IMF In-Person Regional Community Workshop (RCW) - San Diego

Thank you for joining us today!

March 4, 2023, International Myeloma Foundation’s Regional Community Workshop

San Diego

Thank you to our sponsors!

IMF REGIONAL COMMUNITY WORKSHOP

March 4, 2023, Agenda

9:00 – 9:15 AM Welcome and Announcements

Kelly Cox, Director of Support Groups, Senior Director Regional Community Workshops

9:15 – 10:15 AM Myeloma 101 & Frontline Therapy

Caitlin Costello, MD, University of California San Diego

10:15 – 10:30 AM Q&A with Panel

10:30 – 11:15 AM Maintenance Therapy

David Vesole, MD, PhD, FACP - MedStar Georgetown University Hospital

11:15 – 11:30 AM Q&A with Panel

11:30 – 12:15 PM Relapsed Therapy

David Vesole, MD, PhD, FACP - MedStar Georgetown University Hospital

12:15 – 12:30 AM Q&A with Panel 12:30 – 1:15 PM LUNCH BREAK

March 4, 2023, Agenda

1:15 – 2:00 PM Clinical Trials

David Vesole, MD, PhD, Medstar Georgetown University Hospital

2:00 –

2:15 PM Q&A

2:15 –

3:00 PM Life is a Canvas, You are the Artist

Sandra Rome, RN, MN, AOCN, CNS, Cedars-Sinai Medical Center, IMF Nurse Leadership Board

3:00 –

3:15 PM Q&A

3:15 –

3:30 PM Local Patient & Care Partner Panel

Tom Tucker, Patient Advocate and Helen Tucker, Care Partner

3:30 – 3:40 PM Q&A

3:40 – 3:55 PM Community Resource

3:55 – 4:00 PM Closing Remarks

4:00 PM Coffee / Network

Multiple Myeloma affects patients and families

. The IMF provides FREE resources to help both patients and families.

Established in 1990, the IMF’s InfoLine assists over 4600 callers annually and answers questions across a wide variety of topics including:

Frequent topics:

ü Newly Diagnosed MM/Myeloma 101

ü Treatment Options

ü Transplant

ü Maintenance

ü Side Effects

ü Relapsed/Refractory MM

ü Clinical Trials

ü Resources for Drug Access/Financial Support/Local Support

ü Referrals to Myeloma Specialists Within/Outside the US

ü Health Issues Related to Myeloma

ü Caregiver Support

Paul Hewitt, Missy Klepetar, and Deb

Educational Publications

edge education to the myeloma community.

Myeloma 101 and Frontline Therapy Caitlin Costello, MD

University of California San Diego

Objectives

The Basics of Blood

• The blood is an “organ” made up of both cells and liquid “plasma”

Think of wine (red/white/rose)

1. Red Cells – carry Oxygen…trucks

2. White Cells – immune system…army

3. Platelets – help with clotting…ambulance

All produced in the blood factory = Bone Marrow

What is Multiple Myeloma?

Multiple Myeloma* is a blood cancer that starts in plasma cells from the center of bones (bone marrow).

This is where stem cells mature into red blood cells, white blood cells, and platelets

Myeloma cells are abnormal plasma cells that make an abnormal antibody called “M protein”

M = monoclonal (“identical” or cancerous)

* Myeloma is NOT a bone cancer or skin cancer (melanoma), it is a type of blood cancer.

The “Microenvironment” is Key To Myeloma Cell Survival

Myeloma Cell JAK – STAT

MAPK

NFkB AKT SHP2 MEK MEK/MAPK

Angiogenesis Migration Growth

T Cells NFkB – IkB complex Protein kinases LFA1 FADD cFLIP Cell organelles Fibronectin cFLIP/FADD NFkB BindingSite IL-6 TNFα VLA4 VCAM1 NFkB NFkB – IkB complex Myeloma

NFkB

BM Stromal Cells

Increase in cytokine production and adhesion molecules

Dendritic Cells

Natural-Killer Cells TNFα

Inhibition of Anti-Myeloma Immunity

Monocytes

Myeloma Is a Cancer of Plasma Cells

• Cancer of plasma cells

• Healthy plasma cells produce immunoglobulins G, A, M, D, and E

• Myeloma cells produce abnormal immunoglobulin

“paraprotein” or monoclonal protein (=M protein)

Bone marrow of patient with multiple myeloma

Image courtesy of American Society of Hematology

Kyle et al. Mayo Clin Proc. 2003;78:21-33;

FAST STATS

1.8% of all cancers;

17% of hematologic malignancies in the United States

Most frequently diagnosed in ages 65 to 74 years (median, 69 years)

The average age of diagnosis of 4-5 years younger in African American and Hispanic patients

Multiple Myeloma Snapshot

National MM Statistics

Approx 35,000 Estimated New Cases in 2022

Approx 13,000 Estimated Deaths in 2021

The Average Survival of patients with myeloma is IMPROVING!

Trends in MM Natural History by Race

MM Incidence Ø Higher incidence in AA vs White patients:

• 15.9 vs 7.5 cases per 100,000 per year

MM Mortality Ø Higher mortality in AA vs White patients:

• 5.6 vs 2.4 MM deaths per 100,000

Ø 5-year relative survival evolution from 1973 to 2005

The expected survival is nearly 10 years for all patients, but still less than 5 years in patients with high risk disease

MM Survival

• Survival for White patients increased significantly from 26.3% to 35%

• Survival for AA patients increased from 31% to 34.1%

Types of Monoclonal Protein (M Protein) in Multiple Myeloma

• IgG+kappa

• IgG+lambda

• IgA+kappa

• IgA+lambda

• etc…

• 80% of myeloma cases

Jones protein

• 18% of all myeloma cases

• Renal failure more common in light chain multiple myeloma; creatinine >2 mg/dL in 1/3 of cases

protein present

• Less than 3% of cases of multiple myeloma

Multiple Myeloma - Types

• Subtypes of MM are determined based on the kind of abnormal protein

M spike in gamma region

Diagnosis of multiple myeloma: Monoclonal immunoglobulin

- both “heavy” and ”light” chains

Multiple Myeloma Typically Preceded by Premalignant Conditions

Premalignant Malignant

* In clinical trial (preferred) or offer treatment for those likely to progress within 2 years

1. Kyle RA, et al. N Engl J Med. 2007;356:2582-90.

2. International Myeloma Working Group. Br J Haematol. 2003;121:749-57.

3. Jagannath S, et al. Clin Lymphoma Myeloma Leuk. 2010;10(1):2843

4. Kyle RA, et al. Curr Hematol Malig Rep 2010;5(2):62-69.

5. Mateos M-V, et al. Blood. 2009;114:Abstract 614.

6. Durie BG, Salmon SE. Cancer. 1975;36:842-854.

7. Durie BG, et al. Leukemia. 2006;20(9):1467-1473.

8. Rajkumar SV, et al. Lancet Oncology 2014; 15:e538-e548.

Multiple Myeloma Diagnosis Can Be Challenging

Fatigue

Bone Pain

Kyle RA. Mayo Clin Proc. 2003;78:21-33.

Anemia

2014 IMWG Active Myeloma Criteria: MyelomaDefining Events

Clonal bone marrow ≥10% or bony/extramedullary plasmacytoma

AND any one or more Myeloma-Defining Events

C

R A B

alcium elevation

enal complications

nemia one disease

Clonal bone marrow ≥60%

BM, bone marrow; FLC, free light chain; MRI, magnetic resonance imaging; sFLC, serum free light chain. Rajkumar et al. Lancet Oncol 2014;15:e538-e548. Kyle et al. Leukemia 2010;24:1121-1127.

Active Multiple Myeloma

Not CRAB but now SLiM CRAB

• S (60% Plasmacytosis)

• Li (Light chains I/U >100)

• M (MRI 1 or more focal lesion)

• C (calcium elevation)

• R (renal insufficiency)

• A (anemia)

• B (bone disease)

Rajkumar SV, et al. Lancet Oncol. 2014;15:e538-e548.

More About the Common “CRAB” Symptoms

Low Blood Counts

• May lead to anemia and infection

• Anemia is present in 60% at diagnosis

Decreased Kidney Function

• Occurs in over half of myeloma patients

Bone Damage

• Affects 85% of patients

• Leads to fractures

Bone Turnover

• Leads to high levels of calcium in blood (hypercalcemia)

Weakness

Fatigue

Infection

Weakness

Bone pain

Loss of Appetite & Weight loss

About 10% to 20% of patients with newly diagnosed myeloma will not have any symptoms.

Staging Myeloma: The Importance of Genomic Testing

Mutant Cell Corrupted DNA

Conventional cytogenetic analysis (karyotyping)

DNA

FISH (fluorescence in situ hybridization)

Advances

• Genetic expression profiling [GEP]

• Whole-genome/ whole-exome sequencing

• Plasma cell next generation sequencing

Staging Myeloma: FISH helps to Assign Risk in Myeloma

Risk Category

Findings on Chromosome (FISH) Analysis Results in the Bone marrow

High Risk

FISH:

• Deletion 17th chromosome

• Gain of chromosome 1q

• Translocation 4 and 14

FISH:

Standard Risk

• Hyperdiploid: More than 1 pair of chromosomes (Trisomies)

• Translocation 11 and 14

• Translocation 6 and 14

• Translocation 14 and 16

• Translocation 14 and 20

NGS: p53 mutation (on chrom 17)

• Double Hit Myeloma: 2 high risk

genetic abnormalities

• Triple Hit Myeloma: 3 or more high risk genetic abnormalities

• Others

• Normal

Myeloma Stage:

Staging refers to the degree to which the cancer has progressed

Stage 1

β2-microglobulin under 3.6 mg/L

Stage 2

β2-microglobulin

Between 3.5 & 5.4mg/L

Stage 3

β2-microglobulin over 5.5 mg/L

Normal

Lactate Dehydrogenase (LDH)

AND

NO High Risk

Cytogenetics (FISH)

NO High Risk

Cytogenetics (FISH)

HIGH Lactate Dehydrogenase (LDH)

AND/OR

High Risk Cytogenetics (FISH)

Deletion 17 chromosome

Translocation 4th and 14th

Translocation 14th and 16th

Translocation 14th and 20th

Learn Your Labs

CBC Counts the number of red blood cells, white blood cells, and platelets

CoMP

Measures levels of albumin, calcium, and creatinine to assess kidney and liver functions, bone status ,and the extent of disease

Beta2 MicroG

Determines the level of a protein linked to MM and kidney function: USED FOR STAGE

LDH Lactate Dehydrogenase

Determines the level of myeloma cell production and extent of MM : USED FOR STAGE

Serum Protein EP Detects the presence and level of M protein = how much myeloma

Immuno Fixation

Identifies the type of abnormal antibody proteins: IgG, IgA, IgM

Serum Free Light Chain Measures myeloma free light chains (kappa or lambda) in blood = how much myeloma

Urine Protein EP Detects Bence-Jones proteins (otherwise known as myeloma light chains) in urine (to determine if it’s present or not present)

24 hr Urine Analysis 24 hours of urine collected to test the presence and levels of Bence Jones protein in the urine = how much myeloma

Treatment Planning

Treatment Planning is the process of thinking about the treatment steps you can take with your doctor, based on your goals and preferences. Treatment decisions are based on:

The results of biomarker tests, cytogenetic (FISH) test, and the stage of multiple myeloma

Your values, goals, and preferences

Your age

Your health and symptoms (if you have kidney disease, heart disease, anemia, or other issues)

Your medical history and past treatments for multiple myeloma

How to Choosing a Treatment Plan

Lifestyle Goals of Therapy

Age

Patient Preference

Myeloma Symptoms

Second/Expert Opinion

You have the right to get a second opinion. Insurance providers may require second opinions.

A second opinion can help you:

Confirm your diagnosis

Give you more information about options

Talk to other experts

Introduce you to clinical trials

Help you learn which health care team you’d like to work with, and which facility

Relapsing Nature of Multiple Myeloma: Clones Change over Time

SYMPTOMATIC REFRACTORY RELAPSE

MGUS = monoclonal gammopathy of undetermined significance

Adapted from Dr. Brian Durie and Keats JJ, et al. Blood. 2012;120:1067-1076.

