IMF Patient & Family Webinar - New Frontiers In Myeloma Care by International Myeloma Foundation

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IMF Patient and Family Webinar AGENDA *all times listed in Pacific Time Zone 10:00 – 10:05 AM

Welcome Announcements with Dr. Brian G.M. Durie

10:05 – 10:30 AM

Myeloma 101 Dr. Brian G.M. Durie

10:30 – 11:00 AM

Side Effects & Symptom Management Ann McNeill, RN, MSN, APN

11:00 – 11:30 AM

Diagnosis, Monitoring & Early Disease Management Dr. Brian G.M. Durie

11:30– 11:40 AM

Panel Discussion

11:40– 11:55 AM

BREAK

IMF Patient and Family Webinar AGENDA *all times listed in Pacific Time Zone 11:55AM – 12:25 PM

Latest Advances in Immune Therapies: A Focus on CAR T-cell Therapies Dr. Yi Lin

12:25 – 12:55 PM

Approaches to Relapsed Myeloma: What are the Current Bispecifics & Novel Agents? Dr. Nikhil Munshi

12:55 – 1:05 PM

Summary Panel Discussion Webinar Survey & Closing Remarks

IMF Patient and Family Webinar

Myeloma 101 Brian G.M. Durie, MD Cedars-Sinai Outpatient Cancer Center Los Angeles, CA

Myeloma is treatable  Over 90% of patients respond to current therapies  Average first remission is 4 years or more  In 2022, average survival is at least 7-10 years  Some patients live over 15-20 years  New therapies are constantly improving the outlook 7

Myeloma Expert Consultation Helps!  Good to do early!  Virtual consults can be explored.  Sets path for future  Guides local doctor SEE: Questions to ask your doctor

https://www.myeloma.org/resource-library/tip-card-ask-your-doctor-these-important-questions

Careful testing required for diagnosis and monitoring  Bone marrow indicates % myeloma  X-rays/ scans show where lesions* are located X-ray image of myeloma lesions in arm

Myeloma cells as seen in a bone marrow aspirate

See further discussion: “What is a lesion?” https://www.myeloma.org/bone-disease

More Test Details  Bone marrow FiSH shows chromosome results  MRI and PET/CT show more lesions than x-rays FISH

PET

MRI F

D D D

FiSH – Fluorescent in Situ Hybridization See: https://www.myeloma.org/videos/imaging-studies-or-scans-should-myeloma-patients-undergo

D D

Colored spots show translocations: t(11;14)

PET F = Focal D = Diffuse

Managing Myeloma: The Components Transplant Eligible Patients

Transplant Ineligible patients

Transplant

Maintenance

Initial Therapy Consolidation/ Maintenance/ Continued therapy

Supportive Care

Reference: https://onlinelibrary.wiley.com/doi/full/10.1002/ajh.25791

Treatment Combinations: Now and Then NEW

VD Rev/Dex CyBorD VTD VRD KRD IRD Dara + triplet

SCT VD/VRD

Front line treatment

Induction

OLD

Thal/Dex VAD DEX

Consolidation

SCT

Thalidomide Bortezomib Lenalidomide Lenalidomide Carfilzomib Bortezomib Ixazomib Pomalidomide Ixazomib Daratumumab Daratumumab Isatuximab Pomalidomide Elotuzumab Panobinostat Bendamustine Selinexor Belantamab Mafodotin Melphalan Flufenamide (Melflufen)

Maintenance

Post consolidation

Nothing Prednisone Thalidomide

Relapsed

Rescue

Few options

S0777 Trial: VRd vs Rd Eight 21-day Cycles of VRd

Randomization N = 525 Newly diagnosed MM

• •

Stratification: ISS (I, II, III) Intent to transplant @ progression (yes/no)

Bortezomib 1.3/mg2 IV Days 1, 4, 8, and 11 Lenalidomide 25 mg/day PO Days 1-14 Dexamethasone 20 mg/day PO Days 1, 2, 4, 5, 8, 9, 11, 12

Six 28-day Cycles of Rd Lenalidomide 25 mg/day PO Days 1-21 Dexamethasone 40 mg/day PO Days 1, 8, 15, 22

6 month of triplet followed by doublet Reference: Durie BGM, et al. Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): a randomised, open-label, phase 3 trial. Lancet. 2017 Feb 4;389(10068):519-527. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5546834

13 13

S0777 Trial: VRd vs Rd

41 months

Durie et al. Blood Cancer Journal (2020) 10:53 https://www.nature.com/articles/s41408-020-0311-8

OS 80% = 4 years 55% = 7 years

14 14

What to Expect with Treatment First “biochemical” relapse

100% Myeloma protein level

Deep first response 50%

MRD Undetected

Second response Later relapse from MRD undetected

Possible MRD undetected

5 years

10 years 15

Treatment Options

 “Triple therapy”: 3 drugs recommended • Most common = VRd* [Rd for older/frail] (Velcade®/ Revlimid®/ dexamethasone)  ASCT (Autologous Stem Cell Transplant)  Can be considered to achieve better response (after 3-6 months of VRd) Plus

Zometa®/ Aredia or denosumab for bone lesions

* Other options include VCd (CyBorD); KRd; Dara + Rd; Vd



Treatment Strategies in 2022 Triplets or quadruplets in frontline



Maintenance based upon risk



Decisive early relapse treatment (triplets if feasible)



Earlier use of new immune therapies 17

IMF Publications

Publications available at no-charge: https://www.myeloma.org/publications

IMF Website – http://www.myeloma.org http://www.myeloma.org

IMF Patient and Family Webinar

Ann McNeill, RN, MSN, APN John Theurer Cancer Center at Hackensack University Medical Center, IMF Nurse Leadership Board

Side Effects and Symptom Management 21

May 14, 2022

LIFE IS A CANVAS, YOU ARE THE ARTIST

Ann McNeill, RN, MSN, APN John Theurer Cancer Center at Hackensack University Medical Center, IMF Nurse Leadership Board

Patient Education Slides 2022

OBJECTIVES COLOR WHEEL OF TREATMENT

Myeloma and treatment side effects & symptom management

FRAMING YOUR CARE

Know your care team, Telehealth & Meeting Prep, & Shared Decision Making

INFECTION PREVENTION and COVID 19

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 • Minimize side effects • Allow for good quality of life

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

• Improved overall survival

DISCUSS GOALS AND PRIORITIES WITH YOUR HEALTHCARE TEAM 25

CAR T: A NEW TREATMENT APPROACH

CAR T: UNIQUE SIDE EFFECTS Nausea / vomiting

Shortness of Breath

Diarrhea

Headache

Weakness

Fatigue

CRS IS A COMMON BUT USUALLY MILD SIDE EFFECT WITH CAR T

CRS Fever

Confusion

CRS = cytokine release syndrome. Oluwole OO, Davila ML. J Leukoc Biol. 2016;100:1265-1272. June CH, et al. Science. 2018;359:1361-1365. Brudno JN, Kochenderfer JN. Blood. 2016;127(26):3321-3330. Brudno JN, Kochenderfer JN. Blood Rev. 2019:34:45-55. Shimabukuro-Vornhagen, et al. J Immunother Cancer. 2018;6:56. Lee DW, et al. Biol Blood Marrow Transplant. 2019;25:625-638.

CAR T: UNIQUE SIDE EFFECTS Hallucinations

Ataxia

Altered wakefulness

Apraxia

Facial nerve palsy

Confusion

Headache

Encephalopathy

Neurotoxicity

NEUROTOXICITY IS A RARE BUT SERIOUS SIDE EFFECT OF CAR T

Tremors

Seizures

CRS = cytokine release syndrome; ICANS = immune effector cell–associated neurotoxicity syndrome; ICE = Immune Effector Cell Encephalopathy screening tool; MRI = magnetic resonance imaging. Brudno JN, Kochenderfer JN. Blood. 2016;127(26):3321-3330. Lee DW, et al. Biol Blood Marrow Transplant. 2019;25:625-638.

