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

Welcome Announcements

Brian G.M. Durie, MD Chairman of the Board & Chief Scientific

Officer of International Myeloma Foundation

Thank You for Joining!

2023 West Coast Patient and Family Webinar May 17, 2023

A replay of this program will be made available shortly after the conclusion. Slides will also be made available.

Agenda

– all times are listed in Pacific Time Zone

4:00 – 4:05 PM – Welcome and Announcements w/ Dr. Brian G.M. Durie

4:05 – 4:30 PM – Myeloma 101 Dr. Brian G.M. Durie, International Myeloma Foundation

4:30 – 4:45 PM – Q&A

4:45 – 5:10 PM – Taking the Reins of Your Myeloma Care

Ann McNeill, The John Theurer Cancer Center, Hackensack

University Medical Center, IMF Nursing Leadership Board

5:10 – 5:25 PM – Q&A

5:25 – 5:35 PM - BREAK

Agenda

– all times are listed in Pacific Time Zone

5:35 – 6:05 PM – Frontline Therapy

Dr. Rafat Abonour, Indiana University School of Medicine

6:05 – 6:20 PM – Q&A

6:20 – 6:45 PM – Relapse & Immune Therapies

Dr. Saad Usmani, Memorial Sloan Kettering Cancer Center

6:45 – 7:00 PM – Q&A 7:00 PM – Closing Remarks

Thank you to our Sponsors!

IMF Patient and Family Seminar

Brian G.M. Durie, MD

International Myeloma Foundation

Studio City, CA

Myeloma 101

Myeloma 101: What Patients Need to Know

Brian G.M. Durie, MD

➢ Long Remissions Common

➢ CURE on the Horizon

Importance of Early Diagnosis

➢ Screening can be a new tool

➢ Start discussions with HR SMM

Potential New Myeloma or Smoldering Myeloma

Potential New Myeloma or Smoldering Myeloma

Any Myeloma Defining Events?

CRAB, >60% PC, FLC >100, MRI >1 focal

No Myeloma Defining Events (SMM)

High Risk SMM (Median TTP ~2 years)

Intermediate or Low Risk SMM

Treat as Myeloma

Early Therapy with Len or Rd x 2 years

Clinical Trials

Observation

Evolution of Treatment Options 15 Years Ago

First Therapy Relapse

VAD (Chemo) +

Velcade and Revlimid

Treatment Options in 2023

Median PFS: 47.3 vs 35 mo

Median PFS: 67.5 vs 46.2 mo

Benefit: maintenance until PD!

GRIFFIN Study Design: VRd +/- Dara

GRIFFIN Responses

 Alkylators

 Steroids

 Anthracyclines

Active Drugs in MM

Anti-SLAMF7 monoclonal antibody (moAB)

 Elotuzumab

 Selinexor (XPO1 inhibitor)

 Venetoclax (BCLinhibitor, unique MOA)

Anti-BCMA CAR-T

 Cilta-cel

 Ide-cel

 JCARH125

Anti-CD38 moABs

 Daratumumab

IMiDs

 Thalidomide

 Lenalidomide

 Pomalidomide

 Isatuximab

 Felzartamab (MOR202)

 TAK 079

 SAR 442085

 TAK 573 (Modakafusp Alfa)

Anti-BCMA Bispecifics

 Teclistamab

 Linvoseltamab (REGN5458)

 Alnuctamab

 Elranatamab

 TNB 383B

Novel Bispecifics

 Talquetamab (GPRC5D/CD3)

Proteasome Inhibitors

 Bortezomib

 Carfilzomib

 Ixazomib

Anti-BCMA antibody drug conjugate

 Belantamab*

CELMoDs

 Iberdomide

 Mezigdomide

 Cevostamab

 (FcRH5/CD3)

*Belantamab was recently withdrawn from the US market

What Are The Options?

• Immune approaches

• BCMA ADC – Belantamab*

• BCMA CAR T – (Ide-cel, Cilta-Cel)

• BCMA Bispecific - Teclistamab

• Targeted agents

• XPO1 inhibitor - Selinexor

BCMA ADC- Belantamab

• Venetoclax – Bcl2 inhibitor

*Belantamab was recently withdrawn from the US market

Key Points for Ongoing Care

 Keep Track of Follow-up Tests

- CBC; SPEP/UPEP; Freelite; SCANS; BM if needed

- FiSH for t[11;14] or high-risk [17P-; 1q+…]

 Alert Doctor to Changes (myeloma/side effects)

 Be Aware of Potential Future Options

 Be Proactive in Seeking Expert Advice

Set Expectations with Your Primary Doctor

Q&A

Taking The Reins of Your Multiple Myeloma Care

Ann McNeill RN, MSN, APN

John Theurer Cancer Center at HMH

IMF Nurse Leadership Board Member

Today’s Topics

STABLE OF TREATMENT

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

FINDING YOUR GAIT

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

STABLE OF TREATMENT

FINDING YOUR GAIT

GOING THE DISTANCE

GOING THE DISTANCE

Healthful living, infection prevention, renal and bone health

Stable of Treatment

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

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.