Clone 1.1

Clone 1.2

Clone 2.1 Clone 2.2

Steroids

Tools of the Trade Standard Drug Overview

Revlimid (lenalidomide)

Monoclonal Antibodies

Cytoxan (cyclophosphamide)

or Evomela (melphalan)

Decadron (dexamethasone)

Darzalex (daratumumab)

Sarclisa (isatuximab)

Empliciti (elotuzumab)

XPO1 Inhibitors Xpovio (selinexor)

Class

Tools of the Trade Novel Immunotherapy Drug Overview

Drug Name

Abbreviation Administration

Peptide Drug Conjugate* Pepaxto (Melphalan Flufenamide) Melflufen Intravenous

BCMA Targeted Antibody Drug Conjugate (ADC)*

Blenrep (Belantamab mafodotin) B Intravenous

Abecma (idecabtagene vicleucel)

CAR T Cell therapy

Bispecific Antibodies

Carvycti (ciltacabtagene vicleucelel) Cilta-cel

Ide-cel Intravenous (IV) or subcutaneous injectionSC (under the skin)

Cytoxan (cyclophosphamide) C Oral or intravenous

??? MORE TO COME!!

* these agents are currently off the market but available through special programs

Monoclonal Antibody-Based Therapeutic Targeting of Myeloma

Antibody-dependent Cellular cytotoxicity (ADCC)

Effector cells:

Complement-dependent Cytotoxicity (CDC)

• Daratumumab

• SAR650984/Isatuximab (CD38)

• Lucatumumab or Dacetuzumab (CD40)

• Elotuzumab (CS1; SLAMF7)

• Daratumumab, SAR650984/Isatuximab (CD38)

• XmAbâ5592 (HM1.24)

• huN901-DM1 (CD56)

• nBT062-maytansinoid (CD138)

• Siltuximab (1339) (IL-6)

• BHQ880 (DKK1)

• RAP-011 (activin A)

• Daratumumab, SAR650984/Isatuximab (CD38)

Adapted from Tai & Anderson Bone Marrow Research 2011

Antibody-Drug Conjugates

The Process of CAR T Cell Therapy

Bispecific Antibodies

Mechanism of Action

• Incorporates 2 antibody fragments to target and bind both tumor cells and T cells

• Brings target-expressing MM cells and T cells into close proximity, enabling T cells to induce tumor-cell death

Bispecific Molecule Targets Vary

“Off the Shelf” Advantage

• No manufacturing process, unlike CAR T-cell therapy (but like ADC/belantamab therapy)

• Thus, no delay between decision to treat and administration of drug

ADC = Antibody-Drug Conjugate; BCMA = B-Cell Maturation Antigen; CD3 = Cluster of Differentiation 3; FcRH5 = Fc receptor-homolog 5;

GPRC5D = G-protein coupled receptor family C group 5 member D

Image Source: Shah N, et al. Leukemia. 2020;34:985–1005. Creative Commons License: CC BY 4.0.

Barilà G, et al. Pharmaceuticals (Basel). 2021;14(1):40

Bi-Specific Antibodies

Targets on the Myeloma Cell Surface and Therapeutic Antibodies

Talquetamab

CAR-T

Bi-Specific Antibodies

CAR-T

Antibody Drug

Elotuzumab

Bi-Specific Antibodies

Antibody Drug

Daratumumab and Darzalex Faspro

Isatuximab

TAK-079

MOR202

Immune Therapies

Ide cel CAR T

Cilta cel CAR T

Teclistamab

Other Bi-Specific Antibodies

Other CAR-Ts

Treatment Sequence and Regimens for Myeloma

Frontline treatment Maintenance Relapsed

Induction

• Velcade/Revlimid/Dex:(VRD)

• Velcade/Thalomid/Dex:(VTD)

• Velcade/Cytoxan/Dex:(CyBorD)

• Darzalex/Revlimid/Dex:(DRD)

• Darzalex/Velcade/Melphalan/Dex

• Darzalex/Velcade/Thalidomide/Dex

• Kyprolis/Revimid/Dex(KRD)

• Darzalex/Velcade/Revlimid/Dex: Dara-RVD

• Ninlaro/Revimid/Dex(IRD)

• Clinical trials

Consolidation

Maintenance

• Stem Cell Transplant

• Continue Induction

• Clinical trial

Rescue

• Revlimid

• Velcade

• Ninlaro

• Observation

• Thalidomide

• Revlimid/Dara

• Clinical trial

Dara+Pomalyst+Dex

Kyprolis+Pomalyst+Dex

Cytoxan+Pomalyst+Dex

Ninlaro+Pomalyst+Dex

Elo+Pomalyst+Dex

Elo+Thaliomide+Dex

Dara+Kyprolis+Dex

Kyprolis+Revlimid+Dex

Elo+Revlimid+Dex

Dara+Revlimid+Dex

Dara+Velcade+Dex

Elo+Velcade+Dex

Cytoxan+Kyprolis+Thalidomide+dex

4 drug therapies of novel agents

Ninlaro+Cytoxan+Dex

Velcade+ Cytoxan+Dex

Velcade+ Pomalyst+Dex

Chemotherapy

Selinexor+Dex

Selinexor+Velcade

Selinexor+ Dara

Isatuximab(Sarclisa)+

Pomalyst+Dex

Darzalex Faspro (under skin)

Ide-cel CAR-T (FDA approved 3/26/2021)

Cilta-cel CAR-T (FDA approved 2/28/2022)

Teclistamab (FDA approved 10/25/2022)

CLINICAL TRIALS!

The Evolution of Myeloma Therapy

Panobinostat

Idecabtagene

Elotuzumab Isatuximab

Ciltacabtagene

A Call to Action – Facts About African Americans and Myeloma

1. There is a longer time from symptoms to diagnosis among African Americans

2. African Americans are younger by about 5 years on average at diagnosis

3. MM and MGUS are more than 2x as common in African Americans

4. African Americans are less likely to receive the four T’s: Transplant, Triplets, Trials and CAR T

5. African Americans have biologic differences with more t(11;14) and less high-risk cytogenetics with deletion 17p

6. Survival outcomes in African Americans are HALF of what is seen in White Americans

7. African Americans can achieve equal or better outcomes when they receive therapy

M-Power = Myeloma Power

The IMF has created the M-Power program:

The core vision of this initiative is to improve the short- and long-term outcomes of African American patients with myeloma.

We want to empower patients and communities to CHANGE the current course of myeloma…

Increase Awareness

Engage the community

Shorten the time to diagnosis

Educate providers about culturally sensitive care

Frontline Therapy

Objectives

l Review the importance of DEPTH of response in early treatment of myeloma and the increasing use of MRD testing

l Discuss emerging approaches in transplant eligible patients, including quadruplet therapy and stem cell transplantation

l Outline the approach to a patient not going to transplant and how to optimize continuous therapy

Goals of Therapy: The Iceberg Model of Myeloma

Partial response

50% reduction in M protein

Very good partial response

90% reduction in M protein

immunofixation positive only

Complete remission

No M-protein

immunofixation negative

Minimal Residual Dis

Minimal Residual Dis

Next Generation Molecular testing

Depth of response matters!

MRD refers to the persistence of residual tumor cells after treatment and is responsible for relapse1

Current techniques can detect MRD with a sensitivity of 10-6 for MM cells2

MINIMAL RESIDUAL DISEASE DETECTION

MR , minimal response; neg, negative; pos, positive; R, relapse

1. Adapted from Hauwel M, Matthes T. Swiss Med Wkly 2014:144:w13907

2. Biran N, et al. Curr Hematol Malig Rep 2014;9:368–78

MRD is Prognostic – Both for PFS and OS

Personalized Approach to Frontline Therapy

Newly Diagnosed MM and Risk Stratified

Factors to be considered for ASCT

Age, performance status (PS), comorbidities (R-MCI score, HCT-Cl) and organ function

ASCT Eligible

ASCT Ineligible

General Principles of Initial Therapy

1. Most patients will be given a combination of drugs to control the disease quickly

2. We don’t “save the best for last” because early therapies have a long term effect on survival

3. We seek a DEEP and DURABLE response

4. We mix and match from the 3 major classes of drugs and add steroids: Proteasome Inhibitors – most often botezomib (Velcade)

Immunomodulatory Drugs – lenalidomide (Revlimid)

Monoclonal Antibodies – daratumumab (Darzalex)

5. We decide early on whether or not someone will have a stem cell transplant

Treatment Sequence and Regimens for Myeloma

Frontline treatment Maintenance Relapsed

Induction

• Velcade/Revlimid/Dex:(VRD)

• Velcade/Thalomid/Dex:(VTD)

• Velcade/Cytoxan/Dex:(CyBorD)

• Darzalex/Revlimid/Dex:(DRD)

• Darzalex/Velcade/Melphalan/Dex

• Darzalex/Velcade/Thalidomide/Dex

• Kyprolis/Revimid/Dex(KRD)

• Darzalex/Velcade/Revlimid/Dex: Dara-RVD

• Ninlaro/Revimid/Dex(IRD)

• Clinical trials

Consolidation

Maintenance

• Stem Cell Transplant

• Continue Induction

• Clinical trial

Rescue

• Revlimid

• Velcade

• Ninlaro

• Observation

• Thalidomide

• Revlimid/Dara

• Clinical trial

Dara+Pomalyst+Dex

Kyprolis+Pomalyst+Dex

Cytoxan+Pomalyst+Dex

Ninlaro+Pomalyst+Dex

Elo+Pomalyst+Dex

Elo+Thaliomide+Dex

Dara+Kyprolis+Dex

Kyprolis+Revlimid+Dex

Elo+Revlimid+Dex

Dara+Revlimid+Dex

Dara+Velcade+Dex

Elo+Velcade+Dex

Cytoxan+Kyprolis+Thalidomide+dex

4 drug therapies of novel agents

Ninlaro+Cytoxan+Dex

Velcade+ Cytoxan+Dex

Velcade+ Pomalyst+Dex

Chemotherapy

Selinexor+Dex

Selinexor+Velcade

Selinexor+ Dara

Isatuximab(Sarclisa)+

Pomalyst+Dex

Darzalex Faspro (under skin)

Ide-cel CAR-T (FDA approved 3/26/2021)

Cilta-cel CAR-T (FDA approved 2/28/2022)

Teclistamab (FDA approved 10/25/2022)

CLINICAL TRIALS!

IFM 2009 Study design: VRD vs VRD + Transplant

maintenance 13 cycles (10-15 mg/d)

Median follow up 89.8 months

Median PFS 47.3 months (Transplantation, arm B)

Median PFS 35 months (RVD alone, arm A)

HR (95CI) 0.70 [0.59;0.83]

30% reduction in the risk of progression or death in patients receiving transplant

Overall Survival

Median follow up 89.8 months

HR (95CI) 1.03 [0.8;1.32]

8y-OS 62.2% (Transplantation, arm B)

8y-OS 60.2% (RVD alone, arm A)

More than 60% of the patients in the two arms are alive after 8 years of follow -up

RVD +Stem Cell Transplant vs. RVD without Transplant DETERMINATION Trial of Newly Diagnosed MM: DESIGN

-Patients aged 18-65 yrs with symptomatic newly diagnosed MM following 1 cycle of RVD -56 sites within the United States from 2010 to 2018

End Points of Study and Follow-up

• Primary end point: progression-free survival (time to next relapse)

• Secondary end points included:

• Response rates, overall survival, quality of life, and adverse events

• Follow-up on participant status : median of 6 years

Primary endpoint: Progression-free survival (PFS)

Key secondary endpoint: Overall survival (OS)

Data cut off:12/12/21

*p-value adjusted using Bonferroni’s correction to control overall family-wise error rate for secondary outcomes

RVD +Stem Cell Transplant vs. RVD without Transplant DETERMINATION

Trial of Newly Diagnosed MM Quality of Life

Global Health Status/QoL, Physical Functioning

DETERMINATION Discussion

• ASCT remains very relevant and important in prolonging PFS in younger and eligible patients • BUT it may not be mandatory in all eligible patients upfront • As with other agents, we INDIVIDUALIZE the sequencing patterns

• ASCT does carry genuine toxicity, short term and long term

• We may become callous to these toxicities

• Maintenance therapy remains an important part of myeloma therapy

But can we do better than triplets?