CAR T: TIPS •

CAR T CELLS Viral vector

Patient own T cell

• •

Cytotoxic cytokines

scFv BCMA

Different CAR T-cell therapy products have differences in efficacy, safety, manufacturing process, and centers where they are available Ask for a referral to CAR T-cell therapy center as soon as it is possible as next treatment option (ie, before relapse)

– –

Insurance preauthorization required (weeks, maybe longer)

– –

Must be able to wait or have bridging therapy

Your own T cells are engineered and grown, which takes ≈ 4 to 6 weeks

MM cell

MM cell death

• • • •

CAR = chimeric antigen receptor.

Must have sufficient blood count and organ function to be eligible

Manufacturing CAR T-cell therapy is limited: center-specific “wait list” processes

• • •

Need to be “known” by the center. How frequently do you or your myeloma doctor need to check in with the CAR T center to let them know your status? How will this happen? Opportunity for telehealth visits? How are slots allocated? Advocate for yourself—ask for help navigating the process

In patient for ~1 week when CAR T administered Patients need a caregiver and must stay within proximity of CAR T-cell therapy center for ≈ 1 month after the infusion No driving for 8 weeks after CAR T One and done…BUT will need ongoing monitoring; some patients need transfusion support

Catamero D, et al. J Adv Pract Oncol [in press]. Shah UA, Mailankody S. BMJ. 2020;370:m3176.

BISPECIFIC ANTIBODIES •

BISPECIFIC ANTIBODIES

T cell

Cytotoxic cytokines

CD3

BCMA

Bispecific antibody

MM cell

Different bispecific antibodies have differences in efficacy, side effects

• • •

About 7 in 10 patients responded CRS is common Some had skin/nail disorders

•

Not yet FDA approved; currently available in clinical trials

•

Off-the-shelf treatment; no waiting for engineering cells

•

Infusion (every 2 weeks by may vary)

MM cell death

BCMA = B-cell maturation antigen; CAR = chimeric antigen receptor; MM = multiple myeloma; scFV = single chain fragment variable. Shah N, et al. Leukemia. 2020;34(4):985-1005. Yu B, et al. J Hematol Oncol. 2020;13:125.

CLINICAL TRIALS: EARLY ACCESS TO PROMISING TREATMENTS Preclinical PHASE 1

PHASE 2

ANIMAL STUDIES FIRST INTRODUCTION OF AN INVESTIGATIONAL DRUG INTO HUMANS

• • •

Determine metabolism and PK/PD actions, MTD, and DLT Identify AEs Gain early evidence of effectiveness, studied in many conditions; typically, 20 to 80 patients; everyone gets agent

EVALUATION OF EFFECTIVENESS IN A CERTAIN TUMOR TYPE

• •

Determine short-term AEs and risks; closely monitored Includes up to 100 patients, typically

PHASE 3

GATHER ADDITIONAL EFFECTIVENESS AND SAFETY INFORMATION COMPARED TO STANDARD OF CARE

PHASE 4

APPROVED AGENTS IN NEW POPULATIONS OR NEW DOSE FORMS

• •

Placebo may be involved if no standard of care exists; 100s to several thousand patients Often multiple institutions; single or double blind

AE = adverse event; DLT = dose-limiting toxicity; MTD = maximum tolerated dose; PD = pharmacodynamics; PK = pharmacokinetics. Faiman B, et al. Adv Pract Oncol. 2016;7:17-29.

HOW TO FIND CLINICAL TRIALS

Clinicaltrials.gov https://clinicaltrials.gov/

IMF Infoline US & Canada 800-452 CURE (2873) Worldwide: 1-818-487-7455 infoline@myeloma.org

CLINICAL TRIAL MYTHS: DISPELLING INACCURACIES MYTH: If I participate in a clinical trial, I might get a placebo, not active treatment MYTH: If I participate in a clinical trial, I can’t change my mind

• Phase 1 and 2, everyone gets active treatment • Phase 3 standard of care vs new regimen: often standard regimen with/without additional agent in MM trials • Patients can withdraw their consent for clinical trial participation at any time

MYTH: Patients (whatever demographic/ distance from clinic/etc) never participate in clinical trials so I won’t mention it

• Mention the option and give the patient the opportunity; implicit and explicit biases can limit participation • Some groups may need more information about clinical trials to feel comfortable with participation

MYTH: Clinical trials are dangerous because they have new medicines and practices

• Some risk is involved with every treatment, but medicines are used in clinical trials with people only after they have gone though testing to indicate that the drug is likely to be safe and effective for human use

MYTH: Clinical trials are expensive and not covered by insurance

• Research costs are typically covered by the sponsoring company • Standard patient care costs are typically covered by insurance • Check with clinical trial team/insurers; costs such as transportation, hotel may not be reimbursed and are paid by patient

MM = multiple myeloma.

PhRMA website. Accessed April 15, 2022. https://phrma.org/-/media/Project/PhRMA/PhRMA-Org/PhRMA-Org/PDF/A-C/CLINICAL-TRIALS-MYTH-FACTPRINT.pdf?hsCtaTracking=f6689b95-1626-40d9-8c87-c6b8d31600a4%7C35221aa8-d487-4db3-9416-b9c3c35e3bac.

IMPORTANCE OF DIVERSITY IN CLINICAL TRIALS “[P]eople from racial and ethnic minority and other diverse groups are underrepresented in clinical research. This is a concern because people of different ages, races, and ethnicities may react differently to certain medical products.” –FDA

Regnante JM, et al. J Oncol Pract. 2019;15(4):e289-e299. FDA website. Clinical Trial Diversity. Accessed March 31, 2022. https://www.fda.gov/consumers/minority-healthand-health-equity/clinical-trial-diversity. International Myeloma Foundation website. Accessed March 31, 2022. https://www.myeloma.org/node/4797.

THE BRIGHT

DARK SIDE TO STEROIDS

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

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

(insomnia), fatigue

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

• Increased risk of

infections, heart disease • Muscle

weakness, cramping

• Increase in blood

pressure, water retention

• Blurred vision, cataracts • Flushing/sweating • Stomach bloating,

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.

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

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

Smith LC, et al. CJON.2008;12(3)suppl:37-52. Faiman B. CJON. 2016;20(4):E100-E105.

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. 37

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, activity, surgical intervention, radiation therapy, etc • Complementary therapies (Mind-body, medication, yoga, supplements, acupuncture, etc)

Faiman B, et al. CJON. 2017;21(5)suppl:19-36.

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

Report symptoms of peripheral neuropathy early to your health care provider; nerve damage from PN can be permanent if unaddressed

Faiman B, et al. CJON. 2017;21(5)suppl:19-36. Tariman, et al. CJON.2008;12(3)suppl:29-36.

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

FATIGUE, ANXIETY & DEPRESSION

Physical Psychological

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 • Psychologic: fear, anxiety, stress • Physiologic: sleep apnea, heart issues, pain 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.

INFECTION PREVENTION AND COVID-19 IN PEOPLE WITH MULTIPLE MYELOMA

Patient Education Slides 2021

INFECTION CAN BE SERIOUS FOR PEOPLE WITH MYELOMA Multiple myeloma

Treatment

Immune dysfunction

General Infection Prevention Tips • Good personal hygiene (skin, oral) • Environmental control (wash hands, avoid crowds and sick people, etc)

7-10 fold increased risk of bacterial and viral infections for people with myeloma Report fever of more than 100.4°F, shaking chills even without fever, dizziness, shortness of breath, low blood pressure to HCP as directed.

