

LIVE LIFE IN COLOR

Healthful Living, infection prevention, Learn Lots, Laugh renal and bone Much, health Love Life 28

FRAMING YOUR CARE Know your care team, Shared Decision Making & Reliable Resources

You are central to the care team

Pharmacist

CARE TEAM COLLAGE General Hem/Onc Myeloma Specialist

Communicate with your team • Myeloma is a chronic disease • Understand the roles of each

team member and who to contact for your needs • Participate in support network

Be empowered • Ask questions, learn more • Participate in decisions • Know your history –

Myeloma ManagerTM Personal Care AssistantTM

Primary Care Provider (PCP)

You and Your Caregiver(s) Support Network

Subspecialists Allied Health Staff

SHARED DECISION-MAKING Be empowered to be part of the treatment decision-making • Ask for time to consider options (if needed/appropriate) • Understand options; consider priorities • Use reliable sources of information • Use caution considering stories of personal

experiences • Consider your goals/values/preferences • Get a 2nd opinion, Meet with a Myeloma expert

Data From Research

HCP Clinical Experience TREATMENT DECISION

• Express your goals/values/preferences; create a

dialog

• My top priority is [goal/value]; additional [preferences] are also important. • I think [treatment] may be a good choice given my priorities… What do you think?

• Arrive at a treatment decision together

Your Preference Philippe Moreau. ASH 2015.

KNOWLEDGE IS POWER USE REPUTABLE SOURCES Website: http://myeloma.org

IMF TV Teleconferences

eNewsletter: Myeloma Minute

IMF InfoLine 1-800-452CURE 9am to 4pm PST Download or order at myeloma.org

COLOR WHEEL OF TREATMENT Treatment options, side effects, symptom management, & supportive care

GALLERY OF GOALS MYELOMA TREATMENT • Rapid and effective disease control • Durable disease control • Improved overall survival • Minimize side effects

SUPPORTIVE THERAPIES • Prevent disease- and treatmentrelated side effects • Optimize symptom management • Allow for good quality of life

• Allow for good quality of life

DISCUSS GOALS AND PRIORITIES WITH YOUR HEALTHCARE TEAM 34

PATIENT-REPORTED SYMPTOMS A meta-analysis identified the most common patient-reported symptoms and impact on QOL and were present at all stages of the disease. Symptoms resulted from both myeloma disease and treatment, including transplant, and were in these categories:

Physical

Psychological

• Fatigue

• Depression

• Constipation

• Anxiety

• Pain

• Sleep Disturbance

• Neuropathy

• Decreased Cognitive Function

• Impaired Physical Functioning • Sexual Dysfunction

Ramsenthaler, et al. 2016. https://doi.org/10.1111/ejh.12790.

Financial • Financial burden (80%) • Financial toxicity (43%)

• Decreased Role & Social Function

COLOR WHEEL OF TREATMENT OPTIONS -Mibs

Frontline

Velcade® (bortezomib)

Maintenance

Velcade® (bortezomib)

Relapse

Kyprolis® (carfilzomib) Ninlaro® (ixazomib)

-MAbs

-Mides

Steroids

Darzalex® (daratumumab)

Thalomid® (thalidomide) Revlimid® (lenalidomide)

Dexamethasone Prednisone Prednisolone SoluMedrol

Others

Melphalan Cyclophosphamide

Darzalex® (daratumumab) Empliciti® (elotuzumab) Sarclissa® (Isatuximab)

Thalomid® (thalidomide) Revlimid® (lenalidomide) Pomalyst® (pomalidomide)

Dexamethasone Prednisone Prednisolone SoluMedrol

Melphalan Cyclophosphamide Bendamustine

CelMods • Iberdomide • CC-92480

Neuropathy Carfilzomib: Cardiac

ImmunoTherapy

Cellular Therapies Melphalan + ASCT

Revlimid® (lenalidomide)

Pending FDA Approval Noted Side effects

Alkylators

Infusion reaction

DVT/PE

See steroid slide

Myelosuppression

Blenrep® (Belantamab mafodotin) “Belamaf”

Xpovio® (Selinexor) Doxil (liposomal doxorubicin) Farydak® (panobinostat)

Abecma® (Ide-Cel, CAR-T)

ADCs BSAs Ex: Teclistamab, Talquetamab Cevostamab

Venclexta® (venetoclax)

Other CAR-T • Cilta-Cel

Infusion reaction Blenrep®: Keratopathy

Myelosuppression, GI Selinexor: Low sodium

Infection risk CAR-T: CRS and neurotoxicity

DVT – Deep Vein Thrombosis; PE – Pulmonary Embolism; ADC – Antibody Drug Conjugates; BSA – Bi-Specific Antibodies; ASCT – Auto Stem Cell Transplant

Melphalan + ASCT

THE BRIGHT

DARK SIDE TO STEROIDS

Steroid Synergy Steroids are a backbone and work in combination to enhance myeloma therapy

Managing Steroid Side Effects • Consistent schedule (AM vs. PM) • Take with food • Stomach discomfort: Over-the-counter or

prescription medications • Medications to prevent shingles, thrush, or other infections

Do not stop or adjust steroid doses without discussing it with your health care provider

Steroid Side Effects • Irritability, mood swings, depression • Difficulty sleeping

• Blurred vision, cataracts

(insomnia), fatigue

• Flushing/sweating

• Increased risk of

• Stomach bloating,

infections, heart disease

• Muscle weakness,

cramping

• Increase in blood

pressure, water retention

hiccups, heartburn, ulcers, or gas

• Weight gain, hair

thinning/loss, skin rashes

• Increase in blood

sugar levels, diabetes

Rajkumar SV, Jacobus S, Callander NS, Fonseca R, Vesole DH, Williams ME, Abonour R, Siegel DS, Katz M, Greipp PR, Eastern Cooperative Oncology Group (2010) Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial. Lancet Oncol 11(1):29–37. King T, Faiman B. Steroid-Associated Side Effects: A Symptom Management Update on Multiple Myeloma Treatment. Clin J Oncol Nurs. 2017 Apr 1;21(2):240-249. doi: 10.1188/17.CJON.240-249. PMID: 28315528.

HIGHLIGHT YOUR CARE:

ADDITIONAL TOOLS TO COMPLETE THE PICTURE DVT/PE Prevention

Medications

Non-medication Therapies

Lifestyle Options

Bone Health

Blood thinners Ex: Aspirin, DOACs

Bone Strengthening Agents Calcium Vitamin D

Compression stockings

Radiation Surgery Immobilization Physical therapy

Activity Stop smoking Weight loss

Activity

Renal Health

Infection Prevention

Peripheral Neuropathy

GI Symptoms

Med dose reduction Avoid harmful meds

Antibacterial Antiviral Antifungal IVIG GCSF

Antidepressants Anti-neuroleptic Analgesia Vitamins Dose adjustments

Anti-nausea Anti-diarrheal Laxatives & stool softeners Fiber-binding agents

Dialysis

Masking Activity

Massage Acupuncture Cocoa Butter

Dietary choices Relaxation

Hydration

Handwashing Avoid crowds & sick people Monitor for fever COVID precautions

Activity Diabetes management

Avoid greasy foods Activity Hydration

GI SYMPTOMS: PREVENTION & MANAGEMENT Diarrhea may be caused by medications and supplements • • • •

Laxatives, antacids with magnesium Antibiotics, antidepressants, others Milk thistle, aloe, cayenne, saw palmetto, ginseng Sugar substitutes in sugar free gum

Avoid caffeinated, carbonated, or heavily sugared beverages Take anti-diarrheal medication • Imodium®, Lomotil®, or Colestid if recommended • Fiber binding agents – Metamucil®, Citrucel®, Benefiber® • Welchol® if recommended

Physical

Constipation may be caused by • Opioid pain relievers, antidepressants, heart or blood pressure medications, others • Supplements: Calcium, Iron, vitamin D (rarely), vitamin B-12 deficiency

Increase fiber • Fruits, vegetables, high fiber whole grain foods • Fiber binding agents – Metamucil®, Citrucel®, Benefiber®

Fluid intake can help with both diarrhea and constipation, and good for kidneys. Discuss GI issues with health care providers to identify causes and make adjustments to medications and supplements.

Smith LC, et al. CJON.2008;12(3)suppl:37-52. Faiman B. CJON. 2016;20(4):E100-E105. Miceli, T. et al. (2021). Cancer Treatment and Res Com, 100476.

PAIN: PREVENTION AND MANAGEMENT

Physical

Pain can significantly compromise quality of life Sources of pain include bone disease, neuropathy and medical procedures

Management • Prevent pain when possible • Bone strengtheners to decrease fracture risk; anti viral to prevent shingles; sedation before procedures

• Interventions depends on source of pain • May include medications, physical therapy, surgical intervention, radiation therapy, etc

• Complementary therapies • Mind-body, meditation, yoga, supplements, acupuncture, activity, etc

Faiman B, et al. CJON. 2017;21(5)suppl:19-36. Miceli, T. et al. (2021). Cancer Treatment and Res Com, 100476.

Tell your health care provider about any new bone pain or chronic pain that is not adequately controlled

PERIPHERAL NEUROPATHY MANAGEMENT Peripheral neuropathy: damage to nerves in extremities (hands, feet, or limbs) • • • • • •

Numbness Tingling Prickling sensations Sensitivity to touch Burning and/or cold sensation Muscle weakness

Physical

Prevention / Management: • Bortezomib once-weekly or subcutaneous administration • Massage area with cocoa butter regularly • Supplements:

• B-complex vitamins (B1, B6, B12) • Folic acid, and/or amino acids but do not take on day of Velcade® (bortezomib) infusion

• Safe environment: rugs, furnishings, shoes

If PN worsens, your HCP may: Report symptoms of peripheral neuropathy early to your health care provider; nerve damage from PN can be permanent if unaddressed

• Change your treatment • Prescribe oral or topical pain medication • Suggest physical therapy

Faiman B, et al. CJON. 2017;21(5)suppl:19-36. Tariman, et al. CJON.2008;12(3)suppl:29-36. Miceli, T. et al. (2021). Cancer Treatment and Res Com, 100476.

FATIGUE, ANXIETY & DEPRESSION

Physical Psychological

Physical symptoms impact mental well being. All can affect quality of life and relationships.

• Fatigue is the most common reported symptom (98.8%) Sources include anemia, pain, reduced activity, insomnia, treatment toxicity, bone marrow suppression

• Anxiety reported in >35% • Depression nearly 25% Financial concerns, disease progression, end-of-life, and change in social and sexual function were highlighted sources

Often, people do not share these symptoms with their provider. Talk to your provider about symptoms that are not well controlled or thoughts of self harm. Help is available. Ramsenthaler, et al. 2016. https://doi.org/10.1111/ejh.12790. Catamero D et al. CJON. 2017; 21(5)suppl:7-18.

REST AND RELAXATION CONTRIBUTE TO GOOD HEALTH � Adequate rest and sleep are

essential to a healthful lifestyle

Short and disturbed sleep increase risk of • Heart related death • Increase anxiety • Weaken immune system • Worsened pain • Falls and personal injury

� Things that can interfere with sleep • Medications : steroids, stimulants, herbal

supplements, alcohol • Psychologic: fear, anxiety, stress • Physiologic: sleep apnea, nocturia, pain, inactivity, heart issues Rod NH et al 2014. PloS one. 9(4):e91965; Coleman et al. 2011. Cancer Nurs. 34(3):219-227. National Sleep Foundation. At: http://sleepfoundation.org/ask-the-expert/sleep-hygiene

Psychological

� Sleep hygiene is necessary for

quality nighttime sleep, daytime alertness

• Engage in exercise but not too near • • • • • •

bedtime Increase daytime natural light exposure Avoid Daytime napping Establish a bedtime routine - warm bath, cup of warm milk or tea Associate your bed ONLY with sleep Sleep aid may be needed Avoid before bedtime: • Caffeine, nicotine , alcohol and sugar • Large meals and especially spicy, greasy foods • Computer screen time

Mustian et al. Journal of clinical Oncology. Sep 10 2013;31(26):3233-3241. Stan DL, et al. Clin J Oncol Nurs. Apr 2012;16(2):131-141. Zeng Y et al., Complementary therapies in medicine. Feb 2014;22(1):173-186.