Daratumumab (DARA) + Lenalidomide, Bortezomib, and Dexamethasone (RVd) in Patients With Transplant-eligible Newly Diagnosed Multiple Myeloma (NDMM): Final Analysis

of GRIFFIN

Douglas W. Sborov,1 Jacob Laubach,2 Jonathan L. Kaufman,3 Brandi Reeves,4 Cesar Rodriguez,5

Ajai Chari,5 Rebecca Silbermann,6 Luciano J. Costa,7 Larry D. Anderson Jr.,8 Nitya Nathwani,9

Nina Shah,10 Naresh Bumma,11 Sarah A. Holstein,12 Caitlin Costello,13 Andrzej Jakubowiak,14

Robert Z. Orlowski,15 Kenneth H. Shain,16 Andrew J. Cowan,17 Huiling Pei,18 Annelore Cortoos,19

Sharmila Patel,19 Thomas S. Lin,19 Paul Richardson,2 Saad Z. Usmani,20 Peter M. Voorhees21

1Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, USA; 2Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; 3Winship Cancer Institute, Emory University, Atlanta, GA, USA; 4University of North Carolina – Chapel Hill, Chapel Hill, NC, USA; 5Icahn School of Medicine at Mount Sinai, New York, NY, USA; 6Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA; 7University of Alabama at Birmingham, Birmingham, AL, USA; 8Department of Internal Medicine, Division of Hematology/Oncology, UT Southwestern Medical Center, Dallas, TX, USA; 9Judy and Bernard Briskin Center for Multiple Myeloma Research, City of Hope Comprehensive Cancer Center, Duarte, CA, USA; 10Department of Medicine, University of California San Francisco, San Francisco, CA, USA; 11Division of Hematology, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA; 12University of Nebraska Medical Center, Division of Oncology and Hematology Department of Internal Medicine, Omaha, NE, USA; 13Moores Cancer Center, University of California San Diego, La Jolla, CA, USA; 14University of Chicago Medical Center, Chicago, IL, USA; 15Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 16Department of Malignant Hematology, H. Lee Moffitt Cancer Center, Tampa, FL, USA; 17Division of Medical Oncology, University of Washington, Seattle, WA, USA; 18Janssen Research & Development, LLC, Titusville, NJ, USA; 19Janssen Scientific Affairs, LLC, Horsham, PA, USA; 20Memorial Sloan Kettering Cancer Center, New York, NY, USA; 21Levine Cancer Institute, Atrium Health, Charlotte, NC, USA

Scan the QR code.

https://www.congresshub.com/Oncology/IMS20

22/Daratumumab/Sborov

The QR code is intended to provide scientific information for individual reference, and the information should not be altered or reproduced in any way.

GRIFFIN: Responses Deepened Over Time

sCR, P = 0.0079a

≥CR, P = 0.0005a

• Rates of ≥CR improved over time and the deepest responses occurred at the end of study maintenance

• At all timepoints, response rates for D-RVd were consistently higher versus RVd

PR, partial response; SD/PD/NE, stable disease/progressive disease/not evaluable. a P value was calculated using the Cochran–Mantel–Haenszel chi-squre test. b Response rates are from the primary analysis cutoff (median follow-up: 13.5 months), and the response-evaluable population included 196 patients (D-RVd, n = 99; RVd, n = 97). cResponse rates for the maintenance phase were evaluated at the time of final analysis (median follow-up: 49.6 months), and the response-evaluable population included 198 patients (D-RVd, n = 100; RVd, n = 98).

GRIFFIN: PFS in the ITT Population

• Median follow-up: 49.6 months

• Median PFS was not reached in either group

• PFS was longer for D-RVd/DR versus RVd/R, with a clinically meaningful 55% reduction in the risk of disease progression or death

• The separation of the PFS curves occurred beyond 1 year of maintenance

a HR and 95% CI from a Cox proportional hazards model with treatment as the sole explanatory variable and stratified with ISS staging (I, II, III) and baseline creatinine clearance (CrCl [30-50 mL/min or >50 mL/min]) at randomization. A hazard ratio <1 indicates an advantage for D-RVd. P-value is based on the log-rank test stratified with ISS staging and baseline creatinine clearance at randomization.

The first phase 3 study evaluating Isa + RVd for induction and maintenance in Te NDMM patients

Myeloma to evaluate PAd vs VCD induction prior to HDT followed by maintenance – final analysis on induction therapy

Mathias Haenel2, Igor W. Blau2, Dirk Hose1, Anna Jauch1, Baerbel Schurich1, Kai Neben2, Anja Seckinger1, Barbara Zeis2, Christian Gerecke2, Ingo G. H. Schmidt-Wolf2, Katja Weisel2, Christof Scheid2, Hans Salwender2 Germany, 2GMMG, Germany, 3Division of Biostatistics, German Cancer Research Center Heidelberg, Germany

Induction phase (3 x 6-week cycles)

Results

In the PAd group 91.2% and in the VCD group 96.0% of the patients completed three planned induction cycles. Applied total bortezomib dose over all three cycles was comparable in both, PAd and VCD arms. Response rates were similar in both induction regimens (PAd vs. VCD) with 34.3% vs. 37.0% of patients achieving VGPR or better. Non-inferiority of VCD compared to PAd was shown (one-sided p=0.0013). Similar results were obtained in the PP analysis. CR rates were 4.4% and 8.4% (PAd vs. VCD) and 21.1% and 22.3% (PAd vs. VCD) for near complete response (nCR) or better.

Partial response (PR) or better was reached in 72.1% vs. 78.1% of the patients (PAd vs. VCD) (figure 3).

Maintenance phase (4-week cycles)

Isa (IV) 10 mg/kg Cycle 1 Cycle 2–3

equally distributed for ISS and Durie-Salmon disease stage, cytogenetic abnormalities deletion (17p), translocation t(4;14) and significant differences in patient age and distribution of WHO

characteristics

Bor (SC) 1.3 mg/m² Len (PO) 25 mg

The proportion of patients with any adverse event was comparable in PAd vs. VCD (61.3% vs. 64.0%, p=0.58), but more serious adverse events (SAEs) were observed during PAd induction (32.7% vs. 24.0%, p=0.04). VCD led to a significantly higher proportion of leukocytopenia and neutropenia CTCAE grade 3 and 4 (PAd 11.3% vs. VCD 35.2%, p=<0.001). The number of infections (≥ CTCAE grade 2) and infection-related SAE was similar (PAd 24.6% vs. VCD 22.4% for AE, p=0.60 and PAd 12.9% vs. VCD 10.8% for SAE, p=0.49). Compared to the infection rate (AE ≥ CTCAE grade 2) of 49% during PAD (dexamethasone 40 mg on days 1-4, 9-12, 17-20) in the HOVON65/GMMG-HD4trial, a reduction in MM5 during induction was observed. Preliminary data (412 patients) of numbers of collected CD34+ stem cells were comparable (PAd median 9.8x106 vs. VCD median 9.4x106 kg bodyweight, p=0.15). In the PAd arm more deaths were observed compared to the VCD arm (5 vs 1).

Dex (PO) 20 mg

Isa (IV) 10 mg/kg: Cycle 1 Cycle 2–3 Cycle 4+ Len (PO) 10 mg increased to 15 mg after 3 months

Dex (PO) 20 mg: first cycle

Days 1–28

ASCT, autologous stem cell transplant; D, day; d/Dex, dexamethasone; HDT, high-dose therapy; Isa, isatuximab; IV, intravenous; NDMM, newly diagnosed multiple myeloma; PD, progressive disease; PO, oral; R/Len, lenalidomide; SC, subcutaneous; Te, transplant eligible; V/Bor, bortezomib; RVd is off label use in some countries according to the lenalidomide summary of product characteristics. 1. ClinicalTrials.gov: NCT03617731

Figure 3: Response rates after induction PAd or VCD induction therapy.

Table 2: Toxicity during induction

Myeloma to evaluate PAd vs VCD induction prior to HDT followed by maintenance – final analysis on induction therapy

Mathias Haenel2, Igor W. Blau2, Dirk Hose1, Anna Jauch1, Baerbel Schurich1, Kai Neben2, Anja Seckinger1, Barbara Zeis2, Christian Gerecke2, Ingo G. H. Schmidt-Wolf2, Katja Weisel2, Christof Scheid2, Hans Salwender2 Germany, 2GMMG, Germany, 3Division of Biostatistics, German Cancer Research Center Heidelberg, Germany

Randomized (n = 504)

Patients with MRD negativity at the end of induction therapy

OR 1.83 (95% CI 1.34–2.51)

Results

Patients not receiving allocated intervention due to:

- non-compliance (n = 1)

withdrawal of consent (n = 2)

In the PAd group 91.2% and in the VCD group 96.0% of the patients completed three planned induction cycles. Applied total bortezomib dose over all three cycles was comparable in both, PAd and VCD arms. Response rates were similar in both induction regimens (PAd vs. VCD) with 34.3% vs. 37.0% of patients achieving VGPR or better. Non-inferiority of VCD compared to PAd was shown (one-sided p=0.0013). Similar results were obtained in the PP analysis. CR rates were 4.4% and 8.4% (PAd vs. VCD) and 21.1% and 22.3% (PAd vs. VCD) for near complete response (nCR) or better. Partial response (PR) or better was reached in 72.1% vs. 78.1% of the patients (PAd vs. VCD) (figure 3).

VCD (n = 251) Received allocated intervention (n = 249) 20

One patient excluded from ITT (due to unconfirmed diagnosis of multiple myeloma requiring systemic therapy) received VCD therapy and was included in safety analysis

= 234 30

1) 10

Excluded from PP analysis

= PAd VCD Percent (%) 0

and (n CR nCR PR MR SD PD

- incomplete induction therapy (n = 5)

- missing response assessment (n = 3)

equally distributed for ISS and Durie-Salmon disease stage, cytogenetic abnormalities deletion (17p), translocation t(4;14) and significant differences in patient age and distribution of WHO

= 244 40 Response rates (ITT) VGPR missing PAd VCD P value patients % in PAd arm no of patients % in VCD arm 58.6 / 41.4 153 / 98 61.0 / 39.0 0.65 59.4 (37 - 70) 58.7 (33 - 70) 0.04 10.8 / 88.2 30 221 12.0 / 88.0 0.78 39.4 / 31.9 28.7 94 82 / 75 37.5 / 32.7 29.9 0.91 85.7 / 11.9 / 2.4 230 / 21 0 91.6 / 8.4 0.0 0.01 18.4 44 17.5 0.82 15.9 31 12.3 0.31

- one patient not ITT not PP but Safety (see above)

n = 240 Characteristic PAd VCD P value No of patients % in PAd arm No of patients % in VCD arm AE ≥ 3º (or ≥ 2º for infections, cardiac disorders, PNP and thromboembolic events) 152 61.3 160 64.0 0.58 Any SAE 81 32.7 60 24.0 0.04 Leukocyto-/Neutropenia ≥ 3º 28 11.3 88 35.2 <0.01 AE Infections and Infestations ≥ 2º 61 24.6 56 22.4 0.60

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

The proportion of patients with any adverse event was comparable in PAd vs. VCD (61.3% vs. 64.0%, p=0.58), but more serious adverse events (SAEs) were observed during PAd induction (32.7% vs. 24.0%, p=0.04). VCD led to a significantly higher proportion of leukocytopenia and neutropenia CTCAE grade 3 and 4 (PAd 11.3% vs. VCD 35.2%, p=<0.001). The number of infections (≥ CTCAE grade 2) and infection-related SAE was similar (PAd 24.6% vs. VCD 22.4% for AE, p=0.60 and PAd 12.9% vs. VCD 10.8% for SAE, p=0.49). Compared to the infection rate (AE ≥ CTCAE grade 2) of 49% during PAD (dexamethasone 40 mg on days 1-4, 9-12, 17-20) in the HOVON65/GMMG-HD4trial, a reduction in MM5 during induction was observed. Preliminary data (412 patients) of numbers of collected CD34+ stem cells were comparable (PAd median 9.8x106 vs. VCD median 9.4x106 kg bodyweight, p=0.15). In the PAd arm more deaths were observed compared to the VCD arm (5 vs 1).

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

n = 249 HD7 66

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

Figure 3: Response rates after induction PAd or VCD induction therapy.

Table 2: Toxicity during induction

Will MRD guide us to stop therapy?

MASTER Trial - 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

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

Progression-Free and Overall Survival

Frontline Therapy and Transplant -

We are transitioning to quadruplets in frontline eligible patients

• BUT the optimal length of a quadruplet is still to be determined!

