Welcome!
Thank you for joining us today for the April 13th, 2024, International Myeloma Foundation’s Regional Community Workshop –Atlanta
Thank you to our sponsors!
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
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InfoLine@myeloma.org
Contact the InfoLine: 800-452-CURE (2873)
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
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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
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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
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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 %
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):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.
Condition MGUS1-4 (Monoclonal Gammopathy of Undetermined Significance) SMM1-5,8 (Smoldering Multiple Myeloma) Active Multiple Myeloma6-8 Clonal plasma cells in bone marrow <10% 10%-60% >10% Presence of Myeloma Defining Events None None Yes Likelihood of progression ~1% per year ~10% per year Not Applicable Treatment No; observation Yes for high risk*; No for others Yes
Multiple Myeloma Diagnosis Can Be Challenging
Kyle RA. Mayo Clin Proc. 2003;78:21-33. Fatigue Anemia Bone Pain
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)
BM FLC MRI sFLC ratio >100
Clonal bone marrow ≥60%
>1 focal lesion by MRI
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.
Rajkumar SV, et al. Lancet
Oncol.
Ghobrial IM, et al. Blood. 2014;124:3380-3388; mSMART.org; NCCN.org This Photo by Unknown Author is licensed under CC BY-SA-NC
CBC= Complete Blood Count; WBC = White Blood Cell C R A B S L i M
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
Rajkumar SV, et al. Lancet Oncol. 2014;15:e538-3548. Ghobrial IM, et al. Blood. 2014;124:3380-3388; mSMART.org;
versus
S L i M C R A B
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)
Rajkumar SV, et al. Lancet Oncol. 2014;15:e538-3548. Ghobrial IM, et al. Blood. 2014;124:3380-3388; mSMART.org; NCCN.org This Photo by Unknown Author is licensed under CC BY-SA
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
Image Credit: IMF Patient Deletions Translocations Gain 1p17pp53 mutation t(4;14) t(14;16) t(14;20) 1q+ High Risk FISH Results
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
Initial Therap y Transplant (ASCT) Maintenan ce Treatme nt of Relapse d disease
Supportive Care
Transplan t Eligible Patients
Myeloma Treatment Schema HCP Clinical Experience Research Results Your Preference TREATMENT DECISION
ASCT = Autologous Stem Cell Transplant
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.
RELAPSE MGUS or SMOLDERING MYELOMA ACTIVE MYELOMA MP r o t e i n g / L 2 5 10
PLATEAU REMISSION Therapy Time MGUS = monoclonal gammopathy of undetermined significance Clone 1.1 Clone 1.2 Clone 2.1 Clone 2.2 Misc
SYMPTOMATIC REFRACTORY RELAPSE
ASYMPTOMATIC
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)
Class Drug Name Abbreviation Administration
Inhibitors
(selinexor) X or Sel Oral
XPO1
Xpovio
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
Class Drug Name Abbreviation Administration
Drug Conjugate* Pepaxto (Melphalan Flufenamide) Melflufen Intravenous
B
Peptide
BCMA Targeted Antibody Drug Conjugate (ADC)* Blenrep (belantamab mafodotin) Bela, Belamaf, or
Intravenous CAR T Cell therapy
Tec Talq Elra SC or IV ??? MORE TO COME!!
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)
• XmAb5592 (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
2011
Antibody-Drug Conjugates
Effector cell
The Process of CAR T Cell Therapy
Manufacture of CAR T Cells
Hucks G, Rheingold SR. Blood Cancer J. 2019;doi:10.1038/s41408-018-0164-6.
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.