As recommended by your health care team

• Growth factor (Neupogen [filgrastim]) • Immunizations (NO live vaccines) • Medications (antibacterial, antiviral)

Brigle K, et al. Clin J Oncol Nurs. 2017;21(5)suppl:60-76. Faiman B, et al; IMF Nurse Leadership Board. Clin J Oncol Nurs. 2011;15(Suppl):66-76. Miceli TS, et al. Clin J Oncol Nursing. 2011;15(4):9-23.

ASH Website. COVID-19 Resources. Accessed January 30, 2022. https://www.hematology.org/covid-19/covid-19-and-multiple-myeloma

Manage stress

HEALTHFUL LIVING STRATEGIES: PREVENTION

• 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.

HEALTHFUL LIVING STRATEGIES: KEEP ACTIVE Do Keep a log or journal of your activity • Notify your healthcare provider about sudden onset of pain, progressive weakness, headaches, blurred vision, numbness, and tingling •

•

Dehydration can lead to low blood pressure, falls

Movement therapies can reduce stress, promote sleep Yoga, Pilates, Tai Chi Shown to improve sleep and sleep quality, • Improved quality of life & mood •

Do Not: Overdo it • Force exercise • Try things without discussing with provider • Consider weight lifting limits •

Myeloma bone disease may affect your ability to do certain movement activities. Review your activity interests with your health care provider!

Boullosa DA, et al., Jul 2013;45(7):1223-1228. Faiman B et al., Clinical Journal of Oncology Nursing. 2008;12(0):53-62; Rome S et al., Clin J Oncol Nurs. Aug 2011;15 Suppl:41-52. Miceli T et al., Clinical Journal of Oncology Nursing. 2011;15:9-23; Coleman EA et al.,Oncol Nurs Forum. May 2008;35(3):E53-61.

FRAMING YOUR CARE Know your care team, Telehealth & Meeting Prep, & Shared Decision Making

You are central to the care team Be empowered • Ask questions, learn more • Participate in decisions Communicate with your team • Understand the roles of each

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

Pharmacis t

CARE TEAM COLLAGE General Hem/Onc Myeloma Specialist

Primary Care Provider (PCP)

You and Your Caregiver(s) Support Network

Subspecialists Allied Health Staff

PREPARE FOR VISITS & CONSIDER TELEMEDICINE Come prepared: • Bring a list of current medications, prescribed and • • •

• •

over the counter Write down your questions and concerns. Prioritize them including financial issues Have there been any medical or life changes since your last visit? Current symptoms - how have they changed (improved, worsened, stable)? Keep a symptom diary. Bring it along Communicate effectively: your health care team can’t help if they don’t know Know the “next steps”, future appointments, medication changes, refills, etc

IMF Telemedicine Tip Sheet. In development.

Check with your healthcare team – Is telemedicine an option? Similar planning for “in-person” appointment PLUS: • What is the process and what technology is needed? • Plan your labs: are they needed in advance? Do you need an order? • Plan your location: quiet, well-lit location with strong wi-fi is best • Plan yourself: consider if you may need to show a body part and wear accessible clothing • Collect recent vital signs (blood pressure, temp, heart rate) self-serve blood pressure cuff is available at many pharmacies and for purchase

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

• 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

Data From Research

HCP Clinical Experience TREATMENT DECISION

Your Preference Philippe Moreau. ASH 2015. 49

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

IMF TV Teleconferences

eNewsletter: Myeloma Minute

Download or order at myeloma.org

IMF InfoLine 1-800-452-CURE 9am to 4pm PST 50

YOU ARE NOT ALONE

IMF Patient and Family Webinar

Brian G.M. Durie, MD Cedars-Sinai Outpatient Cancer Center Los Angeles, CA

Diagnosis, Monitoring & Early Disease Management 53

Diagnosis, Monitoring & Early Disease Management

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 55

MGUS Can iStopMM transform the landscape?  Screening becomes routine?  Understand causes/ triggers  Improve all outcomes  Allow early interventions Lead the way forward

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 57

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 58

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 59

Many diverse outcomes of iStopMM Tumor microenvironment Risk scores

Cancer screening

Renal amyloidosis Genetics Mental health Early intervention

MGRS

Pain Flow cytometry Correlative science

Neuropathy Survival

Cardiac amyloidosis

Psychological impact

The significance of the “unknown significance”

Polyclonal immunoglobulins

Waldenströms

Smoldering Multiple Myeloma (SMM)  SMM more common than reported?  SMM risk scoring is essential  Better predictors are coming!  Best management is evolving

Risk Score to Predict Progression Risk At 2 Years Score 0 2 3 5 0 3 4 0 2 3 5 6 2

100 High-risk group >12 80

% 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%)

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): KRd + ASCT/ ~ 2 Years of Therapy 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

Mos

0 30

 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 64

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) 65

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 69

COVID will be with us! • Vaccination • Boosters • Masks • Other protections COVID and Myeloma: What you need to know https://www.myeloma.org/covid19-myeloma-patients

Despite COVID… The future is bright with high likelihood of improved outcomes 71

Audience Q&A

Break 74

IMF Patient and Family Webinar

Latest Advances in Immune Therapies: A Focus on CAR T-cell Therapies

Dr. Yi Lin

Mayo Clinic, Rochester, MN

IMF Patient and Family Webinar Latest Advances in CAR-T Yi Lin, MD, PhD

Associate Professor, Medicine Mayo Clinic Division of Hematology Chair, Cellular Therapeutics Cross-Disciplinary Group Mayo Clinic Cancer Center Mayo Clinic

Scottsdale, Arizona

Rochester, Minnesota

Jacksonville, Florida

Disclosures Research Support/P.I.

Janssen, Kite/Gilead, Celgene/BMS, BlueBird Bio, Merck, Takeda

Employee

No relevant conflicts of interest to declare

Consultant

Vineti

Major Stockholder

No relevant conflicts of interest to declare

Speakers Bureau

No relevant conflicts of interest to declare

Honoraria

No relevant conflicts of interest to declare

DSMB

Sorrento

Scientific Advisory Board

Amgen, BlueBird Bio, Pfizer, Gamida Cells, Janssen, Kite/Gilead, Celgene/BMS, JUNO, Legend, Novartis, NexImmune.

All above funding made to the institution. No personal compensation.

CAR-T has entered standard of care for multiple myeloma Feb 2022 Cilta-cel (CARVYKTI)

These are the first regulatory approved CAR-Ts that are not targeting CD19. Presenter: Yi Lin, M.D.Ph.D.

Myeloma current treatment landscape 2nd Line

3rd Line

4th Line

• Selection Based on Response to Prior Therapy • Changes between PI & IMiDs classes and or next generation

Idecabtagene vicleucel (ABECMA) Ciltacabtagene autoleucel (CARVYKTI)

Backbone of major regimens: Proteasome inhibitor (PI), Immune modulatory drug (IMiD) With and without CD38 antibodies Elotuzumab (CS1 antibody) combinations Selinexor Selinexor/Bortezomib/DEX Melflufen Belantamab: BCMA antibody drug conjugate Presenter: Yi Lin, M.D.Ph.D.

BCMA is the target with the most CAR-T trials in myeloma B-Cell Maturation Antigen (BCMA) is member of the TNF receptor superfamily • Expressed nearly universally on myeloma cells • Expression largely restricted to plasma cells and some mature B cells • Plays critical role in plasma cell survival

Njau & Jacob. Nat Immunol ‘14. 15:219. Presenter: Yi Lin, M.D.Ph.D.