Transplant still has a role in MM even with long term use of novel agents

Consolidation therapy may deepen responses and should be considered in patients who have not achieved VGPR

MRD guided discontinuation may be possible in lower risk groups but not high risk patients

How do we decide who is eligible for transplant?

ASCO: What criteria are used to assess eligibility for autologous stem cell transplant (SCT)?

Recommendation

Patients should be referred to a transplant center to determine transplant eligibility

Evidence Rating

Type: Evidence based

Evidence quality: Intermediate, benefit outweighs harm

Strength of recommendation: Moderate

Chronologic age and renal function should not be the sole criteria used to determine eligibility for SCT.

Type: Evidence based

Evidence quality: Intermediate, benefit outweighs harm

Strength of recommendation: Moderate

Several Indices for Myeloma ‘Frailty’ assessment

IMWG score of 1 = Intermediate-Fit

3-year OS was 76% (HR=1.61; 95% CI 1.02-2.56; p=.042)

Toxicities 16.7% (HR 1.23, 95% CI 0.89-1.71; p=.217) and

Discontinuation 20.8% (HR=1.41; 95% CI 1.00-2.01; p=.052).

Upfront Therapy for Myeloma: Patients Ineligible for Transplant NCCN Guidelines

MAIA Study Design – DRD

vs RD

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

Key eligibility criteria

• TIE NDMM

• ECOG PS score 0-2

• CrCl

≥30 mL/min

1:1 randomisation

D: 16 mg/kg IV

TIE,

aOn

R: 25 mg PO Days 1-21 until PD

da: 40 mgb PO or IV Days 1, 8, 15, 22 until PD

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

Rd

R: 25 mg PO Days 1-21 until PD

d: 40 mg PO Days 1, 8, 15, 22 until PD

D -Rd Cycles: 28 days

End-oftreatment visit (30 days after last dose)

Primary endpoint

• PFS

Longterm follow-up

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

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.

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.

Demographics and Baseline Characteristics

Demographics and baseline characteristics were well balanced between arms

ORRa

Median

Primary:

Update: 56.2 months

• 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

• 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

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

Conclusions in Transplant Ineligible Patients

• Although ASCT remains the standard of care, use is likely to decline in patients who are 65-75 or with significant comorbidities

• Continuous therapy has resulted in better outcomes

• The balance of toxicity and efficacy is particularly important in this population

• ESPECIALLY with dexamethasone

• Most common approach is to select 2 agents from the 3 Novel Classes (PIs, IMiDs and MoAbs)

• Most will use DRD in standard risk patients

• Some may favor VRD in certain high risk patients

• DRD is more easily delivered and feasible

• D-VRD may well be a future standard of care even in these patients

The Evolution of Myeloma Therapy

Panobinostat

Idecabtagene

Elotuzumab Isatuximab

Ciltacabtagene

Audience Q&A

Maintenance Therapy

David Vesole, MD, PhD, FACP

MedStar Georgetown University Hospital

Maintenance Therapy

David H. Vesole, MD, PhD, FACP

Director, Myeloma Program

MedStar Georgetown University Hospital

Professor of Medicine

Georgetown University School of Medicine

Co-Chief, Myeloma Division

Director, Myeloma Research

John Theurer Cancer Center at Hackensack UMC

Professor of Medicine

Hackensack Meridian School of Medicine

David.Vesole@hmhn.org

Understanding the Terms

• Induction: Intense and short term therapy with goal to achieve rapid remission

• Consolidation: Intense and shorter term therapy with goal of deep remission

• Maintenance: Less intense longer term therapy with goal of better PFS and OS

What does the Ideal Maintenance therapy look like? • Deepen remission • Prolong remission

• Easy to administer

Minimal toxicity

McCarthy et al. J Clin Oncol. 2017, 35:3279-3289.

Key Results of Initial Meta-Analysis

3 randomized trials: 1,209 patients:

Median follow up 6.6 years

• PFS 52.8 months for lenalidomide vs 23.5 in placebo

Median overall survival: 86 months v. not reached: P = 0.001

Benefit for ≤ PR as well as VGPR/CR patients

29% discontinuation rate with lenalidomide

Second primary malignancy rate higher at 6.1% vs 2.8% in placebo after PD

Meta-analysis of all four randomized studies evaluating lenalidomide

maintenance

HR 0.47

HR 0.72

But can we do better than lenalidomide alone?

FORTE Trial design

474 NDMM patients, transplant-eligible and younger than 65 years

4x KCd

K: 36^ mg/m2 d 1-2,8-9,15-16

C: 300 mg/m2 d 1,8,15

d: 20 mg. d 1-2,8-9,15-16,22-23

4x KRd

K: 36^ mg/m2 d 1-2,8-9,15-16

R: 25 mg d 1-21

d: 20 mg. d 1-2,8-9,15-16,22-23

Single ASCT

Intensification with high-dose melphalan followed by autologous stem-cell reinfusion MOBILIZATION

4x KRd

K: 36^ mg/m2 d 1-2,8-9,15-16

R: 25 mg d 1-21

d: 20 mg. d 1-2,8-9,15-16,22-23

4x KRd

K: 36 mg/m2 d 1-2,8-9,15-16

R: 25 mg d 1-21

d: 20 mg. d 1-2,8-9,15-16,22-23

4x KCd

K: 36 mg/m2 d 1-2,8-9,15-16

C: 300 mg/m2 d 1,8,15

d: 20 mg. d 1-2,8-9,15-16,22-23

4x KRd

K: 36 mg/m2 d 1-2,8-9,15-16

R: 25 mg d 1-21

d: 20 mg. d 1-2,8-9,15-16,22-23

R: 10 mg days 1-21, until progression or intolerance

K: 36 mg/m2 d 1, 2, 15, 16 up to 2 years*

R: 10 mg days 1-21, until progression or intolerance

K: 36 mg/m2 d 1-2,8-9,15-16

R: 25 mg d 1-21

d: 20 mg. d 1-2,8-9,15-16,22-23

^20 mg/m2 on days 1-2, cycle 1 only. *Carfilzomib 70 mg/m2 days 1, 15 every 28 days up to 2 years for patients that have started the maintenance treatment from 6 months before the approval of Amendment 5.0 onwards.

NDMM, newly diagnosed multiple myeloma, R1, first randomization (induction/consolidation treatment); R2, second randomization (maintenance treatment); ASCT, autologous stem-cell transplantation; K, carfilzomib; R, lenalidomide; C, cyclophosphamide; d, dexamethasone; KCd_ASCT, KCd induction-ASCT-KCd consolidation; KRd_ASCT, KRd induction-ASCT-KRd consolidation; KRd12, 12 cycles of KRd.

4x KRd

Progression-free survival

KRd_ASCT vs. KRd12 vs. KCd_ASCT KR vs. R

Median follow-up from Random 1: 51 months (IQR 46‒55)

Median follow-up from Random 2: 37 months (IQR 33‒42)

KRd_ASCT vs. KCd_ASCT: HR 0.54, 95% CI 0.38-0.78, p<0.001

KRd_ASCT vs. KRd12: HR 0.61, 95% CI 0.43-0.88, p=0.0084

KRd12 vs. KCd_ASCT: HR 0.88, 95% CI 0.64-1.22, p=0.45

KR vs. R: HR 0.64, 95% CI 0.44-0.94, p=0.02294

3-year PFS reported in the figure. Random 1, first randomization (induction/consolidation treatment); ASCT, autologous stem-cell trasplantation; K, carfilzomib; R, lenalidomide; C, cyclophosphamide; d, dexamethasone; KCd_ASCT, KCd induction-ASCT-KCd consolidation; KRd_ASCT, KRd induction-ASCT-KRd consolidation; KRd12, 12 cycles of KRd; Random 2, second randomization (maintenance treatment); p, p-value; HR, hazard ratio; CI, confidence interval

Progression-free survival: Random 2

KR vs. R

Presented by Francesca Gay in 2021 ASCO Annual meeting

Conclusions about FORTE

• It appears that dual maintenance therapy prolongs PFS

• This occurs in both standard risk AND high risk patients

• It further opens the door to other dual maintenance strategies currently being used and explored:

• Lenalidomide + Bortezomib

• Lenalidomide + Ixazomib

• Lenalidomide + Daratumumab

• Others??

What about Daratumumab?

• Recall that GRIFFIN gave Dara for 2 years with lenalidomide in maintenance

• Responses continued to deepen with Dara

• CASSIOPEIA randomized pts to no maintenance vs dara q 8 weeks

• Overall there was a benefit to having dara maintenance vs placebo

• However, if dara had been given at induction, that benefit did not seem to continue (ie If you had dara upfront, it didn’t add more to maintenance)

• Two large international trials comparing daratumumab + lenalidomide versus lenalidomide alone: Perseus and Auriga; others in planning stages

How long should maintenance last?

Defining

maintenance after autologous

lenalidomide

stem cell transplant –

from the Myeloma XI trial. Charlotte Pawlyn1,2, Tom Menzies3, Faith Davies4, Ruth de Tute5, Rowena Henderson3, Gordon Cook3,6 , Matthew Jenner7, John Jones8, Martin Kaiser1,2, Mark Drayson9, Roger Owen8, David Cairns3 , Gareth Morgan4, Graham Jackson10

1) The Institute of Cancer Research, London, UK; 2) The Royal Marsden Hospital, London, UK; 3) Clinical Trials Research Unit, Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, UK; 4) Perlmutter Cancer Center, NYU Langone Health, New York, US; 5) HMDS, Leeds Cancer Centre, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom; 6) Leeds Cancer Centre, Leeds Teaching Hospitals NHS Trust, Leeds, UK; 7) University Hospital Southampton NHS Foundation Trust, Southampton, UK; 8) Kings College Hospital NHS Foundation Trust, London, UK; 9) Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK; 10) Department of Haematology, University of Newcastle, Newcastle-upon-Tyne, UK

On behalf of the Myeloma XI Trial Management Group and NCRI Haem-Onc Clinical Studies Group

the optimum duration of

data

Myeloma XI Trial: Study Design

• Open-label, randomized phase III study with 3 randomizations: induction (allocation by ASCT eligibility), intensification (allocation by response to induction therapy), and maintenance treatment

• Current analysis: maintenance with lenalidomide monotherapy vs observation following ASCT

Maintenance Phase

Patients with newly diagnosed, symptomatic, transplant-eligible MM completing Myeloma XI induction protocols* and ASCT; responded to lenalidomide; without PD (N = 1248)

Lenalidomide 10 mg/day on Days 1-21/28 (n = 730) Observation (n = 518)

Continued until disease progression

• Median follow-up: 44.7 mo (IQR: 32.4-62.7); median duration of lenalidomide therapy: 28 cycles (range: 1-96) with 45% of patients (330/730) still on therapy

• Endpoints: Overall PFS, PFS2; landmark PFS by genetic risk subgroups and MRD status

*Cyclophosphamide/thalidomide/dexamethasone or cyclophosphamide/lenalidomide/dexamethasone or carfilzomib/cyclophosphamide/lenalidomide/dexamethasone.

Pawlyn. ASH 2022. Abstr 570.

Myeloma XI Trial: PFS and PFS2 From Maintenance Randomization

Pawlyn. ASH 2022. Abstr 570. Reproduced with permission.

Myeloma XI Trial: PFS From Maintenance Randomization by Cytogenetic Risk Status

Pawlyn. ASH 2022. Abstr 570. Reproduced with permission.

Myeloma XI Trial: Investigators’ Conclusions

• Long-term results from Myeloma XI phase III trial demonstrated ongoing PFS improvement with continuing lenalidomide maintenance beyond 4-5 yr in patients with newly diagnosed MM after response to protocol-specified induction and ASCT

• Continuing lenalidomide maintenance for ≥3 yr benefited patients with sustained MRD negativity, but benefit of additional lenalidomide maintenance is unclear

• In MRD-positive patients, results support continuing lenalidomide until disease progression

• No evidence of cumulative hematologic toxicity observed with long -term lenalidomide maintenance

• Investigators concluded that additional data from ongoing studies needed to determine optimal duration of lenalidomide maintenance

Audience Q&A

Relapsed Myeloma

David Vesole, MD, PhD, FACP

MedStar Georgetown University Hospital

Relapsed/Refractory Multiple Myeloma

David H. Vesole, MD, PhD, FACP

Director, Myeloma Program

MedStar Georgetown University Hospital

Professor of Medicine

Georgetown University School of Medicine

Co-Chief, Myeloma Division

Director, Myeloma Research

John Theurer Cancer Center at Hackensack UMC

Professor of Medicine

Hackensack Meridian School of Medicine

David.Vesole@hmhn.org

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 heterogeneity

• MM is clonally heterogeneous at diagnosis and throughout treament

• The genomic heterogeneity of MM contributes to treatment resistance and relapse3

• Wide variety of mutations found within a single patient may result in treatment resistance and refractory disease

• Furthermore, subclones continually mutate over time, including after treatment, which may contribute to resistance and result in disease progression1,5

Definitions: What is relapsed/refractory disease and a line of therapy?

