IMF Patient & Family Webinar 2023 - Understanding The New Myeloma Landscape

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Agenda – all times are listed in Eastern Time Zone 5:30 - 5:35 PM – Welcome and Announcements w/ Dr. Brian G.M. Durie 5:35 – 6:00 PM – Myeloma 101 Brian G.M. Durie, MD, International Myeloma Foundation

6:00 – 6:15 PM – Q&A 6:15 – 6:40 PM – Taking the Reins of Your Myeloma Care Mary Steinbach, DNP, APRN, Hunstman Cancer Institute, University of Utah, IMF Nurse Leadership Board Member

6:40 – 6:55 PM – Q&A 6:55 – 7:05 PM - BREAK

Agenda – all times are listed in Pacific Time Zone 7:05 – 7:30 PM – Frontline Therapy Rafat Abonour, MD, Indiana University School of Medicine

7:30 – 7:45 PM – Q&A 7:45 – 8:15 PM – Relapse & Immune Therapies Ajai Chari, MD, University of California San Francisco

8:15 – 8:30 PM – Q&A 8:30 PM – Closing Remarks

IMF Patient and Family Webinar

Myeloma 101 November 2, 2023

Brian G.M. Durie, MD International Myeloma Foundation Studio City, CA

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What is Myeloma?

Multiple myeloma is a cancer of the bone marrow.

• The malignant cell is a MYELOMA CELL • Symptoms are CRAB features • Tracked using Monoclonal (M) protein • Very treatable with current therapies 2

CRAB Clinical Features

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Monoclonal Protein Analysis

4

Immunofixation

5

Skeletal Survey

6

MRI Scan

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PET/CT Scan

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Investigations for Diagnosis

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Tests to do at Baseline for Prognosis

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Myeloma is treatable ► Over 90% of patients respond to current therapies ►Average first remission is 4 years or more ►In 2023, average survival is at least 7-10 years ►Some patients live over 15-20 years ►New therapies are constantly improving the outlook 11

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

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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

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

PET

MRI F

F

D D D

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

F

D D

D

Colored spots show translocations: t(11;14)

F

PET F = Focal D = Diffuse

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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

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Treatment Combinations NEWER

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

SCT VD/VRD

Front line treatment

Induction

OLD

Thal/Dex VAD DEX

Consolidation

SCT

Lenalidomide Bortezomib Ixazomib Daratumumab Pomalidomide

Maintenance

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

Relapsed

Post consolidation

Rescue

Nothing Prednisone Thalidomide

Few options

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Immunotherapy

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Immunotherapy Timeline

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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

118 9

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

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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 21

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 22

Treatment Strategies in 2023 ►

Triplets or quadruplets in frontline

►

Maintenance based upon risk

►

Decisive early relapse treatment (triplets if feasible)

►

Earlier use of new immune therapies 23

IMF Publications

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

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

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Q&A

with panel

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Taking The Reins of Your Multiple Myeloma Care Mary Steinbach, DNP, APRN Huntsman Cancer Institute University of Utah

STABLE OF TREATMENT FINDING YOUR GAIT GOING THE DISTANCE

Today’s Topics

STABLE OF TREATMENT Myeloma and treatment options, side effects, symptom management, & supportive care

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FINDING YOUR GAIT Know your care team, telehealth & meeting prep, & shared decision making

GOING THE DISTANCE Healthful living, infection prevention, renal and bone health

Stable of Treatment Treatment options, side effects, symptom management, and supportive care

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STABLE OF TREATMENT FINDING YOUR GAIT GOING THE DISTANCE

STABLE OF TREATMENT FINDING YOUR GAIT GOING THE DISTANCE

Treatment Goals

Myeloma Therapies

Rapid and effective disease control Durable disease control Improved overall survival Minimize side effects Allow good quality of life

Supportive Treatment

Prevent disease- and treatment-related side effects Optimize symptom management Allow good quality of life

Discuss goals and priorities with your healthcare team.

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Stable of Treatment Options -Mibs

-MAbs

-Mides

Steroids

FRONTLINE

Velcade® (bortezomib)

Darzalex® (daratumumab)

Thalomid® (thalidomide) Revlimid® (lenalidomide)

Dexamethasone Prednisone Prednisolone SoluMedrol

MAINTENANCE

Velcade® (bortezomib) Ninlaro® (ixazomib)

Darzalex® (daratumumab) - ECOG clinical trial

Revlimid® (lenalidomide)

RELAPSE

Kyprolis® (carfilzomib) Ninlaro® (ixazomib)

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

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

Dexamethasone Prednisone Prednisolone SoluMedrol

Alkylators

ImmunoTherapy

STABLE OF TREATMENT FINDING YOUR GAIT GOING THECellular Others DISTANCE Therapies

Melphalan Cyclophosphamide

Melphalan Cyclophosphamide Bendamustine

ASCT

Tecvayli™ Teclistamab Talvey™ Talquetamab

Xpovio® (Selinexor) Doxil (liposomal doxorubicin)

ASCT CAR-T cell therapy Ide-Cel Cilta-Cel

Venclexta® (venetoclax)

Other CAR-T

• Bispecific PENDING FDA APPROVAL

NOTED SIDE EFFECTS

Antibodies ‒ Cevostamab • Antibody Drug Conjugates* ‒ Belantamab mafodotin

• CelMods ‒ Iberdomide ‒ CC-92480

Neuropathy Carfilzomib: Cardiac

Infusion reaction

DVT/PE

See steroid slide

Myelosuppression

CRS and Myelosuppression, GI neurotoxicity; infection risk; Selinexor: Low sodium Blenrep: Keratopathy

38 ASCT = autologous stem cell transplant; CAR-T cell therapy; CRS = cytokine release syndrome; DVT = deep vein thrombosis; PE = pulmonary embolism *Withdrawn from FDA but still available in certain situations IMF Nurse Leadership Board ONS Symposia 2022; NCCN Guidelines. Multiple Myeloma. V3.2022. Accessed January 13, 2023.

Infection risk CAR-T: CRS and neurotoxicity

CAR T: A New Treatment Approach

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STABLE OF TREATMENT FINDING YOUR GAIT GOING THE DISTANCE

CAR T: Tips

• Ask for a referral to CAR T-cell therapy center before relapse – – – –

Insurance preauthorization required (weeks, maybe longer) Must have sufficient blood count and organ function to be eligible Must be able to wait or have bridging therapy Manufacturing CAR T-cell therapy is limited: center-specific “wait list” processes

• 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

CAR T-CELLS

Viral vector

Patient own T cell Cytotoxi c cytokine s

sc Fv MM cell

• No driving for 8 weeks • One and done…BUT will need ongoing monitoring; some patients need

transfusion support 40

• CRS, neurotoxicity, or infection are possible side effects

STABLE OF TREATMENT FINDING YOUR GAIT GOING THE DISTANCE

MM cell death

BCMA

STABLE OF TREATMENT FINDING YOUR GAIT GOING THE DISTANCE BISPECIFIC ANTIBODIES

Horse of Another Color: Bispecific Antibodies also Target BCMA

• Different bispecific antibodies have differences in efficacy, side effects

About 7 in 10 patients responded CRS is common Some had skin/nail disorders • Tecvayli™ (teclistamab) is the first but more expected • Off-the-shelf treatment; no waiting for engineering cells • Route of administration and dosing schedule will vary depending on product • CRS, neurotoxicity, or infection are possible side effects – – –

Cytotoxic cytokines MM cell

T cell

CD3

Bispecific antibody

MM cell death

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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.

BCMA

STABLE OF TREATMENT FINDING YOUR GAIT GOING THE DISTANCE

CAR T and Bispecific Antibodies: Unique Side Effects

Fever Confusion

Weakness

Fatigue

CRS

Headache

CRS is a common but usually mild side effect

Nausea / vomiting

Diarrhea Shortness of Breath

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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 and Bi-specific Antibodies: Unique Side Effects

Headach e Confusio Encephalop athy n Seizures NEUROTOXICITY

Hallucinati ons

Tremors Facial nerve palsy

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Altered wakefuln ess

Apraxia

STABLE OF TREATMENT FINDING YOUR GAIT GOING THE DISTANCE

Neurotoxicity is a rare but serious side effect

Ataxia

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.

