Best Myeloma Management in the Era of COVID - 19 by International Myeloma Foundation

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IMF Patient and Family Webinar Agenda

*times listed in US Pacific Time Zone

10:00 – 10:10 AM 10:10 – 10:30 AM

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

10:30 – 11:00 AM

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

Kevin Brigle 11:00 – 11:20 AM

Best Myeloma Management in the Era of COVID-19 Dr. Brian G.M. Durie

11:20 – 11:35 AM

Panel Discussion

11:35 – 11:45 AM

BREAK

IMF Patient and Family Webinar Agenda

*times listed in US Pacific Time Zone

11:45 – 12:15 PM

Immune Therapies: Treatments That Work With Our Own Immune Systems Dr. Noopur Raje

12:15 – 12:45 PM

Approaches to Relapse: What are current relapse options? Dr. Rafat Abonour

12:45 – 1:00 PM

Summary Panel Discussion Webinar Survey & Closing Remarks

IMF Patient and Family Webinar

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

Myeloma is treatable  Over 90% of patients respond to current therapies  Average first remission is 4 years or more

 In 2021, average survival is at least 7-10 years  Some patients live over 15-20+ years  New therapies are constantly improving the outlook 5

Myeloma Expert Consultation Helps!  Good to do early!

 Virtual consults more available.  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

IMF Patient and Family Webinar

Smoldering Myeloma

New SMM Risk Score Tool* 2/20/20 Model FLC Ratio Serum M Protein Bone Marrow Plasma Cell %

20 2 g/dl 20%

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

Coefficient

Odds Ratio (95% CI)

P-value

Score

0.69 0.96 1.56

1.99 (1.15, 3.45) 2.61 (1.36, 4.99) 4.73 (2.88, 7.77)

0.014 0.004 <0.0001

0 2 3 5

0.95 1.30

2.59 (1.56, 4.31) 3.65 (2.02, 6.61)

0.0002 <0.0001

0 3 4

0.57 1.01 1.57 2.00

1.77 (1.03, 3.06) 2.74 (1.6, 4.68) 4.82 (2.5, 9.28) 7.42 (3.23, 17.02)

0.04 0.0002 <0.0001 <0.0001

0 2 3 5 6

0.83

2.28 (1.53, 3.42)

<0.0001

Risk Score

Low Risk High Risk

*689 of the original 2286 had complete data for all risk factors. Logistic regression analysis was performed. Principal Investigators: Mateos; Kumar; San Miguel; Durie. International Myeloma Working Group risk stratification model for smoldering multiple myeloma (SMM) Blood Cancer J. 2020 Oct 16;10(10):102. doi: 10.1038/s41408-020-00366-3. https://www.nature.com/articles/s41408-020-00366-3

When Should Treatment Be Initiated? Potential New Myeloma or Smoldering Myeloma

Any Myeloma Defining Events? •CRAB •≥60% PC •FLC ≥100 •MRI >1 focal lesion

Treat as Myeloma

No Myeloma Defining Events (SMM)

High-Risk SMM (Median TTP ≈2 years)

Clinical Trials

Intermediate or Low-Risk SMM

Observation 9

HR-SMM: Management in 2021  • 

Low risk of progression Observe/ monitor Intermediate

•

Consider therapy

•

Options are trial/ 2/3/4 drugs 10

HR-SMM: Management in 2021  •

Ultra high risk (score ≥ 12) Therapy recommended with minimum of single agent (e.g. Revlimid®)

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

IMWG diagnostic criteria for multiple myeloma (Myeloma Defining Events)

*CRAB Criteria C

R A B

https://www.myeloma.org/resource-library/international-myeloma-working-group-consensus-criteria-response-minimal-residual

More Test Details  Bone marrow FiSH shows chromosome results

 MRI and PET/CT show more lesions than x-rays F

FISH

PET

MRI

F D

Colored spots show translocations: t(11;14) FiSH – Fluorescent in Situ Hybridization

PET F = Focal D = Diffuse

Managing Myeloma: The Components Transplant Eligible Patients

Transplant

Maintenance

Initial Therapy Transplant Ineligible patients

Consolidation/ Maintenance/ Continued therapy

Supportive Care

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

Treatment Combinations: Now and Then NEW

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

SCT VD/VRD

Front line treatment

Induction

OLD

Thal/Dex VAD DEX

Consolidation

SCT

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

Maintenance

Post consolidation

Nothing Prednisone Thalidomide

Relapsed

Rescue

Few options

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

Randomization N = 525 Newly diagnosed MM

• •

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

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

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

6 month of triplet followed by doublet Durie BGM, et al. ASH 2015

17 17

S0777 Trial: VRd vs Rd

41 months

OS 80% = 4 years Durie et al. Blood Cancer Journal (2020) 10:53 https://www.nature.com/articles/s41408-020-0311-8

55% = 7 years

18 18

What to Expect with Treatment First “biochemical” relapse

100% Deep first response

Myeloma protein level 50%

MRD Undetected

Second response

Later relapse from MRD undetected

Possible MRD undetected

5 years

10 years 19

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 20

MAIA Study: Dara + Rd for transplant-ineligible

https://www.myeloma.org/videos/overall-survival-results-daratumumab-lenalidomide-dexamethasone-transplant-ineligible-MAIA

Progression Free Survival (PFS) data 60-month PFS rate

% surviving without progression

100 80 52.5%

D-Rd: median, NR 28.7%

Rd: median, 34.4 months 20

HR, 0.53; 95% CI, 0.43-0.66; P <0.0001

0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66 69 Months No. at risk Rd 369 333 307 280 255 237 220 205 196 179 172 155 146 133 123 113 105 94 63 36 12 4 D-Rd 368 347 335 320 309 300 290 276 266 256 246 237 232 222 210 199 195 170 123 87 51 17

2 5

0 0

• D-Rd continued to demonstrate a significant PFS benefit, with median PFS not reached with D-Rd • These data provide a new PFS benchmark in patients with NDMM who are transplant ineligible

Overall Survival (OS) data 60-month OS rate 100

% surviving

66.3% D-Rd: median, NR

53.1%

Rd: median, NR 40 20

HR, 0.68; 95% CI, 0.53-0.86; P = 0.0013

0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66 69 72 Months No. at risk Rd 369 351 343 336 324 317 308 300 294 281 270 258 251 241 232 223 213 183 134 85 42 14 5 D-Rd 368 350 346 344 338 334 328 316 305 302 297 286 280 273 266 255 249 228 170 118 63 22 6

1 1

0 0

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 23

Treatment Options  Maintenance: used to sustain remission

•

Most common = Revlimid® ± Velcade®/ Ninlaro® (ixazomib)

Articles for Reference Durie B, et al. Blood Cancer Journal 2020 May 11;10(5):53. Longer term follow-up of the randomized phase III trial SWOG S0777: bortezomib, lenalidomide and dexamethasone vs. lenalidomide and dexamethasone in patients (Pts) with previously untreated multiple myeloma without an intent for immediate autologous stem cell transplant (ASCT) https://www.nature.com/articles/s41408-020-0311-8 Kumar S, et al. Leukemia. 2019; 33(7): 1736–1746. Ixazomib, lenalidomide, and dexamethasone in patients with newly diagnosed multiple myeloma: long-term follow-up including ixazomib maintenance https://www.nature.com/articles/s41375-019-0384-1 Usmani S, et al. Blood Cancer Journal 2018 Nov 23;8(12):123. Clinical predictors of long-term survival in newly diagnosed transplant eligible multiple myeloma - an IMWG Research Project https://www.nature.com/articles/s41408-018-0155-7



Treatment Strategies in 2021 Triplets or quadruplets in frontline



Maintenance based upon risk



Decisive early relapse treatment (triplets if feasible)



Earlier use of new immune therapies 25

Caregivers Need Care Too!