BCMA Expression on myeloma cells (brown color = BCMA protein)

BCMA targeting novel therapies Accessibility Antibody drug • Off-the-shelf conjugate (ADC) Belantamab Bi-specific • Off-the-shelf Antibody • Likely can be given at more centers Anticipate FDA review: Teclistamab • Individual CAR-T manufacturing Ide-cel • Infusion and monitoring at certified centers only Cilta-cel

Presenter: Yi Lin, M.D.Ph.D.

Treatment

Toxicities

• Repeat dosing until progression

• Ocular • Peripheral neuropathy

• Repeat dosing until progression

• Cytokine release syndrome • Neurotoxicities

• • • •

• Cytokine release syndrome • Neurotoxicities • Prolonged cytopenia • ? Genetic mutation risk

Lymphodepletion chemotherapy Single Dose Currently no maintenance therapy Highest requirement for patient fitness

What is a CAR T cell? Native T Cell Receptor APC pMHC

CD28L

T cell receptor (TCR)

Co-stimulatory receptor Ex. CD28 CD3ζ

Chimeric Antigen Receptor scFv or parts of antibody (ex. Target BCMA on plasma cells) Costimulatory Signal 2: ex. CD28, 41BB Essential Signal 1 (TCR): CD3ζ

The FDA-approved CAR-T cells are • Permanently genetically altered to express CAR receptors on the cell surface • Can recognize cell surface antigen without MHC presentation • Become activated upon antigen recognition

Chimeric Antigen Receptor T cells (CARTs) T cell CAR-T cell Lentiviral vector

Native TCR Anti-BCMA CAR construct BCMA

Dead tumor cell

Tumor cell Adapted from S. Kenderian; ASTCT CAR-T Education slides.

CAR-T therapy patient journey

1. Screening

Local/primary hematologist refer patient for evaluation. Coordination of salvage treatment

7. Ongoing

Monitoring

Done by local/primary hematologist. CAR-T team available for guidance.

Potential delay with insurance approval

Often done together in 1 visit if possible. Average 1-2 weeks.

Evaluation

Full eligibility assessment

4. Bridging

Patient may return home for monitoring or bridging treatment while their CAR-T cells are manufactured. Average time 1 month. Close communication with CAR-T team.

3. Cell

collection Plan to stay at CAR-T center

4. Chemo +

CAR-T infusion

5. Post-Infusion

Typically 2-3 days of evaluation, 5 days of treatment.

Monitoring

Typically for 1 month post CAR-T infusion

Adapted from Mayo Clinic Kern Center for Innovation. Presented by Yi Lin, MDPhD.

KarMMa-1 Registration Study (Ide-cel)

• PFS increased with higher target dose & depth of response • median PFS was 12 mo at 450 × 106 CAR+ T cells • median PFS was 20 mo in patients with CR/sCR Presenter: Yi Lin, M.D.Ph.D.

Regulatory agency approved Dose

Munshi NC et al. N Engl J Med 2021;384:705-716.

KarMMA-1 Study (Ide-cel) Long Term Follow-up • OS is not decreased for elderly, those with extramedullary or triple refractory disease. • OS is decreased with patients with R-ISS stage.

OS in high-risk patient subgroups

Anderson L et al. ASCO 2021. Abstr 8016.

KarMMa-1 (Ide-cel) comparison with other therapies Ide-cel (KarMMa-1) vs Real World Experience1

Presenter: Yi Lin, M.D.Ph.D.

Ide-cel (KarMMa-1) vs Belantamab (DREAMM-2)2

1. Jagannath S et al. BCJ 2021. 11: 116. 2. Rodriguez-Otero P et al. ASH 2021. Abstr 1978.

Autologous BCMA CAR-T in Pivotal Trials Ciltacabtagene autoleucel (Cilta-cel, JNJ-68284528)

Idecabtagene vicleucel (Ide-cel, bb2121, Abecma)

Orvacabtagene autoleucel (Orva-cel, JCARH125)

Binding domains

VHH

4-1BB

ide-cel CAR design MND

Anti-BCMA scFv

Promoter

CD8

4-1BB

CD3ζ

Linker Tumor binding domain

FDA Approved

Signaling domains

FDA Approved

Study Discontinued. Next generation CAR-T in trial.

1. Lin Y et al ASH 2020. 2. Madduri et al, ASH 2020. 3. Mailankody et al, ASCO 2020.

CARTITUDE-1 Registration Study (Cilta-cel) ORR: 97.9% (95/97)

• Study population

• Median 2-YR follow-up

80% Patients, %

• 3 or more prior lines of therapy • Triple class and CD38 mAb exposed

100%

60%

82.5%

40%

≥VGPR: 94.9%

20% 0%

12.4%

3.1% Best response =

sCR

VGPR

Martin T et al. ASH 2021, abstr 549.

CARTITUDE-1 Registration Study (Cilta-cel) Progression-Free Survival

100

2-year PFS: 71.0% (95% CI, 57.6–80.9) Median PFS not reached (95% CI, 25.2–NE)

Patients (%)

2-year PFS: 60.5% (95% CI, 48.5–70.4)

Median PFS not reached (95% CI, 22.8 months–NE)

2-year OS: 74.0% (95% CI, 61.9–82.7) Median OS not reached (95% CI, 27.2 months–NE)

Overall Survival

100

0 0

Patients at risk All patients 97 sCR patients 80

19 19

4 4

1 1

0 0

Months 95 80

85 78

77 73

74 71

67 64

63 61

36 35

Patients at risk All patients 97

All patients Martin T et al. ASH 2021, abstr 549.

sCR patients

18 21 Months 78

Cilta-cel CARTITUDE-1 vs LocoMMotion Real World Prospective Study: PFS and OS is better with CAR-T • LocoMMotion (NCT04035226) patients with RRMM, triple class exposed treated with SOC regimens • LocoMMotion patient distribution 91% Europe, 9% US.

Mateos M et al. ASH 2021, abstr 550.

CAR-T side-effects: cytokine release syndrome (CRS)

• • • •

• •

Can progress to low blood pressure and or shortness of breath If left unchecked, can cause multi-organ failure and risk of death

Can be correlated with tumor burden Can be correlated with CAR-T expansion (usually around 1-2 weeks) Not required to occur to achieve clinical response Inflammatory markers, CRP and ferritin, are the most commonly readily available clinical labs included in monitoring • Tocilizumab, IL-6 receptor antibody, is FDA approved as first line treatment for CRS • •

Current treatment is based on patients’ signs and symptoms, not strictly based on labs Active treatment of CRS do not negatively impact clinical response

Serum Cytokine (fold change from baseline)

• Often starts with fevers, with associated myalgia, arthralgia, poor appetite

IL-1β IL-6 IFN- γ

1000

TNF-α IL-2R IL-2 IL-10 IL-1RA

100

0.1

Day after Infusion

Grupp et al, NEJM 2013

Types of Neurologic Side-Effects Acute • Concurrent with CRS and high fevers • Associated with elevated cytokines • Common; some degree of neurotoxicity occurs in nearly all CAR T patients • Symptoms include decreased attention, confusion, disorientation, delirium and ataxia • Can respond sometimes to steroid

Cerebral Edema • Rare • Idiosyncratic • Rapid acute onset • Requires immediate ICU transfer and intervention with mannitol with or without anti-seizure medications • May be fatal

Delayed • Occurs within weeks to months; often after resolution of CRS • Range of symptoms •

confusion, mental status changes, encephalopathy, aphasia

•

Cranial nerve palsies, neuropathies

•

Parkinsonism: tremor, rigid muscles, slowed movement, difficulty to initiate movement, speech and writing changes, poor posture and balance

• May resolve on its own. Can take days to months to resolve.