STABLE OF TREATMENT FINDING YOUR GAIT GOING THE DISTANCE

Infection Awareness & Prevention

Infection Prevention Tips Good personal hygiene (skin, oral)

Environmental control (wash hands, avoid crowds and sick people, etc)

Growth factor (Neupogen [filgrastim])

Immunizations (NO live vaccines)

Medications (antibacterial, antiviral)

As recommended by your health care team

COVID: The Best Way to Prevent Illness Is to Avoid Being Exposed to the Virus

Spread mainly through respiratory droplets that are produced by cough, sneezing and talking.

More droplets with louder talking, yelling, singing 44

Get COVID Vaccine + Booster: Excellent protection against severe disease, but vaccine effectiveness may be lower in people with compromised immune systems Wear a High-quality Mask: Respiratory droplets can spread disease; a high-quality mask can prevent exposure to airborne viral particles Avoid Crowds & Sick People Physical Distance & Outdoors: Close contact and indoor locations increases risk of spread Wash Your Hands: Less common to get from a hard surface

CDC website. How to Protect Yourself & Others. Accessed June 17, 2021.

• Report fever of more than 100.4°F, shaking chills even without fever, dizziness, shortness of breath, low blood pressure to HCP as directed.

• Compromised immune function comes from multiple myeloma and from treatment.

• Infection is serious for myeloma patients!

STABLE OF TREATMENT FINDING YOUR GAIT GOING THE DISTANCE

Supportive Care to Address Side Effects

• • •

It is important to stay on myeloma treatment to control myeloma cells and get the most from each treatment.

Responses deepen over time.

Talk to your team if side effects are bothersome. Your team may be able to help, but only if they know.

DVT/PE Prevention

Bone Health

Blood thinners Ex: Aspirin, DOACs

Bone Strengthening Agents Calcium Vitamin D

Non-medication Therapies

Compression stockings

Radiation Surgery Immobilization Physical therapy

Lifestyle Options

Activity Stop smoking Weight loss

Supportive Medications

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Don’t change horses midstream

Activity

Renal Health

Infection Prevention

Peripheral Neuropathy

GI Symptoms

Med dose reduction Avoid harmful meds

Antibacterial Antiviral Antifungal IVIG GCSF

Anti-depressants Anti-neuroleptic Analgesia Vitamins Dose adjustments

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

Dialysis

Masking

Massage Acupuncture Cocoa Butter Scrambler therapy

Dietary choices Relaxation

Hydration

Handwashing Avoid crowds & sick people Monitor for fever COVID precautions

Activity Diabetes management

Avoid greasy foods Activity Hydration

STABLE OF TREATMENT FINDING YOUR Symptoms of Multiple Myeloma GAIT GOING THE DISTANCE A meta-analysis identified the most common patient-reported symptoms and their impact on QOL. Symptoms

were present at all stages of disease.

Symptoms resulted from both disease and treatment, including transplant, and were in these categories:

Physical

• Fatigue • Constipation • Pain • Neuropathy • Impaired Physical Functioning • Sexual Dysfunction

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

Psychological

• Depression • Anxiety • Sleep Disturbance • Decreased Cognitive Function • Decreased Role & Social Function

Financial

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

Steroids: The Good, The Bad, The Ugly

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

Steroid Side Effects • Irritability, mood swings, depression

• Difficulty sleeping (insomnia),

fatigue

• Blurred vision, cataracts

• Flushing/sweating

• Increased risk of infections, heart

• Stomach bloating, hiccups,

disease

• Muscle weakness, cramping

• Increased blood pressure, water

retention

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STABLE OF TREATMENT FINDING YOUR GAIT GOING THE DISTANCE

heartburn, ulcers, or gas

• Weight gain, hair thinning/loss, skin

rashes

• Increased 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.

STABLE OF TREATMENT FINDING YOUR GAIT GOING THE DISTANCE

GI Symptoms: Prevention & Management

Diarrhea may be caused by medications

Constipation may be caused by medications and

Avoid caffeinated, carbonated, or heavily sugared beverages

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

and supplements

Take anti-diarrheal medication if recommended

supplements

Fluid intake can help with both diarrhea and constipation and helps kidney function. Discuss GI issues with health care providers to identify causes and make adjustments to medications and supplements.

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

Pain Prevention and Management

Pain can significantly compromise quality of life

STABLE OF TREATMENT FINDING YOUR GAIT GOING THE DISTANCE

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) Scrambler therapy for neuropathy

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

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

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

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

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

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

STABLE OF TREATMENT FINDING YOUR GAIT GOING THE DISTANCE

If neuropathy worsens, your provider may: • Change your treatment • Prescribe oral or topical pain

medication • Suggest physical therapy

Why the Long Face?

98.8%

Fatigue

STABLE OF TREATMENT FINDING YOUR GAIT GOING THE DISTANCE

Fatigue is the most commonly reported symptom.

Sources include anemia, pain, reduced activity, insomnia, treatment toxicity, bone marrow suppression

Anxiety

Depression

>35%

~25%

of patients

of patients

Often, people do not share these symptoms with their provider.

Talk to your provider about symptoms that are not well controlled or if you have thoughts of self harm. Help is available.

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Rest and Relaxation Contribute to Good Health

• Adequate rest and sleep are essential to a healthful lifestyle Shortened and disturbed sleep increase risk of Heart related death Increase anxiety Weakened 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 – – – – – –

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STABLE OF TREATMENT FINDING YOUR GAIT GOING THE DISTANCE Sleep hygiene is necessary for quality nighttime sleep and

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

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 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.

Financial Burden

• Financial burden comes from • Medical costs

Premiums Co-payments Travel expenses Medical supplies • Prescription costs • Loss of income – Time off work or loss of employment – Caregiver time off work – – – –

• – – – –

STABLE OF TREATMENT FINDING YOUR GAIT GOING THE DISTANCE Funding and assistance may be available

Federal programs Pharmaceutical support Non-profit organizations Websites: • Medicare.gov • SSA.gov • LLS.org • Rxassist.org • NeedyMeds.com • HealthWellFoundation.org • Company-specific website

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

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Finding Your Gait Be an empowered patient; engage in your care

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STABLE OF TREATMENT FINDING YOUR GAIT GOING THE DISTANCE

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

Pharmacist

Don’t Ride Alone

General Hem/Onc

STABLE OF TREATMENT FINDING YOUR GAIT GOING THE Myeloma DISTANCE

Specialist

Primary Care Provider (PCP) You and Your Care Partner(s)

Support Network Subspecialists

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Allied Health Staff

STABLE OF TREATMENT FINDING YOUR GAIT GOING THE DISTANCE

IMF: Knowledge Is Power

Website: http://myeloma.org

Download or order at myeloma.org

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

IMF Videos

eNewsletter: Myeloma Minute

Going the Distance Healthful living, infection prevention, renal and bone health

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STABLE OF TREATMENT FINDING YOUR GAIT GOING THE DISTANCE

Healthful Living Strategies: Prevention 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 and/or walking Bone strengthening agents

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

Maintain a healthy weight Nutrition Activity / exercise

STABLE OF TREATMENT FINDING YOUR GAIT GOING THE DISTANCE

Manage stress • Rest, relaxation, sleep hygiene • Mental health / social engagement • Complementary therapy

An ounce of prevention is worth a pound of cure.

Benjamin Franklin

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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 Movement therapies can reduce stress, promote sleep

Yoga, Pilates, Tai Chi • Shown to improve sleep and sleep quality • Improved quality of life & mood

Do:

STABLE OF TREATMENT FINDING YOUR GAIT GOING THE DISTANCE

• 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 • Consider weightlifting limits Do Not:

• Overdo it • Force exercise • Try things without discussing with provider

Myeloma bone disease may affect your ability to do certain movement activities.

Review your activity interests with your health care provider!

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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.