Stable of Treatment Options

-Mibs -MAbs -Mides Steroids Alkylators

FRONTLINE Velcade® (bortezomib)

Darzalex® (daratumumab)

Thalomid® (thalidomide)

Revlimid® (lenalidomide)

Dexamethasone

Prednisone

Prednisolone

SoluMedrol

Melphalan

Cyclophosphamide

MAINTENANCE

Velcade® (bortezomib)

Ninlaro® (ixazomib)

RELAPSE Kyprolis® (carfilzomib)

Ninlaro® (ixazomib)

Darzalex® (daratumumab)

- ECOG clinical trial

Darzalex® (daratumumab)

Empliciti® (elotuzumab)

Sarclissa® (Isatuximab)

Revlimid® (lenalidomide)

Thalomid® (thalidomide)

Revlimid® (lenalidomide)

Pomalyst® (pomalidomide)

• CelMods

Dexamethasone

Prednisone

Prednisolone

SoluMedrol

Melphalan

Cyclophosphamide

Bendamustine

PENDING FDA APPROVAL

‒ Iberdomide

‒ CC-92480

NOTED SIDE

EFFECTS

Carfilzomib: Cardiac

STABLE OF TREATMENT FINDING YOUR GAIT GOING THE DISTANCE

ImmunoTherapy Others Cellular Therapies

ASCT

Tecvayli™

Teclistamab

Xpovio® (Selinexor)

Doxil (liposomal doxorubicin)

• Bispecific Antibodies

‒ Talquetamab

‒ Cevostamab

• Antibody Drug Conjugates*

‒ Belantamab

mafodotin

CRS and neurotoxicity; infection risk;

Blenrep: Keratopathy

Venclexta® (venetoclax)

ASCT

CAR-T cell therapy

Ide-Cel

Cilta-Cel

Myelosuppression, GI

Selinexor: Low sodium

Other CAR-T

Infection risk

CAR-T: CRS and neurotoxicity

CAR T: A New Treatment Approach

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

• No driving for 8 weeks

• One and done…BUT will need ongoing monitoring; some patients need transfusion support

• CRS, neurotoxicity, or infection are possible side effects

Horse of Another Color:

• 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

Bispecific Antibodies also Target BCMA MM cell death

ANTIBODIES

Cytotoxic cytokines

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.

Bispecific antibody

BCMA CD3

T cell MM cell

CAR

CRS

CAR T and Bi-specific Antibodies: Unique Side Effects

NEUROTOXICITY

Neurotoxicity is a rare but serious side effect

Tremors

Facial nerve palsy

Apraxia

CRS = cytokine release syndrome; ICANS = immune effector cell–associated neurotoxicity syndrome; ICE = Immune Effector Cell Encephalopathy screening tool; MRI = magnetic resonance imaging.

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)

STABLE OF TREATMENT FINDING YOUR GAIT GOING THE DISTANCE

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

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!

Infection Guidelines

Type of prophylaxis

Recommendation(s)

HSV/VZV Standard prophylaxis recommended for all patients with MM

PJP

STABLE OF TREATMENT FINDING YOUR GAIT GOING THE DISTANCE

Opportunistic infections have been noted with bispecific agents and CAR T therapy; consider PJP prophylaxis

Bacterial & Fungal Standard prophylaxis recommended for ANC < 500 cells/μL

COVID-19 Consider monoclonal antibody therapy for patients receiving BCMA-bispecifics or CAR T therapy; based on institution-specific protocols

Hypogammaglobulinemia IVIg for IgG < 400 mg/dL or recurrent infections

GCSF 2 or 3 times/wk (or as frequently as needed) to maintain ANC > 1000 cells/μL and maintain dose intensity

BCMA = B-cell maturation antigen; GCSF = granulocyte colony-stimulating factor; HSV = herpes simplex virus; IVIg = intravenous immunoglobulin; PJP = Pneumocystis jirovecii pneumonia;

VZV = varicella zoster virus

National Comprehensive Cancer Network. Prevention and Treatment of Cancer -Related Infections. Version 3.2022. Published October 28, 2022. Accessed May 1, 2023.

https://www.nccn.org/professionals/physician_gls/pdf/infections.pdf

Supportive Care to Address Side Effects

Don’t change horses midstream

• 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.

Non-medication

Symptoms of Multiple Myeloma

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

Psychological

• Depression

• Anxiety

• Sleep Disturbance

• Decreased Cognitive Function

• Decreased Role & Social Function

Financial

• Financial burden (80%)

• Financial toxicity (43%)

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

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

STABLE OF TREATMENT FINDING YOUR GAIT GOING THE DISTANCE

Steroid Side Effects

• Irritability, mood swings, depression

• Difficulty sleeping (insomnia), fatigue

• Blurred vision, cataracts

• Flushing/sweating

• Increased risk of infections, heart disease

• Stomach bloating, hiccups, heartburn, ulcers, or gas

• Muscle weakness, cramping

• Weight gain, hair thinning/loss, skin rashes

• Increased blood pressure, water retention

• 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.

GI Symptoms:

Prevention & Management

Diarrhea may be caused by medications and supplements

Avoid caffeinated, carbonated, or heavily sugared beverages

Take anti-diarrheal medication if recommended

Constipation may be caused by medications and supplements

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 helps kidney function. Discuss GI issues with health care providers to identify causes and make adjustments to medications and supplements.

Pain Prevention and Management

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)

–

Scrambler therapy for neuropathy

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

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.

If neuropathy worsens, your provider may:

• Change your treatment

• Prescribe oral or topical pain medication

• Suggest physical therapy

Why the Long Face?