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Agent Tumor Cell Target T-Cell Target Teclistamab BCMA CD3 Talquetamab GPRC5d CD3 Cevostamab FcRH5 CD3
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
BCMA CD38 GPRC5D SLAMF7 FcRH5
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
Induction Consolidation Front line treatment Post consolidation Maintenance Rescue Relapsed New
Isa-VRD D-KRD Isa-KRD
++++++++ Now
VTD VRD KRD D-VMP DRD D-VRD SCT +/- More induction
Lenalidomide Carfilzomib Pomalidomide Selinexor Panobinostat Daratumumab Ixazomib
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
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ENGAGE ENHANCE EDUCATE empower
more
at
You can learn
about this
m-power.myeloma.org
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
L MI GA
Resources Myeloma.org Thank you
Q&A
48
Taking The Reins of Your Multiple Myeloma Care
Charise Gleason, MSN, NP-C, AOCNP
Winship Cancer Institute of Emory University & IMF Nurse Leadership Board
49
49
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
50
GAIT GOING THE DISTANCE
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.
52
OF GAIT GOING
STABLE
THE DISTANCE
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
GAIT GOING THE DISTANCE Immunotherapies
= autologous stem cell transplant; CAR = chimeric antigen receptor; CRS = cytokine release syndrome; DVT = deep vein thrombosis; PE = pulmonary embolism *Withdrawn from FDA but still available in certain situations IMF Nurse Leadership Board ONS Symposia 2023; NCCN Guidelines. Multiple Myeloma. V2.2024. Accessed February 6, 2023. Prescribing information.
Alkylators Bispecific Antibodies Cellular Therapies Others
STABLE OF
ASCT
-Mibs -MAbs -Mides Steroids
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
54 STABLE OF GAIT GOING THE
P H A S E 1 P H A S E 2 P H A S E 3 Miceli T, et al. Clin J Oncol Nurs. 2013;17(6)suppl:13-24. NCCN Guidelines. Multiple Myeloma. V2.2024. Accessed February 6, 2023.
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
55
OF
STABLE
= chimeric antigen receptor; CRS = cytokine release syndrome; ICANS = Immune Effector
Neurotoxicity Syndrome
CAR
Cell-Associated
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.
56
OF
cell MM cell
Bispecific
MM cell death Target CD3 Cytotoxic cytokines Bispecific antibody T
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.
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CAR T and Bi-specific Antibodies: Unique Side Effects
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JN,
JN. Blood. 2016;127(26):3321-3330. Lee DW, et al. Biol Blood Marrow Transplant. 2019;25:625-638.
CAR = chimeric antigen receptor. Brudno
Kochenderfer
Confusio n Altered wakefuln ess
NEUROTOXICITY Headach e
Hallucinati ons Ataxia Apraxia Facial nerve palsy Tremors Seizures Encephalop athy
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
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Rajkumar SV, et al. Lancet Oncol 11(1):29–37. King T, Faiman B. Clin J Oncol Nurs. 2017;21(2):240-249.
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.
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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)
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.2022;9(2):143–161. IMF Nurse Leadership
ONS Symposia 2023.
RAJE NS, et al. Lancet Haematol
Board
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.
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Skin Changes: Talvey™ (talquetamab)
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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
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OF TREATMENT FINDING YOUR GAIT GOING THE DISTANCE
IMF Nurse Leadership Board
. Photos: Mount Sinai Hospital, NY, NY
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.
64
Catamero D, Purcell K, Ray C, et al. Presented at the 20th International Myeloma Society (IMS) Annual Meeting Nurse Symposium; September 27–30, 2023; Athens, Greece.
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 )
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Smith LC, et al. Clin J Oncol Nurs. 2008;12(3)suppl:37-52. Faiman B. Clin J Oncol Nurs. 2016;20(4):E100-E105.
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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
66 STABLE OF GAIT
GOING THE DISTANCE
Faiman B, et al. CJON. 2017;21(5)suppl:19-36.
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
67
NH et al
PloS one.
.
Mustian et al. Journal of clinical Oncology. Sep 10 2013;31(26):3233-3241; Stan DL, et al. Clin J Oncol Nurs. Apr 2012;16(2):131-141; Zeng Y et al., Complementary therapies in medicine. Feb 2014;22(1):173-186.
Rod
2014.
