Atlanta RCW Slide Deck

Welcome!

Thank you for joining us today for the April 13th, 2024, International Myeloma Foundation’s Regional Community Workshop –Atlanta

9:00 – 9:15 AM

9:15 – 9:45 AM

9:45 – 9:55 AM

9:55 – 10:40 AM

IMF Regional Community Workshop

April 13th, 2024 - Agenda

Welcome & Introductions, Robin Tuohy

Myeloma 101, Jonathan Kaufman, MD

Q&A

Taking the Reins of Your Multiple Myeloma Care, Charise

Gleason, MSN, NP-C, AOCNP

10:40 – 10:50 AM

10:50 – 11:00 AM

11:00 – 11:45 AM

11:45 – 11:55 AM

Q&A

Coffee Break

Frontline Therapy, Nisha Joseph, MD

Q&A

11:55 AM – 12:40 PM LUNCH

12:40 – 1:00 PM

1:00 – 1:10 PM

1:10 – 1:30 PM

1:30 – 1:40 PM

1:40 – 2:25 PM

2:25 – 2:35 PM

2:35 – 2:45 PM

2:45 – 3:00 PM

IMF Regional Community Workshop

April 13th, 2024 – Agenda after lunch

Local Patient & Care Partner Panel, Sandy & Joe Brown, Jim & Lisa Mahoney

Q&A

Maintenance Therapy, Nisha Joseph, MD

Q&A

Relapsed Therapies & Clinical Trials, Jonathan Kaufman, MD

Q&A

Closing Remarks

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:

 Treatment questions along the spectrum of care

 Clinical Trial access and understanding

 Side effect management and health issues

 Financial resources for myeloma-related expenses

 Myeloma Specialist Referral contact information

 Support group information

 Caregiver Support

Paul Hewitt, Missy Klepetar, & Teresa Miceli

Educational Publications

A core mission of the IMF is to provide thorough and cutting-edge education to the New publications

The IMF Support Group Team is Here For You!

Shared Experiences Help to Better

Understand the Myeloma Journey

• Support Groups Empower Patients & Care Partners with information, insight, & hope

• The IMF provides educational support to a network of over 150 myeloma specific groups

We are happy to help connect you with an existing support group or help form a new one! We assist with virtual, in-person, and hybrid options for meetings. Reach out to us at SGTeam@myeloma.org Support.myeloma.org

Local Support Groups: You Are Not Alone!

 The Atlanta Area Multiple Myeloma Support Group

 Meets virtually on 1st Saturday of each month at 11am Eastern

 The Southside Atlanta Multiple Myeloma Support Group

 Meets virtually on the 4th Saturday of each month at 10am Eastern

IMF – Special Interest Virtual Groups

Special interest groups are designed as a supplemental support for specific populations of patients, in addition to their local Support Groups

 Las Voces de Mieloma

 Designed for Spanish speaking patients only

 Living Solo & Strong with Myeloma

 Designed for patients without a care partner

Coming Soon!

Care Partners Only

 Designed to address the needs of care partners only

 Smolder Bolder

 Created for people living with Smoldering Multiple Myeloma

 MM Families

 High Risk Multiple Myeloma

 Designed to address the needs of the high-risk MM population

 MGUS 4 Us

 Created for people living with MGUS

 For patients/care partners with young children

Myeloma 101

Jonathan Kaufman, MD

Winship Cancer Institute of Emory University

Atlanta, GA

Objectives

• Review the basics of blood and cancer

• Define multiple myeloma and its key features

• Discuss the staging and classification of myeloma

• Outline the approach to therapy of myeloma

• Appreciate the importance of health disparities in myeloma

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.

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 2023 Approx 13,000 Estimated Deaths in 2023

The Average Survival of patients with myeloma is IMPROVING!

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

Trends in MM Natural History by Race

MM Incidence  Higher incidence in AA vs White patients:

• 15.9 vs 7.5 cases per 100,000 per year

MM Mortality  Higher mortality in AA vs White patients:

• 5.6 vs 2.4 MM deaths per 100,000

MM Survival  5-year relative survival evolution from 1973 to 2005

• 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

• For example:

• IgG+kappa

• IgG+lambda

• IgA+kappa

• IgA+lambda

• etc…

• 80% of myeloma cases

Bence 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

IgG – 55% IgA – 25%

IgD – 1-2%

IgM – 1%

Light Chain Disease only – 20%

Non Secretors 1-2 %

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):28-43.

4. Kyle RA, et al. Curr Hematol Malig Rep. 2010;5(2):6269.

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:e538e548.

Multiple Myeloma Diagnosis Can Be Challenging

2014 IMWG Active Myeloma Criteria: Myeloma-Defining Events

R A B alcium elevation enal complications nemia one disease C Clonal bone marrow ≥10% or bony/extramedullary plasmacytoma

AND any one or more Myeloma-Defining Events

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.

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)

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

Weakness

Fatigue Infection

Weakness

Bone Damage

• Affects 85% of patients

• Leads to fractures

Bone Turnover

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

Bone pain

Loss of Appetite & Weight loss

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

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

LDH

Lactate

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

Dehydrogenase

Serum Protein EP

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

Immuno Fixation

Detects the presence & level of M protein = how much myeloma. No Heavy Chain = No M-Spike

Serum Free Light Chain

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

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

Testing To Determine A Diagnosis of Myeloma: Blood & Urine

Test Name

CBC + differential

Complete metabolic panel

Beta-2 Microglobulin (B2M)

Lactate Dehydrogenase (LDH)

Serum Immunofixation and Protein

electrophoresis (SPEP+IFE)

Immunoglobulins (G, A, M, D, E)

Free light chain assay with kappa/lambda ratio

Urine immunofixation & protein

electrophoresis (UPEP+IFE)

What it means

Hemoglobin, WBC, Platelets

Creatinine, Calcium, Albumin, Liver function

Part of staging and risk stratification

Measures the level of normal and clonal protein

Identifies the type of clonal protein

Measures the level of normal and clonal protein

Identifies the type of clonal protein

2014;15:e538-3548.

Testing To Determine A Diagnosis of Myeloma: Imaging

Healthy bone

Imaging:

– Skeletal survey: Series of X-rays; less sensitive than other techniques

– Whole body low dose (CTWB-LD CT )

– Positron Emission Tomography (PET/CT)

– Magnetic Resonance Imaging (MRI)

myeloma bone disease

versus

This Photo by Unknown Author is licensed under CC BY-NC-ND

Testing To Determine A Diagnosis of Myeloma: Bone Marrow

Bone marrow biopsy & aspirate

• Bone marrow plasma cells (%)

• Congo Red staining if concern for AL-Amyloid

Bone marrow genetics

• Cytogenetics

• Fluorescence in situ hybridization (FISH)

• Next generation sequencing (NGS)

Image Credit: IMF Patient Handbook

Image Credit: IMF Patient Handbook

Staging and Risk Stratification

Fluorescence in situ hybridization (FISH) and Chromosomal abnormalities

Image Credit: IMF Patient Handbook

Myeloma Stage:

Staging refers to the degree to which the cancer has progressed. Most important at time of diagnosis.

Stage 1

β2-microglobulin under 3.6 mg/L

Normal Lactate Dehydrogenase (LDH)

Stage 2

β2-microglobulin

Between 3.5 & 5.4mg/L

Stage 3

β2-microglobulin over 5.5 mg/L

NO High Risk Cytogenetics (FISH) AND

NO High Risk Cytogenetics (FISH)

HIGH Lactate Dehydrogenase (LDH)

High Risk Cytogenetics (FISH)

Deletion 17thchromosome

Translocation 4th and 14th

Translocation 14th and 16th

Translocation 14th and 20th AND/OR

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

Transplan t Ineligible Patients Consolidation / Maintenance Continued therapy

Everyone

Philippe Moreau. ASH 2015.