98.8%

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

>35% of patients

~25% 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.

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

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

• 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

YOU

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

Going the Distance

Healthful living, infection prevention, renal and bone health

Healthful Living Strategies: Prevention

Maintain renal health

• Myeloma management

• Hydration

• Avoid renally-toxic medications

– Dose adjust to renal function

• Diabetes management

Preventative health care

Health screenings, vaccinations

Prevent falls, injury, infection

Stop smoking

Dental care

Protect your bones

Nutrition, Calcium + D supplement

Weight-bearing activity and/or walking

Bone strengthening agents

Manage stress

• Rest, relaxation, sleep hygiene

• Mental health / social engagement

• Complementary therapy

Maintain a healthy weight

Nutrition

Activity / exercise

An ounce of prevention is worth a pound of cure.

Faiman B, et al. CJON. 2017;21(5)suppl:19-36. Dimopoulous M, et al. Leukemia. 2009;23(9):1545-56.

Benjamin Franklin

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:

• Keep a log or journal of your activity

FINDING YOUR GAIT GOING THE DISTANCE

• 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!

Boullosa DA, et al., Jul 2013;45(7):1223-1228. Faiman B et al., Clinical Journal of Oncology Nursing. 2008;12(0):53-62;

. 2011;15:9-23; Coleman EA et al.,Oncol Nurs Forum. May 2008;35(3):E53-61.

Nurse Leadership Board

In 2006, the IMF founded the Nurse Leadership Board® as a professional partnership to represent oncology nurses who are experts in the care of multiple myeloma patients at leading medical centers. The NLB is improving the nursing care and self-care of patients with multiple myeloma via publications, symposia, multimedia, and research.

Agenda after break

all times are listed in Pacific Time Zone

5:35 – 6:05 PM – Frontline Therapy

Dr. Rafat Abonour, Indiana University School of Medicine

6:05 – 6:20 PM – Q&A

6:20 – 6:45 PM – Relapse & Immune Therapies

Dr. Saad Usmani, Memorial Sloan Kettering Cancer Center

6:45 – 7:00 PM – Q&A

7:00 PM – Closing Remarks

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 for MM

• 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 cytoreduction to relieve symptoms

• Minimize treatment-related toxicity

• Prolong survival – Overall Survival

Depth of Response Influence Time to Progression

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

Munshi et al. Blood Advances 2020; 4:23

MRD May Abrogate Other Risk Factors = Optimal Dynamic Risk Assessment Tool

PETHEMA/GEM2012

(MRD < 2 x 10-6)

Goicochea I et al. Blood 2021;137:49

Opportunity for de-escalation

Need to employ new approaches

Downsides of Maintenance Therapy

Deferring Lenalidomide for 7 years:

No therapy

Perrot A et al. ASH meeting 2020

Most patients have not progressed in 7years despite no therapy

-”Saving” of US$ 1.5 million!

-Avoid ~3.5% absolute increase in risk of SPM

-Avoid dozens of extra lab checks/MD visits

-Avoid diarrhea, fatigue, rash

-Avoid “daily reminder I have cancer”

Implications for loss of MRD negativity

The Evolution of Myeloma Therapy

Bortezomib

Lenalidomide

Carfilzomib

Pomalidomide

Selinexor

Panobinostat

Daratumumab

Ixazomib

Elotuzumab

Isatuximab

Belantamab mafodotin

Melphalan flufenamide

Idecabtagene autoleucel

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

Bispecific/Trispecific Antibodies

Cell Modifying Agents

Venetoclax?

PD/PDL-1 Inhibition?

Multiple small

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

Is three drugs better than two?

Three may better in some Patients

MAIA How about Antibodies based!

‒ Patients were enrolled in MAIA from March 2015 through January 2017

D: 16 mg/kg IV

QW Cycles 1-2, Q2W Cycles 3-6, then Q4W thereafter until PD

R: 25 mg PO Days 1-21 until PD

da: 40 mgb PO or IV

Days 1, 8, 15, 22 until PD

Rd

R: 25 mg PO Days 1-21 until PD

d: 40 mg PO

Days 1, 8, 15, 22 until PD

Cycles: 28 days

End-oftreatment visit (30 days after last dose)

Longterm follow-up

Primary endpoint

• PFS

Key secondary endpoints

• OS

• PFS2

• ORR

• CR/sCR rate

• MRD (NGS; 10–5)

MAIA is a multicentre, randomised, open-label, active-controlled, phase 3 study of D-Rd versus Rd alone in patients with NDMM who are transplant ineligible

TIE, transplant-ineligible; ECOG PS, Eastern Cooperative Oncology Group performance status; CrCl, creatinine clearance; IV, intravenous; QW, once weekly; Q2W, once every 2 weeks; Q4W, once every 4 weeks; PD, progressive disease; PO, oral; ORR, overall response rate; CR, complete response; sCR, stringent complete response; MRD, minimal residual disease; NGS, next-generation sequencing; BMI, body mass index.

aOn days when DARA is administered, dexamethasone will be administered to patients in the D-Rd arm and will serve as the treatment dose of steroid for that day, as well as the required pre-infusion medication. bFor patients >75 years of age or with BMI <18.5 kg/m2, dexamethasone was administered at a dose of 20 mg QW.