9(4):e91965; Coleman et al. 2011. Cancer Nurs
34(3):219-227.National Sleep Foundation. At: http://sleepfoundation.org/ask-the-expert/sleep-hygiene
Z Z Z Z Z Z Z Z Z
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
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Faiman B, et al. CJON. 2017;21(5)suppl:19-36. Tariman, et al. CJON.2008;12(3)suppl:29-36. Zhao T, et al. Molecules. 2022;27(12):3909.
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
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69
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.
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.
STABLE OF GAIT GOING THE DISTANCE
Additional Supportive Care
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Prevention Bone Health Fatigue Anxiety
Blood thinners Ex: Aspirin, DOACs Bone Strengthening Agents Calcium Vitamin D Stimulant medications Anti-depressants Anti-anxiety
Compression stockings Radiation Surgery Immobilization Physical therapy Relaxation Meditation Therapy Relaxation Meditation
Options Activity Stop smoking Weight loss Activity Activity Improved sleep Activity Improved sleep
STABLE
GAIT GOING THE DISTANCE DVT/PE
Supportive Medications
Non-medication Therapies
Lifestyle
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.
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.
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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
74 TREATMENT GAIT GOING THE DISTANCE You and Your Care Partner(s) Support Network Allied Health Staff Subspecialists Myeloma General Hem/Onc Primary Care Provider (PCP) P h a r m a c i s t Don’t Ride Alone
YOU are central to the care team
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
75
76 TREATMENT IMF: Knowledge Is Power You are not alone! eNewsletter: Myeloma Minute Website: http://myeloma.org IMF Videos Download or order at myeloma.org IMF InfoLine 1-800-452-CURE 9am to 4pm PST
Going the Distance Healthful and meaningful living
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
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IMF Care Partner Tip Card
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.
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FINDING YOUR GAIT GOING THE DISTANCE
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.
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FINDING YOUR GAIT
THE
Q&A
81
COFFEE BREAK
Thank you to our sponsors!
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
Symptomatic Myeloma >1 Billion
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
U M O R L O A D
DEPTH
MRD is Prognostic – Both for PFS and OS
Lahuerta JJ, Paiva B, et al. J Clin Oncol. 2017; 35(25): 2900–2910
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
Slide credit: clinicaloptions.com N Engl J Med. 2022 Jul 14;387(2):132-147. doi: 10.1056/NEJMoa2204925
S t e m c e l l c o l l e c ti o n Induction Consolidation Maintenance Until Progression RVD cycles 2-3 (n = 357) RVD cycles 2-3 (n = 365) RVD cycles 4-8 RVD cycles 4-5 R (n = 291) R (n = 289)
Melphalan 200 mg/m2 + Stem Cell Support (n = 310)
ASCT:
RVD +Stem Cell Transplant vs. RVD without Transplant
Primary endpoint: Progression-free survival (PFS)
92 Paul G. Richardson, MD
Events –no. (%) Median PFS, months (95% CI) 5-year PFS, % (95% CI) RVd-alone 189 (52.9%) 46.2 (38.1–53.7) 41.5 (35.7–47.2) RVd+ASCT 139 (38.1%) 67.5 (58.6–NR) 55.6 (49.4–61.3) HR 1.53 (1.23–1.91), p<0.0001
CI, confidence interval; HR, hazard ratio; Data cut off: 12/12/21
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
93 Paul G. Richardson, MD Events – no. (%) 5-year OS, % HR (95% CI) RVd-alone 90 (25.2%) 79.2 1.10 (0.73 – 1.65) p=0.99* RVd+ASCT 88 (24.1%) 80.7
RVD +Stem Cell Transplant vs. RVD without Transplant
DETERMINATION Trial of Newly Diagnosed MM Quality of Life
Global Health Status/QoL,
Physical Functioning
N Engl J Med. 2022 Jul 14;387(2):132-147. doi: 10.1056/NEJMoa2204925
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
95
Joseph Mikhael – Discussant DETERMINATION
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
@IDEOlogyHealth
Sonneveld et. al. Late-breaking Abstracts Session, ASH 2023. Accessed from: https://ash.confex.com/ash/2023/webprogram/Paper191911.html
cycles of 28 days 2 cycles of 28 days 28-day
cycles
@IDEOlogyHealth
Sonneveld et. al. Late-breaking Abstracts Session, ASH 2023. Accessed from: https://ash.confex.com/ash/2023/webprogram/Paper191911.html No. at Risk VRd 354 335 321 311 304 297 291 283 278 270 258 247 238 228 219 175 67 13 0 D-VRd 355 345 335 329 327 322 318 316 313 309 305 302 299 295 286 226 90 11 0 58% reduction in the risk of progression or death with D-VRd 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 0 20 40 60 80 100 Months % S u r v i v i n g w i t h o u t p r o g r e s s i o n HR, 0.42; 95% CI, 0.30–0.59; P<0.0001 D-VRd 84.3% Median follow-up: 47.5 months VRd 67.7% 48-month PFS
PERSEUS Phase III: Progression Free Survival
Late-breaking Abstracts Session, ASH 2023. Accessed from: https://ash.confex.com/ash/2023/webprogram/Paper191911.html
@IDEOlogyHealth Sonneveld et. al.