HEALTHFUL LIVING STRATEGIES: PREVENTION Manage stress • Rest, relaxation, sleep hygiene • Mental health / social engagement • Complementary therapy

Maintain a healthy weight • Nutrition • Activity / exercise

Preventative health care • Health screenings, vaccinations • Prevent falls, injury, infection • Stop smoking

Maintain renal health • Myeloma management • Hydration • Avoid renally-toxic medications – Dose adjust to renal function • Diabetes management

Protect your bones • Nutrition, Calcium + D supplement • Weight-bearing activity / walking • Bone strengthening agents

• Dental care

“An ounce of prevention is worth a pound of cure.” Benjamin Franklin Faiman B, et al. CJON. 2017;21(5)suppl:19-36. Dimopoulous M, et al. Leukemia. 2009;23(9):1545-56. Brigle K, et al. CJON. 2017;21(5)suppl:60-76. Faiman B, et al. CJON. 2017;21(5)suppl:19-36. Faiman B, et al. CJON. 2011;15suppl:66-76. Miceli TS, et al. CJON. 2011;15(4)suppl:9-23.

Financial

FINANCIAL BURDEN Financial burden comes from

Funding and assistance may be available

• Medical costs

• Federal programs

• • • •

Premiums Co-payments Travel expenses Medical supplies

• Prescription costs

• Loss of income • Time off work or loss of employment • Caregiver time off work

Contact the Social Services department at your hospital or clinic to talk to a social worker for assistance.

• Pharmaceutical support

• Non-profit organizations • Websites: • • • • • • •

Medicare.gov SSA.gov LLS.org Rxassist.org NeedyMeds.com HealthWellFoundation.org Company-specific website

YOU ARE NOT ALONE

Questions?

IMF Patient and Family Webinar

Advances in Myeloma Treatments: Looking Beyond 2021 Brian G.M. Durie, MD Cedars-Sinai Outpatient Cancer Center Los Angeles, CA 47

Advances in Myeloma Treatments: Looking Beyond 2021

DR. BRIAN DURIE

Brian GM Durie Patient and Family Webinar

Progress in All Areas  Diagnosis, risk criteria and monitoring  Early disease

 Frontline therapy  Consolidation/ maintenance  Early relapse  Later relapse and new drug development 49

MGUS  Early detection (from screening) will:  Reveal possible causes or triggers

 Help improve all outcomes  Enable early interventions for both prevention and treatment 50

iStopMM Project Details Ca 3600 with MGUS Smoldering myeloma N=200

No further work-up N=1200 •

• • • •

Without MGUS/SMM

R IMWG Reccommendations N=1200

Intervention arm N=1200

Followed for progression to multiple myeloma or another malignancy (Cancer Registry) Followed for all diagnoses in inpatient and outpatient clinics throughout Iceland (Patient Registry) Followed for vital status every 2 months (Population Registry) All prescriptions throughout Iceland (Prescription registry) Regular quality of life assessments 51

A Glimpse of the Origins of MGUS 12/1997 No MGUS detected

MGUS – 8/2006

Mass spec positive 24032.4 24032.6

Dr. Kyle – Olmsted County MGUS Study

Role of biobanking in iStopMM Material biobanked Bone marrow • BM biopsy -> formalin fixed

• BM smear • BM aspirate -> plasma + cell sorting Blood and urine • LiHep plasma

• • • • • • •

Cell free Plasma Buffy coat EDTA tube (DeCode) Serum Mononuclear cells PAXgene tube Urine 53

Many diverse outcomes of iStopMM Tumor microenvironment Cancer screeningRenal amyloidosis Risk scores MGRS Mental health Pain Genetics Early intervention Flow cytometry Neuropathy Correlative science Waldenströms Survival Cardiac amyloidosis Psychological impact Polyclonal The significance of the immunoglobulins “unknown significance”

Smoldering Multiple Myeloma (SMM)  SMM risk scoring is essential  Better predictors are coming!  Best management is evolving

Risk Score to Predict Progression Risk At 2 Years Score

100 High-risk group >12

0 2 3 5

0 3 4 0 2 3 5 6 2

% with progression

Risk Factor FLC Ratio 0-10 (ref) > 10-25 > 25-40 > 40 M protein (g/dL) 0-1.5 (ref) > 1.5-3 >3 BMPC% 0-15 (ref) > 15-20 > 20-30 > 30-40 > 40 FISH abnormality

Intermediate-risk group (9-12)

Risk Stratification Groups

Hazard Ratio (95% CI) Versus Low-risk group (censored 2 year)

0-4

Reference

5-8

7.56 (3.77 to 15.2)

9-12

17.3 (8.63 to 34.8)

> 12

31.9 (15.4 to 66.3)

Low-intermediate-risk Group (5-8)

40 Low-risk group (0-4) 20

Total Risk Score

2-year Progression n (%)

0-4

9 / 241 (3.7%)

5-8

67 / 264 (25.4%)

9-12

65 / 133 (48.9%)

> 12

37 / 51 (72.6%)

0 0

Months # at Risk 0-4

241

238

229

213

194

175

153

117

100

5-8

264

256

229

197

174

145

118

9-12

133

119

>12

San Miguel. ASCO 2019. Abstr 8000. Mateos Blood Cancer J. 2020;10:102.

Ultra High Risk

Curative Strategy for High-Risk Smoldering Myeloma (GEM-CESAR) Outcomes including Consolidation & 1 year maintenance 77 patients completed induction, HDT-ASCT, consolidation, and 1 yr of maintenance Induction (KRd x 6) (n = 77)

HDT-ASCT (n = 77)

Consolidation (KRd x 2) (n = 77)

Maintenance (Rd x 1 Yr) (n = 77)

≥ CR

VGPR

Progressive disease

MRD negative

Response, %

≥ CR 81%

MRD 62%

*Biological progressive disease at end of maintenance, MRD positive.

Mateos. ASH 2019. Abstr 781.

Curative Strategy for High-Risk Smoldering Myeloma (GEM-CESAR): PFS and OS 100

100

PFS 35-Mo PFS: 92%

60 40 20 0

Patients (%)

35-Mo OS: 96%

60 40 20

Median follow-up: 35.2 (5.4-53.2) 0

0 30

Mos

 6 patients progressed (biological PD, n = 5) ‒ 4 patients with PD were at ultrahigh risk Mateos. ASH 2019. Abstr 781.

Median follow-up: 35.2 (5.4-53.2) Median follow-up: 35.2 (5.4-53.2) 0

Mos

 3 patients died; only 1 was considered a treatment-related death 58

Blood Testing for Monitoring  Mass spec gives more precision  Blood myeloma cells can be tracked  Immune status can also be monitored  Interim MRD status can be assessed (reducing need for bone marrows) 59

Evidence for role of blood testing

Circulating Tumor Plasma Cell (CTPC) Black Swan Research Initiative Project Publications

Link to articles -- https://pubmed.ncbi.nlm.nih.gov/30455467/ and https://pubmed.ncbi.nlm.nih.gov/31697808/

MRD status systematically discriminates two different risk groups A large meta-analysis establishing the role of MRD in all disease settings

Munshi NC, et al. Blood Adv. 2020;4(23):5988-5999.

Next phase in the search for a CURE Molecular and immune testing

Best Frontline Therapy

MRD Positive or Biochemical relapse

New Immune Therapy Cocktail

Opportunities for 2021-2023  New Trials To achieve MRD undetected at biochemical relapse  Cutting edge disease monitoring Blood MRD sensitivity at 10-8 Mass spectrometry (high sensitivity) Serial immune testing Molecular characterization 63

Frontline Therapy  A dilemma will continue: Triplets (VRd/ VTd/ KRd) Versus

Quadruplets + Dara/Isa  Efficacy/ costs/ access/ toxicities will be debated

MAIA TRIAL: DRd vs Rd

T Facon et al. N Engl J Med 2019;380:2104-2115.

CASSIOPEIA TRIAL: Dara-VTd vs VTd Quadruplets as Initial Therapy

Upfront ASCT  Will become priority if MRD positive

 Will be assessed versus CAR T and other powerful immune therapies

Consolidation  Consolidation will become more important

to achieve MRD undetected:  Extra 2 cycles if needed (6 total)  CAR T or other immune Rx  New agents

Maintenance  Maintenance will include:

 Revlimid®  Proteasome inhibitor  Dara/ Isa With target for ~ 2 year duration

Early relapse (1-3 prior regimens)  Use a triplet if feasible

 Incorporate Dara/Isa early if not use previously  Consider Kyprolis® if high risk  New immune therapies may become top choices!

Later relapses (triple exposed)  Multiple approved new agents such as:

Selinexor®, Belantamab, CAR T  Multiple new agents in trials including: CelMods, bispecifics, new targeted agents

 Studies with “relaxed” entry criteria required to assess real world data/ experience and evidence

and make agents available to poorer-risk patients 71

COVID will be with us! • Vaccination • Boosters • Masks • Other protections

Despite COVID… The future is bright with likely improved outcomes 73

Panel Discussion

Audience Q&A

• Open the Q&A window, allowing you to ask questions to the host and panelists. They can either reply to you via text in the Q&A window or answer your question live. • If the host answers live, you may see a notification in the Q&A window.

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IMF Patient and Family Webinar

IMF Patient and Family Webinar Agenda

*times listed in US Eastern Time Zone

11:30 – 12:00 PM

Immune Therapies: Treatments That Work With Our Own Immune Systems Dr. Adam Cohen

12:00 – 12:20 PM

How to Find What You Need to Know Robin Tuohy, IMF Vice President, Support Groups

12:20 – 12:50PM

When Myeloma Comes Back: Approaches to Relapse Dr. Rafat Abonour

12:50 – 1:00 PM

Summary Panel Discussion Webinar Survey & Closing Remarks 77

IMF Patient and Family Webinar

Adam Cohen, MD

Immune Therapies: Treatments That Work With Our Own Immune Systems

Abramson Cancer Center University of Pennsylvania Philadelphia, PA

Immunotherapies: CAR T cells and Bispecific Antibodies for Multiple Myeloma Adam D. Cohen, MD Abramson Cancer Center University of Pennsylvania Philadelphia, PA, USA IMF Patient and Family Webinar

October 30, 2021

Division of Hematology/Oncology

Disclosures ‣ Consulting/Advisory Boards: Celgene, BMS, Takeda, Janssen, Seattle Genetics, AstraZeneca, Genentech/Roche, Oncopeptides, GlaxoSmithKline ‣ Research support: Novartis, GlaxoSmithKline ‣ Intellectual property licensed by institution to: Novartis

Types of Immunotherapy Directly targeting myeloma cell markers

Boosting myelomafighting T cells

Monoclonal and Bispecific antibodies

CAR T cells

Rodriguez-Otero P et al. Haematologica. 2017;102:423.

IMiDs/CelMODs, checkpoint inhibitors

Vaccines

Overcoming immune suppression

Activating myelomaspecific immunity

T cells can recognize and kill cancer cells BUT…in patients • Cancer cells learn to evade the T cells • T cells lose their activity over time T cell HOW TO OVERCOME THIS? • Checkpoint blockade • Cellular therapy • Bispecific antibodies/T cell engagers (BiTEs)

Groscurth P, Filgueira L. Physiology. 1998;13:17-21.