Treatment Exposure and Patient Disposition

Median duration of follow-up, 56.2 months

42% of patients in the D-Rd arm and 18% of patients in the Rd arm remained on treatment; more patients discontinued Rd for AEs

Overall Response Rate

• D-Rd induced deeper responses with significantly higher rates of ≥CR and ≥VGPR, compared with Rd

• With >28 months of additional follow-up, responses deepened with continued DARA therapy

Time without Relapse (PFS)

• D-Rd continued to demonstrate a significant PFS benefit, with median PFS not reached with DRd

• These data provide a new PFS benchmark in patients with NDMM who are transplant ineligible

Overall Survival

D-Rd demonstrated a significant benefit in OS, with a 32% reduction in the risk of death, in patients with NDMM who are transplant ineligible

Subsequent Therapy

‒ Median time to next treatment was not reached with D-Rd versus 42.4 months with Rd (HR, 0.47; 95% CI, 0.37-0.59; P <0.0001)

‒ 114 patients in the D-Rd arm and 186 patients in the Rd arm received subsequent therapy; of these:

• A PI-containing regimen without an IMiD was the most common first subsequent therapy

(53% vs 54% with D-Rd and Rd, respectively)

• 15% of patients in the D-Rd arm and 46% of patients in the Rd arm received daratumumab as any subsequent therapy

Conclusions

‒ After almost 5 years of follow-up, a significant OS benefit of D-Rd versus Rd given to progression was demonstrated in patients with transplant-ineligible NDMM

• The estimated 5-year OS rate was 66.3% with D-Rd and 53.1% with Rd

‒ The significant PFS benefit of D-Rd versus Rd was maintained, with a 47% reduction in risk of disease progression or death (median PFS for D-Rd, not reached)

• The estimated 5-year PFS rate was 52.5% with D-Rd and 28.7% with Rd

‒ These PFS and OS results have been achieved in a study population with 44% of patients aged 75 to 90 years

‒ No new safety concerns were identified with continuous therapy and longer follow-up

These results strongly support upfront D-Rd as a new standard of care for patients with transplant-ineligible NDMM

How about Four Drugs regimen?

Daratumumab (DARA) Plus Lenalidomide, Bortezomib, and Dexamethasone (RVd) in Patients (Pts) With Transplant-eligible

Newly Diagnosed Multiple Myeloma (NDMM):

Updated Analysis of GRIFFIN After 24 Months of Maintenance

Presented at the 63rd American Society of Hematology (ASH) Annual Meeting & Exposition; December 11-14, 2021; Atlanta, GA/Virtual

ASH2021/Daratumumab/Laubach

*Presenting author.

GRIFFIN: Study Design of the Randomized Phase

• Phase 2 study of D-RVd versus RVd in transplant-eligible NDMM, 35 sites in the United States with enrollment between December 2016 and April 2018

Stem cell mobilization with G-CSF ± plerixaforb

GRIFFIN: Responses Deepened Over Timea

• Response rates for sCR and ≥CR were greater for D-RVd versus RVd at all time points, with the deepest responses occurring after 2 years of maintenance therapy

GRIFFIN: MRD Negativitya (10–5) After 2 Years of Maintenance Therapy

GRIFFIN: Time to MRD Negativity

• Median time to MRD negativity (10–5) was 8.5 months for D-RVd and 34.6 months for RVd

– At the 10–6 threshold, time to MRD negativity was 33.9 months for D-RVd and not reached for RVd

• Median time to MRD negativity was shorter for D-RVd versus RVdb

GRIFFIN: PFS in the ITT Population

• Median follow-up: 38.6 months

• Median PFS was not reached in either group

• There is a positive trend toward improved PFS for D-RVd/DR versus RVd/R

• The separation of the PFS curves begins beyond 1 year of maintenance and suggests a benefit of prolonged DR 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

COMMIT- Academic Consortium to Overcome Multiple Myeloma through Innovative Trials

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

Treatment

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

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

Best MRD response by phase of therapy

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

Progression-Free and Overall Survival

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

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

Primary endpoint: MRD negativity at the end of induction phase

Induction phase (3 x 6-week cycles)

Maintenance phase (4-week cycles)

MRD (bone marrow aspirate)

Primary endpoint:

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

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

Patients with MRD negativity at the end of induction therapy

OR 1.83 (95% CI 1.34–2.51)

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

First primary endpoint, end of induction MRD negativity by NGF (10-5), was met in ITT analysis

Response rates after induction therapy

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

Addition of Isa to RVd had limited impact on safety profile

A comparable number of patients discontinued induction therapy due to AEs in the

*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

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.

The future: MASTER 2 The Dream Trial

Sequential Therapy in Multiple Myeloma Guided by MRD Assessments

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

T-cell Redirecting therapy

T-cell Redirecting therapy

Relapsed Multiple Myeloma: Novel and Cellular Therapies in 2023

Saad Z. Usmani, MD MBA FACP Chief of Myeloma Service

Disclosures

• Research funding: Amgen, BMS/Celgene, GSK, Janssen, Merck, Pharmacyclics, Sanofi, Seattle Genetics, Takeda.

• Consulting/Advisory Board: Abbvie, Amgen, BMS, Celgene, Genentech, Gilead, GSK, Janssen, Sanofi, Seattle Genetics, SecuraBio, SkylineDX, Takeda, TeneoBio.