Each type of neurological toxicity is likely due to different manifestations of CAR T therapy (different underlying physiologies), responds to different mechanisms, and has a different likelihood of reversibility

BCMA CAR-T Pivotal Trials: Toxicities Ide-Cel – Phase 1 (CRB-401)1 N = 62

Ide-Cel – Phase 2 (KarMMA-1)2 N = 128

Cilta-Cel – Phase 1b/II CARTITUDE-13 N = 97

76% / 6.5%

84% / 5%

95% / 5%

Onset day median (range)

2 (1 – 19)

1 (1 – 12)

7 (1 – 12)

Duration, days median (range)

5 (1 – 32)

5 (1 – 63)

4 (1 – 97)

36% / 1.6%

18% / 3%

21% / 10%*

CRS, Any Gr / ≥ Gr 3

ICANS, Any Gr / ≥ Gr 3

Toci: 29% Drug use Steroid: 16%

Toci: 52% Steroid: 15%

Toci: 69% Steroid: 22% Anakinra: 19%

* Delayed onset movement and neurocognitive symptoms noted in 12.4%, 9.3% Gr3 or higher. 1. Lin Y et al ASH 2020. 2. Munshi et al ASCO 2020. 3. Madduri D ASH 2020.

Cilta-cel CARTITUDE-1 vs LocoMMotion Real World Prospective Study: Quality of Life is better with CAR-T

Mateos M et al. ASH 2021, abstr 550.

Patient Selection Considerations

• Is there an age cut-off? • • • •

Most clinical trials do not restrict upper age limit Subjects up to age 78 treated on phase II registration studies in myeloma No evidence for decreased response in elderly Likely performance status and organ functions impact inclusion of otherwise fit elderly and excludes younger, but frail subjects • ECOG, Karnofsky, myeloma frailty score

• High risk disease not formally studied in protocols yet • CNS involvement • Plasma cell leukemia • Concurrent amyloidosis

• Renal dysfunction

• Fludarabine dose adjustment for renal impairment has been allowed • No formal study of CAR-T for subjects on hemodialysis

CAR-T Access remain an issue Median (range) 10-50 MM CAR-T infusion volume in 2021 (<5,50-100) Number of FDA approved CAR-T slots 1 (0-4) given per month Patients on wait list 20 (5-100) (FDA approved CAR-T) Duration a patient is on waiting list 6 (2-8) months Outcomes of patients on wait list FDA approved CAR-T 25% (0%-64%) CAR-T trial 25% (0-50%) non-CAR-T trial 25% (0-50%) hospice or death 25% (0%-75%)

Survey of 20 centers. Responses from 17 centers. Kourelis T et al. ASCO 2022.

Challenge in CAR-T therapy: Making it to CAR-T dosing • Most common CAR-T manufacturing time is ~1 month • Avg 10 – 20% of the patients who have cells collected are unable to receive infusion • Most common cause due to disease progression during manufacturing • Reducing manufacturing time could enable more patients to receive therapy • Shortening manufacturing time could reduce T cell exhaustion from ex vivo expansion • Allogeneic CAR-T as “off-the-shelf” option

CAR-T Innovation: Other manufacturing approach (PRIME Study)

• Low rate of CRS, 17% total, no Gr 3. Gr3 or higher ICANS: 3.8%. • P-BCMA-101 Nanoplasmid appears to induce deeper response than standard plasmid Costello C. et al. ASH 2020, abstr 134.

CAR-T Innovation: Rapid manufacturing GC012F dual BCMA/CD19 targeted CAR-T

PHE885 – Humanized BCMA CAR-T

• Manufacturing overnight

• T-Charge platform < 2 days

• 2 Grade 3 CRS. No severe ICANS.

• Expansion of Tscm population

• CAR-T detectable up to 60 weeks post infusion.

• 2 (13%) Grade 3 CRS. No severe ICANS.

Jiang H. et al. ASCO 2021. Abstr 8014.

Less CAR-T cell dose is used with rapid manufacturing.

Spelling A et al. ASH 2021. Abstr 3864.

CAR-T Innovation: Academic center manufacturing (ARI0002H)

Median follow-up 13 months. Fernandez de Larrea C et al. ASH 2021. Abstr 2837.

CAR-T Innovation: allogeneic CAR-T UNIVERSAL Study (ALLO-715, NCT04093596) Phase I, Open-label study enrolling in 11 US centers

ALLO-715 Dose Escalation:

1. TALEN-mediated CD52 KO allows selective lymphodepletion with ALLO-647 2. TALEN-mediated TRAC KO eliminates TCRα expression to minimize risk of GvHD

Mailankody S et al. ASH 2020.

40, 160, 320, 480 x 106 CAR+ T cells

Lymphodepletion Regimens (FCA*, CA† )

Doses

Fludarabine

30 mg/m2/day x 3 days

Cyclophosphamide

300 mg/m2/day x 3 days

ALLO-647

13 to 30 mg x 3 days

* FCA conditioning with fludarabine, cyclophosphamide and ALLO-647 † CA conditioning with cyclophosphamide and ALLO-647

CAR-T Innovation: allogeneic CAR-T UNIVERSAL Study (ALLO-715, allogeneic BCMA CAR-T) Clinical Response • Median time to dosing was 5 days • No GVHD to date • CRS (56%) and ICANS (14%) mainly low grade; low use of tocilizumab (23%) and steroids (14%) • ORR achieved in 17 (71%) patients with 6 (25%) CR/sCR rate for the FCA 320M cell dose group • mDOR 8.3 months

Mailankody S et al. ASH 2021. Abstr 651.

October 8, 2021 FDA placed partial hold on all AlloGene Studies Subject on Allo-501A study with pancytopenia post infusion. Chromosome abnormality found in CD19 CART cells. FDA hold lifted in 2022. Studies resumed.

Global myeloma CAR-T activities

April 2022

CAR-T investigations in earlier lines of therapy 2nd Line

3rd Line

4th Line

• Selection Based on Response to Prior Therapy • Changes between PI & IMiDs classes and or next generation

US FDA Approved LoT

Idecabtagene vicleucel (Ide-Cel, bb2121, Abecma)

Ciltacabtagene autoleucel

(JNJ68284528, Carvykti)

KarMMa-2: Ide-cel in high-risk MM, early relapse after 1L/ASCT. KarMMa-4: Ide-cel in high risk newly diagnosed MM CARTITUDE-5: Cilta-cel in NDMM, transplant not considered

KarMMa-3: Randomized, controlled study for Ide-cel vs SOC triplet regimens. CARTITUDE-4: Cilta-cel vs SOC triplet regimens in randomized, controlled study

CARTITUDE-2: Cilta-cel in multiple exploratory cohorts

Factors that can impact CART efficacy & areas of investigation Decrease anti-CAR immunogenicity • Fully human BCMA scFv (CT053, Carsgen NCT03915184; NCI NCT03602612) • Deimmunized ddBCMA (Arcellx, NCT04155749) • ARI0002h (Spain, fractionated dose, NCT04309981) Combination approaches • BCMA CART + lenalidomide (MSK, NCT03070327) • Ide-cel + iberdomide, GSI, others (KarMMa-7) • Cilta-cel + Len +/- Dara (CARTITUDE-2)

Modulate tumor antigen expression • BCMA CART with gamma-secretase inhibitor to increase BCMA expression (Fred hutch, NCT03502577) Host Immunity

Treatment LD chemo Dosing

CAR-T Composition Strategies • Memory like T cell functions (bb21217, BlueBird, NCT0327419) • CD8 only (Cartesian Therapeutics, NCT03448978, NCT03994705) Manufacturing • NEXT-T, CC-98633 (JUNO/BMS, NCT04394650) • T-Charge PHE885 (Novartis, NCT04318723)