From CAR T Working Group, ASTCT slide library

CAR (Chimeric Antigen Receptor)

Chimera

‣ Combines recognition domain of antibody with signaling domain of T cell ‣ Uses gene transfer (eg. lentiviral vector) to stably express CAR on T cells  allows recognition of cancer cell

‣ Addition of co-stimulatory domains (CD28, 4-1BB) augments proliferation and survival of the T cells 83

Building CAR T cells T cell

CTL019 cell Lentiviral vector

1. Cytotoxicity 2. Cytokine production 3. Long-term persistence

“Living drug”

Native TCR Anti-CD19 CAR construct

CD19

Dead tumor cell

Tumor cell

Courtesy of D. Porter

Overview of CAR T cell therapy

Courtesy of D. Porter

CD19-specific CAR T cells for B-cell cancers ‣ Acute lymphoblastic leukemia (ALL) ‣ Chronic lymphocytic leukemia (CLL) ‣ B-cell Non-Hodgkin lymphomas ‣ Initial trials reported in 2010-2011 • • • •

Memorial Sloan Kettering Cancer Center/New York University of Pennsylvania/Philadelphia National Institutes of Health/Bethesda Fred Hutchinson Cancer Center/Seattle

4 FDA approved CD19 CAR T products: Kymriah Yescarta Tecartus Breyanzi

‣ Dramatic responses seen in highly-refractory patients • Can be durable, >10 years in some earliest-treated patients https://vimeo.com/54668275 www.emilywhiteheadfoundation.org 86

CAR T cell Toxicity 1. CRS (>80% of patients; <10% Gr3-4) 1. 2. 3.

Occurs between 1 hour and 10 days after infusion Lasts between 3-5 days Symptoms: 1.

Fever, chills, HA, fatigue and malaise [flu-like]

2. 3.

Low blood pressure, fast heart rate Shortness of breath, need for oxygen,

Treatment: tocilizumab +/- dexamethasone

2. Neurotoxicity (<30%; <10% G3-4) 1. 2. 3.

Occurs between 2 days to ~30 days, some later Lasts between 3-14 days, few have longer symptoms Symptoms 1. 2. 3.

Confusion, delirium, aphasia Tremor, Parkinson-like symptoms, nerve palsies Brain swelling is rare

3. Cytopenias 1. 2. 3.

Low WBC Low platelets Anemia

4. Infection 1.

Viral, Bacterial, fungal and unusual infections

BCMA (B-cell Maturation Antigen): a new target for myeloma ‣ Expressed on normal plasma cells ‣ Highly expressed on myeloma cells ‣ Soluble BCMA in patient serum  Promotes MM growth and survival  Multiple approaches targeting BCMA • Antibody-drug conjugates • Bispecific Antibodies • CAR T cells

Frigyesi et al, Blood 2014; Tai et al, Blood 2014; Carpenter et al, Clin Can Res 2013; Tai et al, Blood 2016

BCMA CAR T cells highly active in relapsed/refractory myeloma

Studies started 2015 2016

# lines

% hi risk†

Dosing

ORR

ORR (optimal doses)

VGPR/CR (optimal doses)

Trial

CAR

Conditioning

NCI1

26*

Murine, CD3/CD28

Cy/Flu

7.5

42%

0.3 – 9 x 106/kg

58%

81% (13/16)

63% (10/16)

Penn2

Human, CD3/41BB

None or Cy

76%

0.5 – 5 x 108

48%

64% (7/11)

36% (4/11)

Bluebird bb21213

Murine, CD3/41BB

Cy/Flu

7.5

40%

0.5 – 8 x 108

85% (28/33)

90% (27/30)

80% (24/30)

Legend4

Llama, CD3/41BB

0.07-2.1 x106/kg

88%

88% (50/57)

74% (42/57)

*2 treated twice; counted separately for response. † FISH +t(4;14), t(14;16), del 17p Cy = cyclophosphamide, Flu = fludarabine

‣ BCMA CAR T cell products: • Idecabtagene vicleucel (ide-cel) Abecma (FDA approved) • Ciltacabtagene autoleucel (cilta-cel) (under FDA review)

1Brudno,

J Clin Oncol 2018; 2Cohen, J Clin Invest 2019; 3Raje, NEJM 2019; 4Zhou, J Hematol Oncol 2018

Ph 2 - KarMMa-1: Study Design

bb2121 CAR Design MND SP Anti-BCMA scFv Promot er

CD8 Linke r

Tumor binding domain

4-1BB

CD3z

Signaling Domains

Ide-cel Median 6 prior lines, 84% triple-refractory

52% got tocilizumab

CAR, chimeric antigen receptor; CR, complete response; CRR, complete response rate; CRS, cytokine release syndrome; CTCAE, common criteria for adverse events; MRD, minimal residual disease; NE, not evaluable; ORR, overall response rate; PR, partial response; sCR, stringent complete response; CAR

Munshi et al. ASCO 2020; abstract 8503 (oral presentation)

Ciltacabtagene autoleucel (cilta-cel; JNJ-68284528; LCAR-B38M)

‣ Madduri et al. ASH 2020; abstract 177 (oral presentation)

CARTITUDE-1 (cilta-cel) updated phase 1/2 data Median 6 prior lines, 88% triple-refractory

FDA review date 11/29/21 ‣ Usmani et al. ASCO 2021; #8005

Ongoing ide-cel and cilta-cel CAR T cell trials Ide-cel ‣ KarMMa-2 • Phase 2 study in r/r MM and high-risk MM (relapse early after induction)

‣ KarMMa-3 • Phase 3 randomized study of ide-cel vs SOC in r/r MM

‣ KarMMa-4 • Phase 1 study in newly diagnosed high-risk MM

Cilta-cel ‣ CARTITUDE-2 • Phase 2 study in multiple cohorts – – – – – –

A: 1-3 prior therapies B: Relapse early after induction +/- SCT C: After prior BCMA-targeted treatment D: <CR after SCT (combo with Revlimid maint) E: newly-diagnosed high risk F: standard risk after induction therapy

‣ CARTITUDE-4 • Phase 3 randomized study of cilta-cel vs SOC in r/r MM

Other CAR-based approaches in myeloma ‣ Autologous BCMA CAR T cells • • • • • • •

JCARH125 (orva-cel) FCARH125 P-BCMA-101 bb21217 CT053 FHVH-BCMA-T CT103A

‣ Bispecific CAR T cells

‣ “Off-the-shelf” allogeneic CAR products • • • • • • •

ALLO-715 ALLO-605 UCARTCS1 CTX120 CYAD-211 PBCAR269A P-BCMA-ALLO1

• FT576 (CAR-NK)

• GCF012 (CD19/BCMA-targeted) • BM38 (BCMA/CD38-targeted) • BCMA/GPRC5D (pre-clinical) Mailankody et al, ASH 2020, #129; Goodridge et al, ASH 2020, #1402

Types of Antibodies (Antibody-drug conjugate)

Bispecific Antibodies/T-cell Engagers for Myeloma

AMG420

Shah N et al, Leukemia 2020; www.clinicaltrials.gov (search 10/09/21)

Phase 1 study of Teclistamab (BCMA x CD3 bispecific Ab)

Krishnan et al, ASCO 2021, #8007

Phase 1 study of Elranatamab (BCMA x CD3 bispecific Ab)

Bahlis et al, ASCO 2021, #8006

100

Beyond BCMA?

Chari et al. ASH 2020; #290; Cohen et al. ASH 2020; #292

101

Redirecting T cells: CARs vs. Bispecific Antibodies CAR T cells

‣ Advantages • • •

One-time treatment Toxicities front-loaded Durable remissions seen

Bispecific Abs

‣ Advantages • • • •

Off-the-shelf Lower frequency/severity of CRS, ICANS No lymphodepletion needed Durable remissions seen

‣ Disadvantages •

Manufacturing headaches –

•

Need for lymphodepletion –

•

Prolonged cytopenias, risk of MDS

Higher frequency/severity of CRS, ICANS –

•

slot allocation, need for apheresis, manufacturing failures, disease progression

Need for hospitalization

‣ Disadvantages • •

Response rates a bit lower Repeated (?indefinite) administration –

• •

Ongoing risk of toxicity

Hospitalization for step-up dosing Shorter follow-up in trials to date

Not “curative” in triple class-refractory setting

102

Sequencing Bispecific Abs with CAR T cells Apheresis

BCMA BsAb

BCMA CAR

Apheresis

Non-BCMA BsAb

BCMA CAR

BCMA BsAb

Apheresis

BCMA BsAb

BCMA CAR

Non-BCMA BsAb

Apheresis

Non-BCMA BsAb

BCMA CAR

BCMA BsAb

BCMA CAR

Non-BCMA BsAb

103

Summary/Take-home points ‣ BCMA CAR T cells induce deep responses in relapsed/refractory MM patients • Registration studies completed for ide-cel (Abecma) and cilta-cel – Phase 3 studies vs standard regimens and Phase 2 studies in less heavily-treated pts ongoing – Durability of responses (median PFS 12-24 months) good but needs improvement – CRS and neurotoxicity remain issues but high grade uncommon (≤10%)

• Ongoing phase 1 studies for next-generation autologous CAR T products • Proof-of-principle safety/activity with off-the-shelf allogeneic BCMA CAR product (ALLO-715) – CAR-NK cell products to start trials in 2021/2022

‣ BCMA and non-BCMA-targeted bispecific antibodies/T cell-engagers (BsAb/BiTEs) induce deep responses in relapsed/refractory MM patients • Response durability promising but follow-up shorter • Optimal dose/schedule to be determined

‣ Challenges: choosing between products, optimal sequencing, combining with standard myeloma drugs

104

IMF Patient and Family Webinar

How to Find What You Need to Know Robin Tuohy International Myeloma Foundation Vice President, Support Groups 105

IMF Patient and Family Webinar

When Myeloma Comes Back: Approaches to Relapse Paul Richardson, MD Dana-Farber Cancer Institute Boston, MA

106

The Evolving Role of Novel Therapy in the Treatment Paradigm of Relapsed and Refractory Multiple Myeloma Paul G. Richardson, MD RJ Corman Professor of Medicine Harvard Medical School Clinical Program Leader, Director of Clinical Research Jerome Lipper Multiple Myeloma Center Dana-Farber Cancer Institute Boston, Massachusetts

Boston MA 2021

Disclosures • Advisory Committees

• Celgene/BMS, Takeda, Janssen, Oncopeptides, Sanofi, Secura-Bio, Karyopharm, GSK, Regeneron • Research Funding

− Celgene/BMS, Takeda, Oncopeptides

Multiple Novel Agents Are Now Available to Treat Newly Diagnosed and Relapsed/Refractory Myeloma 2021 How do we sequence and strategize therapies to ensure the best outcomes for our patients?

15 Approved Novel Agents in MM…..and more coming!

Doxil

Lenalidomide

Pomalidomide

Bortezomib

Ixazomib

Thalidomide

Carfilzomib

Daratumumab

Elotuzumab

1st line

2nd line st

1 line

? Panobinostat

Selinexor

Melflufen

Isatuximab

3rd line Andnd 2 line beyond

Belamaf

Adapted from Laubach JP et al. Leukemia. 2016. Moreau P et al. Lancet Oncol. 2021. Idecel

Treating Multiple Myeloma Is a Marathon, Not a Sprint!

Strategic vs. tactical considerations ~ Tolerability AND efficacy key with combination regimens

Adapted from Borrello I. Leuk Res. 2012;36:S3 Richardson PG, San Miguel J et al. Blood Cancer Journal 2018 “Translating Clinical Trial Results to Real World Practice”.

Key Targets in MM 2021 Genomic abnormalities: • Target and overcome mutations • Critical Role of Combination and Continuous Therapy • Evolving Position and Timing of ASCT Excess Protein Production: • Target Protein Degradation Immune Suppression: • Restore anti-MM immunity Richardson PG et al, MMRF 2021

112

Definition of RRMM • IMWG criteria for PD1 • ≥25% increase from nadir in: • Serum/urine M-protein (absolute increase ≥0.5 g/dLa and ≥200 mg per 24 h, respectively) or • Difference between involved and uninvolved FLC levelsb (absolute increase >100 mg/L) or • BM plasma cellsc (absolute increase ≥10%) or • New lesions (≥50% increase in SPD of >1 lesion or longest diameter of previous lesion >1 cm in short axis) or • Circulating plasma cells (≥50% increase [minimum 200 cells/μL] if only measure of disease)

• Criteria for RRMM2-5 • Meets IMWG criteria for PD1 • RRMM: progression on tx in patients who obtain at least minor response or progression within 60 days on most recent tx • Primary refractory MM: not achieving at least minor response on a given tx • Relapsed MM: meets IMWG criteria for PD but not RRMM or primary refractory MM

BM, bone marrow; FLC, free light chain; IMWG, International Myeloma Working Group; MM, multiple myeloma; PD, progressive disease; SPD, sum of the products of the maximal perpendicular diameters of measured lesions. If lowest M component ≥5 g/dL, increase must be ≥1 g/dL; b In patients without measurable serum/urine M-protein; c In patients without measurable serum/urine Mprotein or involved FLC. a

1. Kumar. Lancet Oncol. 2016;17:e328. 2. Nooka. Blood. 2015;125:3085. 3. Rajkumar. Blood. 2011;117:4691. 4. Richardson PG NEJM 2003. Richardson PG, et al. Cancer. 2006;106:1316-1319.