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

IMF Patient and Family Webinar

Kevin Brigle, PhD, ANP Massey Cancer Center, Virginia Commonwealth University, Richmond, VA

Life Is A Canvas, You Are The Artist: Side Effects & Symptom Management 29

Patient & Family Seminar August 14th, 2021

LIFE IS A CANVAS, YOU ARE THE ARTIST SIDE EFFECTS & SYMPTOM MANAGEMENT

Kevin Brigle, PhD, NP Virginia Commonwealth University Massey Cancer Center

Patient Education Slides 2021

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

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

• Allow for good quality of life

DISCUSS GOALS AND PRIORITIES WITH YOUR HEALTHCARE TEAM 31

COLOR WHEEL OF TREATMENT OPTIONS -Mibs

Frontline

Maintenance

Relapse

Velcade® (bortezomib)

-MAbs

-Mides

Steroids

Darzalex® (daratumumab)

Thalomid® (thalidomide) Revlimid® (lenalidomide)

Dexamethasone Prednisone Prednisolone SoluMedrol

Velcade® (bortezomib)

Kyprolis® (carfilzomib) Ninlaro® (ixazomib)

Others

Melphalan Cyclophosphamide

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

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

Dexamethasone Prednisone Prednisolone SoluMedrol

Melphalan Cyclophosphamide Bendamustine Pepaxto® (melphalan flufenamide) “Melflufen”

CelMods • Iberdomide • CC-92480

Neuropathy Carfilzomib: Cardiac

ImmunoTherapy

Cellular Therapies Melphalan + ASCT

Revlimid® (lenalidomide)

Pending FDA Approval

Noted Side effects

Alkylators

Infusion reaction

DVT/PE

See steroid slide

Myelosuppression

Blenrep® (Belantamab mafodotin) “Belamaf”

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

• Antibody Drug Conjugates • Bispecific Antibodies eg.  Teclistamab  Talquetamab  Cevostamab

Venclexta® (venetoclax)

Other CAR-T • Cilta-Cel

Infusion reaction Blenrep: Keratopathy

Myelosuppression, GI Selinexor: Low sodium

Infection risk CAR-T: CRS and neurotoxicity

Melphalan + ASCT Ide-Cel (CAR-T)

THE BRIGHT

DARK SIDE TO STEROIDS

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

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

(insomnia), fatigue

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

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

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

• Increased risk of

infections, heart disease

• Muscle

weakness, cramping

• Increased blood

pressure, water retention

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

hiccups, 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 highdose 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.240249. PMID: 28315528.

ADDITIONAL TOOLS TO COMPLETE THE PICTURE

Non-medication Therapies

Lifestyle Options

DVT/PE Prevention

Bone Health

Compression stockings

Radiation Surgery Immobilization Physical therapy

Activity Stop smoking Weight loss

Activity

Renal Health

Infection Prevention

Peripheral Neuropathy

GI Symptoms

Dialysis

Masking Activity

Massage Acupuncture Cocoa Butter

Dietary choices Relaxation

Hydration

Handwashing Avoid crowds & sick people Monitor for fever COVID precautions

Activity Diabetes management

Activity Hydration Avoid greasy foods

PATIENT-REPORTED SYMPTOMS 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

Psychological

• Fatigue

• Depression

• Constipation

• Anxiety

• Pain

• Sleep Disturbance

• Neuropathy

• Decreased Cognitive Function

• Impaired Physical Functioning • Sexual Dysfunction

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

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

• Decreased Role & Social Function

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

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

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

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

Physical

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

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

Fluid intake can help with both diarrhea and constipation and helps kidney function. Discuss GI issues with health care providers to identify causes and make adjustments to medications and supplements. 36

PAIN PREVENTION AND MANAGEMENT

Physical

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

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

• Interventions depends on source of pain • May include medications, activity, surgical intervention, radiation therapy, etc • Complementary therapies (Mind-body, medication, yoga, supplements, acupuncture, etc)

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

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

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

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

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

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

Physical

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

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

• Safe environment: rugs, furnishings, shoes

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

FATIGUE, ANXIETY & DEPRESSION

Physical Psychological

All can affect quality of life and relationships

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

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

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

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

essential to a healthful lifestyle

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 Rod NH et al 2014. PloS one. 9(4):e91965; Coleman et al. 2011. Cancer Nurs. 34(3):219-227. National Sleep Foundation. At: http://sleepfoundation.org/ask-the-expert/sleep-hygiene

Psychological

� Sleep hygiene is necessary for

quality nighttime sleep 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

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

FINANCIAL BURDEN Financial burden comes from

Funding and assistance may be available

• Medical costs

• Federal programs

• • • •

Premiums Co-payments Travel expenses Medical supplies

• Prescription costs

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

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

• Pharmaceutical support

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

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

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

IMF TV Teleconferences

eNewsletter: Myeloma Minute

Download or order at myeloma.org

IMF InfoLine 1-800-452-CURE 9am to 4pm PST 42

IMF Patient and Family Webinar

Best Myeloma Management in the Era of COVID-19 Brian G.M. Durie, MD Cedars-Sinai Outpatient Cancer Center Los Angeles, CA 43

Global cases of COVID-19 reported

Data from the CDC and WHO. The data includes cases as of August 13, 2021. https://covid.cdc.gov/covid-data-tracker/#global-counts-rates and https://covid19.who.int/

Overall U.S. COVID-19 Data Tracker

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

Delta Variant: Infections and Spread

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

Vaccination for Myeloma Patients  YES!!!  Impact of ongoing treatment unclear  Use common sense

 Antibody responses suboptimal 47

Vaccination for Myeloma Patients  Checking neutralizing antibody levels = OK! nd (if feasible at ~2-3 weeks post 2 dose) 

rd 3

(booster) dose approved by FDA

Which vaccine?  Pfizer/ Moderna – Excellent!

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

(slightly reduced)  Blood clot risk

100% reduction of hospitalizations and deaths

Masks – still required! Airborne transmission dominant Variants a serious challenge Beware asymptomatic spread

Watch out for young people! Still avoid travel Indoor space a severe problem 50

Masks – still required! So: use best masks possible – N95 or double (nose and mouth) Consider googles/ glasses – if risk situation Remember: antibody levels may be low post vaccination CDC: Your Guide to Masks https://www.cdc.gov/coronavirus/2019-ncov/prevent-getting-sick/about-face-coverings.html

What Can You Do Once You’re Vaccinated?

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

When you’ve been fully vaccinated

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

Patient Guidance Question: Can I go for a walk?

• Yes Question: Can I go to the dentist?