• Relapsed: recurrence (reappearance of disease) after a response to therapy

• Refractory: progression despite ongoing therapy

• Progression: change in M protein/light chain values

• Line of therapy: change in treatment due to either progression of disease or unmanageable side effects

• Note: initial (or induction) therapy + stem cell transplant + consolidation/ maintenance therapy = 1 line of therapy

Biochemical Relapse or Clinical Relapse

Timing of therapy

Biochemical

• Patients with asymptomatic rise in blood or urine M protein, free light chains, or plasma cells

initiation/escalation dependent on many factors

Requires immediate

Clinical

• Based on direct indicators of increasing disease and/or end-organ dysfunction

initiation/escalation of therapy

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)

Choosing Therapy for First or Second Relapse

Choices are broadest and guided by

Disease biology

Nature of relapse

Patient preference

Factors to consider

Prior autologous stem cell transplant

Prior therapies

Aggressiveness of relapse

Comorbidities

Psychosocial issues

Access to care

Options for Relapsed/Refractory Disease Continue to Increase

IMiDs Proteasome inhibitors Chemotherapy

anthracyclines Chemotherapy

alkylators Steroids

Novel mechanisms of action

Monoclonal antibodies

Cellular therapy

Thalomid (thalidomide)

Velcade (bortezomib) Adriamycin

Cytoxan (cyclophosphamide) Dexamethasone

XPOVIO (selinexor)

Empliciti (elotuzumab)

Revlimid (lenalidomide)

Kyprolis (carfilzomib)

Doxil (liposomal doxorubicin)

Pomalyst (pomalidomide)

Ninlaro (ixazomib)

Bendamustine Prednisone

Melphalan

Venclexta (venetoclax)*

Farydak (Panobinostat)†

Pepaxto (melflufen)†

Darzalex (daratumumab)

Sarclisa (isatuximab)

Blenrep (belantamab mafodotin)‡

Tecvayli (teclistamab)§

Abecma (idecabtagene vicleucel)

Carvykti (ciltacabtagene autoleucel)

*Not yet FDA-approved for patients with multiple myeloma; †Withdrawn from the US market in 2021; ‡

Antibody-drug conjugate; §Bispecific antibody

GREAT NEWS WE HAVE OPTIONS

Myeloma: first relapse – IMWG Guidelines

First Relapse

Preferred options: DRd (or KRd)

Not Refractory to Lenalidomide

Refractory to Lenalidomide

Alternatives: DVD, Kd, DaraKd, IsaKd, IRd, Erd

When Dara, Isa, K not available: Rd, Vd, VTD, VCD, VMP

Preferred options: PVd DaraKd IsaKd

Consider salvage auto transplant in eligible patients

DKd,daratumumab/carfilzomib/dexamethasone; DPd, daratumumab/pomalidomide/dexamethasone; DRd, daratumumab/lenalidomide/ dexamethasone; DVd, daratumumab/bortezomib/dexamethasone; Elo–Rd, elotuzumab/lenalidomide/dexamethasone; Ipd, ixazomib/pomalidomide/dexamethasone; Ird, ixazomib/lenalidomide/dexamethasone; Isa–Kd, isatuximab/carfilzomib/dexamethasone; Kd, carfilzomib/dexamethasone; KPd, carfilzomib/pomalidomide/dexamethasone; KRd, carfilzomib/lenalidomide/ dexamethasone; PVd, pomalidomide/bortezomib/dexamethasone; Rd, lenalidomide/dexamethasone; SVd, selinexor/bortezomib/dexamethasone; VCd, bortezomib/cyclophosphamide/dexamethasone; Vd, bortezomib/dexamethasone; VMP, bortezomib/melphalan /prednisone; VTd, bortezomib/thalidomide/dexamethasone.

Second options

DaraVd;Kd

Other options: KPd; DaraPd; Ipd

When Dara, isa, K or P not available: VCD, Vd, VMP

Moreau P, et al. IMWG Recommendations for RRMM. Lancet Oncol. 2021;22(3):e105-e118.

Combination is Better.

Key eligibility criteria

• RRMM

• ≥1 prior line of therapy

• Prior lenalidomide exposure, but not refractory

• Creatinine clearance

≥30 mL/min

DRd (n = 286)

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

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

Primary endpoint

• PFS

Secondary endpoints

• TTP

• OS

• ORR, VGPR, CR

• MRD

• Time to response

• Duration of response

Stratification factors

• No. of prior lines of therapy

• ISS stage at study entry

• Prior lenalidomide

Cycles: 28 days

Statistical analyses

• Primary analysis: ~177 PFS events

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.

a On daratumumab dosing days, dexamethasone 20 mg was administered as pre-medication on Day 1 and Day 2.

Multicenter, randomized (1:1), open-label, active-controlled, phase 3 study

POLLUX

not reached

17.5 months

Median follow-up: 32.9 months (range, 0 - 40.0 months)

56% reduction in risk of progression/death for DRd versus Rd

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

Proteasome Inhibitor– and Immunomodulatory Drug–Based Regimens for Early Relapse

Currently Available Agents for One to Three Prior Lines of Therapy

Drug Formulation Approval

Velcade (bortezomib)

Kyprolis (carfilzomib)

Ninlaro (ixazomib)

Revlimid (lenalidomide)*

Pomalyst (pomalidomide)*

XPOVIO (selinexor)

• IV infusion

• SC injection

• IV infusion

• Weekly dosing

Once-weekly pill

• For relapsed/refractory myeloma

• For relapsed/refractory myeloma as a single agent, as a doublet with dexamethasone, and as a triplet with Revlimid or Darzalex plus dexamethasone

• For relapsed/refractory myeloma as a triplet with Revlimid and dexamethasone

Once-daily pill

• For relapsed/refractory myeloma in combination with dexamethasone

Once-daily pill

• For relapsed/refractory myeloma in combination with dexamethasone

Once-weekly pill

• For relapsed/refractory myeloma as a triplet with Velcade and dexamethasone

*Black box warnings: embryo-fetal toxicity; hematologic toxicity (Revlimid); venous and arterial thromboembolism

IV, intravenous; SC, subcutaneous

Proteasome Inhibitor – and Immunomodulatory Drug –Based Regimens for Early Relapse

OPTIMISMM

• Velcade-Pomalystdex (VPd) vs Vd Regimens compared

ASPIRE TOURMALINE-MM1 BOSTON

• Kyprolis-Revlimiddex (KRd) vs Rd

• Ninlaro-Rd (IRd) vs Rd

• XPOVIO-Velcade-dex (XPO-Vd) vs Vd

Median progression-free survival favored

• VPd: 11 vs 7 months

• KRd: 26 vs 17 months

• IRd: 21 vs 15 months

• XPO-Vd: 14 vs 9 months

Clinical considerations

• Consider for relapse on Revlimid

• VPd associated with more low blood counts, infections, and neuropathy than Pd

• KRd associated with more upper respiratory infections and high blood pressure than Rd

• IRd an oral regimen

• Gastrointestinal toxicities and rashes

• Lower incidence of peripheral neuropathy

• XPO-Vd associated with low platelet counts and fatigue with triplet, but less neuropathy than the Vd

Important Considerations for Use of Proteasome Inhibitors

Velcade

• Risk of peripheral neuropathy (PN; numbness, tingling, burning sensations and/or pain due to nerve damage)

- Avoid in patients with severe existing PN

- Reduced with subcutaneous once-weekly dosing

• High risk of shingles

- Use appropriate vaccination

• No dose adjustment for kidney issues; adjust for liver issues

Kyprolis

• Less PN than Velcade

• High risk of shingles

- Use appropriate vaccination

• Monitor for heart, lung, and kidney side effects

- Use with caution in older patients with cardiovascular risk factors

• High blood pressure

• No dose adjustment for kidney issues; adjust for liver issues

Ninlaro

• Less PN than Velcade

• High risk of shingles

- Use appropriate vaccination

• Monitor for rashes and gastrointestinal (GI) side effects

- GI effects occur early

• Needs to be taken at least 1 hour before or 2 hours after a meal

Important Considerations for Use of Immunomodulatory Drugs

Revlimid*

• Rash

- Consider antihistamines

• Diarrhea

- Consider bile acid sequestrants

• Risk of blood clots

• Risk of second primary malignancies

• Dose adjustment based on kidney function

Pomalyst*

• Low blood counts

• Less rash than Revlimid

• Risk of second primary malignancies

• Risk of blood clots

Important Considerations for Use of XPOVIO

Gastrointestinal Low Na Sodium 22.990

Begin prophylactic anti-nausea medications. Consult with your doctor if nausea, vomiting, or diarrhea occur or persist.

Fatigue

blood counts (cytopenias)

Monoclonal Antibody–Based Regimens at Relapse

Currently Available Naked Monoclonal Antibodies for One to Three Prior Lines of Therapy

Drug Formulation

Approval

Darzalex (daratumumab)

SC once a week for first 8 weeks, then every 2 weeks for 4 months, then monthly

• For relapsed/refractory myeloma as a single agent and as a triplet with Revlimid or Velcade or Kyprolis or Pomalyst plus dexamethasone

Empliciti (elotuzumab)

IV once a week for first 8 weeks, then every 2 weeks (or every 4 weeks with pom)

• For relapsed/refractory myeloma as a triplet with Revlimid or Pomalyst and dexamethasone

Sarclisa (isatuximab)

IV once a week for first 4 weeks, then every 2 weeks

• For relapsed/refractory myeloma as a triplet with Pomalyst or Kyprolis and dexamethasone

Monoclonal Antibody–Based Regimens for Early Relapse: Darzalex

POLLUX

Regimens compared

• Darzalex-Revlimiddex (DRd) vs Rd

CASTOR CANDOR APOLLO

• Darzalex-Velcade-dex (DVd) vs Vd

• Darzalex-Kyprolis-dex (DKd) vs Kd

• Darzalex-Pomalystdex (DPd) vs Pd

Median progressionfree survival favored

• DRd: 45 vs 18 months

• DVd: 17 vs 7 months

• DKd: 29 vs 15 months

• DPd: 12 vs 7 months

• Consider for relapses from Revlimid or Velcade maintenance

Clinical consider-ations

• DRd associated with more upper respiratory infections, low blood white blood cell counts, and diarrhea

• Consider for patients who are Revlimid - refractory without significant neuropathy

• DVd associated with more low blood cell counts

• Consider for younger, fit patients who are doublerefractory to Revlimid and Velcade

• DKd associated with more respiratory infections

• Sever side effects (possibly fatal) in intermediate fit patients 65 and older

• Consider in patients who are double - refractory to Revlimid and a proteasome inhibitor (Velcade, Kyprolis, Ninlaro)

• Severe low white blood cell counts

Monoclonal Antibody–Based Regimens for Early Relapse: Sarclisa and Empliciti

ELOQUENT-2

ELOQUENT-3 ICARIA-MM IKEMA

Regimens compared

• Empliciti-Revlimiddex vs Rd

• EmplicitiPomalyst-dex vs Pd

Median progressionfree survival favored

• Empliciti-Rd: 19 vs 15 months

• Empliciti-Pd: 10 vs 5 mos

• Sarclisa-Pomalyst-dex vs Pd

• Sarclisa-Kyprolis-dex vs Kd

Clinical considerations

• Consider for non - Revlimid refractory, frailer patients

• Overall survival benefit with Empliciti- Rd

• Empliciti- Rd associated with more infections

• Sarclisa-Pd: 12 vs 7 mos

• Sarclisa-Kd: 41 vs 19 mos

• Consider for patients refractory to Revlimid and a proteasome inhibitor (Velcade, Kyprolis, Ninlaro)

• Consider for patients refractory to Revlimid and a proteasome inhibitor (Velcade, Kyprolis, Ninlaro)