Late-breaking Abstracts Session, ASH 2023. Accessed from: https://ash.confex.com/ash/2023/webprogram/Paper191911.html
@IDEOlogyHealth Sonneveld et. al.
PERSEUS: Overall Survival
@IDEOlogyHealth
Sonneveld et. al. Late-breaking Abstracts Session, ASH 2023. Accessed from: https://ash.confex.com/ash/2023/webprogram/Paper191911.html No. at Risk VRd 354 343 337 334 328 322 322 319 317 315 310 307 303 298 296 263 127 27 1 0 D-VRd 355 347 343 341 338 335 331 329 329 326 325 323 321 316 312 284 135 21 1 0 D-VRd (n = 355) VRd (n = 354) Events, n (%) 34 (9.6) 44 (12.4) HR, 0.73 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 0 20 40 60 80 100 Months % S u r v i v i n g D-VRd VRd
PERSEUS: Safety
@IDEOlogyHealth
Event, n (%)a D-VRd (n = 351) VRd (n = 347) Any grade Grade 3 or 4 Any grade Grade 3 or 4 Hematologic Neutropenia 243 (69.2) 218 (62.1) 204 (58.8) 177 (51.0) Thrombocytopenia 170 (48.4) 102 (29.1) 119 (34.3) 60 (17.3) Anemia 78 (22.2) 21 (6.0) 72 (20.7) 22 (6.3) Febrile neutropenia 34 (9.7) 33 (9.4) 38 (11.0) 35 (10.1) Non-Hematologic Diarrhea 214 (61.0) 37 (10.5) 188 (54.2) 27 (7.8) Peripheral sensory neuropathy 188 (53.6) 15 (4.3) 179 (51.6) 14 (4.0) Constipation 119 (33.9) 8 (2.3) 118 (34.0) 6 (1.7) Pyrexia 111 (31.6) 8 (2.3) 109 (31.4) 9 (2.6) Insomnia 95 (27.1) 8 (2.3) 61 (17.6) 6 (1.7) Asthenia 94 (26.8) 12 (3.4) 89 (25.6) 9 (2.6) Cough 85 (24.2) 1 (0.3) 51 (14.7) 0 Fatigue 84 (23.9) 10 (2.8) 92 (26.5) 18 (5.2) Rash 82 (23.4) 9 (2.6) 94 (27.1) 17 (4.9) Back pain 80 (22.8) 2 (0.6) 66 (19.0) 1 (0.3) Peripheral edema 72 (20.5) 4 (1.1) 74 (21.3) 1 (0.3) Nausea 71 (20.2) 2 (0.6) 58 (16.7) 2 (0.6) Infections 305 (86.9) 124 (35.3) 266 (76.7) 95 (27.4) COVID-19 123 (35.0) 12 (3.4) 83 (23.9) 4 (1.2) Upper respiratory tract infection 111 (31.6) 2 (0.6) 87 (25.1) 6 (1.7) Pneumonia 64 (18.2) 37 (10.5) 38 (11.0) 21 (6.1) Sonneveld et. al. Late-breaking Abstracts Session, ASH 2023. Accessed from: https://ash.confex.com/ash/2023/webprogram/Paper191911.html
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
HD7
Week
Week 3 Week 4
1
2
D1 D15
Days 1–28 D8 D22
D22 Week 1 Week 2 Week 3 Week 4 Week 5 Week 6 29 30 25 22 11 8 15 33 26 23 9 D1 D8 D15 D22 D29 D1 D8 D22 D29 D4 D11 D25 D32
Days 22–35 D1 2 4 5 12 32 D1 D15 D29 D1 D15 D1
D1
D15
D8
Days 1–14
Isa + RVd RVd R a n d o m i z a t i o n 1 : 1
Induction phase
Maintenance phase
R a n d o m i z a t i o n HDT + ASCT NDMM N=662
10 3
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
Series1 0% 1000% 2000% 3000% 4000% 5000% 6000% 5010.0% 3560.0% Isa-RVd RVd P<0.001*