Q&A

with panel

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BREAK 61

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STABLE OF TREATMENT FINDING YOUR GAIT ENJOYING THE RIDE

Agenda after break

all times are listed in Pacific Time Zone

7:05 – 7:30 PM

Frontline Therapy Rafat Abonour, MD, University of Indiana, Indianapolis, IN

7:30 – 7:45 PM

Q&A with Panel

7:45 – 8:15 PM

Relapse & Immune Therapies Ajai Chari, MD, University of California San Francisco

8:15 – 8:30 PM

Q&A with Panel

8:30 PM

Closing Remarks

Upfront Therapy for Multiple Myeloma Rafat Abonour, M.D. Harry and Edith Gladstein Professor of Cancer Research Professor of Medicine, Pathology and Laboratory Medicine Director, Multiple Myeloma, Waldenstrom's Disease and Amyloidosis Program Indiana University School of Medicine

Treatment Goals •

•

Symptom Control • Ameliorate pain and other disease-related symptoms • Prevent further organ damage • Preserve and improve performance status and quality of life Disease Response and Survival • Rapid myeloma eradication.

• Minimize treatment-related toxicity • Prolong survival – Overall Survival

Depth of Response Influence Time to Relapse Getting rid of myeloma is a good thing

PR=partial response, VGPR=very good partial response, CR=complete remission, MRD= minimal residual disease

Minimal Residual Disease (MRD) Testing • MRD is emerging as an important marker of lasting clinical benefit • MRD can be tested: − Using flowcytometry. Sensitive at 10-5 and can be done

anytime on bone marrow samples and does not require knowing what the patient myeloma sequences were at diagnosis

− Using next generation sequences Sensitive at 10-6 but

require knowing what the patient myeloma sequences were at diagnosis.

MRD Strongly Predicts outcomes If patient achieved Negative MRD their myeloma stay under control longer and they live longer

Munshi et al. Blood Advances 2020; 4:23

MRD May Abrogate Other Risk Factors High risk patients achieving MRD- do better Opportunity for de-escalation

Need to employ new approaches

Goicochea I et al. Blood 2021;137:49

PETHEMA/GEM2012 (MRD < 2 x 10-6)

The Evolution of Myeloma Therapy Many New Drugs and Many New Combinations Now

VD Rev/Dex CyBorD VTD VRD SCT KRD Tandem ASCT (?)

D-VMP DRD Front line treatment

Induction

New

D-VRD Isa-VRD D-KRD Isa-VRD

Nothing Thalidomide?

Bortezomib Ixazomib Lenalidomide Combinations Maintenance

Consolidation

Post consolidation

“more” induction?

Daratumumab?

Carfilzomib?

Lenalidomide + PI

ASCT, autologous stem cell transplant; CAR, chimeric antigen receptor; Cy, cyclophosphamide; ddaratumumab; D/dex, dexamethasone; isa, isatuximab; K, carfilzomib; M, melphalan; PD-L1, programmed death ligand-1; PI, proteasome inhibitor; Rev, lenalidomide; V, bortezomib

Panobinostat Bortezomib Lenalidomide Daratumumab Ixazomib Carfilzomib Pomalidomide Elotuzumab Isatuximab Selinexor Belantamab mafodotin Melphalan flufenamide Idecabtagene Relapsed autoleucel

Rescue

CAR T Cell Therapy Bispecific/Trispecific Antibodies Cell Modifying Agents Venetoclax?

PD/PDL-1 Inhibition?

Multiple small molecules ++++++++

How does your doctor decide?

Upfront therapy

• Combination therapy continues to prove superiority in providing long remission and long survival.

• The patient is at good place as options are becoming more prevalent.

• Lenalidomide, bortezomib and dexamethasone continues to be an effective regimen.

• Daratumumab in combination with lenalidomide is an excellent option for “frail patient” • But wait there are more to come

How did we start?

Is three drugs better than two?

Three drugs better in some Patients Myeloma under control longer and you live longer

SWOG 0777

The Newer Three Drugs Regimen Phase III MAIA Study Design: Adding daratumumab to lenalidomide and steroid regimen

Transplant-not preferred NDMM ECOG PS 0-2 CrCl ≥30 mL/min (N = 737)

1:1

Daratumumab 16 mg/kg IVa + Lenalidomide 25 mg/d PO, d 1-21 + Dexamethasone 40 mg/w PO or IV (n = 368)

Lenalidomide 25 mg/d PO, d 1-21 + Dexamethasone 40 mg/w PO or IV (n = 369)

Primary endpoint: PFS Secondary endpoints: CR, VGPR, MRD negativity, ORR, OS, safety

28-day cycles until PD

Median age: 73 years (45-90) 99% of patients age ≥ 65 years

Stratification: • ISS (I, II, III) • Region (N America vs other) • Age (<75 y vs ≥75 y) Facon T, et al. 2018 ASH. Abstract LBA2.

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

aQW cycles 1-2, Q2W cycles 3-6, Q4W cycle ≥7.

Phase III MAIA: better response rates, and Sustained MRD-Negativity Rates

 





Median follow-up: 64.5 months Daratumumab favored in most subgroups, including for both PFS and OS endpoints Reduced risk of progression or death with MRD negativity in both arms Responses deepened over time

Kumar S, et al. ASH 2022. Poster 4559.

Facon T, et al. EHA 2021. Abstract LB1901. Facon T, et al. Lancet Oncol. 2021;22:1582-1596

MAIA: Is It Safe to Use 3 Drugs TEAE, %

Daratumumab + Rd (n = 364)

Rd (n = 365)

Any Grade

Grade 3/4

Any Grade

Grade 3/4

57 35 19 18

50 12 7 15

42 38 19 12

35 20 9 11

57 41 40 38 34 32 32 23 12

7 2 8 2 3 4 1 14 6

46 36 28 29 26 25 23 13 13

4 <1 4 <1 3 4 <1 8 6

41

3

--

--

Hematologic Neutropenia Anemia Thrombocytopenia Lymphopenia Nonhematologic Diarrhea Constipation Fatigue Peripheral edema Back pain Asthenia Nausea Pneumonia DVT and/or pulmonary embolism Infusion-related reaction Invasive second primary malignancy

3

4

TEAE resulting in death

7

6

 No new safety concerns were identified with longer follow up Facon T, et al. 2018 ASH. Abstract LBA2; Facon T, et al. N Engl J Med. 2019;380:2104-2115. Facon T, et al. EHA 2021. Abstract LB1901. Facon T, et al. Lancet Oncol. 2021;22:1582-1596. Kumar S, et al. ASH 2022. Poster 4559.

Can you use three drugs before transplant!!

IFM 2009: RVD ± ASCT (The French version) Transplant-preferred NDMM RVD x 3 cycles, ASCT collection, Cy 3 g/m2 • RVD cycles 4-8

RVD x 3 cycles, ASCT collection, Cy 3 g/m2 • ASCT with MEL 200 • RVD cycles 4, 5

Lenalidomide 10-15 mg daily x 12 months

36 mo

mPFS (44 mo fu)1

50 mo

35 mo

mPFS (90 mo fu)2

47.3 mo

60.2%

8-y OS (90 mo fu)2

62.2%

44-mo follow up

PFS=Progression free survival, OS= overall survival Attal M, et al. N Engl J Med. 2017;376;1311-20. 2. Perrot A, et al. ASH 2020

IFM 2009 Study of RVD± ASCT: PFS by MRD Status

Perrot A, et al. ASH 2020. Abstract 143.

Why is this French Study Important!

Downsides of Continuous Maintenance Therapy

IFM 2009

No therapy

Deferring Lenalidomide for 7 years: -”Saving” of $1.5 million!

-Avoid ~3.5% absolute increase in risk of SPM

Most visits patients have not progressed in 7years despite no therapy Perrot A et al. ASH meeting 2020

-Avoid dozens of extra lab checks/MD -Avoid diarrhea, fatigue, rash -Avoid “daily reminder I have cancer”

DISCLOSURE NOT ALL MYELOMA EXPERTS AGREE ON THIS

Why not 4 drugs regimen!!