• Yes, with care 54

 

   

Common Issues Pandemic fatigue/ stress Not feeling resilient Healthcare team not coordinated Not prepared for Zoom or appointments Need electronic help! Contacts with unknown COVID-19 status 55

Pandemic Fatigue  Real for everyone!

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

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

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

What does the future hold?

 Vaccination essential.

 Masks required.  Caution in indoor spaces.

Other IMF Resources: Ask Dr. Durie Videos

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

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

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

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

against the Delta variant?

Support Group Virtual GoToMeetings

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

Support Group Virtual GoToMeetings

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

We will get through this together! Myeloma has no borders

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

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

Panel Discussion

Type and submit your questions here. Click the Q&A icon circled below if you have minimized the Ask Question window.

IMF Patient and Family Webinar

IMF Patient and Family Webinar Agenda

*times listed in US Pacific Time Zone

11:45 – 12:15 PM

Immune Therapies: Treatments That Work With Our Own Immune Systems Dr. Noopur Raje

12:15 – 12:45 PM

Approaches to Relapse: What are current relapse options? Dr. Rafat Abonour

12:45 – 1:00 PM

Summary Panel Discussion Webinar Survey & Closing Remarks

IMF Patient and Family Webinar

Noopur Raje, MD

Immune Therapies: Treatments That Work With Our Own Immune Systems

Massachusetts General Hospital Boston, MA

Immunotherapies: Treatments that work with our own immune system Noopur Raje, MD

Director, Center for Multiple Myeloma MGH Cancer Center Professor of Medicine Harvard Medical School

Disclosures • Consultant /Advisory Board: Celgene, Takeda, Amgen, Janssen, BMS, Merck, Bluebird, Immuneel, Caribou Biosciences • Research Funding: Astra Zeneca, Bluebird bio • Steering Committee: Amgen, Roche

Harnessing the immune system IMiD

ADCC, antibody-dependent cell-mediated cytotoxicity; ADPC, antibody-dependent cellular phagocytosis; BTZ, bortezomib; cADPR, cyclic ADP-ribose; CDC, complement-mediated cytotoxicity; Dex, dexamethasone; IMiD, Immunomodulatory imide drug; MAC, membrane attack complex; Mel, melphalan; MM, multiple myeloma; NAD, nicotinamide adenine dinucleotide; NAADP, nicotinic acid adenine dinucleotide phosphate; NK, natural killer.

68 Laubach JP, et al. Expert Opinion on Investigational Drugs 2014; 23:445–452.

Potential new immune strategies • New monoclonal antibodies: isatuximab

• Novel immunomodulators: iberdomide (CC220), CC-92480 • Conjugated antibodies

• Bispecific T cell engagers • Cellular therapy: CAR T cells, NK cells

69 CAR, chimeric antigen receptor; DC, dendritic cell; NK, natural killer; PVX, PVX-410 vaccine; SMM, smoldering multiple myeloma.

Precursor Disease States • Does the Immune System See Precursor Lesions ? • Does this recognition correlate with outcome ?

Continuous Lenalidomide vs Observation in Smoldering Multiple Myeloma Continuous lenalidomide (25 mg d1-21 of 28 d) vs observation in SMM using Mayo 2018 Risk Criteria (>20% plasma cells, M protein >2 gm/dL, serum-free light chain ratio >20)

High Risk

• • • •

Intermediate Risk

Decreased progression of high risk SMM to to MM 11.4% vs 3.4% secondary malignancies 51% discontinuation rate No OS difference

Low Risk

Myeloma Ag Specific Peptide-based Vaccination  Single Antigen Targeting Peptides-Polyfunctional responses: IFN-γ, cytotoxicity, proliferation, CD107a degranulation to patient MM cells and MM cell lines  Bae et al Blood 2006  Bae et al Blood 2007  Bae et al CCR 2010

 Vaccination Using Cocktail of Peptides

• •

Bae et al, BJH 2012; 157: 687-701. Bae et al, CCR 2012; 17:4850-60.

On Going Clinical Study of Multi-peptide Vaccination with Lenalidomide in Smoldering Myeloma – Immune responses to vaccine; lenalidomide and vaccine cohort enrolling

Vaccine Gradually Induces XBP1/CD138/CS1-Specific CTL in SMM patient Stimulator: XBP1us / XBP1sp / CD138 / CS1 Peptides Baseline (Wk 0)

Post-2 Vac (Wk 4)

Post- 6 Vac (1M FW)

Post- 6 Vac (3M FW)

Post-4 Vac (Wk 8)

SUMMARY Induction of XBP1/CD138/CS1 Peptides-Specific CTL by Vaccine

NOVEL CELMODS: Iberdomide Mechanism of Action •

Iberdomide enhanced in vitro immune stimulatory activity versus lenalidomide and pomalidomide1

Synergizes with bortezomib and daratumumab demonstrating enhanced apoptosis and antibody dependent cellular cytotoxicity 3 Induces NK cell proliferation and may help rescue NK cell depletion by daratumumab3

•

Lenalidomide2

Iberdomide2

IL-2 secretion by treated PBMCs

EC50, nM2

Ikaros

Aiolos

Lenalidomide

Pomalidomide

Iberdomide

0.5

Secreted IL-2 (ng/mL)

1,500

Lenalidomide Pomalidomide Iberdomide

1,000

500

MM cell survival in co-culture with treated PBMCs 120

Live Cells (% DSMO)

•

100 80 60 40

Lenalidomide Pomalidomide Iberdomide

Compound Concentration (nM)

1. Bjorklund C, et al. Unpublished 2. Adapted with permission from Matyskiela ME, et al. J Med Chem. 2018;61:535–42 © 2018 American Chemical Society. 3. Amatangelo M, et al. Blood. 2018;132(Suppl1): Abstract 1935.

CELMod CC-92480 and Dexamethasone in RRMM

BCMA as target for myeloma therapy BCMA Immunoglobulin BM Pro-B Pre-B Transitional

LN Naive

GC B

Memory Plasmablast

BM, LN

Short-lived PC

PC Long-lived PC

• • • • • •

• •

BCMA TACI BAFF-R

BCMA is an antigen expressed specifically on PCs and myeloma cells Cell surface receptor of TNF superfamily Higher expression in myeloma cells than normal PCs Not expressed in other tissues Key role in B-cell maturation and differentiation Promotes myeloma cell growth, chemotherapy resistance, and immunosuppression in the bone marrow microenvironment Expression of BCMA increases as the disease progresses from MGUS to advanced myeloma Additional ligands for BMCA include APRIL and TACI

77 APRIL, a proliferation-inducing ligand; BAFF-R, B-cell activating factor receptor; GC, germinal center; sBCMA, soluble BCMA; TACI, transmembrane activator and CAML interactor.

Cho SF et al., Front Immunol 2018;9:1821. Moreaux J et al. Blood 2004;103:3148-57. Sanchez E et al., Br J Haematol 2012;158:727-38.