113

Median Response Duration (mos)

Confronting Disease Relapse in Myeloma Response Duration With Increasing Treatment1 12 10 8 6 4

2 0 First Second Third

Fourth

Fifth

Treatment Regimen EFS, event-free survival.

1. Kumar. Mayo Clin Proc. 2004;79:867. 2. Bahlis. Blood 2017

Sixth

Novel Factors Impacting Treatment Choice in RRMM: Refractoriness to Drug Classes Real-World Progression-Free Survival (months)

• •

•

Outcomes of patients have improved with the advent of new therapies However, as the disease relapses, it becomes increasingly refractory to available treatments, resulting in shorter remissions Quality and duration of response to previous therapies are therefore important prognostic factors when treating patients with RRMM

Figures reproduced from Bruno A. S., et al. Expert Review of Hematology 2020.1 Newer treatments (approval date during/after 2012) were pomalidomide, carfilzomib, elotuzumab, panobinostat, daratumumab, ixazomib, and bortezomib lenalidomide combination rwOS, real-world overall survival; rwPFS, real-world progression-free survival. 1. Bruno A.S. et al., Expert Rev Hematol. 2020 Sep;13(9):1017-1025.

Real-World Overall Survival (months)

115

Effect of Drug Class Refractoriness Double refractory EFS and OS Outcomes1 100

Patients (%)

Events, n/N

Median, mos (range)

170/286

9 (7-11)

EFS

217/286

5 (4-6)

60 40 20 0 0

Months

OS, overall survival. EFS, event-free survival 1. Kumar. Leukemia. 2012;26:149. 2. Gandhi. Leukemia. 2019;33:2266.

Double, triple, quad and Penta- refractory OS2

116

When Should We Start Treatment for Relapse? • Patients with clinical progression/CRAB clearly need treatment • Those with biochemical progression only may not need immediate treatment, or can consider a rational addition to current therapy • Standard-risk disease with slow trend upward CRAB, hypercalcemia, renal failure, anemia, bone disease.

Presentation with renal or neurological complications

High-risk disease with any progression

Rapid doubling of M spike

Indications for treatment

Adapted from Laubach et al , Leukemia 2016 Moreau et al, Lancet Oncol 2021

IMW 2021 How Are New Drug Classes Affecting the Treatment Landscape in RRMM? A Complex Question For a Complex Series of Issues

Triple- or quadruplea-class or penta-drugb refractory

Renal dysfunction Bone marrow reserve Immune deficiency (including T-cell dysfunction)

Elderly and frail

Neuropathy

•

aDefined

•

CD, cluster of differentiation; IMiD, immunomodulatory drug; mAb, monoclonal antibody; PI, proteasome inhibitor.

as refractory to ≥1 IMiD, 1 PI, 1 anti-CD38 mAb and 1 glucocorticoid; bDefined as refractory to ≥2 PIs, ≥2 IMiDs and 1 anti-CD38 antibody.

Recommended Regimens in RRMM (adapted from NCCN guidelines 2020-2021) Treatment at first relapse

Not refractory to LENa

Treatment after multiple relapses

Refractory to LEN

Considerb

DRd1 or KRd2, PVd 9

Frail: IRd,3 ERd4

DVd,5 DPd,6 DKd,7 KPD8 PVd9, EloPd10 Panobinostatbased rx16

Any first relapse options not yet used (2 new drugs; triplet preferred) Additional approved options: Isatuximab-combinations selinexor,15 VTd-PACE, bendamustine-based rx, Panobinostat-based rx16

Frail: Pd,11 IPd,12 VCd,13 PCd14

Investigational options: BCMA-targeting therapy on clinical trial; melflufen17,18, venetoclax

ASCT, autologous stem cell transplant; BCMA, B-cell maturation antigen; BTZ, bortezomib; CFZ, carfilzomib; DKd, dara, CFZ, and DEX; dara, daratumumab; DPd, dara, POM, and DEX; DRd, dara, LEN, and DEX; DVd, dara, BTZ, and DEX; EloPd, elotuzumab, POM, and DEX; ERd, elotuzumab, LEN, and DEX; IPd, ixazomib, POM, and DEX; IRd, ixazomib, LEN, and DEX; LEN, lenalidomide; PCd, POM, cyclophosphamide, DEX; Pd, Pm, DEX; POM, pomalidomide; VCd, BTZ, cyclophosphamide, DEX; VPd, BTZ, POM, DEX; VRd, BTZ, LEN, DEX; KPd, CFZ, POM, DEX; KRd, CFZ, LEN, DEX; KCd, CFZ, cyclophosphamide, and DEX; VDT-PACE, BTZ, DEX, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide. a

Relapse occurring while off all rx, on low doses of single-agent LEN, or on BTZ maintenance; b For those intolerant of LEN, on higher doses of single-agent LEN, with aggressive relapse, or with highrisk disease; c Consider salvage ASCT in eligible patients if first PFS >2 y off maintenance or >4 y with maintenance, or for patients with pancytopenias and heavy BM involvement.

1. Dimopoulos. Haematologica. 2018;103:2088. 2. Stewart. ASH 2017. Abstr 743. 3. Moreau. NEJM. 2016;374:1621. 4. Lonial. ASCO 2018. Abstr 8040. 5. Lentzsch. ASCO 2017. Abstr 8036. 6. Chari. Blood. 2017;130:974. 7. Chari. ASCO 2018. Abstr 8002. 8. Bringhen. Leukemia. 2018;32:1803. 9. Richardson PG et al . Lancet Oncol 2019. 10. Dimopoulos. EHA 2018. Abstr LBA2606. 11. San Miguel. Lancet Oncol. 2013;14:1055. 12. Krishnan. Leukemia. 2018;32:1567-1574. 13. Rajkumar. Am J Hematol. 2014;89:999. 14. Baz. Blood. 2016;127:2561. 15. Vogl. J Clin Oncol. 2018;36:859. 16. Laubach JP et al , Lancet Oncol 2020. 17. Richardson PG et al. ASH 2018. Abstr 600. 18. Richardson PG et al, J Clin Oncol 2021.

IMW 2021 - Improving Outcomes for Patients with RRMM: Patient Perspective •

There are multiple factors of importance to MM patients regarding their treatment that can have an impact on the effectiveness of that treatment in the real-world setting1

Factors of importance to patients in the real-world setting1

Burden

Considerations for optimal treatment

Symptom burden

Symptoms related to the CRAB criteria can be debilitating and may require supportive therapy

Rapid symptom control

Side effects

Side effects can affect treatment adherence and lead to treatment discontinuation

Treatment options with minimal toxicity

Disturbance of daily life

Impairment of activities of daily living due to MM treatment or other comorbidities can be associated with poorer prognosis

The ability to continue with one’s daily routine and physical activities while receiving treatment

Financial toxicity

Direct out-of-pocket costs arising from treatment and its side effects, travel costs

Patient’s ability to cope with the financial toxicity associated with receiving their regimen on a longterm basis

Treatment convenience /route of administration

Cost and logistics associated with frequent hospital/clinic visits

Preference for oral treatment

Traditional Factors Impacting Treatment Choice in RRMM: Frailty Status TTNT in intermediate to frail patients

• Advanced age, functional decline, and comorbid conditions represent components of frailty that are predictive of mortality and toxicity risk in MM

• In the real-world, frailty can have a significant impact on the effectiveness of different treatment options

Traditional Factors Impacting Treatment Choice in RRMM: Extramedullary Disease •

EMD is highly prevalent in RRMM patients and is associated with poor prognosis, making the management of this patient group particularly challenging •

•

Prognosis is usually poorer for patients with hematogenous-spread soft-tissue plasmacytomas than for patients with bone-related plasmacytomas

No standard therapy has been established for this population with high unmet medical need •

Treatments with Selinexor, Isatuximab, Melflufen and CAR T-cell therapy as well as others have shown promising efficacy in patients with RRMM and EMD OS in EMD vs Non-EMD Groups: Melflufen

OS in EMD vs Non-EMD Groups: CAR T-cell Therapy

122

Agents in Relapsed MM Lenalidomide-Based Studies POLLUX DRd vs Rd1

ASPIRE KRd vs Rd2

ELOQUENT-2 ERd vs Rd3,4

TOURMALINE-MM1 IRd vs Rd5

PFS HR (95% CI)

0.37 (0.27-0.52)

0.69 (0.57-0.83)

0.73 (0.60-0.89)

0.74 (0.59-0.94)

ORR, %

≥VGPR, %

≥CR, %

DoR, mos

28.6

20.7

20.5

0.64 (0.40-1.01)

0.79 (0.63-0.99)

0.77 (0.61-0.97)

Outcomes

OS HR (95% CI)

CI, confidence interval; CR, complete response; DoR, duration of response; HR, hazard ratio; NE, not estimable; PFS, progression-free survival; Rd, LEN and DEX; VGPR, very good partial response. 1. Dimopoulos. EHA 2016. Abstr LB238. 2. Stewart. NEJM. 2015;372:142. 3. Lonial. NEJM. 2015;373:621. 4. Dimopoulos. ASH 2015. Abstr 28. 5. Moreau. NEJM. 2016;374:1621.

123

Agents in Relapsed MM PI-Based Studies CASTOR DVd vs Vd1

ENDEAVOR Kd vs Vd2

Panobinostat PVd vs Vd3,4

OPTIMISMM PomVd vs Vd5

PFS HR (95% CI)

0.39 (0.28-0.53)

0.53 (0.44-0.65)

0.63 (0.52-0.76)

0.61 (0.49-0.77)

ORR, %

Median PFS, mos

18.7

12.0

11.2

≥VGPR, %

≥CR, %

12.5

DoR, mos

21.3

13.1

13.7

0.77 (0.47-1.26)

0.79 (0.58-1.08)

0.94 (0.78-1.14)

0.98 (0.73-1.32)

Outcomes

OS HR (95% CI)

Kd, CFZ and DEX; NR, not reached; PVd, POM, BTZ, and DEX. 1. Palumbo. N Engl J Med. 2016;375:754. 2. Dimopoulos. Lancet Oncol. 2016;17:27. 3. San-Miguel. Lancet Oncol. 2014;15:1195. 4. San-Miguel. ASH 2015. Abstr 3026. 5. Richardson PG, et al. Lancet Oncol. 2019;20:781-794.

OPTIMISMM: PVd versus Vd in RR MM Study Design1,2 Phase 3 trial comparing the efficacy and safety of PVd vs Vd in LEN-exposed RRMM patients. Funded by Celgene Corporation

21-day cycles

LT follow-up

PVd (n = 281) POM BORT

RRMM • 1-3 prior regimens, ≥ 2 cycles of LEN • ECOG PS ≤ 2 • Prior BORT allowed (PD with 1.3 mg/m2 twice weekly dose excluded)a N = 559

LoDEX

R 1:1

4 mg Days 1-14 1.3 mg/m2 SC Cycles 1-8: Days 1, 4, 8, 11 Cycles 9+: Days 1 and 8 20 mg (≤ 75 years) or 10 mg (> 75 years) day of and day after BORT

Vd (n = 278) BORT

LoDEX

Tx discontinued due to PD

Follow-up visit 28 days after Tx discontinuation PD or unacceptable toxicity

1.3 mg/m2 SC Cycles 1-8: Days 1, 4, 8, 11 Cycles 9+: Days 1 and 8 20 mg (≤ 75 years) or 10 mg (> 75 years) day of and day after BORT

PD, subsequent antimyeloma Tx, and survival Tx discontinued prior to PD

Enter PFS follow-up periodb

NCT01734928

Stratification • Age (≤ 75 years vs > 75 years) • Prior regimens (1 vs > 1) • β2-microglobulin at screening (< 3.5 mg/L vs ≥ 3.5 to ≤ 5.5 mg/L vs > 5.5 mg/L)

1°

PFS (time from randomization to disease progression or death)

2°

OS, ORR by IMWG criteria, DOR, safety

Data cutoff: • October 26, 2017

Study Endpoints

TTR, PFS2, efficacy analysis in

Key subgroups, including refractoriness to exploratory LEN and number of prior lines of therapyc, and HRQoL

a Patients

with PD during therapy or within 60 days of the last dose of a BORT-containing therapy under the approved dosing schedule of 1.3 mg/m2 twice weekly were excluded. b Efficacy evaluated every 21 days (± 3 days) until PD. c These subgroups were predefined in the statistical analysis plan.