Randomized Phase 2 GRIFFIN Trial of DRVd vs RVd with transplant

Stratification factors •ISS disease stage (I, II, or III) •CrCl (30-50 or >50 mL/min)

Induction: Cycles 1-4

Consolidation: Cycles 5-6c

Maintenance: Cycles 732

D-RVd

D-RVd

D-R

D: 16 mg/kg IV Days 1, 8, 15 R: 25 mg PO Days 1-14 V: 1.3 mg/m2 SC Days 1, 4, 8, 11 d: 20 mg PO Days 1, 2, 8, 9, 15, 16

RVd

R: 25 mg PO Days 1-14 V: 1.3 mg/m2 SC Days 1, 4, 8, 11 d: 20 mg PO Days 1, 2, 8, 9, 15, 16 21-day cycles

TRANSPLANT

Key eligibility criteria • Transplant-preferred NDMM • 18-70 years of age • ECOG PS score 0-2 • CrCl ≥30 mL/mina

1:1 RANDOMIZATION

• 35 sites in the United States with enrollment between December 2016 and April 2018

D: 16 mg/kg IV Day 1 R: 25 mg PO Days 1-14 V: 1.3 mg/m2 SC Days 1, 4, 8, 11 d: 20 mg PO Days 1, 2, 8, 9, 15, 16

RVd

R: 25 mg PO Days 1-14 V: 1.3 mg/m2 SC Days 1, 4, 8, 11 d: 20 mg PO Days 1, 2, 8, 9, 15, 16 21-day cycles

D: 16 mg/kg IV Day 1 Q4W or Q8Wd R: 10 mg PO Days 1-21 Cycles 7-9; 15 mg PO Days 1-21 Cycles 10+

R

R: 10 mg PO Days 1-21 Cycles 7-9; 15 mg PO Days 1-21 Cycles 10+

Endpoints and statistical assumptions Primary endpoint: • sCR rate (by end of consolidation); 1-sided alpha of 0.10 • 80% power to detect 15% improvement (50% vs 35%), N = 200 Other endpoints: • Rates of MRD negativitye (NGS), ORR, ≥VGPR, CR, PFS, OS

28-day cycles

Stem cell mobilization with G-CSF ± plerixaforb; High-dose therapy (melphalan 200 mg/m2)

• Median age ~60; ISS3 14%, High risk 15% • Lower ASCT rate in RVd arm due to early discontinuations

ECOG PS, Eastern Cooperative Oncology Group performance status; CrCl, creatinine clearance; IV, intravenous; PO, oral; SC, subcutaneous; G-CSF, granulocyte colony-stimulating factor; D-R, daratumumab plus lenalidomide; Q4W, every 4 weeks; Q8W, every 8 weeks; NGS, next-generation sequencing; ORR, overall response rate; VGPR, very good partial response; CR, complete response; PFS, progression-free survival; PFS2, PFS on next subsequent line of therapy; OS, overall survival. aLen dose adjustments were made for pts w/ CrCl ≤50 mL/min. bCyclophosphamide-based mobilization was permitted if unsuccessful. cConsolidation was initiated 60 to 100 days post-transplant. dProtocol amendment 2 allowed for the option to dose DARA Q4W based on pharmacokinetic results from study SMM2001 (NCT02316106). eTo measure MRD negativity at a minimum threshold of 10–5, bone marrow aspirates were collected at first evidence of suspected CR or sCR (including patients with ≥VGPR and suspected DARA interference), after induction but before stem cell collection, at the post-transplant consolidation disease evaluation, and at 12 mo and 24 mo (±3 weeks) of maintenance therapy.

Sborov D, et al. IMS Annual Meeting 2022.

GRIFFIN Final Analysis: PFS in the ITT Population (Median Follow-up: 49.6 Mo) • Median PFS was not reached in either group • PFS was longer for D-RVd/D-R versus RVd/R, with a clinically meaningful 55% reduction in the risk of disease progression or death • Regardless of R therapy continuation after end of study treatment, a PFS benefit was observed in the D-RVd group versus the RVd group • OS not reached/not mature; longer follow up would be needed to evaluate; 4year OS: 92.7% D-RVd vs 92.2% RVd Sborov D, et al. IMS Annual Meeting 2022.

GRIFFIN: Rates of Durable MRD Negativity (10-5) Lasting ≥ 6 Months or ≥ 12 Months—D-RVd vs RVd

Labauch JP, et al. ASH 2021. Abstract

Summary: Upfront therapy with SCT 350 vs 350

DETERMINATIO N RVd-SCT vs RVd + R to PD 365 vs 357

90

76

50.9

49.6

N/A 78 vs 69 N/A

98 vs 95 83 vs 80 33 vs 28 68 vs 46 1.53 (1.23-1.91) P < .001

97 vs 94 89 vs 87 46 vs 44 NR vs 55.3 0.88 (0.64-1.22) P = .45

99 vs 92 96 vs 77 67 vs 48 NR vs NR 0.45 (0.21-0.95) P = .0324

NR vs NR 1.10 (0.73-1.65) P > .99

NR vs NR 0.94 (0.54-1.63) P = .81

NR vs NR 0.90 (0.31-2.56) P = 0.8408

IFM 2009 RVd-SCT vs RVd + 1y Ra Total N Median follow up, mo ORR, % ≥VGPR, % sCR, % mPFS, mo HR (95% CI) P

47 vs 35 0.70 (0.59-0.83) P = .0001

OS HR

NR vs NR 1.03 (0.8-1.32)

FORTE KRd-SCT vs KRdb

Griffin SCT DaraVRd +2 y DR vs VRd + 2 y Rc

158 vs 157

104 vs 103

a. Results post 1 y maintenance. b. Results post induction, intensification, and consolidation. c. Results post 2 y maintenance.

NR, not reached; NS, no significant difference.

Attal et al. N Engl J Med. 2017; Richardson P, et al. N Engl J Med. Jun 5 2022; Perrot ASH 2020; Gay F, et al. Lancet Oncol. 2021;22:1705-1720. Gay F, et al ASCO 2019/ASH 2020; Sborov D, et al. IMS 2022.

Can we use Sustain MRD to guide our therapy?!!

Daratumumab, Carfilzomib, Lenalidomide and Dexamethasone (Dara-KRd), Autologous Transplantation and MRD Response-Adapted Consolidation and Treatment Cessation-Final Primary Endpoint Analysis of the MASTER Trial

Luciano J. Costa1, Saurabh Chhabra2, Natalie S. Callander, MD3 , Eva Medvedova4, Bhagirathbhai Dholaria5, Rebecca Silbermann4, Kelly Godby1, Binod Dhakal2, Susan Bal1, Smith Giri1, Anita D’Souza2, Timothy Schmidt3, Aric Hall3, Pamela Hardwick1, Robert F. Cornell5, Parameswaran Hari2 1- University of Alabama at Birmingham; 2- Medical College of Wisconsin; 3- University of Wisconsin at Madison; 4- Oregon Health and Science University; 5- Vanderbilt University

COMMIT- Academic Consortium to Overcome Multiple Myeloma through Innovative Trials

Treatment decision based on response Dara-KRd Daratumumab 16 mg/m2 days 1,8,15,22 (days 1,15 C 3-6; day 1 C >6) Carfilzomib (20) 56 mg/m2 Days 1,8,15 Lenalidomide 25 mg Days 1-21 Dexamethasone 40mg PO Days 1,8,15,22

MRD assessment by NGS *24 and 72 weeks after completion of therapy

Consolidation

Dara-KRd x 4

Dara-KRd x 4

2nd MRD (-) (<10-5)

2nd MRD (-) (<10-5)

MRD→

MRD→

Dara-KRd x 4

AHCT

Consolidation

MRD→

Induction

MRD→

• • • •

Lenalidomide Maintenance

2nd MRD (-) (<10-5)

”MRD-SURE” -Treatment-free observation and MRD surveillance*

MASTER trial

Progression-Free and Overall Survival Based on Presence of High-Risk Features

2-year PFS

0 HRCA

91%

1 HRCA

97%

2+ HRCA

58%

2-year OS

0 HRCA

96%

1 HRCA

100%

2+ HRCA

76%

High risk cytogenetics abnormalities. HRCA = gain/amp 1q, t(4;14), t(14;16), t(14;20) or del(17p)

MASTER

Conclusions • NGS-MRD response-adapted therapy is feasible in ~96% of patients in multi center setting – 72% reaching MRD-SURE. • Patients with standard and high-risk NDMM have similar depth of response and low risk of MRD resurgence or progression when treated with Dara-KRd/AHCT and MRDadapted treatment cessation.