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

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

IMiD

immunomodulatory drug

Tools of the Trade Standard Drug Overview

Proteasome inhibitor

Chemotherapy

Steroids

Monoclonal Antibodies

Pomalyst (pomalidomide) P or Pom Oral

Revlimid (lenalidomide) R or Rev

Thalomid (thalidomide)

Velcade (bortezomib)

Kyprolis (carfilzomib)

Ninlaro (ixazomib)

T or Thal

V or Vel or B

C or K or Car

Intravenous (IV) or subcutaneous injection -

SC (under the skin)

N or I Oral

Cytoxan (cyclophosphamide) C

Alkeran or Evomela (melphalan) M or Mel

Decadron (dexamethasone)

Dex or D or d

Prednisone P or Pred

Darzalex (daratumumab)

Sarclisa (isatuximab)

Empliciti (elotuzumab)

Dara

Isa Elo

Oral or intravenous

Oral or intravenous

Intravenous (IV or SC)

Bispecific Antibodies

Tools of the Trade Novel Immunotherapy Drug Overview

Carvycti (ciltacabtagene vicleucelel) Cilta-cel

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

Tecvayli (teclistimab)

Talvey (Talquetamab)

Elrexfio (Elranatamab)

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

ADCC

Monoclonal Antibody-Based Therapeutic Targeting of Myeloma

Antibody-dependent Cellular cytotoxicity (ADCC)

Effector cells:

Complement-dependent Cytotoxicity (CDC)

CDC MM C1q C1q

Apoptosis/growth arrest via targeting signaling pathways

MM FcR

• Lucatumumab or Dacetuzumab (CD40)

• Elotuzumab (CS1; SLAMF7)

• Daratumumab, SAR650984/Isatuximab (CD38)

• XmAb5592 (HM1.24)

• Daratumumab

• SAR650984/Isatuximab (CD38)

MM

• 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

Antibody-Drug Conjugates

The Process of CAR T Cell Therapy

Manufacture of CAR T Cells

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

Antibody Drug

Elotuzumab

Bi-Specific Antibodies

Bi-Specific Antibodies

CAR-T

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

The Evolution of Myeloma Therapy

Bortezomib

Lenalidomide

Bortezomib Ixazomib

Lenalidomide + PI

Carfilzomib

Combinations

CAR T or Bispecifics? Daratumumab?

Elotuzumab Isatuximab

Idecabtagene autoleucel

Ciltacabtagene autoleucel

Teclistamab

Talquetamab

Elranatamab

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

Novel CAR T Cell Therapies

Bispecific/Trispecific Antibodies

CelMod Agents

Venetoclax?

Modakafusp

Multiple small molecules

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 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 course of myeloma…

Engage the community to increase awareness and provide support

Shorten the time to diagnosis by educating primary care providers to recognize the disease and order the right tests Enhance access to optimal care by educating myeloma providers about the disparity and how to reduce it

M-Power Is Both a National and Local Movement

Local Efforts

NY NC F

Grand Rounds MD

Collaborate with key Stakeholders

PCP Postcards

Community Workshops

Community events

National Efforts

Free CE course for PCPs

Social Media Campaigns

Publications

Free CE course for Nurses

Educational Postcards

Mentorship of Medical Students

Facebook Live

Q&A

Taking The Reins of Your Multiple Myeloma Care

Charise Gleason, MSN, NP-C, AOCNP

Winship Cancer Institute of Emory University & IMF Nurse Leadership Board

Today’s Topics

STABLE OF TREATMENT

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

FINDING YOUR GAIT

Know your care team & be an empowered patient

GOING THE DISTANCE

Healthful and meaningful living

Stable of Treatment

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

Treatment Goals

Myeloma Therapies

Rapid and effective disease control

Durable disease control

Improved overall survival

Minimize side effects

Promote good quality of life

Supportive Treatment

Prevent disease- and treatment-related side effects

Optimize symptom management

Promote quality of life

Discuss your goals and priorities with your healthcare team.

Stable of Treatment Options

FRONTLINE

MAINTENANCE

Velcade® (bortezomib)

Darzalex® (daratumumab)

Velcade® (bortezomib)

Ninlaro® (ixazomib)

Kyprolis® (carfilzomib)

RELAPSE

PENDING FDA

APPROVAL

Ninlaro® (ixazomib)

Darzalex® (daratumumab) in clinical trial

Darzalex® (daratumumab)

Empliciti® (elotuzumab)

Sarclisa® (Isatuximab)

Revlimid® (lenalidomide)

Thalomid® (thalidomide)

Revlimid® (lenalidomide)

Thalomid® (thalidomide)

Revlimid® (lenalidomide)

Pomalyst® (pomalidomide)

• CelMods

‒ Iberdomide

‒ Mezigdomide

Dexamethasone

Prednisone

Prednisolone

SoluMedrol

Dexamethasone

Prednisone

Prednisolone

SoluMedrol

Melphalan Cyclophosphamide

Melphalan + ASCT

Melphalan

Cyclophosphamide

Bendamustine

Elrexfio™ (elranatamab)

Tecvayli® (teclistamab)

Talvey™ (talquetamab)

Other Bispecific Antibodies

‒ Cevostamab

Melphalan + ASCT

CAR-T

− Ide-Cel

− Cilta-Cel

Xpovio® (Selinexor)

Doxil (liposomal doxorubicin)

Other CAR-T Venclexta® (venetoclax):BCL2 inhibitor for t(11;14) Blenrep (belantamab mafodotin)*: antibody drug conjugate

NOTED SIDE

EFFECTS Neuropathy

Carfilzomib: Cardiac

Infusion reaction

DVT/PE

See steroid slide

Myelosuppression

CRS and neurotoxicity; infection risk

Talvey: skin/nail/GI Infection risk

CAR-T: CRS and neurotoxicity

Myelosuppression, GI Xpovio: low sodium Blenrep: eye-related

The Old Horse: Stem Cell Transplant

ELIGIBILITY

Measuring treatment response

Determining Transplant Eligibility

Insurance authorization

Collecting stem cells

TRANSPLANT

High Dose Chemotherapy, stem cell infusion

Supportive Care Engraftment

Duration:

Approximately 2 weeks

Duration: Approximately 3-4 weeks

Location: Transplant Center POSTTRANSPLANT

Location: Transplant Center

Restrengthening

Appetite recovery

“Day 100” assessment

Begin maintenance therapy

Duration: Approximately 10-12 weeks

Location: HOME

Upfront stem cell transplant remains the standard of care for eligible patients

CAR T: Another Treatment Approach

Ask for a referral to CAR Tcell center as soon as it is possible as next treatment option (ie, before relapse)

GAIT GOING THE DISTANCE

No driving for 8 weeks

“One & Done” with continued monitoring

T-Cell Collection

Manufacturing takes ≈ 4 to 6 weeks

Bridging therapy may be needed

• Away from home

• Often some hospital stay

• Care Partner needed

• Side effect management

• CRS, ICANS

• Low blood counts

• Fatigue and fever

• Some patients need ongoing transfusion support

Horse of Another Breed:

Antibodies

•Different bispecific antibodies have differences in efficacy, side effects

– Available after 4 prior lines of therapy (or clinical trial)

– About 7 in 10 patients respond

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

– CRS and neurotoxicity

– Risk of infection

•BCMA target: greater potential for infection

– Tecvayli® (teclistamab)

– Elrexfio™ (elranatamab)

STABLE

GAIT GOING THE DISTANCE

BISPECIFIC ANTIBODIES

•GPRC5D target: potential for skin and nail side effects, GI issues of taste change, anorexia and weight loss

– Talvey™ (talquetamab)

BCMA = B-cell maturation antigen; CAR = chimeric antigen receptor; GPRC5D = G protein–coupled receptor, class C, group 5, member D; MM = multiple myeloma; scFV = single chain fragment variable; CRS = cytokine release syndrome. Shah N, et al. Leukemia. 2020;34(4):985-1005. Yu B, et al. J Hematol Oncol. 2020;13:125.