BCMA-Targeted Immunotherapy in MM bb2121, LCAR-B38M, P-BCMA-101

BCMA CAR T bb21217 JCARH125 MCARH171 FCARH143 CT053 BCMA-CART Descartes-08

BCMA CAR T

BCMA-T Bi Ab

TNB-383B, PF-06863135, JNJ-64007957, EM801

T AMG 420; AMG 701

BCMA-BiTE

Apoptotic MM cells

MM cell lysis

GSK2857916, MEDI2228

BCMA-ADC M

AMG 224

NK , Monocyte

BCMA CD3 Cytotoxic granule (perforin, granzyme B)

Belantamab Mafodotin Targets BCMA Four mechanisms of action: 1. ADC mechanism 2. ADCC mechanism 3. Immunogenic cell death 4. BCMA receptor signaling inhibition

• Humanized, afucosylated IgG1 anti-BCMA antibody drug conjugate • Cytotoxic agent: MMAF (non-cell permeable, highly potent auristatin)

ADC

• Afucosylation enhances ADCC • Neutralizes soluble BCMA • Preclinical studies demonstrate its selective and potent activity ADCC=antibody-dependent cell-mediated cytotoxicity; BCMA=B-cell maturation antigen; IgG=immunoglobulin G; MMAF=monomethyl auristatin F. Tai YT, et al. Blood. 2014;123(20):3128–3138; Trudel S, et al. Abstract 741; Presented at ASH 2017; Atlanta, Georgia; Lancet Oncology. 2018.

BCMA BCMA

Lysosome

3 3 4

BCMA 4

BCMA

Fc receptor

Effector cell

• Linker stable in circulation

ADCC

Malignant plasma cell

Cell death

Overview of DREAMM-2 Study Design IDMC recommended study continue as planned to primary analysis

Randomize 1:1

Screening

N=99 Discontinue 1 arm if deemed inferior per protocol; patients to switch over to the other arm if eligible

Belantamab mafodotin 3.4 mg/kg Q3W

ORR futility analysis Belantamab mafodotin 2.5 mg/kg Q3W

N=97

*According to the 2016 IMWG Response Criteria by Independent Review Committee. Lonial S, et al. Lancet Oncol. 2020;21(2):207-221.

N=25/arm

Primary endpoint • ORR*

Treatment until PD or discontinuation for other reasons Secondary endpoints • • • • • •

CBR* PFS, DoR, TTR, TTP, OS Safety PK profiles ADAs against belantamab mafodotin PROs

Overview of DREAMM-2: Overall Response Rate 40 35

Response, %

ORR=31%

sCR CR VGPR PR

ORR=34%

25 20 15 10

• Overall IRC-assessed ORR (97.5% CI) • 2.5 mg/kg (n=97): 31% (20.8, 42.6) • 3.4 mg/kg (n=99): 34% (23.9, 46.0) • High concordance between IRC and INC assessment

5 0 2.5 mg/kg

3.4 mg.kg

CR=complete response; NE=not evaluable; ORR=overall response rate; PD=progressive disease; PR=partial response; sCR=stringent complete response; SD=stable disease; VGPR=very good partial response. Lonial S, et al. Lancet Oncol. 2020;21(2):207-221.

Overview of DREAMM-2: Efficacy Data - ProgressionFree Survival Based on IRC Assessment 1.0

Median PFS, mo (95% CI)

Proportion alive and progression free

Dose 0.8 0.6

2.5 mg/kg

2.9 (2.1, 3.7)

3.4 mg/kg

4.9 (2.3, 6.2)

0.4 0.2 0.0

At risk (censored), n 2.5 mg/kg 3.4 mg/kg

97 (0) 99 (0)

64 (24) 62 (24)

54 (33) 54 (32)

3 4 5 6 7 Time from randomization, months 34 (47) 45 (36)

29 (51) 38 (41)

27 (53) 36 (43)

22 (54) 29 (48)

14 (55) 10 (54)

5 (56) 4 (55)

1 (56) 3 (33)

0 (56) 0 (55)

BCMA bispecific antibodies in myeloma • Potential to overcome the limitations of immunosuppressive tumor microenvironment by redirecting T cells to kill tumor target cells

Mechanism of action of CC-93269 BCMA-TCB

• BCMA (B-cell maturation antigen, CD269) • IgG-like bispecific antibody (long serum half-life, retain Fc function):1–3 • • • •

Anti-BCMAxCD3 (Pfizer)4 Ab-957 (GenmabDuoBody/Janssen)1 CC-93269 (EngMab/Celgene)2,3 Bi-Fab5

• Non-IgG like BiTE® (better tissue penetrance, access to epitopes): • BI 836909 (Boehringer Ingelheim; AMG420,

BCMA, B cell maturation antigen; CTL, cytotoxic T cell; Ig, immunoglobulin; TCB, T-cell bispecific.

Amgen)6

-BCMA: bivalent high affinity binding -CD3 chain: monovalent low affinity binding

1.Pillarisetti K, et al. Abstract 2116; Presented at ASH 2016; San Diego, California; 2. Seckinger A, et al. Cancer Cell 2017;31:396–410; 3. Cho S-F, et al. Front Immunol 2018;9:1821; 4 Panowski SH, et al. Abstract 383; Presented at ASH 2016; San Diego, California; 5. Ramadoss NS, et al. J Am Chem Soc 2015;137:5288– 91; 6. Hipp S, et al. Leukemia 2017;31:1743–51.

CC-93269 KEY ENGINEERING CHARACTERISTICS • CC-93269 is a humanized 2+1 IgG1-based TCE that binds to BCMA on myeloma cells and to CD3ε on T cells, enabling specific and tight BCMAbinding1,2 Anti-BCMA (bivalent)1–5 Bivalent binding to BCMA in a 2+1 format for superior potency, tumor targeting, and retention

Anti-CD3ε (monovalent)1–5 Head‐to‐tail geometry of BCMA- and CD3ε-binding Fab domains using a flexible linker Heterodimeric FcγR-silent Fc1–6 No binding to Fc R and C1q to minimize infusionrelated reactions and binding to FcRn retained for IgG-like PK

• CC-93269 induces tumor regression in animal models of myeloma and promotes myeloma cell death in primary patient bone marrow aspirates1,2 BCMA, B-cell maturation antigen; CD3, cluster of differentiation 3; Fab, antigen-binding fragment; FcɣR, Fc gamma receptor, FcRn, neonatal Fc receptor; Ig, immunoglobulin; PK, pharmacokinetics; TCE, T cell engager.

Seckinger A, et al. Cancer Cell. 2017;31:396-410. 2. Vu DM, et al. Blood 2015;128;abstract 2998. 3. Klein C, et al. Cancer Res. 2017;77:abstract 3629. 4. Bacac M, et al. Clin Cancer Res. 2016;22:3286-3297. 5. Lehmann S, et al. Clin Cancer Res. 2016;22:4417-4427. 6. Schlothauer T, et al. Prot Eng Des Sel. 2016;29:457-466.

Best Overall Responsea (%)

CC-93269 PRELIMINARY EFFICACY 100 90 80 70

ORR 88.9%

sCR/CR VGPR PR

44.4

60 50

ORR 35.7% 7.1 7.1

40 30 20 10

ORR 0%

21.4

≤ 3 mg (n = 7)

3→6 mg and 6 mg (n = 14)

33.3 11.1

6→10 mg and 10 mg (n = 9)

Maximum Dose • In all patients (N = 30), the ORR was 43.3% with a sCR/CR of 16.7% • Among patients receiving 10 mg (n = 9), the ORR was 88.9% with a sCR/CR of 44.4% Data as of October 28, 2019. a Response as assessed by the investigator. CR, complete response; ORR, overall response rate (PR or better); PR, partial response; sCR, stringent complete response; VGPR, very good partial response.