• Quadruplet therapy and achievement of confirmed MRD (-) responses enables the exploration of treatment cessation and “MRD-SURE” as alternative to continuous therapy.

Effective novel consolidative strategies should be explored to clear MRD and improve outcomes in patients with ultra-high-risk MM MASTER trial

Addition of Isatuximab to Lenalidomide, Bortezomib and Dexamethasone as Induction Therapy for Newly-Diagnosed, Transplant-Eligible Multiple Myeloma: The Phase III GMMG-HD7 Trial Hartmut Goldschmidt1,2, Elias K. Mai1, Eva Nievergall1, Roland Fenk3, Uta Bertsch1,2, Diana Tichy4, Britta Besemer5, Jan Dürig6, Roland Schroers7, Ivana von Metzler8, Mathias Hänel9, Christoph Mann10, Anne Marie Asemissen11, Bernhard Heilmeier12, Stefanie Huhn1, Katharina Kriegsmann1, Niels Weinhold1, Steffen Luntz13, Tobias A. W. Holderried14, Karolin Trautmann-Grill15, Deniz Gezer16, Maika Klaiber-Hakimi17, Martin Müller18, Cyrus Khandanpour19, Wolfgang Knauf20, Markus Munder21, Thomas Geer22, Hendrik Riesenberg23, Jörg Thomalla24, Martin Hoffmann25, Marc-Steffen Raab1, Hans J. Salwender26, Katja C. Weisel11 for the German-speaking Myeloma Multicenter Group (GMMG) 1Department of Internal Medicine V, University Hospital Heidelberg, Heidelberg, Germany; 2National Center for Tumor Diseases Heidelberg, Heidelberg, Germany;

3Department of Hematology, Oncology and Clinical Immunology, University Hospital Düsseldorf, Düsseldorf, Germany; 4Division of Biostatistics, German Cancer Research Center (DKFZ) Heidelberg, Heidelberg, Germany; 5Department of Internal Medicine II, University Hospital Tübingen, Tübingen, Germany; 6Department for Hematology and Stem Cell Transplantation, University Hospital Essen, Essen, Germany;

7Medical Clinic, University Hospital Bochum, Bochum, Germany; 8Department of Medicine, Hematology/Oncology, University Hospital Frankfurt, Goethe University, Frankfurt am Main, Germany;

9Department of Internal Medicine III, Clinic Chemnitz, Chemnitz, Germany; 10Department for Hematology, Oncology and Immunology, University Hospital Gießen and Marburg, Marburg, Germany;

11Department of Oncology, Hematology and BMT, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; 12Clinic for Oncology and Hematology, Hospital Barmherzige Brueder Regensburg, Regensburg,

Germany; 13Coordination Centre for Clinical Trails (KKS) Heidelberg, Heidelberg, Germany; 14Department of Oncology, Hematology, Immuno-Oncology and Rheumatology, University Hospital Bonn, Bonn, Germany; 15Department of Internal Medicine I, University Hospital Dresden, Dresden, Germany; 16Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Aachen, Germany; 17Clinic for Hematology, Oncology and Palliative Care, Marien Hospital Düsseldorf, Düsseldorf, Germany; 18Clinic for Hematology, Oncology and Immunology, Klinikum Siloah Hannover, Hannover, Germany; 19Medical Clinic A, University Hospital Münster, Münster, Germany; 20Center for Hematology and Oncology Bethanien, Frankfurt am Main, Germany; 21Department of Internal Medicine III, University Hospital Mainz, Mainz, Germany; 22Department of Internal Medicine III, Diakoneo Clinic Schwäbisch-Hall, Schwäbisch-Hall, Germany; 23Hematology/Oncology Center, Bielefeld, Germany; 24Hematology / Oncology Center, Koblenz, Germany; 25Medical Clinic A, Clinic Ludwigshafen, Ludwigshafen, Germany; 26Asklepios Tumorzentrum Hamburg, AK Altona and AK St. Georg, Hamburg, Germany

ASH 2021; Final Abstract Code: 463

Primary endpoint: MRD negativity at the end of induction phase Induction phase (3 x 6-week cycles) Isa + RVd HDT + ASCT RVd After Cycle 3

Screenin MRD (bone marrow aspirate) g

Primary endpoint: • MRD negativity at the end of induction treatment (NGF, sensitivity 10-5) stratified according to R-ISS

Maintenance phase (4-week cycles) Randomization

NDMM N=662

Randomization 1:1

HD7



Aft er HD T



Isa + R

3 years or PD

R After 12 month s



After 24 months



End of study



Secondary endpoints: • CR after induction • Safety Data cut-off: • April 2021 ASCT, autologous stem cell transplant; CR, complete response; d, dexamethasone; HDT, high-dose therapy; Isa, isatuximab; MRD, minimal residual disease; NDMM, newly diagnosed multiple myeloma; NGF, next-generation flow; PD, progressive disease; R, lenalidomide; R-ISS, Revised International Staging System; Te, transplant eligible; V, bortezomib 1. ClinicalTrials.gov: NCT03617731

8 9

HD7

First primary endpoint, end of induction MRD negativity by NGF (10-5), was met in ITT analysis Patients with MRD negativity at the end of induction therapy OR 1.83 (95% CI 1.34–2.51) P<0.001*

60% 40%

50.1%

IsaRVd

35.6%

20% 0% Low number of not assessable/missing† MRD status: Isa-RVd (10.6%) and RVd (15.2%)

Isa-RVd is the first regimen to demonstrate a rapid and statistically significant benefit from treatment by reaching a MRD negativity of 50.1% at the end of induction and to show superiority vs. RVd in a Phase 3 trial *P value derived from stratified conditional logistic regression analysis †Missing NGF-MRD values were due to either patients’ loss to follow-up during induction therapy or to missing bone marrow samples or technical failures in measurement counted as non-responders, i.e. NGF-MRD positive CI, confidence interval; d, dexamethasone; Isa, isatuximab; ITT, intent-to-treat; MRD, minimal residual disease; NGF, next-generation flow; OR, odds ratio; R, lenalidomide; V, bortezomib

9 0

Response rates after induction therapy HD7

P=0.02* P<0.001*

100%

77.3%

80% P=0.15*

60% 40% 20% 0%

P=0.46*

41.7% 36.2%

CR

>nCR ≥

24.2% 21.6%

Isa-RVd† RVd

90.0% 83.6%

60.5%

>VGPR ≥

>PR ≥

Although the rates of CR after induction therapy did not differ between the Isa-RVd and RVd arms, there was a significant increase in ≥VGPR rates and ORR with Isa-RVd *P values derived from Fisher’s exact test †Data adjusted per M-protein interference CR, complete response; d, dexamethasone; Isa, isatuximab; nCR; near-complete response; ORR, overall response rate; PR, partial response; R, lenalidomide; V, bortezomib; VGPR, very good partial response

9 1

Addition of Isa to RVd had limited impact on safety profile

HD7

AEs CTCAE grade ≥3, n (%)

Isa-RVd (n=330)

RVd (n=328)

AEs CTCAE grade ≥3, n (%)

Any AE

210 (63.6)

201 (61.3)

Specific hematologic AE (PT)

Any serious AE (any grade)

115 (34.8)

119 (36.3)

Deaths

4 (1.2)

8 (2.4)

nia†

Investigations* (SOC)

79 (23.9)

77 (23.5)

Blood and lymphatic system disorders (SOC)

85 (25.8)

Infections and infestations (SOC)

Isa-RVd (n=330)

RVd (n=328)

87 (26.4)

30 (9.1)

Lymphopenia

48 (14.5)

65 (19.8)

55 (16.8)

Anemia

13 (3.9)

20 (6.1)

43 (13.0)

34 (10.4)

Thrombocytopenia

21 (6.4)

15 (4.6)

Nervous system disorders (SOC)

28 (8.5)

33 (10.1)