Tumor Target Selection

Tumor TME

CAR-T

Efficacy Response Durability Toxicities

CART Composition

Manufacturing Vector

CAR Construct Design

Antigen targets • GPRC5D (MCARH109, MSKCC, NCT04555551; BMS) • APRIL CAR (Autolus, NCT03287804) • CS-1 ( (NCT03710421) • NKG2D-ligands (NCT02203825) • CD38 (Sorrento, NCT03464916)

CAR-T Constructs • P-BCMA-101, CARTyrin, transposon (Poseida, NCT03288493) Allogeneic UCART • BCMA (NCT03752541; Allogene, Allo715, NCT04093596; CRISPR Therapeutics, CTX120, NCT04244656) • CYAD-211 shRNA BCMA (Celyad) • CS-1 (UCARTCS1, Cellectis, NCT04142619)

bb21217: Next generation Ide-cel • bb21217 uses the same CAR molecule as bb2121,1 but is cultured with the PI3K inhibitor, bb007, to enrich for T cells displaying a memory-like phenotype • CAR T cells enriched for this phenotype may persist and function for longer than non-enriched CAR T cells2 • Persistence of functional CAR T cells after infusion may be one determinant of duration of response3

Memory-like phenotype T-cell plasticity Long-lived Self-renewal

Effector-like phenotype Terminally differentiated Short-lived No self-renewal

• When cultured in the presence of the PI3K inhibitor bb007, donor cells become enriched for memory-like CAR T cells and the percentage of senescent CAR T cells decreases. BCMA, B-cell maturation antigen; CAR, chimeric antigen receptor; CCR7, C-C chemokine receptor type 7; CyTOF, mass cytometry; PD, progressive disease; PI3K, phosphoinositide 3 kinase; TCM/TEFF/TEM/TN/TSCM, central memory/effector/effector memory/naïve/stem cell memory T cell. aMatched samples from five multiple myeloma donors. 1. Friedman KM, et al. Hum Gene Ther. 2018;29:585–601; 2. Fraietta JA, et al. Nat Med. 2018;24:563–571; 3. Berdeja JG, et al. Presented at ASH 2019; Abstract #927.

Presenter: Yi Lin, M.D.Ph.D.

Raje N et al. ASH 2021, abstr 548.

CRB-402 Phase 1 Study (bb21217, NCT03274219)

RP2D is 450x10^6. Patients in the 450x10^6 group treated with bb21217 produced using an updated manufacturing process (n=32) had similar ORR (81%) and CR (41%) to that of the 450x10^6 group as a whole. Presenter: Yi Lin, M.D.Ph.D.

Raje N et al. ASH 2021, abstr 548.

CAR-T Innovation: avoid Immunogenicity Ide-cel: KarMMa-1 Study*

• Anti-CAR antibody became detectable at month 3 and increased over time • Retreatment response were only seen in those without ADA (n=28) • Likely not the only mechanism of resistance – overall median PFS of retreatment 1 month Retreatmen t Response

ADA – Positive (n = 16)

ADA – negative (n = 12)

Yes

6 (50%)

16 (100%)

6 (50%)

*Munshi N et al. NEJM 2021.

CT053 LUMMICAR21 (N = 20)

ddBCMA Study2 (N = 24)

CT103 (China)3 (N = 71)

CRS (>=Gr3)

1 (4.2%)

2.8%

Neuro (>=Gr3)

1 (8%)

2 (8.3%)

ORR

94%

100%

94.4%

CR/sCR

29%

68.4%

50.7%

• CAR-T persistence detected for up to 1 year • No anti-CAR antibody detected to date

1. Kumar et al. ASH 2020, abstr 133. 2. Frigault et al. ASH 2021, Abstr 3832. 3. Li et al. ASH 2021, abstr 547.

Challenge: decreased BCMA expression at relapse after CAR-T treatment BCMA expression is commonly detectable but decreased at relapse/PD

Gamma secretase inhibitor (GSI) can increase cell surface BCMA

Brudno J et al. JCO 2018.

Complete BCMA loss by bi-allelic loss is uncommon However, this may become more prevalent with selection pressure from BCMA therapy

Pont MJ et al. Blood 2019; 134: 1585.

Innovation: Gamma Secretase Inhibitor to increase BCMA expression

• FCARH143 CAR-T, fully human BCMA CAR-T • Enrolled n=18, 7(38.9%) prior BCMA • CRS >=G3, 28% (4 Gr3, 1 Gr4) Cowan A et al. ASH 2021, abstr 551.

CAR-T Innovation: Other antigen target GPRC5D CAR-T (MCARH109)

• Among 17 pts treated, 10 had prior BCMA, 8 prior CAR-T • >=Gr 3 CRS: 7%. >=Gr 3 ICANS: 7%. At highest dose. • MAS 7%. • Nail changes, all grade 1: 56%. • Rash, all Gr 1: 19% • Dysguesia, grade 1, 6% • Median follow-up 17.9 weeks Mailankody, S. et al. ASH 2021. Abstr 827.

Conclusion • Exciting new era of immunotherapy in myeloma • Challenges seen to date in transition of this transformative individualized treatment to standard of care practice • Evolving data continue to reinforce the value of this therapy • Novel investigations will continue to advance the capabilities of CAR-T

Thank you!

115

IMF Patient and Family Webinar

Approaches to Relapsed Myeloma:

Dr. Nikhil Munshi Dana Farber Cancer Center, Boston, MA

What are the Current Bispecifics and Novel Agents?

116

Approaches to Relapsed Myeloma: What Are the Current Bispecifics & Novel Agents Nikhil C. Munshi, MD Professor of Medicine Harvard Medical School Kraft Family Chair Director, Basic and Correlative Science Jerome Lipper Myeloma Center Dana-Farber Cancer Institute Boston VA Healthcare System

Disclosures Advisory Board/Consultant: Adaptive, Abbvie, Amgen, BMS, Beigene, Janssen, Legend, Oncopep, Karyopharm, and Takeda Scientific Founder: Oncopep

Definitions • Relapsed myeloma: Disease that is recurring after a response to the most recent therapy • Refractory myeloma: Disease that is progressing despite ongoing therapy

How Do We Decide Next Treatment? Factors Influencing the Treatment Decision-making at the Relapse Setting Frailty

Disease morbidity

Risk assessment

Age

Refractory disease

ISS

Performance status

Renal impairment

Cyto-genetics

Disability

Bone disease

Co-morbidities

Treatment history Previous therapies

Lifestyle

Patient preference Travel / infusion time

The most effective regimen, safe and maintaining QoL

• Choice of PI- or IMiD-based partner depends on prior treatment • Nearly all phase 3 studies show triplets perform better than doublets • Cross trial comparisons should not be done as Clegg A et al. Lancet 2013;381:752–762; Handforth C et al. Ann Oncol 2015;26:1091–1101; Chen X et al. Clin Interv Aging 2014;9:433–441; Palumbo A et al. Blood 2015;125:2068–2074; Jhaveri D et al. Haematologica 2016;101:1–881 (Abstract E1312); Sonneveld P et al. Leukemia 2013;27:1959–1969; Faiman BM et al. Clin J Oncol Nurs 2011;15:66–76; Miceli TS et al. Clin J Oncol Nurs 2011;15:9–23; Greipp PR et al. J Clin Oncol 2005;23:3412–3420; Binder M et al. Haematologica 2016;101:P665; Merz M et al. Haematologica 2016;101:P650; Chng WJ et al. Leukemia 2016;30:1071–1078; Chung TH et al. PLoS One 2013;20:e66361; Sonneveld P et al. Leukemia 2013;27:1959–1969; Ramsenthaler C et al. BMC Cancer 2016;16:427; Williams LA et al. J Clin Oncol 2016;34:e18127; Ramasamy K et al. Haematologica 2017;102:E1457.