HD7 10 4
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
TE, transplant-eligible; NDMM, newly diagnosed multiple myeloma; FISH, fluorescence in situ hybridization; del, deletion; t, translocation; ISS, International Staging System stage; R, randomization; Isa, isatuximab; K, carfilzomib; R, lenalidomide; d, dexamethasone; IV, intravenous; dd, days; cc, cycles; PO, orally; Cy, cyclophosphamide; G-CSF, granulocyte colony-stimulating factor; MEL, melphalan; ASCT, autologous stem-cell transplantation; MRD, minimal residual disease; NGS, next-generation sequencing; PFS, progression-free survival.
1,15 R
10
PO dd 1-21
20 mg PO dd 1,15
K: 56 mg/m2 IV dd
:
mg
d:
4× KRd
K: 56 mg/m2 IV dd 1,8,15
cc 5-8
1-21
: 25 mg PO daily dd
1,8,15,22
d: 40 mg PO dd
Isa-KRd
Isa: 10 mg/kg IV d 1
56 mg/m
1,15 R: 10 mg PO dd 1-21
: 20 mg PO dd 1,15
K:
2 IV dd
d
4× Isa-KRd
: 10 mg/kg IV dd 1,15 cc
NGS MRD by NGS 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.
NGS, 10-5 NGS, 10-6 Isa-KRd (N=151) KRd (N=151) 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% 77% 67% P a ti e n t s ( % ) OR 1.67, p=0.049 Isa-KRd (N=151) KRd (N=151) 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% 67% 48% P a ti e n t s ( % ) OR 2.29, p<0.001 MRD, minimal residual disease; ITT, intention to treat; NGS, next-generation sequencing; OR, odds ratio; p, pvalue; Isa, isatuximab; K, carfilzomib; R, lenalidomide; d, dexamethasone; CI, confidence interval.
MRD negativity rates improved over time (10
Post induction Post ASCT Post consolidation Post induction Post ASCT Post consolidation 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% 45% 64% 77% 26% 49% 67% P a ti e n t s ( % )
-5)
MRD, minimal residual disease; p, p-value; ASCT, autologous stem-cell transplantation.
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.
0 HRCA 1 HRCA 2+ HRCA 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% 79% 78% 77% 72% 65% 53%
Isa-KRd KRd
P a ti e n t s ( % )
0 HRCA 1 HRCA 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% 65% 69% 48% 53%
(q32.3;q23),
minimal residual disease; NGS, next-generation sequencing; HRCA, high-risk cytogenetic abnormalities; Isa, isatuximab; K, carfilzomib; R, lenalidomide; d, dexamethasone; del, deletion; t, translocation; amp, amplification.
Isa-KRd KRd MRD,
NGS, 10-5 NGS, 10-6
HRCA
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.
Isa, isatuximab; K, carfilzomib; R, lenalidomide; d, dexamethasone; MRD, minimal residual disease; PFS, progression-free survival; OS, overall survival.