Presented by: Saad Z. Usmani, MD MBA FACP, @szusmani

Journey to the First Relapse

Factors in Selecting Relapsed Therapy

Patient

• Age

• Performance status

• Renal insufficiency

• Poor marrow reserve

• Neuropathy

• Comorbidities

• Cardiac disease

• Diabetes

Disease

• Risk Status

• Cytogenetics

• del [17p], t(4;14), t(14;16)

• Rapidity of relapse

• Rate of rise

• Organ damage

• Extramedullary disease

• Plasma cell leukemia

Treatment

• Previous therapy

• Depth

• Duration

• Route of administration

• Single or combination

• Cost

• Toxicity

• Myelosuppressi on

• Neuropathy

Dimopoulos MA, et al. Nat Rev Clin Oncol 2015;12(1):42-54; Baz R, et al. Support Care Cancer 2015;23(9):2789-2797; Agarwal A et al. Clin Lymphoma Myeloma Leuk. 2017;17(2):69-77.

• Thrombosis

• Risk of SPM

We have many options!

Lenalidomide combinations

• Carfilzomib, lenalidomide, dexamethasone

(KRd)

• Ixazomib, lenalidomide, dexamethasone (IRd)

• Elotuzumab, lenalidomide, dexamethasone (EloRd)

• Daratumumab, lenalidomide, dexamethasone

(DRd)

Pomalidomide combinations

• Carfilzomib, pomalidomide, dexamethasone (KPd)

• Elotuzumab, pomalidomide, dexamethasone (EloPd)

• Daratumumab, pomalidomide, dexamethasone (DPd)

• Isatuximab, pomalidomide, dexamethasone (IsaPd)

Carfilzomib combinations

• Daratumumab, carfilzomib, dexamethasone (DKd)

• Isatuximab, carfilzomib, dexamethasone (IRd)

• Carfilzomib, dexamethasone (Kd) with or without cyclophosphamide

Other notable combinations

• Selinexor, bortezomib, dexamethasone (SVd)

• Off-label use of venetoclax, dexamethasone for translocation (11;14) (VenD)

IMWG Guidelines： Treatment at Relapse

Treatment at first relapse

Not

refractory to LEN Refractory to LEN

Treatment after multiple relapses

Any first relapse options not yet used

(2 new drugs; triplet preferred)

Preferred options†: DRd or KRd

Alternatives‡: DVd, Kd, DKd, Isa–Kd, IRd, Elo–Rd, PVd, or SVd (subject to approval)

If daratumumab, isatuximab, or carfilzomib are not available: Rd, Vd, VTd, VCd, or VMP

Preferred options†: D–Kd, or Isa–Kd, or PVd

Alternatives‡: DVd or Kd

Other options: KPd, DPd, or Ipd

If daratumumab, isatuximab, carfilzomib, or pomalidomide are not available: VCd, Vd, or VMP

Investigational options and clinical trial

Autologous Stem Cell Transplant Candidate?

• SCT not performed as part of frontline therapySCT

• Durable remission after 1st SCT (≥24 months on no maintenance therapy, ≥36 months with maintenance therapy)

The Promise of T-cell redirection

Adapted from Cho S-F et al. Front Immunol. 2018;9:1821.

BCMAbispecific antibody

BCM A Myeloma cell

BCMAbispecific T-cell engager

T cell

BCM A Myeloma cell T cell toxin

CD 3

Myeloma cell dying

Presented by: Saad Z. Usmani, MD MBA FACP, @szusmani

BCMA CARTs: Summary

KarMMa-2: Study design and baseline characteristics

Cohort 2a – early relapse after ASCT

Baseline characteristics

aResponse defined as PR or better based on IMWG criteria by investigator assessment; measured from infusion; bPatients with ≥PR (2 patients had minimal response; 4 had stable disease and 0 had progressive disease); cClopper-Pearson CI; dPatients with sCR and CR

ASCT, autologous stem cell transplant; CR, complete response; CRR, complete response rate; ORR, overall response rate; PD, progressive disease; PR, partial response; sCR, stringent complete response; VGPR, very good partial response

Usmani S et al. ASH 2022;abstract 361 (oral presentation)

Presented by: Saad Z. Usmani, MD MBA FACP, @szusmani

GPRC5D-targeting CAR-T cell therapy: CC-95266-MM-001study

Study design

bTreatment schedule and follow-up for Part B (dose expansion) will be the same as Part A.

BCMA, B-cell maturation antigen; CAR, chimeric antigen receptor; MTD, maximum tolerated dose; RP2D, recommended phase 2 dose

Berdeja J et al. ASH 2022;abstract 364 (oral presentation)

Baseline characteristics

GPRC5D-targeting CAR-T cell therapy: Response

ORR in patients with and without experience of BCMA-targeting therapy

BCMA, B-cell maturation antigen; CAR, chimeric antigen receptor; CRR, clinical response rate; ORR, overall response rate; PR, partial response; sCR, stringent response rate; VGPR, very good response rate

Berdeja J et al. ASH 2022;abstract 364 (oral presentation)

Presented by: Saad Z. Usmani, MD MBA FACP, @szusmani

GPRC5D-targeting CAR-T cell therapy: Safety profile TEAEs

• ICANS-type neurotoxicity was infrequent, low grade and reversible with steroid treatment: Any grade 2 (6%), none were grade 3/4