10 mg

RESPONSE OVER TIME †

6→10 mg

• 11 of 13 responses are ongoing • 5 of 30 (16.7%) patients achieved an MRD-negative sCR/CR

† PD

6 mg

†

LTB

– Of 13 responding patients, 92.3% achieved MRD negativity (≤ 1/105) in the bone marrow on or before C4D1 by Euroflowa

PD † PD PD PD

HTB

3→6 mg

• Median time to first response was 4.1 weeks (range 4.0–13.1)

sCR/CR

≤ 3 mg

PD PD † PD

PD PD

VGPR

†

PD † Death

Ongoing

CC-93269 dose

MRD-negative

Time on Study (months) Data as of October 28, 2019. MRD negativity by Euroflow analysis was reported only if a minimum sensitivity of ≤ 1 tumor cell in 105 nucleated cells was achieved and in patients who had ≥ 1 baseline and ≥ 1 post-baseline MRD assessment. HTB, high tumor burden (defined as > 50% bone marrow plasma cells or > 5 extramedullary lesions); LTB, low tumor burden (defined as ≤ 50% bone marrow plasma cells and ≤ 5 extramedullary lesions); MR, minimal response. a

Preliminary Safety, Efficacy, Pharmacokinetics, and Pharmacodynamics of Subcutaneously (SC) Administered PF-06863135, a B-Cell Maturation Antigen (BCMA)–CD3 Bispecific Antibody, in Patients With Relapsed/Refractory Multiple Myeloma (RRMM) Alexander M. Lesokhin, Moshe Y. Levy, Andrew P. Dalovisio, Nizar J. Bahlis, Melhem Solh, Michael Sebag, Andrzej Jakubowiak, Yogesh S. Jethava, Caitlin L. Costello, Michael P. Chu, Michael R. Savona, Cristina Gasparetto, Suzanne Trudel, Jeffrey Chou, Chandrasekhar Udata, Cynthia Basu, Heike I. Krupka, and Noopur S. Raje Poster # 3206 Presented at the American Society of Hematology Annual Meeting 2020 (ASH Virtual), December 5-8, 2020

Background and study objectives •

PF-06863135 (PF-3135) is a full-length, humanized, bispecific antibody (IgG2a) targeting BCMA (highly expressed on multiple myeloma cells) and CD3 (on T cells).1

•

IV dosing of PF-3135 was previously evaluated at 0.1–50 μg/kg once weekly in a phase I, dose-escalation study, with preliminary evidence of anti-myeloma activity in RRMM.2

•

In this part of the study (NCT03269136), we evaluated SC administration of PF-3135 in patients with RRMM, with the intent to achieve a wider therapeutic window. •

Primary objectives of dose escalation were to assess safety and tolerability of PF-3135 administered SC, to determine the maximum tolerated dose and select the recommended phase II dose.

•

Secondary objectives included evaluation of anti-myeloma activity, pharmacokinetics, and pharmacodynamics of PF-3135 administered SC.

1. Panowski SH, et al. Blood 2016;128:383; 2. Raje NS, et al. Blood 2019;134(suppl.1):1869. BCMA=B-cell maturation antigen; RRMM=relapsed/refractory multiple myeloma.

Treatment duration and IMWG response The response rate was 80% (16/20 patients) at the 215 μg/kg to 1000 μg/kg dose levels.

pBCMA: patients had received prior BCMA-targeted therapy. Numbers at the end of bar represent the best percent change in S:serum m-spike if a patient met inclusion criteria serum m-spike ≥ 0.5 g/dL and had not taken daratumumab within 114 day before C1D1 or otherwise F:delta FLC (free light chain). C1D1=cycle 1 day 1; CR=complete response; IMWG=International Myeloma Working Group; MR=minimal response; PD=progressive disease; PR=partial response; sCR=stringent complete response; SD=stable disease; VGPR=very good partial response.

(N of prior regimens), best unconfirmed response

•

Five anti-BCMA bispecific antibodies presented at ASH 2020

Nearly all patients had prior anti-CD38 antibody across these trials Responses shown for: CC-93269: 10 mg dosing, IV weekly (ASH 2019) Teclistamab: recommended phase 2 dose, SC weekly AMG 701: most recent evaluable cohort, IV weekly REGN5458: DL6, IV weekly TNB-383B: 40-60 mg IV q3 weeks Elranatamab (PF-06863135): 215-1000 μg/kg SC

Neurotoxicity (%)

Response rate (%)

CRS (%)

Grade 3+ Grade 1-2

Grade 1-2 neurotoxicity only

Promising responses in patients with ”triple-class exposed” disease, with associated CRS toxicities

Chimeric antigen receptors (CAR) and CAR-T technology • CARs are engineered transmembrane receptors with two distinct functional components: • Antibody fragment or target binding domain that recognizes targets on the surface of cancer cells • Signaling domains that rapidly and powerfully activate the T cell to attack and kill cancer cells

• CAR structure: – Extracellular domain: antibody domain (scFv) against a tumor antigen – Transmembrane domain – Intracellular domain:  First generation CARs: CD3ζ (T cell coreceptor necessary for T cell activation)  Second generation CARs: CD3ζ + either CD28 or 4-1BB (costimulatory domain)  Third generation CARs to come: CD3ζ + two costimulatory domains (CD28, 4-1BB, OX40, ICOS, CD27)

92 CAR, chimeric antigen receptor.

Maus and Levine The Oncologist 2016; Li and Zhao Protein Cell 2017; Chang and Chen Trends Mol Med 2017; Brudno JN & Kochenderfer N. Nat Rev Clin Onc 2018;15:31–46.

How are CAR T cells manufactured?

93 CAR, chimeric antigen receptor; CT, computed tomography; RT-PCR, reverse transcriptase polymerase chain reaction.

Jacobson CA and Ritz J. Blood 2011; 118:4761–4762.

Idecabtagene vicleucel (ide-cel; bb2121) BCMA CAR T-cell construct design Extracellular domain Targeting domain Hinge / TM domain

Anti-BCMA

CD8 hinge / TM domain

Intracellular domain Co-stimulatory domain T-cell activation domain

Ide-cel CAR design MND SP

Anti-BCMA scFv

CD8

4-1BB

Tumor-binding domain

CD3ζ

Ide-cel is a 2nd-generation CAR construct CD3 ζ

Linker

Promoter

4-1BB

Signaling domains

• Autologous T cells transduced with a lentiviral vector encoding CAR specific for BCMA 4-1BB associated with less toxicity and more • Targeting domain: anti-BCMA durable CAR T-cell persistence than CD28 • Co-stimulatory domain: 4-1BB costimulatory domain • T-cell activation domain: CD3 ζ

Raje NS, et al. J Clin Oncol 2018;36:8007. Presented at ASCO 2018.