Confusion

CAR T and Bispecific Antibodies: Unique Side Effects CRS

Weakness

Fever Fatigue

Shortness of Breath Diarrhea

Headache

Nausea / vomiting

CRS is a common but often a mild & manageable side effect

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

CAR T and Bi-specific Antibodies: Unique Side Effects

Steroids: The Good, The Bad, The Ugly

Steroids enhance the effectiveness of other myeloma therapies

Do not stop or alter your dose of steroids without discussing it with your provider

GAIT GOING THE DISTANCE

Steroid Side Effects

• Irritability, mood swings, depression

• Difficulty sleeping (insomnia), fatigue

Managing Steroid Side Effects

•Consistent schedule (AM vs. PM)

•Take with food

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

•Medications to prevent shingles, thrush, or other infections

• Blurred vision, cataracts

• Flushing/sweating

• Increased risk of infections, heart disease

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

• Muscle weakness, cramping

• Weight gain, hair thinning/loss, skin rashes

• Increased blood pressure, water retention

• Increased blood sugar levels, diabetes

Infection Can Be Serious for People With Myeloma

[P]reventing infections is paramount.

Infection remains the leading cause of death in patients with multiple myeloma. Several factors account for this infection risk, including the overall state of immunosuppression from multiple myeloma, treatment, age, and comorbidities (e.g., renal failure and frailty).

IMWG Consensus guidelines and recommendations for infection prevention in multiple myeloma; Lancet Haematol.2022;9(2):143–161.

STABLE

GAIT GOING THE DISTANCE

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

As recommended by your healthcare team: Infection Prevention Tips

Good personal hygiene (skin, oral)

Environmental control (avoid crowds and sick people; use a high-quality mask when close contact is unavoidable)

IMWG = International Myeloma Working Group; HCP = healthcare provider.

Immunizations:

Flu, COVID, RSV & and pneumococcal vaccinations; avoid live vaccines

Preventative and/or supportive medications (next slide)

Medications Can Reduce Infection Risk

Type of Infection Risk

Herpes virus reactivation (HSV/VZV); CMV reactivation

Bacteremia, pneumonia, and urinary tract infection

PJP (P jirovecii pneumonia)

Fungal infections (aspergillus)

IgG < 400 mg/dL or recurrent infections

ANC < 500 cells/μL

COVID-19

Medication Recommendation(s) for Healthcare Team

GOING THE DISTANCE

Consideration

Acyclovir prophylaxis

Consider prophylaxis with levofloxacin

Consider prophylaxis with trimethoprim-sulfamethoxazole

Consider prophylaxis with fluconazole

IVIg

GCSF 2 or 3 times/wk (or as frequently as needed) to maintain

ANC > 1000 cells/μL and maintain treatment dose intensity

Antiviral therapy if exposed or positive for covid per institution

recommendations

Some people receiving BCMA-targeting therapies have experienced infections that are less common like CMV, PJP and fungal infections

ANC = absolute neutrophil count; BCMA = B-cell maturation antigen; CAR = chimeric antigen receptor; CMV, cytomegalovirus; GCSF = granulocyte colony-stimulating factor; HSV = herpes simplex virus; IVIg = intravenous immunoglobulin; PJP = Pneumocystis jirovecii pneumonia; VZV = varicella zoster virus.

RAJE NS, et al.

Lancet Haematol

.2022;9(2):143–161.

Skin Changes: Talvey™ (talquetamab)

Photos: Mount Sinai Hospital, NY, NY

IMF Nurse Leadership Board

Talvey™ (talquetamab): Common Generally Mild and Painless Skin and Nail Side Effects

STABLE

Body Rash:

•Prevent dry skin; apply lotion

– Ammonium lactate 12% lotion

•Steroids:

– Topical for grades 1-2,

– Systemic and topical for Grade 3 and dose hold

•Antihistamines, as needed

Nail Changes:

•Keep your nails short and clean. Watch for “catching and tearing”

•Apply a heavy moisturizer like Vaseline or salve.

Wear cotton hand coverings to bed

•A nail hardener may help with thinning

•Tell the team if you have signs of a fungal infection, like thickened or discolored nails

Management of Talvey™ (talquetamab): Oral Toxicities

STABLE OF TREATMENT

FINDING YOUR GAIT GOING THE DISTANCE

Taste Changes

Dexamethasone oral solutions “swish and spit” have been tried but with no proven benefit yet. Sour citrus or candies before meals are also recommended.

Dry Mouth Dysphagia

OTC dry mouth rinse, gel, spray are recommended. Advise patients to avoid hot beverages.

Glossitis and Thrush

EARLY initiation of nystatin or Mycelex is key to manage symptoms.

• Weight loss and anorexia are associated with taste changes. Nutritionist involvement and dietary modifications are recommended to support patients. Appetite stimulant with Marinol, if indicated, can also be utilized.

Dietary modifications with small bites, eating upright, and sips with food can help manage symptoms.

• Education and emotional support are key strategies to manage oral toxicities.

GI Symptoms:

Prevention & Management

Diarrhea may be caused by medications and supplements

– Laxatives, antacids with magnesium

– Antibiotics, antidepressants, other (check with provider, pharmacist)

– Supplements: milk thistle, aloe, cayenne, saw palmetto, ginseng

Avoid caffeinated, carbonated, or heavily sugared beverages

Take anti-diarrheal medication if recommended

Discuss GI issues with health care providers to identify causes and make adjustments to medications and supplements

Constipation may be caused by medications and supplements

–

Opioid pain relievers, antidepressants, heart or blood pressure medications (check with provider, pharmacist)

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

Increase fiber

•Fruits, vegetables, high fiber whole grain foods

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

Fluid intake can help with both diarrhea and constipation and helps kidney function

Weight Management

Anorexia (difficulty eating)  Weight loss; Steroids  Weight gain

– Monitor weight for significant loss or gain

– Adjust diet (reduce calories or add 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

• Antiviral to prevent shingles

• Sedation before procedures

– Interventions depend on source of pain

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

• May include medications, activity, surgical intervention, radiation therapy, etc

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

• Scrambler therapy for neuropathy

Sufficient Sleep: Important for Good Health

•Adequate rest and sleep are essential to a healthful lifestyle

•Shortened and disturbed sleep cause

– Increased heart-related death

– Increased anxiety

– Weakened immune system

– Worsened pain

– Increased falls and personal injury

•Things that can interfere with sleep

– Medications: steroids, stimulants, herbal supplements

– Psychologic: fear, anxiety, stress

– Physiologic: sleep apnea, heart issues, pain

STABLE OF GOING THE DISTANCE

• Sleep hygiene is necessary for quality nighttime sleep and daytime alertness

– Engage in exercise but not too near bedtime

– Increase daytime natural light exposure

– Avoid daytime napping

– Establish a bedtime routine - warm bath, cup of warm milk or tea

•Associate your bed ONLY with sleep

– Avoid before bedtime:

• Caffeine, nicotine, alcohol and sugar

• Large meals and especially spicy, greasy foods

• Computer screen time

•Sleep aid may be needed

Peripheral Neuropathy Management

Peripheral neuropathy happens when there is damage to nerves in the extremities (hands, feet, limbs). Damage can be the result of myeloma, treatment or unrelated conditions (i.e. diabetes).