• DLTs: prolonged neutropenia and/or thrombocytopenia, 2 patients (25 x 106 and 75 x 106 CAR-T cells)

• MTD has not been reached

• No deaths related to study treatment (1 death prior to treatment)

CAR, chimeric antigen receptor; CRS, cytokine release syndrome; DLTs, dose-limiting toxicities; ICANS, immune effector cell-associated neurotoxicity syndrome; MTD, maximum tolerated dose; TEAEs, treatment-emergent adverse events

Berdeja J et al. ASH 2022;abstract 364 (oral presentation)

Presented by: Saad Z. Usmani, MD MBA FACP, @szusmani

BsAbs – Many Different Platforms

Bispecific T-cell Engager or BiTE (Amgen)

Dual Affinity ReTargeting or DART (Janssen, Macrogenics)

Tandem diabodies or TandAb (Affimed)

T-cell dependent BsAb Xmab (Xencor, Glenmark, Amgen)

BsAb armed activated Tcells or BAT (mostly academic)

CrossMAb (Celgene, Roche)

Duobody (Genmab)

Adapted from Lejeune M et al. Front Immunol 2020 11:762.

Trifunctional Antibody or TriFAb

Presented by: Saad Z. Usmani, MD MBA FACP, @szusmani

Teclistamab – 1st FDA Approved BsAb for MM

Many more BCMA-targeting T-cell redirecting BsAbs in development

Alnuctamab

Elranatamab

bsAb, bispecific antibody; BCMA, B-cell maturation antigen

ABBV-383 (TNB-383B)

Bahlis N et al. ASCO 2021;abstract 8006 (oral presentation); Costello C et al. EHA 2021;abstract S192 (oral presentation); Costa L et al. Blood 2019;134:abstract 143 (oral presentation); Costa L et al. EHA 2020;abstract S205 (oral presentation); Madduri D et al. ASH 2020;abstract 291 (oral presentation; Rodriguez C et al. ASH 2020;abstract 293 (oral presentation); Sebag ASH 2021;abstract 895 (oral presentation); Zonder et al. ASH 2021;abstract 160 (oral presentation); Kumar S et al. ASH 2021;abstract 900 (oral presentation)

Presented by: Saad Z. Usmani, MD MBA FACP, @szusmani

Median prior regimens: 5

Median follow-up: 10.4 months

BICR, blinded independent central review; CR, complete response; PR, partial response; sCR, stringent complete response; VGPR, very good partial response

Bahlis N et al. ASH 2022;abstract 159 (oral presentation)

Presented by: Saad Z. Usmani, MD MBA FACP, @szusmani

Elranatamab (BCMA-CD3 TCE): Phase 2 MagnetisMM-3 trial

Interim safety analysis (n=94) – safety profile

• All CRS events were grade 1 or 2

• Median time to onset 2 days (1 – 9)

• Tocilizumab was used in 27 pts (22.7%)

• TEAEs led to permanent elranatamab discontinuation in 19 (15.4%) patients (8 patients due to infections)

• TEAEs led to death in 21 patients; 2 treatment-related per investigatorb

a Includes preferred terms in COVID-19 (narrow) standardized MedDRA queries

b Other grade 5 TEAEs (n=19) were not treatment-related per investigator and included TEAEs at the MedDRA level of system organ class: disease progression or neoplasms benign, malignant and unspecified (n=11), infections (n=5), cardiac disorders (n=2), and respiratory disorders (n=1)

• Infections were reported in 66.7% (Grade 3/4, 35.0%) of patients

• Median time to first onset of infections was 47.5 d (range, 1.0−295.0)

• Overall, 50 (40.7%) patients received IVIG during the study.

CMV, cytomegalovirus; CRS, cytokine release syndrome; IVIG, intravenous immunoglobulin G; TEAE, treatment-emergent adverse event; TCE, T-cell engager

Bahlis N et al. ASH 2022;abstract 159 (oral presentation)

Alnuctamab: Design, baseline characteristics and safety profile

Safety profile

Phase 1 step-up dosing of alnuctamab (CC-93269)

28-day cycles

Baseline characteristics

• Median follow-up: 4.1 months

aMedian time to resolution of neutropenia (grade ≤2) was 1 week (range 0.1 x 0.1–5.1); b2 grade 1 ICANS events (duration 3 and 5 days); cMost common were COVID-19 n=8), rhinovirus (n=3).

ALT, alanine aminotransferase; CRS, cytokine release syndrome; DLT, dose-limiting toxicity; ICANS, immune effector cell-associated neurotoxicity syndrome; SC, subcutaneous

Wong S et al. ASH 2022;abstract 162 (oral presentation)

Alnuctamab: Responses

• mDOR with SC alnuctamab: not reached

• 26/29 (90%) responses are ongoing

Responses over time with SC alnuctamab

ORR with SC alnuctamab

aPatients who received 10 or 15 mg target doses.