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
Dara-KRd x 4 Induction M R D Lenalidomide Maintenance AHCT Dara-KRd x 4 Consolidation Dara-KRd x 4 Consolidation M R D M R D M R D ”MRD-SURE” -Treatment-free observation and MRD surveillance* 2nd MRD (-) (<10-5) 2nd MRD (-) (<10-5) 2nd MRD (-) (<10-5) MASTER trial
therapy
*24 and 72 weeks after completion of
Progression-Free and Overall Survival
MASTER trial 0 HRCA 91% 2-year PFS 1 HRCA 97% 2+ HRCA 58% 0 HRCA 96% 2-year OS 1 HRCA 100% 2+ HRCA 76% HRCA = gain/amp 1q, t(4;14), t(14;16), t(14;20) or del(17p)
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
Mikhael J, et al. J Clin Oncol. April 1, 2019. DOI:10.1200/JCO.18.02096.
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)
i o
1 : 1 r a n d o m i s a t
n
TIE, transplant-ineligible; ECOG PS, Eastern Cooperative Oncology Group performance status; CrCl, creatinine clearance; IV, intravenous; QW, once weekly; Q2W, once every 2 weeks; Q4W, once every 4 weeks; PD, progressive disease; PO, oral; ORR, overall response rate; CR, complete response; sCR, stringent complete response; MRD, minimal residual disease; NGS, next-generation sequencing; BMI, body mass index.
On 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. MAIA is
NDMM who are
ineligible ‒
a
a multicentre, randomised, open-label, active-controlled, phase 3 study of D-Rd versus Rd alone in patients with
transplant
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.
D-Rd (n = 368) Rd (n = 369) Age, years Median (range) 73.0 (50-90) 74.0 (45-89) Distribution, n (%) <65 4 (1) 4 (1) 65-<70 74 (20) 73 (20) 70-<75 130 (35) 131 (36) ≥75 160 (43) 161 (44) ECOG PS score, n (%) 0 127 (35) 123 (33) 1 178 (48) 187 (51) 2a 63 (17) 59 (16) ISS stage, n (%) I 98 (27) 103 (28) II 163 (44) 156 (42) III 107 (29) 110 (30) D-Rd (n = 368) Rd (n = 369) Type of measurable disease, n (%) IgG 225 (61) 231 (63) IgA 65 (18) 66 (18) Otherb 9 (2) 10 (3) Detected in urine only 40 (11) 34 (9) Detected as serumfree light chain only 29 (8) 28 (8) Cytogenetic profile, n/total n (%) Standard risk 271/319 (85) 279/323 (86) High risk 48/319 (15) 44/323 (14) Median time since initial diagnosis of MM (range), months 0.95 (0.1-13.3) 0.89 (0-14.5)
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
et al.
Engl
ORRa VGPR, very good partial response; PR, partial response. aITT population. 1. Facon T,
N
J Med 2019;380(22):2104-2115.
Note: percentages may not add up to the total due to rounding.