Therapeutic Advances in Multiple Meyloma • 11 new Agents in last 15 years: • • • • • • • • •

Proteasome inhibitors: bortezomib, Carfilzomib, Ixazomib Immunomodulator: thalidomide, lenalidomide, pomalidomide Monoclonal antibodies: elotuzumab, daratumumab, Isatuximab, Blentamab Exportin inhibitor: Selinexor Alkylating Agent: bendamustine, Melphalan, cyclophosphamide Existing older agents: dexamethasone, anthracycline, etoposide, cis-platinum Cell therapy: Ide-cel, Cilta-cel Near approval: venetoclax, BCMA-bispecifics Bcl-2 inhibitor - Venetoclax

• 2-, 3-, 4-drug combinations - effective in relapsed/refractory MM • 28 FDA approvals and median patient survival prolonged 3-4 fold, from 3 to at least 8-10 years, and MM is a chronic illness In many patients.

Therapy for Relapsed MM:Triplets Preferred With Second Generation IMiDs, PIs, MoAbs Active In Len and Bort refractory MM • Carfilzomib Pom Dex (no neuropathy) • Dara Pom Dex ; Dara Carfilzomib Dex (deep responses, FDA approved) • Elo Pom Dex (well tolerated, FDA approved) • Isatuximab Pom Dex (FDA approved) Active in Bort refractory MM • Elotuzumab Len/Dex (indolent relapse), Ixazomib Len • Dex (all oral), Carfilzomib Len Dex (no neuropathy), Dara Len dex (MRDresponses) (all FDA approved) Active in Len refractory MM • Pom Bort Dex, Dara Bort Dex (MRD- responses)(FDA approved)

Management of Patients at First Relapse in Patients Relapsing After Bortezomib based Treatments Lenalidomide-Dexamethasone Combinations First relapse after Bortezomib-based induction1 Doublets Rd

N Efficacy

Ixazomib

Elotuzumab

Carfilzomib*

Daratumumab

IRd vs Rd 722

ERd vs Rd 646

KRd vs Rd 792

DRd vs Rd 569

IRD

RD 23

Median f/u, mos ORR

78.3%

CR Median PFS, mos

Triplets based on Rd DaraRd or KRd or IxaRd or EloRd

EloRD RD

KRD

Min 48 mos 71.5%

DRD

32.9

79%

66%

87%

66.7%

93%

76%

12%

32%

9.3%

55%

23%

14.7

14.9

16.6

17.5

– Median OS, mos

48.3

39.6

– 48.3

40.4

–

Moreau P et al. N Engl J Med. 2016;374:1621; Dimopoulos MA et al. Br J Haematol. 2017;178:896. Stewart AK et al. N Engl J Med. 2015;372:142; Stewart AK et al. Blood. 2017;130: Abstract 743. Dimopoulos M et al. J Hematol Oncol. 2018;11:49; Dimopoulos MA et al. N Engl J Med. 2016;375:1319.

Management of Patients at First Relapse Relapsing After Lenalidomide based Treatments Bortezomib-Dexamethasone Combinations First relapse after IMiD-based induction1 Doublets Kd / Vd

Pomalidomide PVd vs Vd 559

N Efficacy

Median f/p, mos

Control

Triplets based on Bortezomib DaraVD or PanoVD or EloVD or VCD

Daratumumab*

Carfilzomib

Selinexor

Venetoclax

Kd vs Vd 929

SVD vs Vd 195 vs 207

VenVD vs VD 194 vs 97

DVd vs Vd 498 Tx

Control

37.5

26.9

Control

16.5

Control 18.7

ORR

82%

50%

85%

63%

76%

63%

76%

62%

82%

68%

16%

30%

10%

13%

17%

11%

13%

Median PFS, mos

16.7

7.1

18.7

9.4

13.9

9.46

22.4

11.5

47.6

40.0

– MedianOS, mos

Richardson et al. Lancet Oncol 2019; 20: 781–94; Palumbo A et al. N Engl J Med. 2016;375:754; Spencer A et al. Haematologica. 2018; Sep 20 [epub ahead of print]; Dimopoulos MA et al. Lancet Oncol. 2016;17:27; Dimopoulos et al ASCO 2020; Kumar S. EHA 2019.

BOSTON Trial: Selinexor-Vd vs Vd in Patients with Multiple Myeloma Who Had Received 1-3 Prior Therapies (FDA Approved) Median PFS (mos)

SVd 13.93 Vd 9.46

Dimopoulos MA et al Lancet 2020; 396: 1563-73.

BCMA Immuntoxin: Belantamab Mafodotin 3.4mg/kg vs 2.5-mg/kg in RRMM (13 month followup) (FDA Approved 2020) 40%

belantamab mafodotin 2.5mg/kg (n=97)

belantamab mafodotin 3.4mg/kg (n=99)

mOS

14.9 months (95% CI: 9.9-NR)

14.0 months (95% CI: 10-NR)

mDOR

11.0 months (95% CI: 4.2-NR)

6.2 months (95% CI: 4.8-NR)

mPFS

2.8 months (95% CI: 1.6-3.6)

3.9 months (95% CI: 2.0-5.8)

ORR*

31% (97.5% CI: 21.7-43.6)

35% (97.5% CI: 24.8-47.0)

ORR=31% 30%

n=2 n=3

n=2 n=5

20%

n=11

VGPR or better 58% (of ORR)

n=18

VGPR or better 66% (of ORR)

10%

Keratopathy 27% (2.5mg/kg) and 21% (3.4mg/kg) patients 2.5mg/kg chosen for further studies

ORR=35%

n=13

n=12

Belantamab mafodotin 2.5mg/kg (N=97)

Belantamab mafodotin 3.4mg/kg (N=99)

VGPR

sCR

Lonial et al Lancet Oncol 2020; 21: 207-21.; ASCO 2020

Efficacy of Venetoclax in Combination with Bortezomib in : Patients with BCL2high expression, Investigator-Assessed PFS in Patients With BCL2high PFS Median, months HR (95% CI) P value

OS in Patients With BCL2high Ven + Bd Pbo + Bd 30.1 9.9 0.37 (0.21–0.64) .0005

OS Events Median, months HR (95% CI) P value

Ven + Bd Pbo + Bd 17 12 NR NR 0.70 (0.32–1.51) .3624

Median PFS 30.1 months in the Ven + Bd arm vs 9.9 months in the Pbo + Bd arm (P=.0005) Bd, bortezomib + dexamethasone; HR, hazard ratio; NR, not reached; OS, overall survival; Pbo, placebo; PFS, progression-free survival; Ven, venetoclax.