• Sarclisa - Pd associated with severe low white blood cell counts, more dose reductions, upper respiratory infections, and diarrhea

• Consider for patients refractory to Revlimid and Velcade

• Sarclisa - Kd associated with higher MRD negativity rates

• Sarclisa - Kd associated with severe respiratory infections

Myeloma: Second or higher relapse

Second or higher relapse

Refractory to IMiD, PI, Anti-CD38

Refractory to IMiD, PI, Anti-CD38, Alkylators, and Anti-BCMA

Existing drugs:

Combinations with Cyclophosphamide

that do not have IMiD, PI, Anti CD38 (e.g., KCd)

Anti BCMA strategy

Anti-BCMA

Bispecific

BCMA CAR-Ts

Elotuzumab

Selinexor

Venetoclax

Bendamustine

VDT PACE

New Drugs: Iberdomide, Mezigdomide

New bispecifics (Cevostamab, Talquetamab)

New CAR-Ts

New Monoclonals

New ADCs

Currently Available Drugs for Triple -Class Refractory Myeloma

Class

Drug

Formulation

Approval

Nuclear export inhibitor

XPOVIO (selinexor)

Antibody-drug conjugate

Blenrep (belantamab mafodotin)*

Twice-weekly pill

• For relapsed/refractory myeloma in combination dexamethasone (after at least 4 prior therapies disease is refractory to at least 2 PIs, at least 2 IMiDs, and an anti-CD38 mAb

2.5 mg/kg IV over approximately 30 minutes once every 3 weeks

• For relapsed/refractory myeloma (after at least including an anti-CD38 mAb, a PI, and an IMiD

Chimeric antigen receptor (CAR) T cell

Abecma (idecabtagene vicleucel)†

300 to 460 × 106 genetically modified autologous CAR T cells in one or more infusion bags

• For relapsed/refractory myeloma (after 4 or more prior lines of therapy, including an IMiD, a PI, and anti-CD38 mAb

CAR T cell

Bispecific antibody

Carvykti (ciltacabtagene autoleucel)‡

0.5 to 1.0 × 106 genetically modified autologous CAR T cells/kg of body weight

Tecvayli (Teclistamab) ‡ Step up dosing then weekly SQ

IMiD, immunomodulatory agent; PI, proteasome inhibitor; mAb, monoclonal antibody

• For relapsed/refractory myeloma (after 4 or more prior lines of therapy, including a PI, an IMiD, and anti-CD38 mAb

For relapsed/refractory myeloma (after 4 or more therapy, including a PI, an IMiD, and an anti-CD38

†Black box warning: cytokine release syndrome; neurologic toxicities; hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS); prolonged cytopenia

‡Black box warning: cytokine release syndrome; neurologic toxicities; Parkinsonism and Guillain-Barré syndrome; hemophagocytic lymphohistiocytosis/ macrophage activation syndrome (HLH/MAS); prolonged cytopenia

Abecma and Carvykti are available only through a restricted distribution program

XPOVIO + Dexamethasone in Relapsed/Refractory Myeloma

Previous therapies to which the disease was refractory, n (%)

Additional analyses showed clinical benefit with XPOVIO regardless of patient age and kidney function.2,3

Emerging Therapies for Relapsed/Refractory Multiple Myeloma

Bispecific antibodies

• Elranatamab, talquetamab, cevostamab, and others

• Target BCMA, GPRC5D, or FcRH5 on myeloma cells and CD3 on T cells

• Redirects T cells to myeloma cells

Cereblon E3 ligase modulators (CELMoDs)

• Iberdomide

• Targets cereblon

• Enhances tumoricidal and immune-stimulatory effects compared with immunomodulatory agents

Small molecule inhibitors

• Venetoclax

• Targets Bcl-2

• Induces multiple myeloma cell apoptosis

CAR T-Cell Therapy and Bispecific Antibodies

Antibody–Drug

Conjugates

Cho. Front Immunol. 2018;10:1821.

Autologous CAR T-Cell Therapy: Underlying Principles

Leukapheresis Manufacturing Infusion

Collect patient’s white blood cells

Isolate and activate T cells Engineer T cells with CAR gene

Tumor cell

Targeting element (eg, CD19, BCMA, CD20)

Spacer

Transmembrane domain

Expand CAR T cells Infuse same patient with CAR T cells

Activity

CD19

Viral vector with CAR DNA

CARengineered T cell

Costimulatory domain (eg, CD28 or 4-1BB)

CD3� (essential signaling domain)

Median manufacturing time: 17-28 days

Patients undergo lymphodepleting (and possibly salvage/bridging) therapy

CAR T-Cell Therapy Patient Journey

3

Two CAR T-Cell Therapies Approved!

Drug Formulation Approval

Abecma (idecabtagene vicleucel)*

Carvykti (ciltacabtagene autoleucel)

300 to 460 × 106 genetically modified autologous CAR T cells in one or more infusion bags

0.5 to 1.0 × 106 genetically modified autologous CAR T cells/kg of body weight

IMiD, immunomodulatory agent; PI, proteasome inhibitor; mAb, monoclonal antibody

• For relapsed/refractory myeloma (after 4 or more prior lines of therapy, including an IMiD, a PI, and an anti-CD38 mAb)

• For relapsed/refractory myeloma (after 4 or more prior lines of therapy, including a PI, an IMiD, and an anti-CD38 mAb)

*Black box warning: cytokine release syndrome; neurologic toxicities; hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS); prolonged cytopenia

†Black box warning: cytokine release syndrome; neurologic toxicities; Parkinsonism and Guillain-Barré syndrome; HLH/MAS; prolonged cytopenia

Abecma and Carvykti are available only through a restricted distribution program.

Abecma and Carvykti in Relapsed and Refractory Multiple Myeloma

CR or sCR and MRD NE CR or sCR and MRD-

ORR, overall response rate; PR, partial response; VGPR, very good partial response; CR, complete response; sCR, stringent complete response; MRD, minimal residual disease; PFS, progression-free survival

KarMMa Trial. Munshi NC et al. N Engl J Med. 2021;384:705.

CARTITUDE-1 Trial. Berdeja JG et al. Lancet. 2021;398:314; Martin T et al. J Clin Oncol. June 4, 2022 [Epub ahead of print].

Cartitude-4 Schema

• Relapsed/refractory multiple myeloma who received 1 to 3 prior lines of therapy

• Randomly assigned to cilta-cel, pomalidomide (Pomalyst), bortezomib (Velcade), and dexamethasone (PVd); or daratumumab (Darzalex), pomalidomide, and dexamethasone (DPd)

• primary endpoint of the study is PFS; safety, overall survival, minimal residual disease negative rate and overall response rate are secondary endpoints

• Cilta-cel Meets PFS End Point in Relapsed/Lenalidomide-Refractory

Multiple Myeloma: January 27, 2023.

CRS Clinical Manifestations With CAR T-cell Therapy in MM

Nausea Vomiting Anorexia

Fatigue

Headache

Myalgia Arthralgia

Rigors

High Fevers

Hypotension

Tachycardia

Neurologic Change

Dyspnea

Tachypnea

Hypoxia

CAR T: Expected Toxicities

CRS ICANS

Onset 1-9 days after CAR T-cell infusion

Duration 5-11 days

Symptoms

Cytokine release syndrome (CRS) Neurotoxicity (ICANS)

• Fever

• Difficulty breathing

• Dizziness

• Nausea

• Headache

• Rapid heartbeat

• Low blood pressure

Management

• Actemra (tocilizumab)

• Corticosteroids

• Supportive care

Cytopenias Infections

2-9 days after CAR T-cell infusion

3-17 days

• Headache

• Confusion

• Language disturbance

• Seizures

• Delirium

• Cerebral edema

• Antiseizure medications

• Corticosteroids

*Based on the ASTCT consensus; †Based on vasopressor; ‡For adults and children >12 years;

§For children ≤12 years; ‖Only when concurrent with CRS

Xiao X et al. J Exp Clin Cancer Res. 2021;40(1):367. Lee DW et al. Biol Blood Marrow Transplant. 2019;25:625; Shah N et al. J Immunother Cancer. 2020;8:e000734.

CAR-T access remain an issue

Survey of 20 centers. Responses from 17 centers.

Anti-BCMA ALLO-715

• BCMA cell therapy has demonstrated unparalleled efficacy, but it is not readily available to all patients

• Allogeneic CAR T-cell therapy has the potential to make CAR T-cell therapy accessible to all eligible patients on demand and supports redosing

• ALLO-715 is an allogeneic anti-BCMA CAR T-cell product that uses gene editing specifically designed to:

• Disrupt the TCRα constant gene, thereby leading to a reduced risk of GVHD

• Edit the CD52 gene to allow the use of ALLO-647 (a humanized anti-CD52 mAb) to selectively deplete host T-cells while simultaneously protecting donor cells

Knockout of CD52 KO for selective lymphodepletion with ALLO-647

Knockout of TRAC to minimize risk of GVHD

Allogeneic BCMA-targeting CAR T cells in relapsed/refractory

multiple myeloma: phase 1

UNIVERSAL trial interim results

Transplant vs CAR T Cells

Cellular therapies CAR T-cell therapy

Patient’s cells collected

Types of cells collected T

Collected cells are genetically engineered in a lab

Patient given chemotherapy before cells are infused back into patient Yes,

When in the course of myeloma is this usually done?

Side effects of treatment

After multiple relapses As part of initial treatment

Cytokine release syndrome; confusion

*An immune cell that is the “business end” of the system, in charge of maintaining order and removing cells.

†Precursor cells that give rise to many types of blood cells. We actually collect CD34+ve cells.

Fatigue, nausea, diarrhea

Bispecific and Trispecific Antibodies

Bispecific Antibodies

Bispecific antibodies are also referred to as dual specific antibodies, bifunctional antibodies, or T-cell engaging antibodies

Bispecific antibodies can target two cell surface molecules at the same time (one on the myeloma cell and one on a T cell)

Many different bispecific antibodies are in clinical development; none are approved for use in myeloma

Availability is off-the-shelf, allowing for immediate treatment

Examples:

• Elranatamab

• Teclistamab

• TNB-303B (ABBV-383)

• REGN5458

• Cevostamab

• Talquetamab

BCMA, GPRC5D, or FcRH5

Now Approved: Tecvayli, the First Bispecific Ab

Drug Formulation

Approval

Tecvayli (teclistamab)*

Step-up dosing† the first week then once weekly thereafter by subcutaneous injection

• For relapsed/ refractory myeloma (after 4 or more prior lines of therapy, including an IMiD, a PI, and an anti-CD38 mAb)

Median duration of response 18.4 months

IMiD, immunomodulatory agent; PI, proteasome inhibitor; mAb, monoclonal antibody

*Black box warning: cytokine release syndrome; neurologic toxicities

†Patients are hospitalized for 48 hours after administration of all step-up doses.

Tecvayli is available only through a restricted distribution program.

MajesTEC-1: Duration of Response

CR or better median DOR not reached (95% CI: 16.2–NE)

• Overall median DOR of 18.4 months (95% CI: 14.9–NE), and was not yet mature with data from 71 patients (68.3%) censored

• 12-month event-free rate:

• Overall:

Overall median DOR 18.4 months (95% CI: 14.9–NE)

• Patients with CR or better:

68.5% (95% CI: 57.7–77.1)

80.1% (95% CI: 67.6–88.2)

Tecvayli Side Effects

Side Effects

• Cytokine release syndrome

• Injection-related reactions

• Injection-site reaction

• Infections

• Neutropenia

• Anemia

• Thrombocytopenia

• Neurotoxicity

Side Effect Management

• Available only through a Risk Evaluation and Mitigation Strategies (REMS) due to the risk of cytokine release syndrome

• Patients will receive step-up dosing and will be monitored in an inpatient setting

• Cytokine release syndrome is managed in the same fashion as CAR T

• Injection reactions are managed with oral antihistamines and topical steroids

• Infection prevention!