0 20 40 60 80 100 14% 28% 12% 25% 32% 28% 30% 27% 17% 13% 16% 15% 30% 13% 35% 15% O R R , % 93% 81% D-Rd n
= 368 Rd n = 369
D-Rd n
93% 82%
= 368 Rd n = 369
PR VGPR CR sCR
D-Rd Rd
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
NR, not reached; CI, confidence interval. D-Rd: median, NR Rd: median, 34.4 months 52.5% 28.7% 60-month PFS rate Months HR, 0.53; 95% CI, 0.43-0.66; P <0.0001 % s u r v i v i n g w i t h o u t p r o g r e s s i o n 20 40 60 80 100 0 0 3 6 9 12 15 18 42 21 27 24 30 33 36 39 51 45 48 54 57 60 63 66 69 No. at risk Rd D-Rd 369 368 333 347 307 335 280 320 255 309 237 300 220 290 123 210 205 276 179 256 196 266 172 246 155 237 146 232 133 222 94 170 113 199 105 195 63 123 36 87 12 51 4 17 2 5 0 0
D-Rd demonstrated a significant benefit in OS, with a 32% reduction in the risk of death, in patients with NDMM who are transplant ineligible
OS D-Rd: median, NR Rd: median, NR 66.3% 53.1% 60-month OS rate Months HR, 0.68; 95% CI, 0.53-0.86; P = 0.0013 % s u r v i v i n g 20 40 60 80 100 0 0 3 6 9 12 15 18 42 21 27 24 30 33 36 39 51 45 48 54 57 60 63 66 69 72 No. at risk Rd D-Rd 369 368 351 350 343 346 336 344 324 338 317 334 308 328 232 266 300 316 281 302 294 305 270 297 258 286 251 280 241 273 183 228 223 255 213 249 134 170 85 118 42 63 14 22 5 6 1 1 0 0
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
Induction Consolidation Front line treatment Post consolidation Maintenance Rescue Relapsed New
++++++++ Now
Lenalidomide Carfilzomib Pomalidomide Selinexor Panobinostat Daratumumab Ixazomib
Q&A
126
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
2:35 – 2:45 PM
2:45 – 3:00 PM
Thank you to our sponsors!
Local Patient & Care Partner Sandy & Joe Brown
Jim & Lisa Mahoney
Maintenance Therapy
Nisha Joseph, MD
Winship
1 3 1
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
et al. J Clin Oncol. 2017, 35:3279-3289.
McCarthy
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
No. of patients at risk: Lenalidomide Observation 857 694 771 584 675 504 611 413 512 353 444 293 369 247 330 202 265 167 228 132 204 108 169 86 143 64 118 48 90 40 67 25 43 20 27 10 17 3 11 2 4 2 1 1 0 0 Time since randomisation (months) 100 0 P a t i e n t s a l i v e a n d p r o g r e s s i o nf r e e ( % ) 80 60 40 20 0 18 33 51 66 3 6 9 12 15 21 24 27 30 36 39 42 45 48 54 57 60 63 CI, confidence interval; HR, hazard ratio Median PFS, months [95% CI] Lenalidomide (n=857) 36 [31, 39] Observation (n=694) 18 [16, 20] HR=0.45; 95% CI 0.39, 0.52 Log-rank p<0.0001 Jackson et al., Lancet 20:57-73, 2019
Meta-analysis of all four randomized studies evaluating lenalidomide maintenance
PFS
HR 0.47
OS
HR 0.72
al.,
Jackson et
Lancet 20:57-73, 2019
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.
142
R KR
R1 1:1:1 R2 1:1 Single ASCT
M O B I L I Z A T I O N Presented by Francesca Gay in 2021 ASCO Annual meeting
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.
KR
143 0.00 0.25 0.50 0.75 1.00 0 10 20 30 40 50 60 Months 0.51 0.56 0.69 P r o g r e s s i o nf r e e s u r v i v a l Months 0.00 0.25 0.50 0.75 1.00 0 10 20 30 40 0.65 0.75 P r o g r e s s i o nf r e e s u r v i v a l Presented by Francesca Gay in 2021 ASCO Annual meeting
vs. R
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
KR vs. R Standard risk (N=120) High risk (N=172) Double hit (N=105) KR vs. R: HR 0.4, p=0.05
CI, confidence interval; p, p-value. 0.00 0.25 0.50 0.75 1.00 0 10 20 30 40 P r o g r e s s i o nf r e e s u r v i v a l Months 0.73 0.9 0.00 0.25 0.50 0.75 1.00 0 10 20 30 40 P r o g r e s s i o nf r e e s u r v i v a l Months 0.56 0.69 KR vs. R: HR 0.6, p=0.04 0.00 0.25 0.50 0.75 1.00 0 10 20 30 40 P r o g r e s s i o nf r e e s u r v i v a l Months 0.42 0.67 41.8 23.4 KR vs. R: HR 0.53, p=0.1
Random 2, second randomization (maintenance treatment); IQR, interquartile range; K, carfilzomib; R, lenalidomide; HR, hazard ratio;
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
@IDEOlogyHealth
Sonneveld et. al. Late-breaking Abstracts Session, ASH 2023. Accessed from: https://ash.confex.com/ash/2023/webprogram/Paper191911.html
cycles of 28 days
cycles of 28 days 28-day
2
cycles
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
150
Maintenance R 1: 1 NDMM
2 years 3 years 5 years 4 years
Randomisation PFS
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
151
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
153
Relapsed Therapies & Clinical Trials
Jonathan Kaufman, MD
Winship Cancer Institute of Emory University
Atlanta, GA
Relapsed Therapy
155
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
1st Relapse 2nd 3rd 4th 5th and beyond
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!