Slide 3

95 Presented By Nikhil Munshi at TBD

Best Overall Response

96 Presented By Nikhil Munshi at TBD

Progression-Free Survival

97 Presented By Nikhil Munshi at TBD

Cilta-cel is the same construct as LCAR-B38M Development for LCAR-B38M occurred in China; LEGEND-2 study initially presented at ASCO 2017

LCAR-B38M JNJ-68284528 Ciltacabtagene autoleucel

Cilta-cel

Ide-cel (bb2121)

128

Dose

0.75 × 106 cells/kg

450 × 106 cells

150-450 × 106 cells

Median prior lines

6 (3-18)

6 (3-16)

Triple-class refractory

88%

81%

84%

ORR

96.9%

81%

73%

MRD−

54.6%

48%

39%

≥CR

67%

39%

33%

PFS

76.6% at 12 months

12.1 months

8.8 months

ASH 2020

ASCO 2020

Triple-class = at least 1 PI, 1 IMiD, and 1 anti-CD38 antibody MRD− at 10−5 sensitivity by NGS of all treated patients

Anti-BCMA CAR T-cell therapy achieves deep responses in relapsed/refractory multiple myeloma

Cilta-cel

Ide-cel (bb2121)

54*

CRS

94.8%

96%

≥3

5.2%

Tocilizumab

69.1%

67%

Corticosteroids

21.6%

22%

Anakinra

18.6%

ASH 2020

ASCO 2020

Cilta-cel

Ide-cel (bb2121)

54*

Neurotoxicity

20.6%

20%

10.3%

12.4%

Not reported

9.3%

Not reported

ASH 2020

ASCO 2020

≥3 Other (not ICANS)† ≥3

†Other includes movement, neurocognitive changes, nerve palsy, peripheral motor neuropathy

*Target dose of 450M cells

Promising responses and PFS, but await further follow up of “late” neurotoxicities with cilta-cel

Multiple anti-BCMA CAR T-cell therapies in clinical trials, presented at recent meetings

Main differences relate to how they bind to BCMA, manufacturing Too early to know which one is better Different stages in clinical development Ide-cel now approved in March 2021 A different approach: ALLO-715, ”off-the-shelf” allogeneic CAR T-cells; cells manufactured from healthy donors

100

Targeting BCMA may be is a new standard Antibody drug conjugate

Bispecific antibody

CAR T-cell

Approved product

Belantamab mafodotin (August 2020)

Several in phase II

Ide-cel (March 2021)

Efficacy

++ (as single agent; higher in combinations)

+++

++++

How given

IV, q3 weeks, until progression

IV or SC, weekly or q2 weeks until progression

One-and-done

Where given

Community

Academic medical centers

Notable adverse events

Ocular (corneal)

CRS and neurotoxicity

CRS

Not seen

+++

Neurotoxicity

Not seen

Availability

Off-the-shelf; after ophthalmology evaluation

Off-the-shelf

Wait time for manufacturing

101

Mechanisms of resistance to anti-BCMA CAR T cell therapy in MM CAR-T cell intrinsic

Lack of persistence T cell exhaustion

MM cell intrinsic

Microenvironment

BCMA loss BCMA downregulation

This figure was created using Servier Medical Art templates, https://smart.servier.com. Licensed under a Creative Commons Attribution 3.0 Unported License.

Immunesuppressive ligands/molecules

102

bb21217 = bb2121 cultured with PI3 kinase inhibitor

Slide from Shah N et al., ASH 2018

103

Current Understanding and Future Directions • BCMA is a promising target • Conjugates, T cell engagers and cellular products all show efficacy • Future will be to define how to combine /sequence these • Next generation approaches will focus on improving efficacy and DOR

104

Acknowledgements

Our Patients nraje@mgh.harvard.edu @NoopurRajeMD

105

IMF Patient and Family Webinar

Approaches to Relapse: What are current relapse options? Rafat Abonour, MD Indiana University School of Medicine Indianapolis, IN

106

How Do I Treat Relapsed 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

When should we treat relapsed disease? • At biochemical relapse? • When myeloma protein starts rising! • When involved free light chain starts rising! • At Clinical relapse? • CRAB criteria (Anemia, kidney failure, high calcium or new bone disease) • Extramedullary disease (myeloma growing at tumors outsides the bone) 108

When should we treat relapsed disease? • We do not know, but we can speculate! • Most approved treatment in relapsed myeloma were based on biochemical relapse. • Some observations support better outcome when treating biochemical relapse: • Mayo clinic showed better overall survival when treating biochemical relapse (median 125 vs 81 months)

109

Pros and Cons of treating Biochemical Relapse • Con: • 25% of biochemical relapse patients will have a smoldering course. No progression for 2 years. • Pros: • Median time between biochemical relapse and clinical symptoms is about 5-6 months. • If you do not get it right at first relapse you may not get it right at subsequent relapses

110

Response Duration Decreases with each relapse

Median response duration (months)

0 First

Second

Third

Fourth

Treatment Regimen

Fifth

Sixth

111

Genomic Heterogeneity Affects the Course of MM • Most patients with MM have multiple distinct subclonal populations as a result of the expansion of genetically different myeloma cells; this causes intratumoral heterogeneity1 • MM is clonally heterogeneous at diagnosis and throughout treament2 • The genomic heterogeneity of MM contributes to treatment resistance and relapse3 • Wide variety of mutations found within •

Evolution of Clonal Populations of Myeloma Cells 4

a single patient may result in treatment resistance and refractory disease1,3,4 Furthermore, subclones continually mutate over time, including after treatment, which may contribute to resistance and result in disease progression1,5 Republished with permission of American Society of Hematology, from Keats JJ et al. Blood. 2012;120(5):1067-1076; via Copyright Clearance Center, Inc.

112 1. Bolli N et al. Nat Commun. 2014;5:2997. 2. Walker BA et al. Leukemia. 2014;28(2):384-390. 3. Kyrtsonis M et al. Appl Clin Genet. 2010;3:41-51. 4. Keats JJ et al. Blood. 2012;120(5):1067-1076. 5. Abdi J et al. Oncotarget. 2013;4(12):2186-2207.

Clonal heterogeneity in English • Myeloma cells in each patients are a family of odds and aggressive members • The longer this family sticks around the odder and more aggressive it becomes • Family therapy is not going to work, you can not be politically correct here, eradicate them early. • This is making the case for early treatment and with combination regimen 113

Factors influencing the choice of therapy at Relapse • Disease related • Regimen related • Patients related

114

Disease related Factors • Clinical features associated with relapse (elevated calcium, renal failure, anemia, bone lesions) • Expanding or new plasmacytomas or hyperviscosity • High-risk cytogenetics • Extramedullary disease or plasma cell leukemia • High ISS stage

115

Regimen-related Factors • Previous treatment and dose • Duration of prior response • Side effects, tolerability, and toxicity of prior treatment(s) and treatment combinations • Depth and duration of previous transplant

116

Patient-related Factors • Performance status • Patient comorbidities • Transplant eligibility • Frailty • Patient preference • Cost/socioeconomics

117

Currently available Anti-Multiple Myeloma Agents Steroids

Conventional Chemo

ImIDs

Proteasome Inhibitors

HDAC inhibitor

Immunologic approaches

XPO inhibitor

Prednisone

Melphalan

Thalidomide

Bortezomib

Panobinostat

Daratumumab (anti-CD38)

Selinexor

Dexamethasone

Cyclophosphamide

Lenalidomide

Carfilzomib

Isatuximab (anti-CD38)

Doxorubicin

Pomalidomide

Ixazomib

Elotuzumab (anti-CS1)

Belantamab DCEP/D-PACE

(anti-BCMA + MMAF)

ABECMA METRO28 Carmustine Bendamustine

Melflufen

118 INDIANA UNIVERSITY SCHOOL OF MEDICINE

How does your oncologist decide what to do?