1. Dimopoulos M, et al. Poster presented at ASH 2018 [abstract 3278]. 2. Weisel K, et al. Poster presented at ASH 2018 [abstract 1960].

OPTIMISMM: PVd VERSUS Vd IN RRMM PFS ITT AND 1 PRIOR LINE

Response

OPTIMISMM: PVd Versus Vd In RRMM Overall Summary •

•

Study Design • OPTIMISMM is an open-label, randomized, Phase 3 study comparing the efficacy and safety of PVd vs Vd in LEN-pretreated patients with RRMM Results • Primary Efficacy Data • In the ITT population, the median PFS with PVd vs Vd was 11.20 months vs 7.10 months (HR = 0.61 [95% CI, 0.49-0.77]; P < .0001) • In LEN-refractory patients, the median PFS was 9.53 vs 5.59 months (HR = 0.65 [95% CI, 0.50-0.84]; P < .0008) • In patients with 1 prior line of therapy, the median PFS was 20.73 vs 11.63 months (HR = 0.54 [95% CI, 0.36-0.82]; P < .0027) • ORR was 82.2% vs 50.0% (P < .0001) in the ITT population • Safety Data • Most common Grade ≥ 3 hematologic AEs with PVd included neutropenia (42% vs 9% with Vd) and thrombocytopenia (27% vs 29% with Vd) • Most common Grade ≥ 3 nonhematologic AE with PVd was infection (31% vs 18% in the Vd arm); all other Grade ≥ 3 nonhematologic AEs occurred in < 10% of patients • Incidence of SPMs was 3% (2.7 per 100 person-years) with PVd vs 1% (1.2 per 100 person-years) with Vd • A total of 86 patients died in each arm; mostly due to myeloma progression and infections • Discontinuation of the lead drug were reported in 11% in the PVd and 19% of patients in the Vd arm, respectively Richardson PG, et al. Lancet Oncol. 2019; published online May 13. DOI:https://doi.org/10.1016/S1470-2045(19)30152-4.

Panobinostat: HDAC Inhibition for the treatment of RR MM • Panobinostat’s unique multi-modal MOA alters gene expression patterns both directly and via histone modification to overcome resistance to other therapies1-3 Panobinostat

Activation of tumor suppressor genes

Histone-Driven (epigenetic)

Direct (Non-histone) HDAC

HDAC1,2,3

HDAC1,2

Histones

p53

HDAC6

Tubulin

HSP90

Aggresome

Image adapted from Laubach JP, et al. Clin Cancer Res. 2015;21(21):4767-4773. 1. Richardson PG, et al. Blood. 2013;122:2331-2337; 2. Imai Y, et al. Cancers (Basel). 2019;11(4):475; 3. Yeon M, et al. Front Cell Dev Biol. 2020;8:486.

Accumulation of misfolded proteins (critical to MM)

Cell Death

Duration of Response in RR MM: Pano Vd PANORAMA-3 Responders without event, %

100 80

PAN 10 mg TIW PAN 20 mg BIW PAN 20 mg TIW

Median DoR Event months Patients Events Censored rate (95% CI) 44 22 22 50% 10.84 (6.24, 14.49) 56 26 30 46% 11.76 (8.77, 21.26) 51 19 32 37% 22.08 (13.86, NE)

60 40 PAN 10 mg TIW PAN 20 mg BIW PAN 20 mg TIW

20 0 0

At risk, n PAN 10 mg TIW PAN 20 mg BIW PAN 20 mg TIW

44 56 51

39 49 49

33 36 37

23 32 34

17 25 27

14 20 23

8 11 21

6 10 17

16 18 20 Time, months 4 6 13

3 3 12

3 2 11

1 2 8

0 2 6

1 6

1 3

0 1

Laubach JP et al, Lancet Oncology 2020

Monoclonal Antibody-Based Approaches

With a focus on targeting CD38 and SLAMF7

131

CANDOR: Response Rates

ORR

KdD (n=312)

Kd (n=154)

84.3a

74.7a

≥VGPR

69.2

48.7

≥CR

28.5

10.4

MRD negative at 12 mos (10–5 threshold)

17.6

3.9

MRD negative CR at 12 mos (10–5 threshold)

12.5b

Best MRD negative CR (10–5 threshold)

1.3b

Median PFS: NE vs 15.8 mos 1.0 + ++ + +

Proportion Surviving Without Progression

Response, %

+ ++

0.8

0.6

0.4

+++ ++ ++++++++++ +++ + ++ + +++++ ++ + KdD ++ ++ ++++++++++++++++++ ++ + + + + + + + + + + + +++++++++++++ ++ + ++++ ++ + +++ + + +++++++ +++++ ++ +++++++++ +

Kd 0.2

0.0

13.8

3.2

Months After Randomization At risk, n KdD

302

279

236

211

189

165

154

122

100

KdD, CFZ, DEX, and Dara. a

P=0.0040; b P<0.0001. Usmani. ASH 2019. Abstr LBA6. Lancet 2020

132

CANDOR: PFS • Prolonged PFS with KdD vs Kd • Median, NR vs 15.8 mo • HR, 0.63 • 95% CI, 0.46-0.85

Subgroup

HR KdD vs Kd (95% CI)

ISS stage

• 1 or 2 •3

0.61 (0.43-0.85) 0.71 (0.37-1.36)

Cytogenic risk group

Baseline age, y

• ≤64 • 65-74 • ≥75

0.57 (0.38-0.86) 0.72 (0.43-1.20) 0.97 (0.39-2.43)

• High • Standard • Unknown

0.58 (0.30-1.12) 0.55 (0.31-0.97) 0.72 (0.47-1.11)

Number of prior tx

•1 • ≥2

0.70 (0.42-1.17) 0.63 (0.44-0.92)

Region

• North America • Europe • Asia Pacific

0.04 (0.01-0.34) 0.86 (0.60-1.23) 0.49 (0.25-0.93)

Prior LEN exposure

• No • Yes

0.87 (0.56-1.35) 0.52 (0.34-0.80)

Baseline ECOG PS

• 0 or 1 •2

Refractory to LEN

0.69 (0.51-0.94) 0.31 (0.08-1.19)

• No • Yes

0.85 (0.57-1.27) 0.45 (0.28-0.74)

Baseline CrCl, mL/min

• ≥15 to <50 • ≥50 to <80 • ≥80

0.46 (0.21-1.02) 0.78 (0.45-1.33) 0.67 (0.44-1.02)

Prior PI exposure

• No • Yes

0.93 (0.29-3.02) 0.64 (0.47-0.88)

Refractory to BTZ

• No • Yes

0.59 (0.40-0.85) 0.83 (0.49-1.41)

• P=0.0014)

Usmani. ASH 2019. Abstr LBA6. Lancet 2020

HR KdD vs Kd (95% CI)

EQUULEUS: Dara/POM/DEX in RRMM •

Single-arm phase 1b study (N=103; median of 4 prior lines [range: 1-13]; 71% refractory to PIs and IMiDs; 25% with high-risk cytogenetics

ORR (%)

60 50 40

ORR, 60% 17% CR or better

8% 9% 25%

30 20 10 0

42% VGPR or better

PR VGPR CR sCR

18%

Dara + POM/DEX (N=103)

• Of 17 patients in ≥CR, 35%, 29%, and 6% were MRD-negative at thresholds of 10–4, 10–5, and 10–6, respectively • Median OS, 17.5 mos (95% CI, 13.3-NE)

Chari A. et al. Blood. 2017;130:974.

PFS

100 80

PFS (%)

60 40 Median: 8.8 mos (95% CI: 4.6-15.4)

20 0

At risk, n 103

12 9 Months 42 28

• Median PFS with high-risk cytogenetics (n=22), 3.9 mos (95% CI, 2.3-NE)

134

MM-014: Phase I/II trial with Dara-Pd in Relapsed and/or Refractory MM patients based on len-refractory patients • 112 pts after 1 or 2 PL: all pts received prior Len, and 78% received prior Bz; 75% were refractory to most recent prior Len-containing regimen

APOLLO Phase 3 trial, Dara-Pd vs Pd Confirmed these Results….. Siegel et al. Leukemia 2020

APOLLO: Phase 3 Trial of SC Daratumumab, Pomalidomide and Dexamethasone (D-Pd) Versus Pd in RRMM 12-month PFS rateb

% surviving without progression

100

(PFS with median FU 16.9 mo)

52%

35%

D-Pd median: 12.4 months

20 HR, 0.63; 95% CI, 0.47-0.85; P = 0.0018

Pd median: 6.9 months

0 0 No. at risk Pd D-Pd

153 151

121 93 79 135 111 100

61 87

52 80

46 74

36 66

16 18 Months 27 48

17 30

12 20

5 12

5 8

1 5

0 3

0 2

0 1

Median PFS among patients refractory to lenalidomide was 9.9 months for D-Pd and 6.5 months for Pd

Addition of DARA SC to Pd improved PFS, with a 37% reduction in the risk of progression or death

Dimopoulos et al, ASH 2020

Phase III ICARIA-MM: Isatuximab + POM/DEX vs POM/DEX in RRMM Isa-Pd group • • • •

3 prior lines of tx 94% LEN refractory (60% in last line) 77% PI refractory 72% double refractory

Response

Isa-Pd

ORR, %

sCR

VGPR

11.1

13.3

Median DoR, mos

Median follow-up

11.6 mos

Median PFS, mos

100

Isa-Pd Pd

PFS (%)

•

11.53 6.47

60 40 20

HR, 0.596 (95% CI, 0.436-0.814; P=0.001) 0

0 1 2

At risk, n Isa-Pd 154 Pd 153

129 105

3 4

5 6 7 8 9 10 11 12 13 14 15 16 Months 106 89 81 352 14 1 80 63 51 17 33 5 0

• PFS HR (95% CI) • LEN refractory, 0.59 (0.43-0.82) • LEN refractory in last line, 0.50 (0.34-0.76)

ISA, isatuximab.

Attal M, Richardson PG et al. Lancet. 2019;394:2096.

• LEN/PI refractory: 0.58 (0.40-0.84)

Isatuximab Plus Carfilzomib and Dexamethasone vs Carfilzomib and Dexamethasone in RRMM (IKEMA)

Interim PFS analysis of Isa-Kd compared with Kd showed hazard ratio of 0.531 At the time of analysis, overall survival data were immature Moreau et al, ASH 2020

138

IKEMA: Response 100 90 80 70 60 50 40 30 20 10 0

P=0.0004

Isa-Kd

P=0.19 86.6

MRD rate (NGS,a 10-5) 50

82.9 72.6

Isa-Kd

P=0.0011

41.4 40

56.1 39.7 27.6

Patients (%)

Incidence (%)

Best Overall Response (N=302)

29.6

22.9 20 13.0 10

ORR

VGPR or better

CR or better

53/179

16/123 MRD neg ITT

• Deeper responses with Isa-Kd, consistent with striking PFS improvement • MRD negativity rate with Isa-Kd, ~30% in ITT population

Moreau. EHA 2020. Abstr LB2603.