Symptoms:

•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

•Neuroprotective Supplements:

– B-complex vitamins (B1, B6, B12)

– Green tea

•Safe environment: rugs, furnishings, shoes

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

If neuropathy worsens, your provider may:

•Adjust your treatment plan

•Prescribe oral or topical pain medication

•Suggest physical therapy

Understanding Changes to Kidney Function

•Risk Factors

– Active multiple myeloma (light chains, high calcium)

– Other medical issues (ex: Diabetes, dehydration, infection)

– Medications (MM treatment, antibiotics, contrast dye)

•Prevention

– Stay hydrated – drink water

– Avoid certain medications when possible (eg, NSAIDs), dose adjust as needed

•Treatment

– Treatment for myeloma

– Hydration

– Dialysis

Many myeloma patients will experience kidney issues at some point; protecting your kidney function early and over time is important

98.8%

Fatigue

Fatigue is the most commonly reported symptom.

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

Anxiety

>35% of patients

Depression

≈25% of patients

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

Additional Supportive Care

Financial Burden

Financial burden comes from

•Medical costs

– Premiums

– Co-payments

– Travel expenses

– Medical supplies

•Prescription costs

•Loss of income

– Time off work or loss of employment

– Caregiver time off work

•Funding and assistance may be available

GAIT GOING THE DISTANCE

– Federal programs, IRA & Medicare “Extra Help”

– Pharmaceutical support

– Non-profit organizations

– Websites:

• Medicare.gov

• SSA.gov

• LLS.org

• Rxassist.org

• NeedyMeds.com

• HealthWellFoundation.org

• Company-specific website

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

Finding Your Gait

Be an empowered patient; engage in your care

Be empowered

Ask questions, learn more

Express your goals/values/preferences

Ask for time to consider options

Communicate with your team

Understand the roles of each team member and who to contact for your needs

Arrive at a treatment decision together

Create a support network

Don’t Get Left in the Dust:

Communicate How You Feel With Your Team

Unmanaged Myeloma can cause:

Calcium elevation

Renal dysfunction

Low blood counts

Infection Risk

Blood clots

Bone pain

Neuropathy

Fatigue

TREATMENT

Your team may be able to help, but only if they know how you feel.

How You Feel

Side Effects of Treatment can cause:

GI symptoms

Renal dysfunction

Low blood counts

Infection Risk

Blood clots

Neuropathy

Fatigue

Care Partners Are Essential to Going the Distance

If you want to go fast, go alone, if you want to go far, go together African Proverb

•Care partners may help in many ways including medical appointments, managing medication, daily living, physical assistance, emotional support, myeloma knowledge, healthy lifestyle, patient advocacy, financial decisions

•Care partners can be a spouse, close relative, a network of people (family, friends, neighbors, church members, etc)

•Caring for the Care Partner

– Recognize that caregiving is difficult/stressful

– Encourage care partners to maintain their health, interests, and friendships

– The IMF has information and resources to help care partners

Form A Posse: Build Strong Social Ties & Cultivate a Sense of Belonging

•Multiple studies demonstrate that strong social ties are associated with

– Increased longevity including people with cancer

– Improved adherence to medical treatment leading to improved health outcomes

– Lower risk of developing cardiovascular diseases

– Increased sense of purpose and life satisfaction

– Reduced stress and anxiety

– Improved mood and happiness

– Enhanced resilience

Martino J, et al. Am J of Lifestyle Med. 2015;11(6):466-475.

Yang YC, et al. Proc Natl Acad Sci U S A. 2016;113(3):578-583.

Pinquart M and Duberstein PR. Crit Rev Oncol Hematol. 2010; 75(2):122–137.

•Strategies for enhancing social connection

– Deepen existing relationships with family, friends, and loved ones

– Build new relationships by participating in a support group, joining clubs or organizations, or volunteering

Tip: Start with small steps outside your comfort zone. Call a loved one you haven’t spoken to in a while. Invite a person you’d like to know better for lunch, coffee, or a walk.

Hetherington C. Healthnews.

https://healthnews.com/longevity/healthspan/social-connection-andlongevity/#:~:text=Research%20consistently%20demonstrates %20that%20people,of%20fulfillment%20in%20your%20life. Accessed Feb 1 2024.

Maintain Good Health

Have a Primary Care Doctor

Have Recommended Health Screenings

• Blood pressure

• Cholesterol

• Cardiovascular disease

• Diabetes

• Colonoscopy

• Vision

• Hearing

• Dental checkups & cleaning

• Women specific: mammography, pap smear

• Men specific: prostate

Maintain a healthy weight

Good nutrition

Activity or exercise

Sufficient sleep

An ounce of prevention is worth a pound of cure.

Benjamin Franklin

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

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

Q&A

COFFEE BREAK

Frontline Therapy

Nisha Joseph, MD

Winship

Cancer Institute of Emory University Atlanta, GA

Objectives

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

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

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

Goals of Therapy: The Iceberg Model of Myeloma

Treatment

At diagnosis >1 Trillion D i s e a s e B u r d e n ( # o f m y e l o m a c e l l s )

>10 Million 1 myeloma cell in 100K to 1 million normal cells

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

Flow Cytometry

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

R0 R1 R2 R3

MR→PR→

VGPR→CR

→sCR

10–2

MRDhigh

MRDlow

MRDneg

MRDpos

10–6 Induction Consolidation Maintenance Preemptive

TIME T

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

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

Median follow-up 76 months

*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?

NDMM- Transplant Eligible: Phase III PERSEUS Study Design

VRd

V: 1.3 mg/m2 SC

Key eligibility criteria

• Transplanteligible NDMM

• Age 18-70 years

• ECOG PS

≤2 1 : 1 r a n d o m i z a t i o n ( N = 7 0 9 ) a

Days 1, 4, 8, 11

R: 25 mg PO Days 1-21

d: 40 mg PO/IV

Days 1-4, 9-12

D-VRd

DARA: 1,800 mg

SCb

QW Cycles 1-2

Q2W Cycles 3-4

VRd administered as in the VRd group T r a n s p l a n t

Induction Consolidation Maintenance 4

Primary endpoint: PFSc

VRd

V: 1.3 mg/m2 SC

Days 1, 4, 8, 11

R: 25 mg PO Days 1-21

d: 40 mg PO/IV

Days 1-4, 9-12 D-VRd

DARA: 1,800 mg

SCb

Q2W

VRd administered as in the VRd group

Key secondary endpoints: Overall ≥CR rate,c overall MRD-negativity rate,d OS

D-R

DARA: 1,800 mg

SCb Q4W

R: 10 mg PO

Days 1-28 MRD positiv e MRD negati ve R

R: 10 mg PO Days 1-28 until PD

Continue D-R until PD

Discontinue DARA therapy only

Discontinue DARA therapy only after ≥24 months of D-R maintenance for patients with ≥CR and 12 months of sustained MRD negativity

Restart DARA therapy upon confirmed loss of CR without PD or recurrence of MRD

Late-breaking Abstracts Session, ASH 2023. Accessed from: https://ash.confex.com/ash/2023/webprogram/Paper191911.html

Late-breaking Abstracts Session, ASH 2023. Accessed from: https://ash.confex.com/ash/2023/webprogram/Paper191911.html

PERSEUS: Overall Survival

PERSEUS: Safety

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

(3 x 6-week cycles)

(4-week cycles)

Isa + R R

Key eligibility criteria1:  Age 18–70 years  NDMM and eligible for HDT and ASCT 3 years or PD

Isa (IV) 10 mg/kg Cycle 1

Cycle 2–3

Bor (SC) 1.3 mg/m²

Len (PO) 25 mg

Dex (PO) 20 mg Week

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

GMMG and Heidelberg University Hospital | ASH 2021

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

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

Patients with MRD negativity at the end of induction therapy

OR 1.83 (95% CI 1.34–2.51)

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

Isa-RVd is the first regimen to demonstrate a rapid and statistically significant benefit from treatment by reaching a MRD negativity of 50.1% at the end of induction and to show superiority vs. RVd in a Phase 3 trial