Gastrointestinal disorders (SOC)

27 (8.2)

31 (9.5)

Peripheral neuropathy

25 (7.6)

22 (6.7)

Metabolism and nutrition disorders (SOC)

12 (3.6)

26 (7.9)

Thromboembolic events

5 (1.5)

9 (2.7)

Leukocytopenia/Neutrope

Specific non-hematologic AE (PT)

Infusion-related reactions (1.2) A comparable number of patients discontinued induction therapy due to AEs in4 the Isa-RVd arm vs. RVd arm ‡

*SOC considered as “Investigations” as defined by the CTCAE †Includes five episodes of febrile neutropenia during induction: Isa-VRd (n=3) vs. VRd (n=2) ‡Infusion-related reactions of CTCAE grade 2 or higher in the Isa-RVd arm were n=42 (12.7%) AE, adverse event; CTCAE, Common Terminology Criteria for Adverse Events; d, dexamethasone; Isa, isatuximab; NA, not applicable; PT, preferred term; R, lenalidomide; SOC, system organ class; V, bortezomib

NA

9 2

Isatuximab, Carfilzomib, Lenalidomide, and Dexamethasone for the Treatment of High-Risk Newly Diagnosed Multiple Myeloma Lisa B. Leypoldt et al

JCO Published online September 27, 2023.

PMID: 37753960

Isatuximab RVD in High-risk patient for transplant eligible (TE) and Transplant ineligible (TNE)

Isatuximab RVD in High-risk patient for transplant eligible (TE) and Transplant ineligible (TNE)

Upfront Therapy Status..Evolving • • • • • • •

Adding a CD38 antibody to VRD or KRD is feasible with limited incremental toxicity Depth of response is improved, including MRD negativity MRD will be an even more important measure going forward There is a trend to improved PFS This may overcome the high-risk feature of some patients Ultra high-risk disease remains challenging to treat with current strategies What about transplant?? It is still part of most upfront studies.

Is This The future: MASTER 2 The Dream Trial

Sequential Therapy in Multiple Myeloma Guided by MRD Assessments Consolidation

Maintenance

X 3 cycles

MRD (-) randomization

CD38MoAbR x 1 year

CD38MoAbR x 1 year

AHCT Quadruplet x 6 cycles

MRD (+) randomization

AHCT *MRD-SURE – Treatment-free observation and MRD surveillance

← MRD2→

R

T-cell Redirecting therapy

T-cell Redirecting therapy

←MRD1x →

AHCT

MRD1 →

Arm M

Sustained MRD Negativity

CD38MoAb-R X3 cycles

MRDSURE* ← MRD3→

R

← MRD2→

Stem cell collection

Quadruplet

← MRD3→

Intensification

Inducti on

CD38MoAbR x 1 year

(Otherwise SOC R maintenance)

Q&A

with panel

98

Relapse & Immune Therapies Ajai Chari, MD

Professor of Clinical Medicine Director of Multiple Myeloma Program University of California, San Francisco

99

Currently Available Anti-Myeloma Agents in 2023 Steroids

Conventional Chemo

ImIDs

Proteasome Inhibitors

Prednisone

Melphalan

Thalidomide

Bortezomib

Dexamethasone

Cyclophosphamide

Lenalidomide

Carfilzomib

Doxorubicin

Pomalidomide

Ixazomib

DCEP/D-PACE

naked antibodie s

bispecific s

METRO28

Off label:

Immunologic approaches Daratumumab (anti-CD38)

Elotuzumab (anti-CS1) Talquetamab anti-GPRC5d*CD3 Teclistamab anti-BCMA*CD3 Elranatamab anti-BCMA*CD3

Bendamustine

idecabtagene vicleucel: anti-BCMA CART

venetoclax

Selinexor

Isatuximab (anti-CD38)

Carmustine

CART s

XPO inhibitor

ciltacabtagene autoleucel: anti-BCMA CART

CART- Chimeric Antigen Receptor – T cell

Currently Available Anti-Myeloma Agents in 2023: Triple Class Exposure Steroids

Conventional Chemo

ImIDs

Proteasome Inhibitors

Prednisone

Melphalan

Thalidomide

Bortezomib

Dexamethasone

Cyclophosphamide

Lenalidomide

Carfilzomib

Doxorubicin

Pomalidomide

Ixazomib

DCEP/D-PACE

naked antibodie s

bispecific s

METRO28

Off label:

Immunologic approaches Daratumumab (anti-CD38)

Elotuzumab (anti-CS1) Talquetamab anti-GPRC5d*CD3 Teclistamab anti-BCMA*CD3 Elranatamab anti-BCMA*CD3

Bendamustine

idecabtagene vicleucel: anti-BCMA CART

venetoclax

Selinexor

Isatuximab (anti-CD38)

Carmustine

CART s

XPO inhibitor

ciltacabtagene autoleucel: anti-BCMA CART

CART- Chimeric Antigen Receptor – T cell

Currently Available Anti-Myeloma Agents in 2023: Penta Drug Exposure Steroids

Conventional Chemo

ImIDs

Proteasome Inhibitors

Prednisone

Melphalan

Thalidomide

Bortezomib

Dexamethasone

Cyclophosphamide

Lenalidomide

Carfilzomib

Doxorubicin

Pomalidomide

Ixazomib

DCEP/D-PACE

naked antibodie s

bispecific s

METRO28

Off label:

Immunologic approaches Daratumumab (anti-CD38)

Elotuzumab (anti-CS1) Talquetamab anti-GPRC5d*CD3 Teclistamab anti-BCMA*CD3 Elranatamab anti-BCMA*CD3

Bendamustine

idecabtagene vicleucel: anti-BCMA CART

venetoclax

Selinexor

Isatuximab (anti-CD38)

Carmustine

CART s

XPO inhibitor

ciltacabtagene autoleucel: anti-BCMA CART

CART- Chimeric Antigen Receptor – T cell

Currently Available Anti-Myeloma Agents in 2023: T cell Redirection Immune Therapies Steroids

Conventional Chemo

ImIDs

Proteasome Inhibitors

Prednisone

Melphalan

Thalidomide

Bortezomib

Dexamethasone

Cyclophosphamide

Lenalidomide

Carfilzomib

Doxorubicin

Pomalidomide

Ixazomib

DCEP/D-PACE

naked antibodie s

bispecific s

METRO28

Off label:

Immunologic approaches Daratumumab (anti-CD38)

Elotuzumab (anti-CS1) Talquetamab anti-GPRC5d*CD3 Teclistamab anti-BCMA*CD3 Elranatamab anti-BCMA*CD3

Bendamustine

idecabtagene vicleucel: anti-BCMA CART

venetoclax

Selinexor

Isatuximab (anti-CD38)

Carmustine

CART s

XPO inhibitor

ciltacabtagene autoleucel: anti-BCMA CART

CART- Chimeric Antigen Receptor – T cell

Months

Progression Free Survival (PFS) and Duration of Response (DOR) Delta of Recently Approved Therapies in RRMM 40 35 30 25 20 15 10 5 0

PFS

T cell redirection therapies

34.933.9

For > 4 LOT and IMID/PI/anti CD38 exposed

8.3 4.2

7.8 3.7

Richardson P et al Blood 2014;123(12):1826-32 Siegel DS et al. Blood 2012;120(14): 2817–2825 Lonial S et al. Lancet 2016;387:1551-1560 Chari A et al. N Eng J Med 2019;381:727-738

7.4 3.7

NR 14.2

3.74.4

18.4 NRNR 12.2 11.3 11.3

Touzeau et al EHA 2023 Nooka A et al ASCO 2022;abstract 8007 (oral presentation) Lesohkin et al Nat Med 2023 Anderson L et al. ASCO 2021;abstract 8016 (poster presentation) Usmani S et al ASCO 2022;abstract 8028 (poster presentation)

aThis is not a head-to-head comparison and cross-trial comparisons should not be interfered from these data Data represent two populations, PFS includes all patients, DOR includes responding patients only

Complex Immunnotherapies For Multiple Myeloma

•Bispecifics – BCMA and non BCMA •monotherapy + combinations

•CART – phase 1 dose escalation studies and randomized phase 3 studies •BCMA sequencing •Logistics of administering T cell redirection therapy •CART vs bispecfiics

Monoclonal Antibodies in All Human Diseases Would Not be Possible Without Myeloma Cells – 1984 Nobel Prize!