This is a very short menu

119

How does your oncologist decide what to do? This is not a very short menu

GREAT NEWS WE HAVE OPTIONS BAD NEWS YOUR DOCTOR MAY GET CONFUSED

120

Mayo Practical Approach- First Relapse

121

Mayo Practical Approach- 2nd/ later Relapse

122

Combination is Better. Multicenter, randomized (1:1), open-label, active-controlled, phase 3 study

DRd (n = 286) Key eligibility criteria • RRMM • ≥1 prior line of therapy • Prior lenalidomide exposure, but not refractory • Creatinine clearance ≥30 mL/min

Stratification factors

R A N D O M I Z E

Daratumumab 16 mg/kg IV • Qw in Cycles 1 to 2, q2w in Cycles 3 to 6, then q4w until PD R 25 mg PO • Days 1 to 21 of each cycle until PD d 40 mg PO • 40 mg weekly until PD 1:1

Rd (n = 283) R 25 mg PO • Days 1 to 21 of each cycle until PD d 40 mg PO • 40 mg weekly until PD

• PFS Secondary endpoints • TTP • OS • ORR, VGPR, CR • MRD • Time to response • Duration of response Statistical analyses

• No. of prior lines of therapy • ISS stage at study entry

Primary endpoint

Cycles: 28 days

• Primary analysis: ~177 PFS events

• Prior lenalidomide

Pre-medication for the DRd treatment group consisted of dexamethasone 20 mg,a acetaminophen, and an antihistamine ISS, international staging system; DRd, daratumumab/lenalidomide/dexamethasone; IV, intravenous; qw, weekly; q2w, every 2 weeks; q4w, every 4 weeks; PD, progressive disease; R, lenalidomide; PO, oral; d, dexamethasone; Rd, lenalidomide/dexamethasone; PFS, progression-free survival; TTP, time to progression; OS, overall survival; ORR, overall response rate; VGPR, very good partial response; CR, complete response; MRD, minimal residual disease. aOn daratumumab dosing days, dexamethasone 20 mg was administered as pre-medication on Day 1 and Day 2.

123

POLLUX updated analysis: PFS (time without relapse is much better with 3 drugs....)

% surviving without progression

Progression-free survivala 100

30-month PFSb

58%

DRd Median: not reached 35%

Rd Median: 17.5 months

HR 0.44; 95% CI, 0.34-0.55; P <0.0001 0

No. at risk Rd DRd

12 15 18 21 24 27 30 33 36 39 42 Months

283 249 206 181 160 143 126 111 100 89 80 36 286 266 249 238 229 214 203 194 183 167 145 67

5 16

1 2

0 0

Median follow-up: 32.9 months (range, 0 - 40.0 months) 56% reduction in risk of progression/death for DRd versus Rd HR, hazard ratio; CI, confidence interval. aExploratory analyses based on clinical cut-off date of October 23, 2017; bKaplan-Meier estimate.

124 Dimopoulos MA, et al. Presented at ASH 2017 (Abstract 739), oral presentation.

Time From Last Line of Therapy to Study Treatment of > or ≤12 Months >12 Months: Late relapses 18-month PFSa

100

% surviving without progression

83% 80

DRd

60% 60

Rd 40

HR: 0.37 (95% CI: 0.23-0.61; P <0.0001)

0 0

139 133

123 127

111 122

No. at risk Rd >12 DRd >12

149 140

12 15 Months

103 118

26 44

4 9

0 1

0 0

88 109

DRd is superior to Rd regardless of time since last therapy aKaplan-Meier

estimate. population.

bResponse-evaluable

Moreau P, et al. Presented at ASH 2016 (Abstract 1151), oral presentation

125

Isatuximab: CD38 antibody Median PFS, mos 100

PFS (%)

80 60 40 20

Isatuximab-Pd Pd 11.53 6.47

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 No. at risk Mos 314 1 Isa-Pd 154 129 106 89 81 52 153 80 105 63 51 33 17 5 0 Pd

HR: 0.596 (95% CI: 0.4360.814); P = .001

PFS HR (95% CI)  Len refractory: 0.59 (0.43-0.82)  Len refractory in last line: 0.50 (0.340.76)  Len / PI refractory: 0.58 (0.40-0.84)

• Phase III ICARIA-MM: Isatuximab + Pom/Dex vs Pom/Dex in R/R MM • FDA approved isatuximab in combination with Pd for patients with R/R MM who had received ≥ 2 previous lines of treatment, including lenalidomide and a PI

126 INDIANA UNIVERSITY SCHOOL OF MEDICINE

Anti-Multiple Myeloma Novel Immunotherapeutic Agent Structures Antibody Drug Conjugate

T-Cell Bispecific Antibody

T-Cell Trispecific Antibody

Designed ankyrin repeat proteins (DARPins)

Lancman, et al. ASH 2020.

127 INDIANA UNIVERSITY SCHOOL OF MEDICINE

Comparison of Novel Immunotherapeutic Approaches Pros

Chimeric antigen receptor T cells (CAR-T)

Bispecific antibodies

Antibody-drug conjugates

Unprecedented ORR including MRD neg in heavily pre-treated patients

Off the shelf

Deep responses

Encouraging response rates

Limited severe CRS - ? Safety in frail elderly

1 hour infusion every 3 weeks

One time intervention; long chemo holiday resulting in median PFS ~1 year

Cons

Manufacturing time makes impractical for patients with aggressive/rapidly progressing disease Requires complex infrastructure – stem cell lab, RN/ ICU/ER training – thus restricted to accredited centers CRS ? role in frail elderly Impact of bridging chemo on remission duration

Can be given in community settings after 1st cycle ? Need for admissions with initial doses until CRS risk low

No CRS, can be given in community settings Ocular toxicity – requires close collaboration with opthamology & impact on pt quality of life

Dosing/schedule to be determined

Thrombocytopenia

Need for continuous treatment until progression

Toxicities require further study – Modest ORR and PFS in triple infections, neurotoxicty class/penta refractory

Low WBC and plts post CAR-T Cost given relapses even in MRD neg patients; mgmt. challenging especially if soon after flu/cy given impact on T cells

Lancman, et al. ASH 2020.

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BCMA (B-cell maturation antigen) • Receptor for BAFF and APRIL • Expressed on mature B cell subsets, PC’s, and plasmacytoid DC’s • Maintains plasma cell homeostasis • BCMA-/- mice have normal B cell #s, impaired PC survival

Hengeveld et al Bl Cancer J 2015 ; Maus, June, Clin Can Res 2013

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Belantamab Mafodotin: BCMA-Targeted ADC Four mechanisms of action:

• Belantamab mafodotin (GSK2857916): Humanized, afucosylated, IgG1 BCMA-targeted ADC that neutralizes soluble BCMA

1. 2. 3. 4.