GMMG and Heidelberg University Hospital | ASH 2021

*P value derived from stratified conditional logistic regression analysis †Missing NGF-MRD values were due to either patients’ loss to follow-up during induction therapy or to missing bone marrow samples or technical failures in measurement counted as non-responders, i.e. NGF-MRD positive CI, confidence interval; d, dexamethasone; Isa, isatuximab; ITT, intent-to-treat; MRD, minimal residual disease; NGF, next-generation flow; OR, odds ratio; R, lenalidomide; V, bortezomib

IsKia EMN24 Study Design

Induction

Four 28-day cycles

Key eligibility criteria:

TE NDMM patients

aged <70 years

Stratification:

- Centralized FISH (standard risk/missing vs. high risk defined as del(17p) and/or t(4;14) and/or t(14;16);

- ISS (I vs. II and III) R

42 active sites; enrollment: Oct 7, 2020 ‒ Nov 15, 2021 MRD by

Post-ASCT consolidation

Four 28-day cycles

4× KRd

K: 20 mg/m2 IV dd 1 cc 1 only; followed by 56 mg/m2 IV dd

8,15 cc 1 and dd 1,8,15 cc 2-4

R: 25 mg PO daily dd 1-21

d: 40 mg PO dd 1,8,15,22

4× Isa-KRd

Isa: 10 mg/kg IV dd 1,8,15,22

cc 1, followed by 10 mg/kg IV dd 1 and 15 cc 2 to 4.

K: 20 mg/m2 IV dd 1 cc 1 only; followed by 56 mg/m2 IV dd

8,15 cc 1 and dd 1,8,15 cc 2-4

R: 25 mg PO daily dd 1-21

d: 40 mg PO dd 1,8,15,22

MOBILIZATION

Cy: 2-3 g/m2 followed by G-CSF for stem-cell collection and MEL200-ASCT

R

Light consolidation

Twelve 28-day cycles

MEL: 200 mg/m2 followed by ASCT 12× KRd

12×

Isa

5-8

K: 56 mg/m2 IV dd 1,8,15

cc 5-8

R: 25 mg PO daily dd 1-21

d: 40 mg PO dd 1,8,15,22

MRD by NGS

Primary Endpoint: Post-consolidation MRD negativity (ITT analysis)

≥VGPR after consolidation was 94% in both arms; ≥CR 74% vs 72% and sCR 64% vs 67% in the IsaKRd vs KRd arms.

High MRD compliance and sample quality (97-100% of sample evaluable at 10 -5 and 10-6 cut off.

Consistent MRD results were detected by next-generation flow

In the logistic regression analysis, ORs, 95% CIs, and p-values were adjusted for stratification factor.

MRD negativity rates improved over time (10

Isa-KRd (N=151) KRd (N=151)

Post-consolidation MRD negativity by NGS

Subgroup analysis by cytogenetic risk

Very high risk Very high risk 2+

1 HRCA was defined as the presence of one of the following high-risk cytogenetic abnormalities: del(17p13.1), t(4;14) (p16.3;q32.3), t(14;16)

gain(1q21), or amp(1q21); 2+ HRCA was defined as the presence of at least two high-risk cytogenetic abnormalities.

Isa-KRd KRd

(q32.3;q23),

Conclusions

• Isa-KRd significantly increased post-consolidation 10-5 and 10-6 MRD negativity, as compared with KRd

• Isa-KRd significantly increased 10-5 and 10-6 MRD negativity after each treatment phase (Induction, Transplantation, Consolidation) .

• Isa-KRd consistently increased MRD negativity at 10-5 and 10-6 in all subgroups of patients, including high-risk and very high-risk disease.

• Isa-KRd treatment was tolerable, with a toxicity profile similar to that in previous reports.

• 10-6 MRD negativity cut-off is more informative.

• 1-year sustained MRD negativity will be available in 2024

• With a longer follow-up, this trial can offer the opportunity to explore the correlation between depth of MRD negativity and PFS/OS.

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

Progression-Free and Overall Survival

Frontline Therapy and Transplant -

Conclusions

• 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).

Engelhardt M. Haematologica 2016

Facon et al. Leukemia 2020

Bonanad et al. JGO 2015

Palumbo A Blood

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

D: 16 mg/kg IV

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

R: 25 mg PO Days 1-21 until PD

da: 40 mgb PO or IV

Days 1, 8, 15, 22 until PD

Primary endpoint

d: 40 mg PO

Days 1, 8, 15, 22 until PD D-Rd

Cycles: 28 days Rd

End-oftreatment visit (30 days after last dose)

Longterm follow-up

• PFS Key secondary endpoints

• OS

• PFS2

• ORR

R: 25 mg PO Days 1-21 until PD

• CR/sCR rate

• MRD (NGS; 10–5)

Demographics and Baseline Characteristics

Demographics and baseline characteristics were well balanced between arms

ISS, International Staging System; MM, multiple myeloma.

a2 patients had an ECOG PS score >2 (1 patient each with an ECOG PS score of 3 and 4).

Note: percentages may not add up to 100% due to rounding.

bIncludes IgD, IgE, IgM, and biclonal.

Median follow-up

Primary: 28.0 months1

Median follow-up

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

Updated PFS

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

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

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

Bortezomib

VTD VRD KRD D-VMP DRD D-VRD SCT +/- More induction

Lenalidomide

Bortezomib Ixazomib

Lenalidomide + PI

Carfilzomib

Combinations

Elotuzumab Isatuximab

Idecabtagene autoleucel

Ciltacabtagene autoleucel

Teclistamab

Talquetamab

Elranatamab

Isa-VRD

Isa-KRD D-KRD

CAR T or Bispecifics?

Daratumumab?

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

Novel CAR T Cell Therapies

Bispecific/Trispecific Antibodies

CelMod Agents

Venetoclax?

Modakafusp

Multiple small molecules

Q&A

LUNCH BREAK

12:40 – 1:00 PM

1:00 – 1:10 PM

1:10 – 1:30 PM

1:30 – 1:40 PM

1:40 – 2:25 PM

2:25 – 2:35 PM

IMF Regional Community Workshop

April 13th, 2024 – Agenda after lunch

Local Patient & Care Partner Panel, Sandy & Joe Brown, Jim & Lisa Mahoney

Q&A

Maintenance Therapy, Nisha Joseph, MD

Q&A

Relapsed Therapies & Clinical Trials, Jonathan Kaufman, MD

Q&A

Closing Remarks

Coffee / Network

Jim & Lisa Mahoney

Maintenance Therapy

Nisha Joseph, MD

Winship

Cancer Institute of Emory University Atlanta, GA

Objectives

• Discuss the principle of consolidation therapy and its application in myeloma

• Outline the major options for maintenance therapy

• Introduce the newer trend for the use of dual maintenance

• Provide an algorithm for maintenance based on risk status

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

Meta-Analysis of Lenalidomide Maintenance after ASCT

PLACEBO (n = 229)

CALGB 100104 (accrual 8/2005 – 11/2009)

INDUCTION

ASCT

1:1 RANDOMIZATION

“NO EVIDENCE OF PD”

Primary Endpoint: PFS

IFM 2005-02 (accrual 6/2006 – 8/2008)

INDUCTION

ASCT

1:1 RANDOMIZATION

“NO EVIDENCE OF PD”

Primary Endpoint: PFS

LEN: 2 COURSES

LEN MNTCa (n = 231)

PLACEBO (n = 307)

LEN MNTCa (n = 307)

GIMEMA (RV-MM-PI-209) (accrual 11/2007 – 7/2009)

2 × 2 DESIGN

LEN + DEX × 4 INDUCTION

Primary Endpoint: PFS

ASCT

LEN MNTCb (n = 67) NO TREATMENT (n = 68)

MPR: 6 COURSES

LEN MNTCb NO TREATMEN T

Dec 2009

INTERIM AN

INTERIM ANALYSIS AND UNBLINDING

CROSSOVER BEFORE PD ALLOWED

CONTINUED TREATMENT

Jan 2010

CONTINUED

PRIMARY ANALYSIS

TREATMENT NO CROSSOVER BEFORE PD ALLOWED

ALL TREATMENT

DISCONTINUED

Jan 2011

CONTINUED TREATMENT

Target population of patients with NDMM who received LEN maintenance or placebo/no maintenance after ASCT

a Starting dose of 10 mg/day on days 1-28/28 was increased to 15 mg/day if tolerated and continued until PD.

b Patients received 10 mg/day on days 1-21/28 until PD.