Kumar et al, ASH 2021

Teclistamab BCMA× CD3 Bispecific Antibody in RRMM

BCMA

CD3

Myeloma cell

Teclistamab

T cell

T cell activation Cytokine secretion Cytotoxicity Teclistamab humanized BCMA × CD3 bispecific IgG-4 Ab redirects CD3+ T cells to BCMA + MM cells Cell Death

Teclistamab induces T cell-mediated killing of MM patient cells in xenograft models Garfall et al ASH 2020

Teclistamab: JNJ-64007957 Screening

Treatment

Post-treatment

Cohort A (triple-class exposed)

Follow-up

Key eligibility criteria

Teclistamab (JNJ-64007957) is a humanized IgG-4 bispecific DuoBody® antibody that binds to BCMA and CD3

• • •

Measurable MM

•

No prior BCMA therapy

2 years after LPI

RRMM, ≥3PL Prior PI, IMiD, and antiCD38

Screened N = 165

Phase 1 = 40 Phase II = 125

Primary Safety = 165 Primary Efficacy = 150

Patient characteristics2 Time since initial diagnosis, median (range) in yrs

Endpoints • Primary: ORR • Secondary: DOR, TTR, MRD status, PFS, OS, safety, pharmacokinetics, immunogenicity, PRO

Study status as of 07 Sept 2021

6.0 (0.8–22.7)

Prior lines of therapy, median (range) Prior stem cell transplantation, n (%) Refractory status, %

5.0 (2–14) 1

135 (81.8)

Triple-class refractoryf Penta-drug refractoryg Refractory to last line of therapy

128 (77.6) 50 (30.3) 148 (89.7)

Median Duration of Treatment 5.9 mo. Median F/U 7.8 mo. (range: 0.5+–18)

Moreau ASH 2021; abs 896

Teclistamab: Respons rate and Side effects 70

62.0% (93/150)

Patients (%)

60 50 40

Duration of Response

ORRa

21.3%

≥CR: 28.7%

sCR: 21.3%

• 19 patients had a schedule change to less frequent dosing

7.3%

• Responses were durable and deepened over time

sCR

• At data cutoff, 82 responders (88.2%) were alive without subsequent treatment or progressive disease – Only 11 of 93 responders have progressed or died (1 responder is off treatment but still responding)

58.0%

30 20

≥VGPR:

29.3%

VGPR

4.0%

*In with ≥CR, 41.9% MRD-negativity Response:

Safety Analysis Set N=165 AEs ≥20%, n (%)

Any Grade

Grade 3/4

Neutropenia

108 (65.5)

94 (57.0)

Anemia

82 (49.7)

57 (34.5)

Thrombocytopenia

63 (38.2)

35 (21.5)

Lymphopenia

56 (33.9)

53 (32.1)

CRS

118 (71.5)

1 (0.6)

Icans

5 (3.0)

Death (unrelated)

End of treatment status:

sCR

D/CPD

VGPR

D/C-AE

Still being followed

Schedule change:

Biweekly

Moreau ASH 2021; abs 896

D/C- Other Death Monthly

Talquetamab GPRC5D BiTE and Daratumumab T-cell activation (CD25)

Cytokine release (IFN-γ, TNF-α, IL10…)

CD3 arm

Talquetamab

Cell kill

JNJ-64407564 GPRC5DxCD3 antibody GPRC5D arm

Perforin Granzymes

• Talquetamab, binds to GPRC5D and CD3, well tolerated in heavily pretreated patients with RRMM, with at efficacy and safety 800 µg/kg SC Q2W or 405 µg/kg SC QW dosing • QW or Q2W doses of talquetamab: 60-70% ORR in triple-class and penta-refractory patients (30% prior BCMA therapy) Responses were durable and deepened over time • The combination of talquetamab + daratumumab appears tolerable, with ORR (77–85%) in these heavily pretreated patients/ Responses were observed in both CD38–exposed and –refractory patients

Krishnan et al, Chari et al ASH132021 1

BiSpecific Cell Antibodies: Summary Teclistamab1

REGN54582

Elranatamab3 (PF-3135)

AMG-7014

TNB-383B4

CC-932694

Cevostamab⁵ (FcRH5-CD3)

Talquetamab⁶ *(GPRC5D-CD3)

165

118

161

No. of prior regimens, median

5.5

Triple refractory, %

128 (77.6)

14 (19)

57 (98)

72 (61)

136 (84.5)

42 (76.5)

62%

51%

70%

36%

81%

89%

56.7%

68.35%

28.7%

8.3%

30%

1.7%

6.4%

CRS (all grades), %

118 (71.5)

28 (38)

48 (83)

65%

54%

77%

130 (80.7)

41 (74.35)

CRS grade 3/4, %

0.6%

70%

1.2%

1.8%

65.5 (57)

23 (20)

64 (60)

27 (22)

55.5 (48)

Patients

ORR, % CR %

ICANS Neutropenia all grade (grade 3/4), % Infection %

*Talquetamab calculations were generated from two subgroups averaged

(1) Moreau et al. ASH 2021; abs#896. (2) Zonder et al. ASH 2021; abs#201. (3) Sebag et al. ASH 2021; abs #895. (4) Sidana et al. ASCO 2021; abs#8045. (5) Trudel et al. ASH 2021; abs#157. (5) Krishnan et al. ASH 2021; abs#158.

TRIMM-2: Talquetamab GPRC5D BiTE and Daratumumab • The combination of tal + dara appears tolerable, with no overlapping toxicity ⎻ Safety profiles appear consistent with each agent given as a monotherapy and no new AEs were observed

⎻ 55% of patients experienced CRS, all grade 1 and 2, with median time to onset of 2 days and 2 days duration

• Preliminary efficacy data suggest a promising ORR (77–85%) in these heavily pretreated patients ⎻ Responses were observed in both CD38–exposed and –refractory patients

⎻ Responses were durable and appeared to deepen over time, with the majority of patients remaining on treatment

• Tal-mediated induction of cytotoxic T cells (CD38+/CD8+) in the presence of dara supports the rationale for this synergistic combination regimen • These data support tal + dara as a novel immunotherapy-based approach for the treatment of patients with MM

Chari et al ASH 2021

TRIMM-2 Tec/Dara Abstract 1647

MonumenTAL-1 Abstract 158

13 3

Future of CAR T cells and/or BiTES in Multiple Myeloma

Novel Immunomodulatory Drugs Target Cereblon - CelMods Kronke et al, Science, 2014

CELMoDs: 20-30 fold increased CRBN affinity, 30% response In len/pom resistant MM (Lonial et al ASCO, ASH 2019)

Lu et al, Science, 2014

Gandhi AK et al. Brit J Haematol, 2014;164: 811-21.

Iberdomide with Dexamethasone in Relapsed/Refractory Multiple Myeloma: Expansion Phase With or Without Prior BCMA Therapy Key eligibility criteria Cohort D • RRMM • ≥ 3 prior therapiesa • Disease progression on or within 60 days of last antimyeloma therapy • Refractory to an IMiD agent, a PI, a glucocorticoid, and a CD38 mAb

Cohort D IBER (RP2D) + DEX IBER (oral): 1.6 mg days 1-21 DEX (oral): 40 mg on days 1, 8, 15, 22a 28-day cycles

Cohort I • RRMM • ≥ 3 prior therapiesb • Prior treatment with a BCMA targeted therapy • PD on or within 60 days of last antimyeloma therapy (documented PD if CAR T cell therapy as last therapy)

Cohort I (post BCMA) IBER (RP2D) + DEX IBER (oral): 1.6 mg days 1-21 DEX (oral): 40 mg on days 1, 8, 15, 22a 28-day cycles

• Lonial et al ASH 2021

CELMod CC-92480 and Dexamethasone in RRMM

Richardson et al, ASCO 2020

What is the Goal of Traetment in Relapsed Disease? • Obtain the maximal response

Patients with Relapsed Myeloma May Have Similar Survival as Newly-diagnosed if They Receive MRD negativity

Munshi N et al., Blood Adv. 2020

Summary and Future Directions • All options need to be tried sequentially. No good data on optimum sequence or regimen • Cumulative toxicities from prior therapies may influence decision • Choice of therapy for RRMM depends on patient factors (frailty, comorbidity) and prior treatments (PI,IMiD,CD38MoAb) • Triplet therapy for relapsed MM can achieve deep MRD- durable responses • BCMA CAR T and bispecific T cell engager therapies can achieve high rates of deep responses even in MM refractory to all current agents • We are now at cusp of achieving Long-term disease-free survival and potential cure in Myeloma !! All patients should be encouraged to participate in ongoing clinical trials

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