• COVID precautions

Similarities and Differences Between CAR T-Cell Therapy and Bispecific Antibodies

Bispecific Antibodies: >20% Activity

*Based on a recent sampling

TRIMM-2: Response With Teclistamab + Daratumumab in R/R MM

Duration of Response (n = 39)

On Treatment as of April 6, 2022 In follow-up as of April 6, 2022 Dose level (mg/kg) 1.5 QW 1.5 QW 1.5 QW 3.0 QW 3.0 QW Penta-ref; BCMA-ex 3.0 QW CD-38-ex 1.5 QW Penta-ref 1.5 QW Penta-ref 1.5 QW Penta-ref 3.0 Q2W Penta-ref; BCMA-ex 1.5 QW 1.5 QW Triple-ref 3.0 QW CD-38-ex 1.5 QW 3.0 QW Triple-ref 1.5 QW CD-38-ref 3.0 Q2W Triple-ref 3.0 Q2W Penta-ref 3.0 Q2W Triple-ref 1.5 Q2W Triple-ref 3.0 Q2W 1.5 QW Penta-ref; BCMA-ex 1.5 QW Penta-ref; BCMA-ex 1.5 QW 3.0 Q2W Triple-ref 3.0 Q2W CD-38-ref 1.5 QW Triple-ref 3.0 Q2W Penta-ref 3.0 Q2W Penta-ref 3.0 Q2W Penta-ref 3.0 Q2W 3.0 Q2W CD-38-ex 3.0 Q2W 3.0 Q2W CD-38-ex 3.0 Q2W Triple-ref 3.0 Q2W CD-38-ex 3.0 Q2W 3.0 Q2W CD-38-ref 1.5 Q2W Triple-ref

sCR CR VGPR PR MR SD PD

D/C-PD D/C-AE D/C-Other Death

*Response evaluable patients.

Rodriguez-Otero. EHA 2022. Abstr S188.

§ Responses were durable and deepened over time

§ At median follow-up of 8.6 mo (range: 0.3-19.6), 66.7% of responders were alive and continuing on treatment

Tecvayli in Combination With Darzalex and Revlimid

Phase 1b study (MajesTEC-2) in RRMM with 1–3 prior lines of therapy (including an IMiD and a PI).

32 patients—who had received at least 2 prior lines of therapy—received treatment with the triplet with Tecvayli at 2 different doses (0.72 mg/kg and 1.5 mg/kg) subcutaneously.

IMiD, immunomodulatory drug; PI, proteasome inhibitor

Elranatamab in Patients With Relapsed/Refractory Multiple Myeloma

Data from this trial was recently used to submit a Biologics License Application to the U.S. Food and Drug Administration for the treatment of patients with relapsed or refractory multiple myeloma.

Talquetamab in Patients With Relapsed/Refractory Multiple Myeloma

288 patients—with no prior T-cell redirecting therapies—received treatment with talquetamab at 2 different doses (0.4 mg/kg every week and 0.8 mg/kg every other week) subcutaneously. IMiD, immunomodulatory drug; PI, proteasome inhibitor

Data from this trial was recently used to submit a Biologics License Application to the U.S. Food and Drug Administration for the treatment of patients with relapsed or refractory multiple myeloma.

Phase 1/2 study (MonumenTAL-1) in RRMM

Fixed-Duration Therapy With Bispecifics Cevostamab

At the time of this presentation, no patients who achieved an sCR have relapsed!

Expected Toxicities With T-Cell Activating Therapies (CAR T and Bispecific Antibodies)

• Viruses: CMV, EBV

• PCP/PJP

• Ongoing discussions regarding prophylactic measures

- IVIG

- Anti-infectives

Off target effects (with GPRC5D targeted agents)

Cytokine release syndrome (CRS)

Infections

• Usually occurs within first 1–2 weeks

• Frequency (all grade and grade 3–

5) higher with CAR T

Cytopenias

Neurotoxicity (ICANS)

ICANS, immune effector cell-associated neurotoxicity syndrome; CMV, cytomegalovirus; EBV, Epstein-Barr virus; PCP/PJP, pneumocystis pneumonia/pneumocystis jiroveci pneumonia

Cytokeratin changes/rash

Dysgeusia

BCMA-Targeted Bispecific Agents: Summary

Bispecific Antibodies Clinical Trials in Multiple Myeloma future state

Key Points

CAR T and bispecific antibodies are very active even in heavily pretreated patients.

Side effects of CAR T cells and bispecific antibodies include cytokine release syndrome, confusion, and low blood counts, all of which are treatable.

Abecma and Carvykti are only the first-generation CAR T cells and target the same protein. Different CAR Ts and different targets are on the way.

Bispecific antibodies represent an “off-the-shelf” immunotherapy; Tecvayli was approved in October 2022.

Several additional bispecific antibodies are under clinical evaluation.

The Evolution of Myeloma Therapy

Panobinostat Daratumumab Ixazomib

Elotuzumab Isatuximab

Idecabtagene

Ciltacabtagene

Audience Q&A

March 4, 2023, Agenda

1:15 – 2:00 PM Clinical Trials

David Vesole, MD, PhD, Medstar Georgetown University Hospital

2:00 –

2:15 PM Q&A

2:15 –

3:00 PM Life is a Canvas, You are the Artist

Sandra Rome, RN, MN, AOCN, CNS, Cedars-Sinai Medical Center, IMF Nurse Leadership Board

3:00 –

3:15 PM Q&A

3:15 –

3:30 PM Local Patient & Care Partner Panel

Tom Tucker, Patient Advocate and Helen Tucker, Care Partner

3:30 – 3:40 PM Q&A

3:40 – 3:55 PM Community Resource

3:55 – 4:00 PM Closing Remarks

4:00 PM Coffee / Network

Clinical Trials

David

Vesole,

MD, PhD, FACP

MedStar Georgetown University Hospital

Clinical Trials

David H. Vesole, MD, PhD, FACP

Director, Myeloma Program

MedStar Georgetown University Hospital

Professor of Medicine

Georgetown University School of Medicine

Co-Chief, Myeloma Division

Director, Myeloma Research

John Theurer Cancer Center at Hackensack UMC

Professor of Medicine

Hackensack Meridian School of Medicine

David.Vesole@hmhn.org

Why Are Cancer Clinical Trials Important?

• Clinical trials translate results of basic scientific research into better ways to prevent, diagnose, or treat cancer

• The more people that take part, the faster we can:

• Answer critical research questions

• Find better treatments and ways to prevent cancer

Do Many People Participate in Cancer Clinical Trials?

Only 3 percent of U.S. adults with cancer participate in clinical trials

Steps to make an informed decision treatment decision

Clinical Trials

• Cancer clinical trials are

– Carefully controlled research studies

– Conducted by doctors to improve the care and treatment of cancer patients

• The aim of a clinical trial is to

– Study a new therapy or a new use for an already approved therapy

– Compare a new treatment with a standard treatment to find out which one works better and/or has fewer side effects

Clinical trial study design or protocol

• Each cancer clinical trial has a written detailed study design called a protocol that includes:

• Why the clinical trial is needed

• Purpose of the clinical trial

• What drug or drug(s) are being tested, with a treatment and follow-up schedule

• Safety measures throughout the clinical trial program

• How outcomes will be measured

• Who is eligible for the clinical trial

• How the clinical trial will be organized, one site or multiple sites

• If the clinical trial is a multi-site trial, all participating physicians must follow the same protocol

Overview of New Drug Development

Identify a target for therapy in the laboratory

Confirm the anticancer activity in laboratory and animal studies

Clinical trials (human studies) to determine safety, dosing and effectiveness

The whole process costs millions of dollars and years of effort!

How How do clinical trials work?

Phase I investigates for safety and side effects, dosage and best way to give treatment–includes 20 or more people

Phase II determines effectiveness and safety–typically includes fewer than 100 (may include up to 300) people

Phase III looks at effectiveness, side effects and safety in comparison with other treatments–includes 100s to 1000s of people

Phase IV gathers more information after FDA approval & drug is on market

Benefits of Participation

Possible benefits:

•Patients will receive, at a minimum, the best standard treatment

•If the new treatment or intervention is proven to work, patients may be among the first to benefit

•Patients have a chance to help others and improve cancer care

Risks of Participation

Possible risks:

• New treatments or interventions under study are not always better than, or even as good as, standard care

• Even if a new treatment has benefits, it may not work for every patient

• Health insurance and managed care providers do not always cover clinical trials

Why Do So Few Cancer Patients

Participate in Clinical Trials?

Patients may:

• Be unaware of clinical trials

• Lack access to trials

• Fear, distrust, or be suspicious of research

• Have practical or personal obstacles

• Face insurance or cost problems

• Be unwilling to go against their physicians’ wishes

• Be unwilling to “lose control” of a person’s care

• Believe that standard therapy is best

Misconceptions About Cancer Clinical Trials

Misconceptions

I may get a sugar pill (placebo) instead of real therapy.

Facts

No placebos are given alone every patient receives treatment.

I’ll be treated like a guinea pig.

Clinical studies are for people with no other options.

Most patients receive care that exceeds expectations.

Many involve an adjustment to a standard of care that may improve outcome or quality of life

The more people who participate, helps to speed drug development.

Considering Entering a Clinical Trial?

• Discuss whether or not you are eligible for a clinical trial with your physician

• Work with your physician to determine the best trial for you

• Meet with the clinical research nurse or trials coordinator to discuss the trial

• Carefully review the provided “Informed Consent”

• Describes the study and any potential safety concerns related to the experimental medication

Ongoing Trials in Myeloma

• SO many areas being studied right now including…

• CAR T Cell therapy (used earlier in myeloma, new targets, faster manufacturing, even allo CAR T!)

• Novel Bispecific Therapies (with new targets)

• New molecules – CelMods, Modakafusp…

And MANY more!

Audience Q&A

How to Manage Myeloma Symptoms and Side Effects

Sandra Rome, RN, MN, AOCN, CNS

IMF Nurse Leadership Board, CedarSinai Medical Center

March 4, 2023

LIFE IS A CANVAS, YOU ARE THE ARTIST

Sandra Rome, RN, MN, AOCN, CNS

Cedars-Sinai Medical Center

Los Angeles, California

OBJECTIVES

COLOR WHEEL OF TREATMENT

Myeloma treatment

HEALTHY LIVING

Infection and Side Effect Management

FRAMING YOUR CARE

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

COLOR WHEEL OF TREATMENT

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

GALLERY OF GOALS

MYELOMA TREATMENT SUPPORTIVE THERAPIES

• Rapid and effective disease control

• Durable disease control

• Minimize side effects

• Allow for good quality of life

• Improved overall survival

• Prevent disease- and treatmentrelated side effects

• Optimize symptom management

• Allow for good quality of life

DISCUSS GOALS AND PRIORITIES WITH YOUR HEALTHCARE TEAM

Transplant

Eligible Patients

MANAGING MYELOMA: THE COMPONENTS

Transplant

Consolidation

Maintenance

Initial Therapy

Transplant

Ineligible patients

Consolidation/ Maintenance/ Continued therapy

Treatment of Relapsed disease

Everyone

Supportive Care

SHADES OF “AUTO” STEM CELL TRANSPLANT (ASCT)

• There are no black and white answers to deciding to undergo a transplant

• Undergoing transplant is a commitment for both you and your care partner

• Understanding the process will help bring to focus elements needed to decide if/when to undergo transplant

Clinical Experience Data from Research

Patient Preference

Adapted from Philippe Moreau, ASH 2015

HEALTHY LIVING FOR PEOPLE WITH MULTIPLE MYELOMA INFECTION AND SIDE EFFECT MANAGEMENT

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

Physical

• 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%)

THE BRIGHT DARK SIDE TO STEROIDS

&

Steroid Synergy

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

Managing Steroid Side Effects

• Consistent schedule (AM vs. PM)

• Take with food

• Stomach discomfort: Over-the-counter or prescription medications

• Medications to prevent shingles, thrush, or other infections

Steroid Side Effects

• Irritability, mood swings, depression

• Difficulty sleeping (insomnia), fatigue

• Increased risk of infections, heart disease

• Muscle weakness, cramping

• Increase in blood pressure, water retention

• Blurred vision, cataracts

• Flushing/sweating

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

• Weight gain, hair thinning/loss, skin rashes

• Increase in blood sugar levels, diabetes

Rajkumar

SV, Jacobus S, Callander NS, Fonseca R, Vesole DH, Williams ME, Abonour R, Siegel DS, Katz M, Greipp PR, Eastern Cooperative Oncology Group (2010) Lenalidomide plus 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.