CONTINUED TREATMENT

ASCT, autologous stem cell transplant; LEN, lenalidomide; NDMM, newly diagnosed multiple myeloma; MNTC, maintenance; MPR, melphalan, prednisone, and Len; PD, progressive disease.

Attal et al ASCO 2016; McCarthy et al EHA 2016

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

Lenalidomide maintenance and second primary malignancy risk

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

• PFS2 also prolonged 73.3 months vs 56.7 (ie not creating more aggressive clone)

• 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

McCarthy P, et al; JCO 2017, 35, 3279-3289.

Myeloma XI

Induction

NDMM

Treated on Myeloma XI

induction protocols

Maintenance

Lenalidomide

10 mg/day, days 1‒21/28

R 1:1

Observation

N=1551 (TE=828; TNE=723)

Median follow-up: 27 months (IQR 13‒43)

Exclusion criteria

• Failure to respond to lenalidomide as induction IMiD, or development of PD

• Previous or concurrent active malignancies

IQR, interquartile range; NDMM, newly diagnosed multiple myeloma; PD, progressive disease

Jackson et al., Lancet 20:57-73, 2019

Overall PFS

Significant improvement in PFS from 18 to 36 months, HR=0.45

Meta-analysis of all four randomized studies evaluating lenalidomide maintenance

PFS

HR 0.47

OS

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 1-2,8-9,15-16,2223

4x KRd

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

R: 25 mg d 1-21

d: 20 mg. d 1-2,8-9,15-16,2223

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

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 1-2,8-9,15-16,2223

R: 10 mg days 121, until progression or intolerance

4x KRd

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

R: 25 mg d 1-21

d: 20 mg. d 1-2,8-9,15-16,2223

4x KRd

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

R: 25 mg d 1-21

d: 20 mg. d 1-2,8-9,15-16,2223

4x KRd

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

R: 25 mg d 1-21

d: 20 mg. d 1-2,8-9,15-16,2223

4x KRd

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

R: 25 mg d 1-21

d: 20 mg. d 1-2,8-9,15-16,2223

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

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

^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.

Progression-free survival

KRd_ASCT vs. KRd12 vs. KCd_ASCT

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

3-year progression-free survival

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

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?

• 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)

• However, PERSEUS added Dara to Lenalidomide for up to 2 years based on sustained MRD status

• There is still more to learn, but there is much more comfort use dara+len as maintenance, especially in higher risk patients

NDMM- Transplant Eligible: Phase III PERSEUS Study Design

VRd

V: 1.3 mg/m2 SC

Key eligibility criteria

• Transplanteligible NDMM

• Age 18-70 years

• ECOG PS

≤2 1 : 1 r a n d o m i z a t i o n ( N = 7 0 9 ) a

Days 1, 4, 8, 11

R: 25 mg PO Days 1-21

d: 40 mg PO/IV

Days 1-4, 9-12

D-VRd

DARA: 1,800 mg

SCb

QW Cycles 1-2

Q2W Cycles 3-4

VRd administered as in the VRd group T r a n s p l a n t

Induction Consolidation Maintenance 4

Primary endpoint: PFSc

VRd

V: 1.3 mg/m2 SC

Days 1, 4, 8, 11

R: 25 mg PO Days 1-21

d: 40 mg PO/IV

Days 1-4, 9-12 D-VRd

DARA: 1,800 mg

SCb

Q2W

VRd administered as in the VRd group

Key secondary endpoints: Overall ≥CR rate,c overall MRD-negativity rate,d OS

D-R

DARA: 1,800 mg

SCb Q4W

R: 10 mg PO

Days 1-28 MRD positiv e MRD negativ e R

R: 10 mg PO Days 1-28 until PD

Continue D-R until PD

Discontinue DARA therapy only

Discontinue DARA therapy only after ≥24 months of D-R maintenance for patients with ≥CR and 12 months of sustained MRD negativity

Restart DARA therapy upon confirmed loss of CR without PD or recurrence of MRD

How long should maintenance last?

Defining the optimum duration of lenalidomide maintenance after autologous stem cell transplant – data 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

Multiple landmark analyses

• Overall

• By risk

• By MRD status

Induction

Myeloma XI induction protocols and ASCT

N=1248

Median follow up: 44.7 months (IQR 32.4-62.7)

Lenalidomide

10mg/day, days 1-21/28

Observation

Median duration of lenalidomide therapy 28 cycles (range 1-96)

• Patients still on therapy 330/730 (45%)

To PD

Conclusions

• These data suggest an ongoing PFS benefit associated with continuing lenalidomide maintenance beyond at least 4-5 years in the overall patient population

• Even in patients with sustained MRD negativity, there is evidence of benefit from continuing lenalidomide maintenance for at least 3 years in total

• Randomised trials to address the impact of stopping lenalidomide maintenance in patients with sustained MRD negativity could be considered, at no earlier than 3 years

• In patients who are MRD +ve these data support continuing lenalidomide until disease progression

• No evidence of cumulative haematological toxicity was identified

• These findings emphasise the need for long term follow up of maintenance studies to enable the exploration of such questions

• There is a planned powered OS update of Myeloma XI in 2023

Commonly asked maintenance questions

• Should post-transplant maintenance therapy be recommended for all patients?

• Yes

• Which agent should be used?

• Lenalidomide remains the standard of care – we may be adding daratumumab soon

• What is the optimal duration?

• Treatment until progression remains the standard of care

• What should patients with high-risk cytogenetics receive?

• Consider lenalidomide + proteasome inhibitor or daratumumab; clinical trial

• Should MRD status dictate maintenance therapy?

• Not outside of a clinical trial

• What about Second Primary Malignancies?

• They are real, require a discussion and monitoring, but are outweighed by benefit

Q&A

Relapsed Therapies & Clinical Trials

Jonathan Kaufman, MD

Winship Cancer Institute of Emory University

Atlanta, GA

Relapsed Therapy

Objectives

• Discuss an approach to treating relapsed myeloma based on patient, disease and treatment characteristics

• Review the important trend of using an aggressive approach in early treatment of myeloma

• Outline the key results from recent trials in early relapse

• Discuss the approach to late relapse and the use of novel therapies such as CAR T and bispecific antibodies

Early lines treatment are important!

Fewer patient are eligible for therapy in each subsequent line of therapy (LOT)

Figure adapted from: Yong, K et al. Br J Haematol 2016;175(2):252-264

An Approach to Relapsed MM

• It is not a simple algorithm of treatment #1 then 2 then 3…

• Leverage the benefit of multiple mechanisms of action in combination therapy

Categories:

• 1-3 prior lines

• Later Relapse

• Refractory to PI, IMiD and MoAb = Triple Class Refractory

Principles

1. Depth of Response matters…likely incorporate MRD soon

2. High risk vs standard risk…more aggressive Rx in high risk

3. Balance efficacy and toxicity…initially and constantly assess

4. Overcome drug resistance…change mechanism of action when possible

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

NCCN Guidelines – Early Relapse

NCCN Guidelines – Early Relapse contd.