CR, complete response; mDOR, median duration of response; MRD, minimal residual disease; PD, progressive disease; PR, partial response; Q2W, every other week; SC, subcutaneous; sCR, stringent complete response; SD, stable disease; TEAE, treatment-emergent adverse events; VGPR, very good partial response

Wong S et al. ASH 2022;abstract 162 (oral presentation)

Other targets

1. GPRC5D: TALQUETAMAB

Median prior regimens: 5

Prior belantamab: 12.6-9.0%

Median follow-up: 14.9-8.6 months

On target/off tumor toxicities :

-dysgeusia; dysphagia

-weight loss

-skin-related AEs

-nail-related AEs

mPFS

Infections:

-all grade: 57.3 / 50.3%

-grade 3/4: 16.8 / 11.7%

Chari A et al. ASH 2022;abstract 157 (oral presentation); Verkleij CPM et al. Blood Adv 2021;5(8):2196–2215

MonumenTAL-1: Talquetamab in patients with prior T-cell redirecting therapies

ORR in patients with prior T-cell redirecting

Patient’s characteristics:

• Median of 6 prior lines of therapy (range, 3–15)

• 70.6% (n=36) received prior CAR-T cell therapy and 35.3% (n=18) prior bispecific antibody therapy; 3 patients received both

Data cut-off date: September 12, 2022.

• Median follow-up: 11.8 months

• Median duration of response: 12.7 months

• 72.2% ORR (26/36; 95% CI, 54.8–85.8%) in patients with prior CAR-T cell therapy 2200%

• 44.4% ORR (8/18; 95% CI, 21.5–69.2%) in patients with prior bispecific antibody treatment

aIndependent review committee assessment of evaluable patients per 2011 IMWG response criteria; due to rounding, individual response rates may not sum to the ORR.

CAR, chimeric antigen receptor; CR, complete response; PR, partial response; ORR, overall response rate; Q2W, every other week; QW, weekly; SC, subcutaneous; sCR, stringent complete response; VGPR, very good partial response

Chari A et al. ASH 2022;abstract 157 (oral presentation)

Presented by: Saad Z. Usmani, MD MBA FACP, @szusmani

Forimtamig (RG6234): GPRC5D x CD3 phase 1 dose escalation study

Study design

*Q3W dosing in the 18/162/7200 μg IV and the 30/150/4800 μg and 30/300/7200 μg SC cohorts; †Until progression or unacceptable toxicity; ‡doses in μg; §1 patient had previously received an ADC and CAR-T cell therapy.

ADC, antibody-drug conjugate; BCMA, B-cell maturation antigen; CAR, chimeric antigen receptor; CRS, cytokine release syndrome; ECOG, Eastern Cooperative Oncology Group; MTD, maximum tolerated dose; Q2W, every 2 weeks; RP2D recommended phase 2 dose; SC, subcutaneous

Carlo-Stella C et al. ASH 2022;abstract 161 (oral presentation)

Forimtamig (RG6234): Efficacy and CRS

• Median duration of response was 10.8 months for the IV arm and 12.5 months for the SC arm

Forimtamig is highly active in patients with RRMM

CR, complete response; CRS, cytokine release syndrome; IV, intravenous; MRD, minimal residual disease; ORR, overall response rate; PR, partial response; SC, subcutaneous; sCR, stringent complete response; VGPR, very good partial response

• Median time to CRS onset was 5 hours in the IV arm and 24 hours in the SC arm

• Median duration of CRS was 2 days

• Safety profile was consistent with other GPRC5Dtargeting bispecific antibodies

Carlo-Stella C et al. ASH 2022;abstract 161 (oral presentation)

Presented by: Saad Z. Usmani, MD MBA FACP, @szusmani

Cevostamab with tocilizumab pretreatment to reduce incidence of CRS

• Tocilizumab treatment pretreatment with a single 8 mg/kg dose

• Median follow-up: 12.8 months non-TCZ and 8.5 months for TCZ groups

Tocilizumab reduces CRS rates with no negative impacts on antimyeloma activity of cevostamab

ALT, alanine aminotransferase; AST, aspartate aminotransferase; CR, complete response; CRS, cytokine release syndrome; Gr, grade; ORR, overall response rate; PR, partial response; sCR, stringent complete response; TCZ, tocilizumab; VGPR, very good partial response

Trudel S et al. ASH 2022;abstract 567 (oral presentation)

CELMoD (including IMiD agents) agents act as molecular glues

CELMoD agents alter the target protein binding properties of CRBN to promote interaction with protein substrates that would not otherwise be candidates for degradation

IBER (CC-220) is an investigational product, currently not approved by any regulatory agency

CUL4, cullin 4; DC, dendritic cell; DDB1, DNA damage-binding protein 1; IMiD agents, immunomodulatory drug agents; NK, natural killer; ROC1, regulator of cullins-1; Ub, ubiquitin

van de Donk NWCJ et al. ASH 2020;abstract 724 (oral presentation)

CELMoD Iberdomide

+ Dd or Vd in R/R MM: Phase I/II Study Design

• Open-label, dose-escalation/dose-expansion trial

Patients with R/R MM and ≥2 prior regimens (≥1 in cohort F), including len/pom and PI) who progressed within 60 days of last therapy

Dosing schedules

Cohort E (28-day cycles)

Iberdomide D1-21

Dexamethasone D1,8,15,22

Daratumumab C1-2: D1,8,15,22; C3-6: D1,15; C7+: D1

Cohort F (21-day cycles)

Iberdomide D1-14

Dexamethasone D1,8,15

Bortezomib C1-8: D1,4,8,11; C9+: D1,8

Phase II: Dose Expansion

Cohort D at RP2D

Cohort I (post BCMA) at RP2D

Cohort J1 (ND MM, ASCT ineligible)

Cohort J2 (ND MM, ASCT eligible)

 Primary endpoints: identify MTD and RP2D, efficacy

 Secondary endpoint: safety

 RP2D of 1.6 mg/day determined for iberdomide with Dex; cohorts E, F continuing enrollment with 1.6-mg/day dose

Van De Donk. ASH 2020. Abstr 724.