53/123

16/71

0 MRD neg in VGPR…

ELOQUENT-2: Efficacy Outcome

Elotuzumab + LEN/DEX (n=321)

LEN/DEX (n=325)

19.4

14.9

1 y, %

2 y, %

3 y, %

Median time to next tx, mos

ORR, %

43.7

39.6

HR (95% CI)

PFS Median, mos

Interim OS, mos

0.73 (0.60-0.89) P=0.0014

0.62 (0.50-0.77) 0.77 (0.61-0.97) P=0.0257

• PFS benefit seen with elotuzumab in all predefined subgroups

Dimopoulos M, Richardson PG et al. ASH 2015. Abstr 28.

Phase 2 ELOQUENT-3 : Elotuzumab/POM/DEX vs POM/DEX (N=117) PFS

Elotuzumab 40

Controls

100

Surviving Patients (%)

Patients Surviving Without Progression (%)

100

Elotuzumab

Controls 40

HR, 0.54; 95% CI, 0.34-0.86; P=0.008 0

HR, 0.62; 95% CI, 0.30-1.28 0

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22

Months Since Randomization

9 10 11 12 13 14 15 16 17 18 19 20 21 22

Months Since Randomization

Dimopoulos et al . NEJM. 2018;379:1811.

Selected Novel Targeted Agents for RR MM

IMW 2021: How Are New Drug Classes Affecting the Treatment Landscape in RRMM? A Complex Question For a Complex Series of Issues SINEs1

Peptide–drug conjugates3 Antibody–drug conjugates4

Peptide–drug conjugates9

CAR T-cell therapy2

Triple- or quadruplea-class or penta-drugb refractory

Renal dysfunction Bone marrow reserve

SINEs10

Antibody–drug conjugates11

BiTEs5

Bispecific antibodies6

Antibody–drug conjugates8

CELMoDs7

Elderly and frail

Immune deficiency (including T-cell dysfunction)

Neuropathy

Antibody–drug conjugates8

BiTEs12

•

aDefined

•

BiTE, bispecific T-cell engager; CAR, chimeric antigen receptor; CELMoD, cereblon E3 ligase modulator; SINE, selective inhibitor of nuclear export.

•

1. Bassali J, et al. Clinicoecon Outcomes Res. 2020;12:317-325; 2. Munshi NC, et al. N Engl J Med. 2021;384:705-716; 3. Richardson PG, et al. J Clin Oncol. 2021;39:757-767; 4. Becnel MR, Lee HC. Ther Adv Hematol. 2020;11:2040620720979813; 5. Harrison SJ, et al. Abstract 181. ASH Annual Meeting 2020; 6. Usmani SZ, et al. Lancet. 2021;398:665-674; 7. Van De Donk NWCJ, et al. Abstract 724. ASH 2020 Annual Meeting 2020; 8. Offidani M, et al. Drug Des Devel Ther. 2021;15:2401-2415; 9. Pour L, et al. Abstract 1028. EHA Annual Meeting 2021; 10. Grosicki S, et al. Lancet. 2020;396:1563-1573; 11. Lee HC, et al. J Clin Oncol. 2020;38(15_suppl):abstr 8519; 13; 12. Tian Z, et al. J Hematol Oncol. 2021;14:75.

as refractory to ≥1 IMiD, 1 PI, 1 anti-CD38 mAb and 1 glucocorticoid; bDefined as refractory to ≥2 PIs, ≥2 IMiDs and 1 anti-CD38 antibody.

Selective Inhibitors of Nuclear Export (SINEs)

SINEs mechanism of action1

SINEs XPO1 Myeloma cell

Tumour suppressor proteins

Selinexor Phase 3, open-label, global, randomised BOSTON Study (n=402)2 Eligibility criteria: • Aged ≥18 years • ECOG performance status of 0–2 • Previously received 1–3 lines of therapy

Proportion of patients (%)

Inhibition of XPO1 prevents transport of tumour suppressor proteins out of the cell nucleus, leading to their accumulation and activation, and therefore selectively inducing apoptosis of malignant cells1

Best overall response to SVd vs Vd in BOSTON2 100 sCR CR

60 40 20

n=19 n=14 n=54

n=62

VGPR

n=13 n=9 n=45

n=62

SVd (n=195)

Vd (n=207)

SVd (n=195) or Vd (n=207)

1:1

SVd (n=195)

Vd (n=207)

HR (95% CI)

mPFS, months

13.93

9.46

0.70 (0.53–0.93) p=0.0075

mDOR, months

20.3

12.9

0.81 (0.56–1.17) p=0.1364

Most common Grade 3–4 AEs2 SVd (n=195)

Vd (n=204)

Thrombocytopaenia (39%)

Thrombocytopaenia (17%)

Anaemia (16%)

Pneumonia (11%)

Fatigue (13%)

Anaemia (10%)

Pneumonia (11%)

Fatigue (1%)

AE, adverse event; CI, confidence interval; CR, complete response; ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio; mDOR, median duration of response; mPFS, median progression-free survival; PR, partial response; sCR, stringent complete response; SVd, selinexor, bortezomib, dexamethasone; Vd, bortezomib, dexamethasone; VGPR, very good partial response; XPO1, exportin 1. 1. Cheng Y, et al. Mol Cancer Ther. 2014;13:675-686; 2. Grosicki S, et al. Lancet. 2020;396:1563-1573.

Selective Inhibitors of Nuclear Export (SINEs) Selinexor Phase 3, open-label, global, randomised BOSTON Study of SVd vs Vd (n=402)1 A prespecified subgroup analysis for PFS revealed that the risk of progression or death was significantly lower in the SVd group than in the Vd group across a number of subgroups defined according to baseline characteristics: • • • •

Aged ≥65 years (HR 0.55 [95% CI 0.37–0.83]) High-risk cytogenetic abnormalities (HR 0.67 [95% CI 0.45–0.98]) One previous line of therapy (HR 0.63 [95% CI 0.41–0.95]) Previous treatment with lenalidomide (HR 0.63 [95% CI 0.41–0.97])

ORR was also significantly higher in the SVd group than in the Vd group for those patients: Subgroup

Proportion of patients (%)

Phase 2b, multicentre, open-label STORM Study of Sd (mITT n=122)2

100

Partial response or better to Sd in STORM2

sCR VGPR

40 20

n=2 n=6

SVd

p-value

Aged ≥65 years

76.1% [67.0–83.8]

64.4% (55.6–72.5)

1.77 (1.1–2.5)

0.0243

High-risk cytogenetic abnormalities

77.3% (67.7–85.2)

55.8% (45.2–66.0)

2.70 (1.4–5.0)

0.0008

Creatinine clearance 30–60 mL/min

79.2% (65.9–89.2)

56.7% (43.2–69.4)

2.92 (1.3–6.7)

0.0055

One previous line of therapy

80.8% (71.7–88.0)

65.7% (55.4–74.9)

2.20 (1.2–4.2)

0.0082

Previous treatment with bortezomib

77.6% (69.9–84.4)

59.3% (50.8–67.4)

2.38 (1.4–4.0)

0.0005

mPFS, months

3.7 (95% CI 3.0–5.3)

Previous treatment with lenalidomide

67.5% (55.9–77.8)

53.2% (41.5–64.7)

1.83 (0.9–3.5)

0.035

mDOR, months

4.4 (95% CI 3.7–10.8)

n=24 0 Sd (n=122) Sd2

mITT, modified intention-to-treat; OR, odds ratio; ORR, overall response rate; PFS, progression-free survival, Sd, selinexor, dexamethasone. 1. Grosicki S, et al. Lancet. 2020;396:1563-1573; 2. Chari A, et al. N Engl J Med. 2019;381:727-738.

Selective Inhibitors of Nuclear Export (SINEs): Practical Implications Overall response rate to SDd,1 SPd2 and SKd3 in STOMP

Proportion of patients (%)

100

Orally bioavailable4 Available as a monotherapy4 and has been evaluated as a combination therapy3

80 n=4

60 n=11 40

Advantages

n=11

n=7

n=16

n=7

CR VGPR PR

Works in combination therapy to enhance activity of glucocorticoids, including in tumour cells with resistance to glucocorticoids4 A treatment option for patients with penta-refractory disease and with a manageable fiscal impact5 Demonstrated efficacy in patients with high-risk cytogenetic abnormalities and those with renal dysfunction6

Challenges Cytopenias (thrombocytopaenia), gastrointestinal issues (nausea and anorexia) and asthenia are key dose-limiting toxicities7

0 SDd (n=32)

SPd (n=46)

SKd (n=24)

First month is the most challenging time to manage side effects; patients require proactive supportive care to pre-emptively manage side-effect profile8

SDd, selinexor, daratumumab, dexamethasone; SKd, selinexor, carfilzomib, dexamethasone; SPd, selinexor, pomalidomide, dexamethasone; SVd, selinexor, bortezomib, dexamethasone. 1. Gasparetto C, et al. Eur J Haematol. 2021;2:56-65; 2. Chen C, et al. Abstract 653. ASH Annual Meeting 2019; 3. Gasparetto C, et al. Abstract 1366. ASH Annual Meeting 2020; 4. Chen C, et al. Blood. 2018;131:855-863; 5. Bassali J, et al. Clinicoecon Outcomes Res. 2020;12:317-325; 6. Grosicki S, et al. Lancet. 2020;396:1563-1573; 7. Richter J, et al. Ther Adv Hematol. 2020;11:2040620720930629; 8. Mikhael J, et al. Clin Lymphoma Myeloma Leuk. 2020;20:351-357.

Factors Impacting Treatment Choice in RRMM: Drug Resistance and Novel MOAs Emerging treatment options for RRMM

•

Drug resistance is the main cause of relapse in patients with MM and is associated with an unfavorable prognosis1 As new combinations of antimyeloma drugs are introduced in earlier lines of therapy, patients with RRMM often have disease that is refractory to multiple drugs1 Therefore, drugs with novel mechanisms of action are urgently needed1

Figure from Ramasamy et al., Blood Rev. 2021.2

ADCC, antibody-dependent cellular cytotoxicity; ADCP, antibody-dependent cellular phagocytosis; APN, aminopeptidase N; BCMA, B-cell maturation antigen; BiTEs, bispecific T-cell engagers; Bcl-2, B-cell lymphoma 2; CAR, chimeric antigen receptor; CDC, complement-dependent cytotoxicity; CRBN, cereblon; Iber, iberdomide; mAb, monoclonal antibody; NK, natural killer 1. Pinto V. et al., Cancers (Basel). 2020 Feb 10;12(2):407; 2. Ramasamy et al., Blood Rev. 2021 Feb 9:100808.

147

BELLINI: Study Design • Double blind, randomized 2:1, placebo-controlled phase 3 trial • Primary end point: PFS • Key secondary end points • • • •

ORR ≥VGPR OS QoL/PRO parameters

Patients with RRMM and: • 1-3 lines of prior tx • PI nonrefractory • (N=291) Stratification by: BTZ-sensitive vs BTZ-naïve Prior lines of tx (1 vs 2-3)

Kumar. ASCO 2020. Abstr 8509.

Venetoclax 800 mg qd + BTZ 1.3 mg/m2 + DEX 20 mg (n=194)

Placebo + BTZ 1.3 mg/m2 + DEX 20 mg (n=97)

148

BELLINI: Efficacy Outcome

Ven + Vd (n=194)

Pbo + Vd (n=97)

Significance (95% CI)

Median PFS, mos

23.22

11.41

HR, 0.60 (0.43-0.82) P=0.0013

Median OS, mos

33.5

HR, 1.46 (0.91-2.33) P=0.112

P=0.013

≥VGPR

P<0.001

≥CR

P<0.001

<10–4

P<0.001

<10–5

P<0.002

<10–6

P=0.037

Median DoR, mos

12.8

HR, 0.46 (0.30-0.71) P<0.001

Median TTP, mos

12.2

HR, 0.55 (0.38-0.79) P=0.001

ORR, %

MRD, %

Kumar. ASCO 2020. Abstr 8509.

149

BELLINI: PFS and OS in Key Patient Subgroups Group, HR (95% CI)

PFS

All patients

0.63 (0.44-0.89)

1.46 (0.91-2.33)

ISS staging I II III Cytogenetic risk High Standard t(11;14) status Positive Negative

0.41 (0.24-0.71) 0.91 (0.49-1.69) 1.23 (0.50-3.05)

1.05 (0.49-2.23) 1.58 (0.74-3.38) 2.41 (0.89-8.36)

Group, HR (95% CI) t(4;14) status Positive Negative

0.18 (0.05-0.76) 0.66 (0.45-0.97)

Kumar. ASCO 2020. Abstr 8509.