Therapy Selection

Considerations

Disease-Related

• Nature of the relapse

– Biochemical vs symptomatic

• Risk stratification

– High-risk chromosomal abnormalities: del(17p), t(4;14), t(14;16)

• Disease burden

Therapy-Related

• Previous therapies

• Prior treatment-related adverse event

• Regimen-related toxicity

• Depth and duration of previous response

• Cost to patient

Patient-Related

• Renal insufficiency

• Hepatic impairment

• Comorbidities

• Preferences

• Social factors

– Support system

– Accessibility to treatment center

– Insurance coverage

Multiple Myeloma is Not One Disease!

Myeloma: first relapse – IMWG Guidelines

First Relapse

Preferred options: DRd (or KRd)

Not Refractory to Lenalidomide

Alternatives:

DVD, Kd, DaraKd, IsaKd, IRd, Erd

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

Refractory to Lenalidomide

Preferred options: PVd DaraKd

IsaKd

Consider salvage auto transplant in eligible patients

Second options

DaraVd;Kd

Other options: KPd; DaraPd; Ipd

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

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.

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

Early Relapse

General Principles

Use mechanisms of action not previously used

Do not continue to use lenalidomide if progressing on len maintenance

Triplets are preferred over doublets

In real practice - most patients receiving VRD (Bortezomib-Lenalidomide-Dex) like regimens, 1st relapse is typically

Daratumumab + Pomalidomide + Dex (APOLLO)

Isatuximab + Pomalidomide + Dex (ICARIA)

Daratumumab + Carfilzomib + Dex (CANDOR)

Isatuximab + Carfilzomib + Dex. (IKEMA)

Selinexor + Bortezomib + Dex (BOSTON)

First Relapse

Not Refractory to Lenalidomide*

Not refractory to CD38 moAB

Dara-refractory or Relapse while on CD38 moAB

Refractory to Lenalidomide*

Not refractory to CD38 moAB

Dara-refractory or Relapse while on CD38 moAB

DRd

KRd (preferred)

ERd, IRd (Alternatives)

DKd or Isa-Kd Or DPd or Isa-Pd

KCd or KPd

(preferred)

VCd or EPd

(Alternatives)

*Consider salvage ASCT in patients eligible for ASCT who have not had transplant before; Consider 2nd auto SCT if eligible and had >36 months response duration with maintenance to first ASCT

IV,

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

• 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

Once-weekly pill

Once-daily pill

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

• 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

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

Median progression-free survival favored

• VPd: 11 vs 7 months

• KRd: 26 vs 17 months

• Ninlaro-Rd (IRd) vs Rd

• XPOVIO-Velcadedex (XPO-Vd) vs Vd

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: 21 vs 15 months

• XPO-Vd: 14 vs 9 months

• 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

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)

Sarclisa (isatuximab)

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

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

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

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

• Darzalex-Revlimiddex (DRd) vs Rd Regimens compared POLLUX

Monoclonal Antibody–Based Regimens for Early Relapse: Darzalex

CASTOR CANDOR APOLLO

• Darzalex-Velcadedex (DVd) vs Vd

• Darzalex-Kyprolisdex (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

Clinical considerations

• Consider for relapses from Revlimid or Velcade maintenance

• 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

ELOQUENT-2

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

• Empliciti-Revlimiddex vs Rd Regimens compared

ELOQUENT-3 ICARIA-MM IKEMA

• 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

Clinical considerations

• Consider for nonRevlimid refractory, frailer patients

• Overall survival benefit with Empliciti-Rd

• Empliciti-Rd associated with more infections

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

• Sarclisa-Pd: 12 vs 7 mos

• Sarclisa-Kyprolis-dex vs Kd

• Sarclisa-Kd: 41 vs 19 mos

• 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

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

Anti BCMA strategy

Anti-BCMA Bispecific

BCMA CAR-Ts

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

Existing drugs:

Elotuzumab

Selinexor

Venetoclax

Bendamustine

VDT PACE

New Drugs:

Iberdomide, Mezigdomide

New bispecifics (Cevostamab, Talquetamab)

New CAR-Ts

New Monoclonals

New ADCs

NCCN Guidelines – Late Relapse

Currently Available Drugs for Triple-Class Refractory Myeloma

Class Drug Formulation

Nuclear export inhibitor

Antibody-drug conjugate

XPOVIO (selinexor)

Twice-weekly pill

Chimeric antigen receptor (CAR) T cell

Blenrep (belantama b mafodotin)*

Abecma (idecabtage ne vicleucel)

Bispecific antibody

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

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

Tecvayli (Teclistamab)

Approval

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

• For relapsed/refractory myeloma (after at least 4 prior therapies including an antiCD38 mAb, a PI, and an IMiD

• For relapsed/refractory myeloma (after 4 or more

prior lines of therapy, including an IMiD, a PI, and an anti-CD38 mAb

Step up dosing then weekly SQ For relapsed/refractory myeloma (after 4 or more prior

CAR T cell

Carvykti (ciltacabtag ene autoleucel)

0.5 to 1.0 × 106

genetically modified autologous CAR T cells/kg of body weight

• For relapsed/refractory myeloma (after 4 or more

Talquetamab lines of therapy, (PI, an IMiD, and an anti-CD38 mAb

Elranatamab

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

prior lines of therapy, including a PI, an IMiD, and an anti-CD38 mAb

Emerging Therapies for Relapsed/Refractory Multiple Myeloma

Bispecific antibodies

• Cevostamab, Alnuctamab, ABBV383, 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

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

Targeting element (eg, CD19, BCMA, CD20) Spacer

Expand CAR T cells Infuse same patient with CAR T cells

Viral vector with CAR DNA CARengineere d T cell

Transmembrane domain

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

Majors. EHA 2018. Abstr PS1156. Lim. Cell. 2017;168:724. Sadelain. Nat Rev Cancer. 2003;3:35.

Brentjens. Nat Med. 2003;9:279. Park. ASH 2015. Abstr 682. Axicabtagene ciloleucel PI. Tisagenlecleucel PI.

CAR T-Cell Therapy Patient Journey

Abecma and Carvykti in Relapsed and Refractory Multiple Myeloma

CAR T: Expected Toxicities

Cytokine release syndrome (CRS) Neurotoxicity (ICANS)

Cytopenias Infections

Symptoms

• Fever

CRS ICANS

• Difficulty breathing

• Dizziness

• Nausea

• Headache

• Rapid heartbeat

• Low blood pressure

• Headache

• Confusion

• Language disturbance

• Seizures

• Delirium

• Cerebral edema

Management

• Actemra (tocilizumab)

• Corticosteroids

• Supportive care

• 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.

Transplant vs CAR T Cells

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

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 Fatigue, nausea, diarrhea

*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.

Bispecific and Trispecific Antibodies

There are currently 3 approved bispecific antibodies:

Teclistamab (Tecvayli)

Talquetamab (Talvey)

Elranatamab (Elrexfio)

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

BCMA, GPRC5D, or FcRH5

Examples:

• Elranatamab

• Teclistamab

• TNB-303B (ABBV-383)

• REGN5458

• Cevostamab

• Talquetamab

Now Approved: Tecvayli, the First Bispecific Antibody

Drug Formulation

Tecvayli (teclistama b)*

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

Approval

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

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.