ADC ADCC Immunogenic cell death BCMA receptor signaling inhibition ADC

• Preclinical studies demonstrate selective, potent activity

1 1

Belantamab Mafodotin

BCMA BCMA

Afucosylation

Linker

–MMAF (non–cell-permeable, highly potent auristatin) –Enhanced ADCC –Stable in circulation

ADCC

Lysosome

BCMA

Effector cell 2

4 BCMA

Cytotoxic agent

Fc receptor

Malignant plasma cell

Cell death

Tai. Blood. 2014;123:3128. Trudel. Lancet Oncol. 2018;19:1641. Trudel. Blood Cancer J. 2019;9:37.

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Belantamab Mafodotin

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BCMA Antibody Drug Conjugates Study Phase

DREAMM-1

DREAMM-2

DREAMM-4

DREAMM-6

MEDI2228

I/II

Belamaf dose (OP-106): Belamaf Belamaf Belamaf 2.5 mg/kg MEDI2228 (BCMAHORIZON Updated Efficacy and escalation, 2.5 or 3.4 mg/kg 2.5 or 3.4 mg/kg + bortezomib-dex Ig-DNA crossexpansion 3.4 + pembrolizumab linking Safety of Melflufen in Relapsed/Refractory mg/kg pyrrolobenzodiaze pine (PBD) dimer ) Multiple Myeloma Refractory to Daratumumab Patients n=35 n=196 n=13 n=18 n= 82 Median prior lines 5 6-7 8/ 5 3 range 2-11 and/or Pomalidomide Triple-class refractory 37% 100% NR NR NR (100% Treatment (All are IV q 3wk)

ORR % PFS

exposed) Paul G. Richardson, MD1; Albert Oriol, MD2; Alessandra Larocca, MD3; Paula Rodriguez Otero, MD4; Maxim Norkin, MD5; 60% (38.5% if prior 31% / 34% 67% / 14% 78% 61% (25/41) Joan Bladé, MD6; Michele Cavo, MD7; Hani Hassoun, MD8; Xavier Leleu9; Adrián Alegre, MD10; Christopher Maisel, MD11; dara12exposure) (0.14 mg /kg) Agne Paner, MD ; Amitabha Mazumder, MD13; Jeffrey A. Zonder, MD14; Noemí Puig, MD15; John Harran, BSN1; 16; Sara Thuresson, MSc16; Hanan Zubair, MSc16; and Maria-Victoria Mateos, MD, PhD15 Johan Harmenberg, MD(6.8 12 months 2.9 / 4.9 months NR NR NR months if prior 1Dana-Farber Cancer Institute, dara) Harvard Medical School, Boston, MA, USA; 2Hospital Germans Trias i Pujol, Badalona, Spain; 3A.O.U. Città della Salute e della Scienza di Torino - S.C. Ematologia U, Torino, Italy; 4Clínica Universidad de Navarra, Pamplona, Spain; 5University of Florida Health Cancer Center,

AEs- all grade (gr3+) FL, USA; 6Hospital Clínica de Barcelona - Servicio de Onco-Hematología, Barcelona, Spain; 7Policlinico S. Orsola Malpighi, Bologna, Italy; Gainesville, 8Myeloma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; 9CHU de Poitiers, Poitiers, France; 10Hospital Keratopathy 52% (3%) 70% (27%)/ 75% (21%) 67% (33%) 100% (56%) 0% Universitario La Princesa, Madrid, Spain; 11Baylor Scott & White Charles A. Sammons Cancer Center, Dallas, TX, USA; 12Rush University Medical Center, Thrombocytopenia 63% (35%) 35% (20%)/ 58% (34%) 67% (61%) 32% (NR) Chicago, IL, USA; 13 The Oncology Institute of Hope and Innovation, Glendale, CA, USA; 14Karmanos Cancer Institute, Detroit, MI, USA; 15Hospital Clinico 16 Anemia 28% Universitario (17%) 24% (20) / Salamanca, 37% (25%)Spain; and 50% (0%) de Salamanca, Oncopeptides AB, Stockholm, Sweden Infusion reaction 12% (3%) 21% (3%) / 16% (1%) 17% (0%) Photophobia 54% Phase 3 DREAMM studies recruiting: 3: Blmf vs Pd, 7: BlmfVd vs DVd, 8: BlmfPd vs VPd Other Dry eye 20% Rash (29%) Trudel, et al. Blood Cancer J 2019; Lonial, et al. Lancet Oncol 2019; Nooka, et al. Hematology Reports 2020;; Popat, et al. ASH 2020; Kumar, et al. ASH 2020 Pleural eff (20%)

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Melflufen Is a Lipophilic Peptide-Conjugated Alkylator That Rapidly Delivers a Highly Cytotoxic Payload Into Myeloma Cells Peptidase-enhanced activity in multiple myeloma cells Peptidases are expressed in several cancers, including multiple myeloma1-3

Melflufen is rapidly taken up by myeloma cells due to its high lipophilicity4,5

Melflufen rapidly induces irreversible DNA damage, leading to apoptosis of myeloma cells4,8

Melflufen Once inside the myeloma cell, melflufen is immediately cleaved by peptidases5-7

pFPhe (carrier) Peptidase Alkylator payload

The hydrophilic alkylator payloads are entrapped5-7

Melflufen is 50-fold more potent than melphalan in myeloma cells in vitro due to increased intracellular alkylator activity4,5 1. Hitzerd SM, et al. Amino Acids. 2014;46:793-808. 2. Moore HE, et al. Mol Cancer Ther. 2009;8:762-770. 3. Wickström M, et al. Cancer Sci. 2011;102:501-508. 4. Chauhan D, et al. Clin Cancer Res. 2013;19:3019-3031. 5. Wickström M, et al. Oncotarget. 2017;8:66641-66655. 6. Wickström M, et al. Biochem Pharmacol. 2010;79:1281-1290. 7. Gullbo J, et al. J Drug Target. 2003;11:355-363. 8. Ray A, et al. Br J Haematol. 2016;174:397-409.

Richardson PG, et al

EHA 2019

#S1605

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Rapid response in highly resistant myeloma Best Response (%)

Best Response (IMWG1) 100 36

80 46

60 40 20

SD MR PR VGPR sCR

ORR CBR 55%

ORR 28%

9 ITT (n=113)

40%

49 CBR 64%

14 5 Double-Class Refractory a

ORR 22%

15 8 Anti-CD38 Refractory (n=89)

(PI + IMiD incl POM)

CBR 33% ORR

20%

11 12 8

CBR 32%

Triple-Class Refractory (n=83)

(n=22)

• 8 pts did not have available response information at data cutoff; 2 pts response evaluable, PI exposed, but refractoriness to PI subject to confirmation, so excluded from subgroup analysis • One pt with sCR also confirmed as MRD negative (10-6 sensitivity), with ongoing progression-free period of 13.6 mos • Median time to response 1.2 mos aNot

1. Rajkumar SV, et al. Blood. 2011;117:4691-4695.

anti-CD38 refractory.

Data cutoff 06 May 2019.

Richardson PG, et al

EHA 2019

#S1605

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Best therapy for Relapse

• • • • •

Not all relapses are the same. Combination therapies provide better outcomes. Available drugs and combinations are increasing. The optimal therapy is the one based on your needs. We need to get right at first relapse.

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Summary Panel Discussion

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IMF Patient and Family Webinar

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IMF Patient and Family Webinar

Closing Remarks

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Thank you to our sponsors!

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