Iberdomide + Dd or Vd in R/R MM: Safety

• reported in either cohort

Iberdomide + Dd or Vd in R/R MM: Efficacy

• High response rates in heavily exposed and highly refractory patient population

– Among 27 patients in daratumumab cohort,

26 were IMiD refractory, 15 daratumumab refractory, 13 tripleclass refractory; 4 patient refractory to daratumumab achieved PR

– Among 23 patients in bortezomib cohort, 18 were IMiD refractory, 15 PI refractory, 9 bortezomib refractory, 9 triple class refractory; durable responses achieved in patients refractory or with prior exposure to bortezomib

• Addition of daratumumab or bortezomib to iberdomide + dexamethasone shows minimal effect on pharmacodynamics

Van De Donk. ASH 2020. Abstr 724.

Novel CELMoD agent: Mezigdomide (CC-92480) (preclinical data)

Mezigdomide (CC-92480) is a novel CELMoD agent, with a distinct chemical structure from LEN and POM, higher affinity for CRBN, and more efficient substrate degradation

Substrate (Aiolos) degradation efficiency

CC-92480

LEN

POM

Ymin = 35

Ymin = 18

Ymin = 5

CC-92480 is an investigational product, currently not approved by any regulatory agency

Ymin is the lowest point of the dose-response degradation curve and denotes the minimum percentage protein remaining

Hansen JD et al. J Med Chem. 2020;63:6648–76

Mezigdomide: PFS and response

PFS Response rates

Activity of MEZI-DEX is promising in TCR patients as well as those with plasmacytomas and/or prior anti-BCMA therapy

aData cut-off, Sept 16 2022; b≥PR; cIncluding extramedullary soft tissue only disease as well as soft tissue bone-related plasmacytomas; dResponders without adjusting for censoring.

BCMA, B-cell maturation antigen; CR, complete response; MR, minimal response; NE, not evaluable; PD, progressive disease; PFS, progression-free survival; PR, partial response; sCR, stringent complete response; TCR, triple-class refractory; VGPR, very good partial response

Modakafusp alfa: Mode of action

Modakafusp alfa: Study design and baseline characteristics

Study design

Baseline characteristics

BCMA, B-cell maturation antigen; IMiD, immunomodulatory drug; mAb, monoclonal antibody; MTD, maximum tolerated dose; OBD, optimal biological dose; PI, proteasome inhibitor; QW/Q3/4W, weekly/every 3/4 weeks

Modakafusp alfa: Efficacy and safety in the 1.5 mg/kg

Q4W + dexamethasone expansion cohort

• Median follow-up: 5.3 months

• Median duration of response: 12.5 months

• Median PFS: 5.7 months

BCMA, B-cell maturation antigen; CR, complete response; IRR, infusion-related reactions; mAb, monoclonal antibody; MR, minimal response; PFS, progression-free survival; Q4W every 4 weeks;

PR, partial response; TEAEs, treatment-emergent adverse events; VGPR, very good partial response

MSKCC Myeloma Service

TCE, CAR T Cells

Checkpoint Inhibitors

Developmental Therapeutics

Carlyn Tan

MM Precursor diseases

Supportive Care

Bone Health

Urvi Shah

MM Precursor Disease

Nutrition & Modifiable

Risk Factors

Early Relapse

Kylee Maclachlan

MM Precursor Disease, NDMM Trials

Genomics, Immune

Profiling

Neha Korde

NDMM Clinical Trials

Digital Wearables

Supportive Care

Alex Lesokhin

RRMM Immunotherapy

TCE, Checkpoints

Inhibitors

Neoantigens

Microbiota, Immune

Profiling

Hani Hassoun

MM Supportive Care

Alliance Liaison

NDMM/RRMM Trials

Elderly and Frail

Sham Mailankody

RRMM Trials with

CAR T Cells

High-Risk Disease

Malin Hultcrantz

RRMM Trials in TCR

Antibody drug conjugates

Epidemiology

Presented by: Saad Z. Usmani, MD MBA FACP, @szusmani

MSKCC Myeloma TCT Program

Sergio Giralt

Allo/Auto HCT for MM

New Regimens

CAR T Cells

David Chung

T Cell exhaustion

Auto HCT + Vaccines

MM Immunotherapies

Gunjan Shah

HCT Toxicities

Precision Drug Dosing

CAR T Cells

Salvage Auto and Allo HCT

Saad Z. Usmani

High-Risk Disease Biology/Trials

CAR T Cells

Auto HCT for MM

Michael Scordo

HCT Toxicities

Precision Drug

Dosing

CAR T Cells

Heather Landau

Amyloidosis

HCT Toxicities

Homebound HCT

Precision Drug Dosing

Novel Regimens for Salvage

Auto

Oscar Lahoud

Auto HCT and CAR T Cells

Post HCT Therapies

Parastoo Dahi

Auto HCT and CAR T Cells

Post HCT Therapies

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