Faiman B. Steroid-Associated Side Effects: A Symptom Management

BCMA TARGETED THERAPIES ARE ASSOCIATED WITH AN INCREASED RISK OF INFECTIONS

Both viral and bacterial

– Up to a 3rd of patients on clinical trials has serious infections (requiring IV antibodies or hospitalization)

Increased risk of serious COVID complications despite history of vaccination

– Antibody levels

–

Tixagevimab co-packaged with cilgavimab (EVUSHELD)

–

Immediate treatment once diagnosed Nirmatrelvir with Ritonavi (Paxlovid)

• Start as soon as possible; must begin within 5 days of when symptoms start

Multiple myeloma

Immune dysfunction

INFECTION CAN BE SERIOUS FOR PEOPLE WITH MYELOMA

7-10 fold increased risk of bacterial and viral infections for people with myeloma

care team

General Infection Prevention Tips

Good personal hygiene (skin, oral)

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

Growth factor (Neupogen [filgrastim])

Immunizations (NO live vaccines)

• Medications (antibacterial, antiviral)

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

HEALTHFUL LIVING STRATEGIES: PREVENTION

Manage stress

• Rest, relaxation, sleep hygiene

• Mental health / social engagement

• Complementary therapy

Maintain a healthy weight

• Nutrition

• Activity / exercise

Preventative health care

• Health screenings, vaccinations

• Prevent falls, injury, infection

• Stop smoking

• Dental care

Maintain renal health

• Myeloma management

• Hydration

• Avoid renally-toxic medications

– Dose adjust to renal function

• Diabetes management

Protect your bones

• Nutrition, Calcium + D supplement

• Weight-bearing activity / walking

• Bone strengthening agents

Faiman B, et al. CJON. 2017;21(5)suppl:19-36. Dimopoulous M, et al. Leukemia. 2009;23(9):1545-56. Brigle K, et al. CJON. 2017;21(5)suppl:60-76. Faiman B, et al. CJON. 2017;21(5)suppl:19-36. Faiman B, et al. CJON. 2011;15suppl:66-76. Miceli TS, et al. CJON. 2011;15(4)suppl:9-23.

“An ounce of prevention is worth a pound of cure.” Benjamin Franklin

GI SYMPTOMS: PREVENTION & MANAGEMENT

Diarrhea may be caused by medications and supplements

• Laxatives, antacids with magnesium

• Antibiotics, antidepressants, others

• Milk thistle, aloe, cayenne, saw palmetto, ginseng

• Sugar substitutes in sugar free gum

Avoid caffeinated, carbonated, or heavily sugared beverages

Take anti-diarrheal medication

• Imodium®, Lomotil®, or Colestid if recommended

• Fiber binding agents – Metamucil®, Citrucel®, Benefiber®

• Welchol® if recommended

Constipation may be caused by

• Opioid pain relievers, antidepressants, heart or blood pressure medications, others

• Supplements: Calcium, Iron, vitamin D (rarely), vitamin B-12 deficiency

Increase fiber

• Fruits, vegetables, high fiber whole grain foods

• Fiber binding agents – Metamucil®, Citrucel®, Benefiber®

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

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

• Monitor serum calcium levels

• Imaging may be needed depending on type and location of pain (eg, MRI, PET-CT)

• May include medications (eg bone modifying agents), activity, surgical intervention, radiation therapy, etc

• Complementary therapies (Mind-body, medication, yoga, supplements, acupuncture, etc)

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

If PN worsens, your HCP may:

• Change your treatment

• Prescribe oral or topical pain medication

• Suggest physical therapy

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

FATIGUE, ANXIETY & DEPRESSION

All can affect quality of life and relationships

• Fatigue is the most common reported symptom (98.8%)

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

• Anxiety reported in >35%

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

Often, people do not share these symptoms with their provider. Talk to your provider about symptoms that are not well controlled or thoughts of self harm. Help is available.

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

FINANCIAL BURDEN

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

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

CARE PARTNER SUPPORT

Care partner support is essential for the entire transplant and CAR T processes particularly

• Sedated procedures; Education sessions

• Assistance with daily activities, managing medications and alerting the medical team of changes

• Continued support and assistance is often needed in the early days after returning home. Less assistance will be needed as time goes on.

Care partner can be one person or a rotation of many people.

FRAMING YOUR CARE

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

You are central to the care team

CARE TEAM COLLAGE

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

You and Your Caregiver(s) Support Network

Subspecialists

Myeloma Specialist

General Hem/Onc

Provider (PCP)

PREPARE FOR VISITS & CONSIDER TELEMEDICINE

Come prepared:

• Bring a list of current medications, prescribed and over the counter

• Write down your questions and concerns. Prioritize them including financial issues

• Have there been any medical or life changes since your last visit?

• Current symptoms - how have they changed (improved, worsened, stable)? Keep a symptom diary. Bring it along

• Communicate effectively: your health care team can’t help if they don’t know

• Know the “next steps”, future appointments, medication changes, refills, etc

Check with your healthcare team –Is telemedicine an option?

Similar planning for “in-person” appointment PLUS:

• What is the process and what technology is needed?

• Plan your labs: are they needed in advance? Do you need an order?

• Plan your location: quiet, well-lit location with strong wi-fi is best

• Plan yourself: consider if you may need to show a body part and wear accessible clothing

• Collect recent vital signs (blood pressure, temp, heart rate) self-serve blood pressure cuff is available at many pharmacies and for purchase

SHARED DECISION-MAKING

Be empowered to be part of the treatment decision-making

• Ask for time to consider options (if needed/appropriate)

• Understand options; consider priorities

• Use reliable sources of information

• Use caution considering stories of personal experiences

• Consider your goals/values/preferences

• Express your goals/values/preferences; create a dialog

• My top priority is [goal/value]; additional [preferences] are also important.

• I think [treatment] may be a good choice given my priorities… What do you think?

• Arrive at a treatment decision together

Philippe Moreau. ASH 2015.

YOU ARE NOT ALONE

Audience Q&A

Local Patient and Care Partner Panel Tom & Helen Tucker

Tom Tucker – My Amazing Life Trajectory

• Born in Yosemite in 1947

• Father worked for National Park Service

• Graduated Eighth Grade from Yosemite Elementary School 1960

• Moved to San Diego

• Graduated Mission Bay High School 1964

• Member of First Entering Freshman Class at UC San Diego 1964

• Cooperative Physics Trainee at Navy Electronics Laboratory while in college

• Graduated BA Physics from UC San Diego in 1969

Tom Tucker – My Amazing Life Trajectory

• Co-op program included one year off, working full time

• My assignments included at sea time on USS Baya, NEL’s research submarine

• Completed Navy OCS, Nuclear Power Training, Submarine School, reported to USS Plunger in Pearl Harbor April 1971

• Co-op program cancelled when I was returning to complete Senior Year

• Applied for Navy OCS, picked up by NUPOC Program

• ADM Rickover accepted me, after explaining I was a Draft Dodger

• Plunger reassigned to Mare Island Naval Shipyard for SUBSAFE, Refueling Overhaul

September 1971

• Met Army Nurse, Helen Shriver, at Pearl Harbor Officers Club, married her in February 1972

Tom Tucker – My Amazing Life Trajectory

• Plunger 18 Month Overhaul took 27 months

• Had to extend Active Duty for 10 months to complete Submarine Qualification

• Returned to Navy Lab in 1975 after a quarter at UC San Diego Grad School

• Affiliated with Naval Reserve after Release from Active Duty

• Worked Developmental Undersea Surveillance Projects, including significant sea time

• Completed MS, Applied Physics in 1978

• Was Navy Scientific Diver

• Settled in San Diego

• Enjoyed 3 children: Rick born 1973, Kathy born 1975, Mike born 1978

• Helen became School Nurse

• Moved to private sector in 1985

• Advanced Digital Systems, Titan Corp (1985 – 1998)

• Cubic Transportation Systems (1998 -2001)

• Daughter Kathy killed in bicycle accident in 1988

Tom Tucker – My Amazing Life Trajectory

• Retired from Naval Reserve in 1995 after 21 years, 3 Command Tours.

• Diagnosed with Myeloma in October 2006 because of abnormal blood tests in routine physical

• 70% Plasma Cells in Bone Marrow

• Started Induction Therapy with Thalidomide

• Referred to Kaiser LA Bone Marrow Transplant Dept

• Dr. Firoozeh Sahebi recruited me for ASCT Clinical Trial at City of Hope

• Randomized to Tandem Transplant Arm

• ASCTs at City of Hope in April, June 2007

• Bone Marrow Biopsies showed

• Cubic laid me off in 2001

• Returned to Navy Lab

• Picked up 6 months Sick Leave

• Worked up to Autonomous Distributed Networked Systems Branch Head

• 30% Plasma Cells after Induction Therapy

• 15% after First ASCT

• 5% after Second ASCT

• 0% in September 2007

• Cognitive Issues after ASCTs resulted in retiring from Navy Lab in January 2008

Tom Tucker – My Amazing Life Trajectory

• Randomized to No Maintenance Therapy Arm of Clinical Trial

• Relapsed Spring 2013

• Detectable M-Protein, Increasing IgA, Lambda in labs

• Bone Marrow Biopsy 30% Plasma Cells

• Returned to treatment with 10 mg Revlimid® in August 2013

• Disease responded to Revlimid®

• IgA, Lambda in normal range, M-Protein below quantifiable level

• Relapsed late 2010

• Detectable M-Protein, Increasing IgA, Lambda in labs

• Started treatment with 10 mg Revlimid® in January 2011

• Discontinued Revlimid® due to low blood counts (WBC, Platelets)

November 2011

• IgA, Lambda levels back in normal range, no quantifiable M-Protein

• Discontinued Revlimid® November 2015 because of low neutrophils

• Slow Increase in IgA, Lambda in early 2016

• Tried 5 mg Revlimid®, but didn’t control

Tom Tucker – My Amazing Life Trajectory

• Started Velcade® in June 2016

• IgA slowly increasing out of normal range in August 2018

• Bone Marrow Biopsy showed 5% Plasma Cells

• Continued Sub-Q Velcade® based on Bone Marrow Biopsy results

• Added 2 mg Pomalyst® in June 2021 due to rising IgA

• Filgrastim support added October 2021 because of neutropenia

• Discontinued Velcade® in December 2019 due to increasing Peripheral Neuropathy, Stable Disease

• Changed to Darzalex®/Dexamethasone in August 2020 due to rising IgA

• Increased Filgrastim to twice weekly in April 2022 because of low WBC, neutrophil levels

Tom Tucker – My Amazing Life Trajectory

I am incredibly blessed to be a 16 year myeloma survivor

• No such thing as an average myeloma patient

• Some have aggressive disease, others less aggressive

• Patients range across all walks of life, economic levels

• Very conscious that my myeloma has been relatively indolent, allowing treatments to keep me going

• For me, myeloma has been a chronic disease, rather than the near-term terminal disease that was the expectation when I was diagnosed in 2006

• Looking forward to new treatments becoming available to allow me to extend my survival

• Also looking forward to effective treatments for those who have a more aggressive myeloma

• Appreciate having Helen as my partner and caregiver

• Celebrated 50th Anniversary in February 2022

Audience Q&A

Myeloma Support Groups Take Action

THE IMF INVITES YOU TO PARTICIPATE!

A FRIENDLY COMPETITION WITH FELLOW SUPPORT GROUP MEMBERS

For Myeloma Action Month (MAM), let’s join together to increase awareness of myeloma AND support groups all while nurturing ourselves!

The IMF invites support group members to take action through mindfulness, movement and self enrichment. Support Group Members will work individually but together as a group to record the actions accomplished.

PARTICIPATING IS SIMPLE!

ITS AS EASY AS 1-2-3!

1. Sign up: Here

2. Take Action: complete as little or as many activities as you’d like each day

3. Log your activities: Here

How to earn points:

1 point per 15 minutes of each activity completed

•Mindfulness

•Movement

•Self Enrichment

•Share & Educate

How, what and when you do it is up to you!

Thank you to our sponsors!

Upcoming IMF Events

Patient and Family Webinars:

Boca Raton, FL – March 17 & 18, 2023 - with local Myeloma expert Dr. James Hoffman, and a presentation from Professor Sigurður Kristinsson from Iceland.

Virtual PFW – May 17, 2023 – keep an eye on our website for registration for this virtual program. It will air LIVE at 5:30PM PST

Los Angeles – August 18 & 19, 2023 – details to be announced, this event will have an international myeloma expert presenting!

Thank you for attending today's program!

March 4, 2023, International Myeloma Foundation’s Regional Community Workshop –San Diego.

A recording of todays program will be made available on our website in the coming weeks.