3.29 (0.92-11.80) 1.10 (0.64-1.89) 0.72 (0.14-3.60) 1.44 (0.86-2.41)

2.40 (0.88-6.55) 0.53 (0.37-0.75)

3.75 (0.79-17.80) 1.22 (0.72-2.04)

0.52 (0.31-0.89) 1.16 (0.39-3.41)

1.47 (0.71-3.04) 4.05 (0.92-17.90)

0.33 (0.18-0.61) 0.80 (0.52-1.22)

0.92 (0.39-2.16) 2.55 (1.23-5.32)

BCL2 expression (IHC)

High Low 1.21 (0.58-2.52) 0.54 (0.36-0.83)

PFS

BCL2 gene expression (qPCR)

High Low

Peptide–Drug Conjugates (PDCs)

PDCs mechanism of action: example of melphalan flufenamide (melflufen)2

1. The PDC readily diffuses through the cell membrane

3. The alkylating payload induces DNA damage to result in cell death

Myeloma cell 2. The PDC binds aminopeptidases; releasing the alkylating payload

Melphalan flufenamide (melflufen) Phase 2, single-arm, multicentre HORIZON Study (n=157)3 Eligibility criteria: • Aged ≥18 years • ECOG performance status of 0–2 • ≥2 prior lines of therapy (including IMiD and PI) • Refractory to pomalidomide and/or an anti-CD38 mAb

Melflufen 40 mg on D 1 + dexamethasone 40 mg on D 1, 8, 15, and 22 of each 28-day cycle All-treated population (n=157)3

Patient response to melflufen in HORIZON3 Proportion of patients (%)

PDCs are composed of three vital components: a homing peptide, a linker and a cytotoxic payload, which work together to target the selected receptor of a tumour cell and deliver cytotoxins1

50 sCR

VGPR

40 30 20 10

n=1 n=17 n=28

n=13

mPFS, months (95% CI)

4.2 (3.4–4.9)

Median duration of ≥PR, months (95% CI)

5.5 (3.9–7.6)

Most common Grade 3–4 TEAEs in all-treated population (n=157)3

n=18

Neutropaenia (79%)

0 All-treated population (n=157)

Triple-class refractory (n=119)

Thrombocytopaenia (76%)

D, day; PDC, peptide–drug conjugate; TEAE, treatment-emergent adverse event. 1. Cooper BM, et al. Chem Soc Rev. 2021;50:1480-1494; 2. Mateos M-V, et al. J Clin Med. 2020;9:3120; 3. Richardson PG, et al. J Clin Oncol. 2021;39:757-767.

Anaemia (43%)

Peptide–Drug Conjugates (PDCs) HORIZON: subgroup analysis in patients with EMD (n=55):1 • Melflufen + dexamethasone showed activity in patients with advanced RRMM with EMD, a population with high unmet medical need, in the HORIZON study

Patients with EMD (n=55)1 ORR, % (95% CI)

24 (13.2–37.0)

mPFS, months (95% CI)

2.9 (2.0–3.7)

DOR (95% CI)

5.5 (1.8–NE)

aPatients

Phase 1/2a, open-label, ANCHOR Study2 Eligibility criteria: • Aged ≥18 years • ECOG performance status 0‒2 • 1–4 prior lines of therapy • Refractory to (or intolerant of) an IMiDa • Not refractory to PI in last line of therapy • Measurable disease

Patient response to melflufen + Dd or 2,3 100 melflufen + Vd in ANCHOR sCR 90 80 CR n=1 70 n=3 VGPR 60 n=2 50 n=10 PR 40 n=3 30 20 n=11 n=4 10 0 Melflufen + Dd Melflufen + Vd (n=33) (n=14) Next steps: Phase 3 LIGHTHOUSE study: melflufen and dexamethasone in combination with daratumumab compared with daratumumab alone4

Proportion of patients (%)

Melphalan flufenamide (melflufen)

Melflufen 40/30/20 mg + daratumumab 16 mg/kg + dexamethasone 40 mgb or melflufen 40/30/20 mg + bortezomib 1.3 mg/m2 + dexamethasone 20/40 mgb

Most common Grade 3–4 TRAEs Melflufen + Dd (n=33)2

Melflufen + Vd (n=14)3

Neutropaenia (58%)

Thrombocytopaenia (79%)

Thrombocytopaenia (55%)

Neutropaenia (50%)

Anaemia (24%)

Anaemia (43%)

Melflufen + Dd (n=33)2

Melflufen + Vd (n=14)3

mPFS, months (95% CI)

11.5 (6.7–NR)

Not mature

mDOR, months (95% CI)

12.5 (8.3–NR)

Not mature

assigned to the daratumumab arm could not have received prior anti-CD38 mAb therapy; patients assigned to the bortezomib arm could not have been PI-refractory; bDexamethasone 40 mg was administered q1w in the daratumumab arm and as 20 mg on D 1, 4, 8, and 11 then as 40 mg on D 15 and 22 in the bortezomib arm. Dd, daratumumab, dexamethasone; EMD, extramedullary disease; NE, not evaluable; NR, not reached; q1w, once weekly; RRMM, relapsed/refractory multiple myeloma; TRAE, treatment-related adverse event. 1. Richardson PG, et al. Abstract 3214. ASH Annual Meeting 2020; 2. Ocio EM, et al. Abstract 417. ASH Annual Meeting 2020; 3. Hájek R, et al. Poster 8037 ASCO Annual Meeting 2021; 4. ClinicalTrials.gov: NCT04649060. Available at: https://clinicaltrials.gov/ct2/show/NCT04649060. Accessed 1 September 2021.

Peptide–Drug Conjugates (PDCs) Melphalan flufenamide (melflufen) Phase 3, randomised, head-to-head, multicentre OCEAN Study (n=495)1,2 Eligibility criteria: • Aged ≥18 years • ECOG performance status of 0‒2 • 2–4 prior lines of therapy (including lenalidomide and a PI) • Refractory to lenalidomide within 18 months of randomisation and last line of therapy

Primary endpoint

mPFS, months

Secondary endpoints

ORR, % (95% CI) CR, % VGPR, % PR, %

Hazard ratio (95% CI)

OS, months Hazard ratio (95% CI)

Melflufen + dexamethasone (n=246)1

Pomalidomide + dexamethasone (n=249)1

6.8

4.9

1:1

Melflufen 40 mg + dexamethasone 40 mg or pomalidomide 4 mg + dexamethasone 40 mg

Most common Grade 3–4 TEAEs1 Melflufen + dexamethasone (n=228)

Pomalidomide + dexamethasone (n=246)

Thrombocytopaenia (76%)

Neutropaenia (49%)

Neutropaenia (64%)

Infection (22%)

Anaemia (43%)

Anaemia (18%)

Infection (13%)

Thrombocytopaenia (13%)

0.79 (0.64–0.98); p=0.03 33 (27–39) 3 9 20

27 (22–33) 1 7 18

19.8

25.0 1.10 (0.85–1.44)

Data cutoff: 3 February 2021. 1. Schjesvold F, et al. Abstract OAB-50 IMW 2021; 2. ClinicalTrials.gov. Available at: https://clinicaltrials.gov/ct2/NCT03151811. Accessed 1 September 2021.

Selected Immune Therapies • CAR T Therapy • Bispecific T Cell Engagers

• MoAb/drug conjugate: GSK 2857916 (“belamaf”) • Emerging role of CelMods (iberdomide, CC92480)

CAR T, chimeric antigen receptor T cells.

Antibody Drug Conjugates (ADC) – BCMA Auristatin Immunotoxin Induces Strong Anti-MM Effects Macrophage (M )

Apoptotic MM cells MMAF released at lysosome to induce G2/M arrest followed by apoptosis

ADPC ADCC FcRII

Apoptosis FcRII

NK , Monocyte M engulfing MM

GSK2857916

NFB

MM cell lysis

Inhibition of NFB signaling

BAFF

APRIL

Bone Marrow Stromal Cell BCMA

GSK2857916

ADCC, Antibody-dependent cellular cytotoxicity; ADCP; antibody-dependent cellular phagocytosis; APRIL, A proliferation-inducing ligand; BAFF; Bcell activating factor; BCMA, BCMA, B-cell maturation antigen; MM, multiple myeloma; Tai YT et al. Blood. 2014;123(20):3128–3138.

Antibody–Drug Conjugates (ADCs) ADCs are composed of an antibody, which binds to a protein highly expressed in tumour cells, connected by a linker to a cytotoxic small-molecule payload, enabling the targeted delivery of the drug to the tumour1 ADCs mechanism of action: example of belantamab mafodotin1,2

Belantamab mafodotin Phase 2, open-label, two-arm, multicentre DREAMM-2 Study (n=196)2 Eligibility criteria: • Aged ≥18 years • ECOG performance status of 0–2 • Disease progression after ≥3 lines of therapy • Refractory to IMiDs, PIs and refractory and/or intolerant to an anti-CD38 mAb

BCMA Anti-BCMA monoclonal antibody

Myeloma cell

Proportion of patients (%)

MMAF

Response to belantamab mafodotin by dose in DREAMM-22 CR/sCR 50

VGPR

40 30 20

n=3

n=3 n=15

n=17

n=12

n=14

2.5 mg/kg (n=97)

3.4 mg/kg (n=99)

ADC, antibody–drug conjugate; BCMA, B-cell maturation antigen; DOR, duration of response; MMAF, monomethyl auristatin F. 1. Cooper BM, et al. Chem Soc Rev. 2021;50:1480-1494; 2. Lonial S, et al. Lancet Oncol. 2020;21:207-221.

1:1

Belantamab mafodotin • 2.5 mg/kg (n=97) • 3.4 mg/kg (n=99)

2.5 mg/kg (n=97)

3.4 mg/kg (n=99)

mPFS, months (95% CI)

2.9 (2.1–3.7)

4.9 (2.3–6.2)

Probability of DOR of ≥4 months (95% CI)

78% (57–89)

87% (69–95)

Most common Grade 3–4 AEs2 2.5 mg/kg (n=95)

3.4 mg/kg (n=99)

Keratopathy (27%)

Thrombocytopaenia (33%)

Thrombocytopaenia (20%)

Anaemia (25%)

Anaemia (20%)

Keratopathy (21%)

Belantamab Mafodotin in Combination with Pomalidomide and Dex for RRMM With PIs, IMiDs, anti-CD38, BMCA-targeted agents are the 4th pillar of MM treatment BELAMAF is the only anti-BMCA treatment, available for all patients with 30 minute outpatient infusion Bela-Pd demonstrates exceptional efficacy (> VGPR 72%; ORR 98 %) in patients that are IMiD/PI/Dara refractory BELAMAF 1.92 mg/kg Q4W > VGPR 64% and median PFS 14.1 months

Grade 3/4 keratopathy in 25% and < 20/50 BCVA 17% BELAMAF 2.5 mg/kg (SINGLE Loading, SPLIT) > VGPR 74% (100% for the 2.5 mg/kg Q4W) and not yet reached

Grade 3/4 keratopathy in 70% and < 20/50 BCVA 15% Alternative dosing schedules are under evaluation to further optimize efficacy/safety profile Trudel et al ASH 2020

Antibody-Drug Conjugates (ADCs): Practical Implications Overall response rate to belantamab mafodotin + Vd1 and belantamab mafodotin + Pd2 in DREAMM-6 100

Proportion of patients (%)

sCR 80

n=4

VGPR

Advantages Off-the-shelf availability for immediate administration in an outpatient setting, particularly important for patients with rapidly progressing disease3,4 Suitable for use in elderly patients, due to lack of any observed cases of CRS or ICANS3,4

Available as a monotherapy5 PR 60 n=9 n=15

Targeted cytotoxicity means it acts independently of T-cell fitness4 Studies of belantamab mafodotin as part of combination regimens are underway1,2,4

Challenges 20 n=5

n=6

0 Belamaf + Vd (n=18)

Belamaf + Pd (n=29)

Ocular toxicity is a major concern. Patients receiving belantamab mafodotin must be enrolled in a risk evaluation and mitigation strategy programme and must undergo ophthalmic examinations at baseline and prior to each dose. Patients should be advised to use preservative-free lubricant eye drops and avoid contact lenses during treatment5 Dose range and frequency to minimise side effects are being evaluated (e.g. longer infusion times and dosing delays)6

CRS, cytokine-release syndrome; ICANS, immune effector cell-associated neurotoxicity syndrome; Pd, pomalidomide, dexamethasone. 1. Popat R, et al. Abstract 1419. ASH Annual Meeting 2020; 2. Trudel S, et al. Abstract 1419. ASH Annual Meeting 2020; 3. Becnel MR, Lee HC. Ther Adv Hematol. 2020;11:2040620720979813; 4. Offidani M, et al. Drug Des Devel Ther. 2021;15:2401-2415; 5. BLENREP (belantamab mafodotin) [prescribing information]. Brentford, Middlesex, UK: GlaxoSmithKline; 2020; 6. Speaker’s clinical experience.