Gelboin, H et al. Trends in Pharmacological Sciences, 1999.

Wikipedia Adenosine

•

‘84 Georges Köhler, César Milstein, Niels Kaj Jerne shared Nobel Prize in Physiology or Medicine

•

’88 Greg Winter humanized mAbs eliminating the reactions that many monoclonal antibodies (mAbs) caused

•

First mAb for MM not approved until 2015 - 31 years later!

•

Currentlly approved antibodies for MM: • Naked antibodies: daratumumab, isatuximab, elotuzumab • Antibody drug conjugates: belantamb mafadotin

What is a Bispecific Antibody?

Updated from Lancman, et al. ASH 2020.

T/NK Cell Engager Targets in Multiple Myeloma

Lancman, et al. ASH

T/NK cell Engaging Antibody Clinical Trials in Multiple Myeloma Agent AMG420 Pavurutamab AMG701 Alnuctamab CC93269 Elrantamab PF06863135 Linvoseltamab RGN5458 Teclistamab JNJ64007957 ABBV-383 CC-92328 Talquetamab JNJ64407564 Forimtamig RG2634 Cevostamab BFCR4350A GBR1342 AMG424

Targets BCMAxCD3 BCMAxCD3 BCMAxCD3 BCMAxCD3 BCMAxCD3 BCMAxCD3 BCMAxCD3 BCMAxCD16 xNK2GD GPRC5dxCD3 GPRC5dxCD3 * 12 mos FCRH5xCD3 * 12 mos CD38xCD3 CD38xCD3

Phase I I/II I I I/II I I I I I I I/II I

Clinical Trial NCT03836053 NCT03287908 NCT03486067 NCT03269136 NCT03761108 NCT03145181 NCT03933735 NCT04975399 NCT03399799 NCT04557150 NCT03275103 NCT03309111 NCT03445663

Status Completed Closed Ongoing Ongoing Ongoing Ongoing Ongoing Ongoing Ongoing Ongoing Ongoing Ongoing Closed

Updated from Lancman, et al. ASH 2020.

BCMAxCD3 Bispecific Antibodies: Efficacy

Bispecific Antibody

Teclistamab

Elranatamab

Linvoseltamab

ABBV-383

Alnuctamab

HPN217

Treatment

Weekly SC

Weekly SC

Weekly IV

IV every 3 weeks

Weekly -> monthly SQ

Every 2 weeks IV

Patients

n= 165

n= 123

n= 252

n= 174

n= 68

n= 62

Median prior lines

5

5

5

5

4

6

Triple-class refractory

78%

97%

81%

80%

63%

76%

ORR at RP2d

63%

61%

64%

58-61%

65%

73%

PFS

11.3 mos

NE @ 12 mos

NR

13.7 or 11.2 mos

NR

NR

DOR

approval 18.4 Accelerated mos NE @12 mos

89% @ 6 mos

NE

NE

NR

• •

Multiple agents in development, all demonstrating remarkable activity Unprecedented competition is good for the market and ultimately for patients!

110

Cytokine Release Syndrome

Alexander Shimabukuro-Vornhage Journal for ImmunoTherapy of Cancer volume 6, Article number: 56 (2018)

111

BCMAxCD3 Bispecific Antibodies: Safety

Bispecific Antibody

Teclistamab (JNJ-64007957)

Elranatamab (PF-06863135)

Median f/u AEs, (All/(Gr 3+); CRS Infections Neutropenia Neuro # Deaths Hypogamma/IVIg

14.1 mos

10.4 mos

72% (0.6%) 76% (45%) 71% (64%) Neurotoxicity 15% (0.1) 68/(41 due to PD) 75%//39%

58% (0%) 67% (35%) 48% (48%) NR/ PN? 21 (/11 due to PD) 75%/40%

112

BCMA Bispecifics: IgG Levels, Grade 3- 5 Infections, and Benefit of IVIg Protective antibody levels (IgG) on BCMA bispecifics go to zero

•

Replacing the good antibodies with IVIg decreases all severe infections by 80% and severe bacterial infections by 90%

Strategies to reduce infections on BCMA bispecifics: • Vaccinate prior to BCMA bispecific esp COVID • IVIG support for BCMA bispecifics essential • Antibiotics prevention for PJP, shingles • ? less frequent schedule, ? lower maintenance doses, ? fixed duration of therapy (can always retreat later if necc) • good hand hygiene

Lancman, et al. ASH 2022: https://doi.org/10.1182/blood-2022-163733: |. Lancman, et al. Blood Cancer Discovery (2023) vol 4 issue 6

Non-BCMA-Targeted Bispecific Antibodies: Efficacy

Bispecific Antibody

Talquetamab (JNJ-64407564) Phase 1/2 MonumenTAL-1 Study GPRC x CD3

Forimtamig (RG6234) Phase 1 GPRC X CD3 (2:1)

Cevostamab (GO39775) Phase 1 FcRH5 X CD3

Treatment

0.4 mg/kg SQ QW

0.8 mg/kg SC Q2W

Either dose

SQ q 2wk *12 mos

IV q3w * 12 mos

Patients

n=143

n=145

n=51

n=57

n=161

Median prior lines

5

5

6

5

6

Triple-class refractory

74%

69%

63%

85%

ORR @RP2D

74%

73%

64% (at 30-7200 ug)

132-198 mg: (56.7%)

PFS

7.5 mos

11.9 mos

NR

DOR

9.3 mos

13 mos

12.7+ mos

63%

(prior CART/bisp 72%/44%)

Accelerated approval • •

Not only competition within BCMA space but also non BCMA alternatives!

Also highly active in phase 1 studies

12.5 mos

Non-BCMA-Targeted Bispecific Antibodies: Safety

Bispecific Antibody

AEs, (All/(Gr 3+) CRS Infections Neutropenia Anemia Thrombocytopenia ICANS # Deaths Hypogamma/IVIg Other • • •

Talquetamab (JNJ-64407564) Phase 1/2 MonumenTAL-1 Study GPRC x CD3 79% (2%) 57% (17%) 34% (31%) 11% (1.6%) 0 due to AEs NR/13% Dysgeusia 48% (N/A) Skin 56% (0%) Nail 52% (0%)

72% (0.7%) 50% (12%) 28% (22%) 10% (1.8%) 0 due to AEs NR/10% Dysgeusia 46% (N/A) Skin 67% (0.7%) Nail 43% (0%)

Cevostamab (GO39775) Phase 1 FcRH5 X CD3 +prophy toci/80% (2%) -> 36% (2.3%) /90%(3.6%) 43% (19%) 18% (16%) -> Gr3+ 64% vs 39% 6 (3.7%) Diarrhea 26% (1%)

CRS common, but not severe manageable • ? Role for preventative medication tociluzuamb Perhaps less infections/lower of neutrophils • This makes GPRC5d antibodies more combinable – with dara and also with tec, PFS 19-20 months!

Other new target related toxicities with GPRC5d – taste, skin, nails

Do All MM Patients Need to be Treated Continuously?

Early Experience from 1 Year Fixed Duration Therapy

Determinants of the use of bispecifics 

 

Safety- monotherapy CRS Off tumor (? On target) – incidence, time dependency (cumulative?), dose relationship  Infection especially COVID complications and deaths  Dysgeusia  Skin/Nail changes  Neuropathy Safety in combination with mAbs, IMIDs, PIs, novel agents



Convenience





    

Inpatient vs outpatient  Cost  Reimbursement for drug (J code), inpatient hospitalization, toclluzumab (off label for bispecific), IVIg Ability to give in community Need for & number of priming doses Route of administration – SQ > IV Frequency of administration – q mo Fixed duration vs Treatment to progression



Targets and Sequencing within bispecifics and relative to other agents – CARTs etc.