Median duration of response

18.4 months

MajesTEC-1: Duration of Response

months

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:

• Patients with CR or better:

CI:

MajesTEC-1: Overall Safety Profile; watch for infections

Teclistamab was well tolerated; discontinuations and dose reductions were infrequent

• 2 patients (1.2%) discontinued due to AEs (grade 3 adenoviral pneumonia; grade 4 PML)

• 1 patient had dose reduction at cycle 21

• The most common AEs were CRS and cytopenias

• Infections occurred in 126 (76.4%) patients (grade 3/4: 44.8%)

• 123 patients (74.5%) had evidence of hypogammaglobulinemia a

• There were 19 deaths due to AEs, including 12 COVID-19 deaths

• 5 deaths due to teclistamab-related AEs:

• COVID-19 (n=2)

• Pneumonia (n=1)

• Hepatic failure (n=1)

• PML (n=1)

Elranatamab : Duration of Treatment and Best Overall Response

• Median duration of followup was 12.0 mos (range 0.3–32.3)

• ORR = 64% (95% CI, 50–75); CR/sCR rate = 38% (21/55)

• 54% (7/13) of patients with prior BCMA-directed therapy achieved response

• For responders (n = 35), median TTR = 36 days (range 7–262)

Data cutoff 9/30/2022

Swimmer plot depicts disease assessments relevant to first response, confirmation of response, deepening of response, and best response. Mutational analysis was filtered on functional mutations annotated in OncoKB and normal allele frequency <5% in paired peripheral blood mononuclear cell samples. * Prior anti-BCMA ADC. * Prior BCMA-targeted CAR-T.

MR = minimal response; NE = not evaluable; PD = progressive disease; Q2W = every 2 weeks; REL = relapse; SD = stable disease; TTR = time to response.

MonumenTAL-1: ORR With Talquetamab⍭

ORR was similar for QW and Q2W schedules

• Triple-class refractory: 72.6% and 71.0%

• Penta-drug refractory: 71.4% and 70.6%

• ORR was consistent across subgroups including baseline ISS stage III disease, baseline cytogenetic risk, number of prior therapies, and belantamab exposure, except among patients with baseline plasmacytomas

Grade 2: 21 (14.7%)

MonumenTAL-1 Talquetamab⍭: Safety*

CRS

Grade 189 (62.2%)

Grade 3: 3 (2.1%)

(suppl 1): 384-387. *AEs were graded by CTCAE v4.03 with 2–3 step-up doses.

Grade 2: 25 (17.2%)

Grade 3: 1 (0.7%)

Grade 179 (54.5%)

CRS events

• Most CRS events were grade 1/2 and largely confined to step-up doses and first full dose

Non-hematologic AEs

• Low rates of grade 3/4 nonhematologic AEs

• Low discontinuation rates due to AEs

Most common AEs were CRS, skinrelated events, nail-related events, and dysgeusia

Hematologic AEs

• Most high-grade AEs were cytopenias

• Cytopenias were generally limited to first few cycles

Bispecific Antibodies: >20% Activity

*Based on a recent sampling

Bispecific Antibodies: Expected Toxicities

• Cytokine release syndrome (CRS)

• Neurotoxicity (ICANS)

• Usually occurs within first 1–2 weeks

• Frequency (all grade and grade 3–5) higher with CAR T

• Cytopenias

• Target unique

• For example, rash, taste disturbance seen with GPRC5D, but not with BCMA

• Infections

• Incidence for bispecifics at RP2D not yet known

• Viruses: CMV, EBV

• PCP/PJP

• Ongoing discussions regarding prophylactic measures

 IVIG

 Anti-infectives

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

Availability Wait time for manufacturing

Off-the-shelf, close monitoring for CRS and neurotoxicity

Key Points – CAR T and Bispecifics

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, and now Talvey and Elrexfio in August 2023

Several additional bispecific antibodies are under clinical evaluation.

The Evolution of Myeloma Therapy

Bortezomib

VTD VRD KRD D-VMP DRD D-VRD SCT +/- More induction

Lenalidomide

Bortezomib Ixazomib

Lenalidomide + PI

Carfilzomib

Combinations

Elotuzumab Isatuximab

Idecabtagene autoleucel

Ciltacabtagene autoleucel

Teclistamab

Talquetamab

Elranatamab

Isa-VRD

Isa-KRD D-KRD

CAR T or Bispecifics?

Daratumumab?

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

Novel CAR T Cell Therapies

Bispecific/Trispecific Antibodies

CelMod Agents

Venetoclax?

Modakafusp

Multiple small molecules

Clinical Trials

Objectives

• Provide the rationale for clinical trials

• Outline the phases of clinical trials

• Discuss the risks and benefits of clinical trials

• Preview important clinical trials in myeloma

Clinical Trials - Overview

Remember some of the important principles of clinical trials:

• The drive of research has brought us to where we are

• No one is expected to be a “guinea pig” with no potential benefit to them

• Research is under very tight supervision and standards

• Open, clear communication between the physician and the patient is fundamental

Clinical Trials – Why Me??

• Every patient is unique and must be viewed that way

• Benefits of trials are numerous and include:

• Early access to “new” therapy

• Delay use of standard therapy

• Contribution to myeloma world – present and future

• Financial access to certain agents

• Must be balanced with potential risks

• “toxicity” of side effects

• Possibility of lack of efficacy

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

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!

Even Before Phase I

• Most agents are tested in lab models

• Various “myeloma cell lines” = in vitro

• Next step is animal model

• We are more like mice than you think!!

• Earliest study in phase I is called “First in Human”

• Often uses extremely low dose of drug to ensure safety

Clinical Trials - Phases

Phase III Tests safety Tests how well treatment works

Compares new treatment to standard treatment

Phase 1 Clinical Trials

• All patients receive the experimental therapy

• Phase 1 trials find the optimal dose of a new drug or drug combination

• Patients get higher doses as the study continues

• Determine side effects of new drugs or combinations

• Explore how the drug is metabolized by the body

• Important for all stages of myeloma

Phase 2 Clinical Trials

• Determine if a new drug or combination is effective against the cancer

• May be added to a phase 1 study once the ideal dose is found

• Patients usually receive the experimental therapy

• In some cases, the study may include two “arms” comparing either two different doses or a different treatment (another combination of drugs)

Phase 3 Clinical Trials

• Highest form of clinical evidence. Typically a large number of patients are required…usually required for full FDA approval

• Patients receive either an experimental therapy (one or more drugs) or the current standard treatment

• The patient is randomly assigned to a treatment—a process called randomization

• Neither the physician or the patient can determine which treatment is given

• May be placebo controlled, if no standard treatments are available

• Very closely monitored for effectiveness and 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

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 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

• Not have physicians who offer them trials

• Have a disconnect with their healthcare team

Diversity in Clinical Trials

• There has been a lack of diverse representation in clinical trials in myeloma. In the U.S., approximately 20% of all myeloma patients are of African descent, but only 5%–8% of patients in myeloma clinical trials are of African descent.

• This is significant for the following reasons:

All patients of all races and ethnicities should be able to benefit from clinical trials.

Diverse patient representation in clinical trials is required to ensure that the outcomes are applicable to all patients.

• Reasons for underrepresentation in clinical trials are complex and include systemic racism, accessibility of clinical trials, sensitivity to diversity by medical professionals, misconduct in medicine in the past, the lack of trust in the system, and more.

Why Do So Few Cancer Patients

Participate in Clinical Trials?

Doctors might:

• Lack awareness of appropriate clinical trials

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

• Believe that standard therapy is best

• Be concerned that clinical trials add administrative burdens

Commonly Asked Questions

How does the study work? How often will I need to see my doctor or visit the cancer center?

Will I need to undergo additional tests?

What is currently known about the new drug or combination?

What benefits can I expect?

What side effects should I expect? Who should I notify if I have side effects?

Can I take my vitamins or other medications?

Can I get the treatment with my local doctor?

Will my insurance pay for my participation in the 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) and even Trispecifics

• New molecules – CelMods, …

And MANY more!

Q&A

Upcoming IMF Events

Patient and Family Seminars

Minneapolis – July 18th & 19th, 2024 – JW Marriott

Mall of America

Los Angeles – August 16th & 17th, 2024 – Hilton Los

Angeles/Universal City

Regional Community Workshops

May 18th, 2024 – Salt Lake City RCW – Salt Lake City

Marriott University Park

Thank you for attending today’s program!

April 13th, 2024,

International Myeloma Foundation’s Regional Community WorkshopAtlanta