158

IBER enhances in vitro immune-stimulatory activity versus LEN and POM1 LEN2

IL-2 secretion by treated PBMCs3

IBER2

Compound concentration required for degradation of Ikaros or Aiolos protein in vivo:2 EC50, nM2

Ikaros

120

 LEN  POM  IBER

100

Live cells (% DMSO)

Secreted IL-2 (ng/mL)

1500

MM cell survival in co-culture with treated PBMCs3

1000

500

Aiolos

LEN

POM

IBER

0.5

0 20 0

0.1

100 1,000 100,000

Compound concentration (nM)

0.1

100 1,000 100,000

Compound concentration (nM)

Investigational only, not approved. Figure extracted from Matyskiela ME, et al. J Med Chem. 2018;61:535-42. DMSO, dimethylsulfoxide; EC50, half maximal effective concentration; IBER, iberdomide; IL, interleukin; LEN, lenalidomide; MM, multiple myeloma; PBMC, peripheral blood mononuclear cell; POM, pomalidomide. 1. Bjorklund CC, et al. Leukemia 2020;34:1197–201. 2. Matyskiela ME, et al. J Med Chem. 2018;61:535-42. 3. Lonial S, et al. Presented at ASCO 2019; abstract 8006.

Cereblon E3 Ligase Modulators (CELMoDs) CELMoDs, a type of IMiD, target cereblon, leading to myeloma cell apoptosis and immune system stimulation1 CELMoDs mechanism of action: Example of Iberdomide (CC-220)2 Proteasome

Iberdomide (CC-220) Phase 1/2, dose-escalation CC-220-MM-001 study (n=40)3 Eligibility criteria: • Aged ≥18 yearsa • Prior therapies (including lenalidomide and/or pomalidomide, and a PI): – ≥2 for IberDd cohort – ≥1 for IberVd cohort • PD on or within 60 days of last therapy Patient response to IberDd and IberVd in CC-220-MM-0013

Cul4A

RBX1

DDB1 CRBN

CC-220

Substrate

Substrate degradation

aIn

Proportion of patients (%)

Substrate

Most common Grade 3–4 TEAEs of interest3

50 40 30

n=1

n=3

VGPR PR

n=2

20 10

n=4

n=6

IberDd (n=19) or IberVd (n=21)

IberDd (n=19)

IberVd (n=21)

Neutropaenia (50%)

Neutropaenia (20%)

Leukopaenia (22%) Anaemia (22%)

Thrombocytopaeni a (20%)

0 IberDd (n=19)

IberVd (n=21)

•

mDOR was not reached

patients aged <65 years, presence of important comorbid conditions(s) likely to have a negative impact on tolerability of high-dose chemotherapy with ASCT was required for inclusion. CRBN, cereblon; Cul4A, cullin 4A; DDB1, damage-specific DNA binding protein 1; IberDd, iberdomide, daratumumab, dexamethasone; IberVd, iberdomide, bortezomib, dexamethasone; PD, progressive disease; RBX1, RING-box protein 1; Ub, ubiquitin. 1. Bobin A, et al. Cancers (Basel). 2020;12:2885; 2. Gao S, et al. Biomark Res. 2020;8:2; 3. Van De Donk NWCJ, et al. Abstract 724. ASH Annual Meeting 2020.

Cereblon E3 Ligase Modulators (CELMoDs): Practical Implications

100

Patient response to iberdomide 0.3‒1.2 mg + dexmethasone1

Potential advantages

Proportion of patients (%)

VGPR

Higher potency than previous IMiDs3

80 PR 60

Possibility to overcome resistance to certain drugs2,3

Efficacy shown in heavily pre-treated patients in combination regimens1,4 Promising clinical activity among patients refractory to the last regimen and previously exposed to IMiDs, PIs and CD38 mAbs4

n=1

20 n=15

Potential challenges Understanding the relationship between mutational status and clinical response; CELMoDs may be ineffective in cases where IMiD resistance results from CRL4CRBN component or Ikaros mutations3

0 Iberdomide + dexamethasone (n=51)

CRL, cullin-RING E3 ubiquitin ligase; MR, minimal response; SD, stable disease. 1. Lonial S, et al. Abstract 8006. ASCO Annual Meeting 2019; 2. Bobin A, et al. Cancers (Basel). 2020;12:2885; 3. Davis LN, Sherbenou DW. Cancers. 2021;13:1686; 4. Van De Donk NWCJ, et al. Abstract 724. ASH Annual Meeting 2020.

161

CC-92480 is a novel CELMoD® agent specifically designed for rapid protein degradation1,2 Efficient substrate degradation leading to apoptosis and potent antiproliferative activity in LEN and POM resistance3 Aiolos degradation efficiency1

Apoptosis induction kinetics

100

7.5

LEN

Ymin = 35 Ymin = 18 CC-92480

1  10-6

Compound concentration (M)

CC-92480, a potent CELMoD agent1

aDF15R. bDF15,

0.1 µM POM

5.0

2.5

Ymin = 5 0.001

LEN

10,000

Proliferation IC50 (nM)

POM

Caspase-3 induction

Control (%)

LEN-resistant cells (H929-1051) 0.01 µM CC-92480

Antiproliferative activity in LEN/POM resistance

100

150

POM

CC-92480

1,000 100

10 1

No cereblona

0.1

Parental cell lineb Resistant cell linec

0.01

Time (hours)

LEN1

POM1

H929, and OPM-2. cH929R1, H929R2, OPM-2R1, OPM-2R2, and OPM-2R3. CELMoD, cereblon E3 ligase modulator; LEN, lenalidomide; POM,

pomalidomide. 1. Hansen J, et al. J Med Chem 2020;63:6648–6676. 2. Wong L, et al. Blood 2019;134:1815. 3. Richardson PG, et al. Presented at ASCO 2020; abstract 8500.

162

Response, n (%)

CC-92480: Best Response

•

100 80 60 40 20 0

CBR 26.3%

ORR 21.1% 1 (1.3) 6 (7.9) 9 (11.8) 4 (5.3) 37 (48.7)

CBR 50.0%

SD or better 75.0%

ORR 40.0%

ORR 54.5%

2 (20.0)

1 (9.1) 2 (18.2)

2 (20.0) 1 (10.0)

CBR 63.6% SD or better 100%

5 (50.0) 15 (19.7)

All Evaluable (n = 76)

3 (27.3)

DCR 100%

1 (9.1) 4 (36.4)

3 (3.9)

10/14 days x 2 1.0 mg QD (n = 10) MTD

CR VGPR PR MR SD PD NE

21/28 days 1.0 mg QD (n = 11) RP2D

7 of 11 patients at the RP2D of 1 mg QD 21/28 days were triple-class refractory (to ≥ IMID, 1 PI, and 1 anti-CD38 mAb) •

Of these patients, 1 had CR, 1 VGPR, 2 PR, and 1 MR Richardson PG et al, ASCO 2020. Abstr 8500.

163

Responses in patients with EMD • Only patients on continuous schedules are shown Dosing Dose level schedulea

0.1 mg QD 0.2 mg QD

SD PD

10/14 days × 2

0.3 mg QD 0.6 mg QD

21/28 days

10/14 days × 2

1.0 mg QD

SD PD PD SD SD

VGPRa

PRb MR

SD PDc

SD PR SD MR SD

On treatment at time of data cut

PR SD

1.0 mg QD

PD SD PR VGPR PR VGPR PR (case study) SD

PET scan post-CC-92480 C3D1

VGPR PR

21/28 days

C10

0.8 mg QD

PET scan pretreatment

1.0 mg dose active in EMP

patient in the 21/28-day 1.0 mg QD cohort had an unconfirmed VGPR as of the data cutoff date; b1 patient in the 21/28-day 0.8 mg QD cohort had an unconfirmed PR as of the data cutoff date; c1 patient in the 21/28-day 0.8 mg QD cohort had an unconfirmed PD as of the data cutoff date. C, Cycle; CR, complete response; D, Day; EMP, extramedullary plasmacytoma; MR, minimal response; PD, progressive disease; PET, positron emission tomography; PR, partial response; QD, once daily; SD, stable disease; VGPR, very good partial response .

Richardson PG, et al. Presented at ASCO 2020; abstract 8500.

Conclusions ~ Integration and Impact of Novel Agent Combinations in RRMM, including Immune Therapies, and Overcoming Key Challenges… •

Innovations (PIs, IMiDs, mAbs, HDACi’s) to date have produced significant improvements in PFS and OS; recent approvals will augment this – with Quad Combinations emerging as a new standard

•

The treatment landscape for RRMM is ever changing as new therapies are being developed, offering hope to patients

•

Further investigation and clinical practice in the real world will determine how these drugs fit into the treatment landscape for RRMM, through optimisation of dosing and AE management

• • •

Next wave of immune therapies: crucially, are they agnostic to mutational thrust? Baseline immune function is a key barrier to success and is targetable mAbs (including ADCs, BiTEs) represent true new novel mechanisms, as well as other immunotherapeutics (e.g. CAR –T, cellular therapies, vaccines) New insights to mechanisms of drug action are further expanding treatment/immuno-therapeutic opportunities with combinations Next generation small molecules and targeted therapy show great promise – e.g. VENETOCLAX, SELINEXOR and MELFLUFEN, and for new agents in development, e.g. CeLMoDS Further refinement of prognostics, immune profiling, and MRD will guide therapy

• • •

The Impact Of Novel Therapies and the Importance of Sequence in RR MM ~ 2021 2009 – Patient DG, age 62 years High Risk IgG kappa MM DSS 3, ISS 2, Elevated LDH 17 del positive , R-ISS 3 13 del positive (by FISH)

2017

2018

PMH – HTN, requiring triple therapy

RD + Zoledronic acid => RVD (VGPR)

Well tolerated, minimal PN (G1)

2010 ASCT (CY – HDM) (CR) R/Z maintenance 2011 PD – RVD (PR)

2019

2012 PD – Pom VD (VGPR) 2013 PD (aggressive relapse with extra-medullary disease) DARA [501] 16 mg/kg (CR; MRD -) to present ( > 8 years) with multiple future options when needed….now aged 74 years and is a grandmother X3.

“Best I have ever felt since prior to diagnosis, and even despite dealing with the COVID pandemic” Clinic visit @ DFCI 2021

NEJM, 2015

Ongoing MM Collaborative Model for Rapid Translation From Bench to Bedside

Thank YOU! Shawna Corman Investigatorship

Dana and Rob Smith Family Fund For MM Research RJ Corman MM Research Fund

Pharmaceuticals Advocacy

Academia

Progress and Hope NIH NCI

IMF

Paula and Rodger Riney Foundation

MMRF/C IMWG, LLS

FDA EMEA

Counter Myeloma Mike Sheehan

15 Novel Drugs and >30 new FDA-approved drugs/combos/indications in last 18 yrs

Panel Discussion

167

Audience Q&A

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IMF Patient and Family Webinar

Webinar Survey & Closing Remarks 169

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