Time to market BCMA > GPRC5d

CAR-T cell therapy: What is it and how does it work? (1/3)

CAR-T, chimeric antigen receptor-T cell

Image taken from NIH: National cancer institute. CAR-T cell therap. Available at: https://www.cancer.gov/publications/dictionaries/cancer-terms/def/chimeric-antigen-receptor-t-cell-therapy

CAR-T cell therapy: What is it and how does it work? (2/3) Structure of CAR domains

CAR, chimeric antigen receptor; scFv, single-chain variable fragment

•

Tumor binding domain

•

costimulatory endodomains

•

CD3 zeta

June C et al. Science. 2018;359:1361–1365

CAR-T cell therapy: What is it and how does it work? (2/3)

CAR, chimeric antigen receptor

Usmani S. Personal image.

CAR-T cells in myeloma: Currently Available

Phase Target scFv Age, (range) # of lines HR cytog, % EMD, % Triple-R, % ORR, % PFS

Approved CAR-T cells Ide-cel Cilta-cel KarMMa1 CARTITUDE-1 (n = 128) (n = 97) 2,3 II Ib/II BCMA BCMA Chimeric Chimeric mouse Llama 61 (33-78) 61 (56-68) 6 6

35 39 84 81 12.2 m

24 13 88 98 34.9 m

*There, are no head-to-head comparisons of these data and naïve comparison should be conducted with caution BCMA, B-cell maturation antigen; CAR, chimeric antigen receptor; EMD, extramedullary disease; HR cytog, high-risk cytogenetics; NA, not available; NR, not reached/not reported; ScFv, single-chain variable fragment; TCR, T-cell receptor; triple-R, triple-class refractory

CAR-T cells in myeloma: Investigational Therapies

Phase Target scFv Age, (range) # of lines HR cytog, % EMD, % Triple-R, % ORR, % PFS

Alternative Academi manufacturin Human Approved CAR-T c g scFv cells Ide-cel ARI0002h4 P-BCMA-101 Cilta-cel CT0536 CT103A7 1 5,6 LUMMICAR KarMMa CARTITUDE-1 PRIME (n = 128) (n = 30) (n = 53) (n= 79) (n = 24) (n = 97) 2,3 II Ib/II I/II I/II I I/II BCMA BCMA BCMA BCMA BCMA BCMA Chimeric Chimeric Chimeric Humanized Human Human mouse Llama mouse 61 (33-78) 61 (56-68) 61 (36-74) 60 (42-74) 62 (33-76) 57 (39-70) 6 6 4 8 NA 5

35 39 84 81 12.2 m

24 13 88 98 34.9 m

33 20 67 100 53%@18 m

NA NA 60 67 NR

NA NA NA 87 NR

*There, are no head-to-head comparisons of these data and naïve comparison should be conducted with caution BCMA, B-cell maturation antigen; CAR, chimeric antigen receptor; EMD, extramedullary disease; HR cytog, high-risk cytogenetics; NA, not available; NR, not reached/not reported; ScFv, single-chain variable fragment; TCR, T-cell receptor; triple-R, triple-class refractory

34 13 17 95 NR

AlloCAR ALLO-715 UNIVERSAL8 (n = 43) I BCMA

Human 64 (46-77) 5 37 21 91 71 NR

GPRC5 D MCARH OriCAR 1099 -01790 (n= 17 ) (n= 13) I I GPRC5D GPRC5D Humanized Human Bi-epitopic 60 (38-76) 64 (58-68) 6 5.5

76 47 94 71 NR

60 40 15 100 NR

Factors to Consider in BCMA Sequencing

BCMA therapy prior to even ciltacel – PFS is markedly reduced… so sequencing considerations include: mechanism of action, duration of prior BCMA therapy, time since prior BCMA therapy to apheresis/infusion • Loss of BCMA genes • BCMA expression (less likely) - ? Soluble > tissue • Immune T cell fitness (PD-1, TIM3, CD38) and disease burden • Availability of non BCMA directed therapeutics eg. GPRC5d, FCRh5 •

Cohen AD, et al. Blood. 2022:2022015526. Cohen AD, et al. Blood Adv. 2019;3:2487-2490; Samur MK, et al. Nat Commun. 2021;12:868; Da Vià MC, et al. Nat Med. 2021;27:616-619. Lohler et al ASH 2002. Cortes-Selva et al ASH 2022

Pomalidomide/CART/Carfilzomib Randomized Phase 3 Studies % Improvement

40%

40%

40%

50%

75%

40%

40%

35

28.6

Median PFS (mos)

Total N No. prior lines

13.3

12.4

11.53

6.9

6.47

11 .2

19.2

N R

15.2 12

7.1

4.4

ICARIA-MM1 Isa-Pd vs Pd

APOLLO2 D-Pd vs Pd

OPTIMISMM3 PVd vs Vd

CARTITUDE-45 KarMMa-34 Axis TitleCiltacel vs Ide-cel vs SOC DPd or DVd

154 vs 153

151 vs 153

281 vs 278

254 vs:132**

3

2

2

3

208 (175 +20) infus vs 183 or 28 1-3 (~33% 1 LOT)

CANDOR6 DKd vs Kd

IKEMA7 IsaKd vs Kd

312 vs 154

179 vs 123

2

2

CART Side Effects

CARTITUDE-4 Cilta-cel vs Standard of Care Grade 3+ AEs: 97% vs 94% infections 27% vs 25% cytopenias 94% vs 86% CRS: 76% (1% grade 3; no grade 4/5) ICANS: 5% (all grade 1/2) movement and neurocognitive TEAE n=1

Bonifant et al. Molecular therapy oncolytics. 2016.

Considerations in Administration of T cell Redirection Therapies • CRS/ICANS recognition – REMS Program for all involved parties • Floor team - Vital sign frequency • Front line provider- recognition and prompt order entry – consider order sets in EMR (see example on next slide)for • Vitals – to avoid delays in recognition of hypotension/hypoxia requiring interventions • Labs – inflammatory markers, coags, cytokines • Therapeutics - toci, dex, anakinra, siltuximab • Timely drug mixing/administration – pharmacy and floor nurse to coordinate • Notification/training of consultants: neurology, neuroradiology, ICU, infectious disease, ER, outpatient oncology

CAR-T vs Bispecifics In Multiple Myeloma •A hypothetical randomized study without bridging chemo •a CART with a median PFS of < 11-12 mos unlikely to beat an off the shelf bispecific especially with explosive bulky disease •Access and Choice Matter – many more patients have been dosed with bispecifics in clinical trials • including age > 80, including more than several hundreds non-BCMA •What if a CART has median PFS > 2 years?

•PFS, OS, QOL unsurpassed •very limited data for TCE in CKD, EF< 40%, in elderly & frail patients, hx of CNS disorders •Auto SCT widely available and cost-effective yet only 12% of MM in US receive it at accredited SCT centers- so until CART availability markedly increases and cost decreases, what % MM patients globally will benefit from CART?

CAR-T vs Bispecifics In Multiple Myeloma

BCMA

Rolls Royce Phantom –rare , hard to get

GPRC5d

BCMA

FCRh5 Toyota Corolla – nearly 50 million sold globally

Conclusions: Treatment Selection for Triple Class-Exposed Multiple Myeloma GOC/Pt preferences Previous Rx w/therapies approved for TCR MM

Not yet eligible for commercial products (> 4 LOT& TCE) but esp for high risk genomic/ISS3/extramed/functional)

CAR T-cell or bispecific antibody study

Adequate organ function (CBC, Cr Cl, EF)

Fit & Cytopenia due to MM or bridging for CAR T-cell

CAR T-cell slot available @ academic site Indolent, nonbulky PD Able to tolerate Grade 2+CRS/neurotox

Yes 96h infusional chemo

Salvage Auto SCT/Boost (stem cells remaining)

Rapid Progression Near academic center

CAR T-cell study

CD38/K/Pom/Cy/Seli based triplet

Cilta-Cel Ide-Cel

Avoid anti-BCMA prior to BCMA CART if possible

Bispecific study CELMoD Modakafusp alpha

Monitor PFS2/OS

Teclistamab Elranatamab Talquetamab

-

impact of T cell exhaustion & antigen expression impact of flu cy if early PD

Q&A

with panel

130

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