RVD+ASCT+Lenalidomide Maintenance Relapse 1 Relapse 2 Relapse 3 Time: Years! D i s e a s e A c t i v i t y Relapse 1 Relapse 1 Relapse 2
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
Rajkumar SV. 2022
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
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
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
IV, intravenous; SC, subcutaneous
• 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
Rajkumar SV. 2022
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.
Slide credit: clinicaloptions.com
CD19 Tumor cell Activity
CAR T-Cell Therapy Patient Journey
3 Lymphodepletion (chemotherapy) 4 Infusion 1 Apheresis 2 (Manufacturing) Patients return home Immune cells from the patient are collected
are used
CAR T cells to expand
1 day 4–6 weeks 3 days 2 weeks Within 2 weeks 5 Follow up
Fludarabine and Cytoxan
to create “immunologic space” to
Standard of care therapy is permitted until CAR T cells are ready for infusion
Abecma and Carvykti in Relapsed and Refractory Multiple Myeloma
Abecma Carvykti Ide-cel (n=128) 0 10 20 30 40 50 60 70 80 90 100 21 20 7 26 PR VGPR CR or sCR and MRD NE CR or sCR and MRDP a ti e n t s ( % ) ORR 73% Average PFS 9 months ORR, overall response rate; PR,
VGPR,
CR, complete response; sCR, stringent complete response; MRD, minimal residual disease; PFS,
KarMMa
Cilta-cel (n=97) 0 10 20 30 40 50 60 70 80 90 100 3 12.4 82.5 PR VGPR sCR P a ti e n t s ( % ) ORR 97.9% 27-month PFS 55%
partial response;
very good partial response;
progression-free survival
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].
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.
Onset 19 days after CAR T-cell infusion 29 days after CAR T-cell infusion Duration 511 days 317 days
CAR-T access remain an issue
Survey of 20 centers. Responses from 17 centers.
Median (range) MM CAR-T infusion volume in 2021 10-50 (<5,50-100) Number of FDA approved CAR-T slots given per month 1 (0-4) Patients on wait list (FDA approved CAR-T) 20 (5-100)
a patient is on waiting list 6 (2-8) months
of patients on wait list FDA approved CAR-T CAR-T trial non-CAR-T trial hospice or death 25% (0%-64%) 25% (0-50%) 25% (0-50%) 25% (0%-75%) Kourelis T et al. ASCO 2022.
Duration
Outcomes
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.
Cellular therapies CAR T-cell therapy Autologous stem cell transplantation Patient’s cells collected Yes Yes Types of cells collected T cells* Stem cells† Collected
genetically
lab Yes No
cells are
engineered in a
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
A et al. Clin Cancer Res.
Cohen
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
4.2% 19.4% 6.7% 32.7% sCR CR VGPR PR ≥VGPR: 58.8% ≥CR: 39.4% 63.0% (104/165) P a t i e n t s ( % ) Moreau P et al. N Engl J Med. 2022;387:495.
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:
186
10 4 10 1 3 5 1 7 0 Month s 0 0 3 6 9 1 2 1 5 1 8 2 1 2 4 2 0 4 0 6 0 P a t i e n t s ( % ) 8 0 10 0 0 2 7 6 5 6 5 8 96 0 7 45 5 2 8 1 6 7 6 2 2 0 0 CR or better DOR Patients at risk Overall
18.4
68.5% (95% CI: 57.7–77.1) 80.1% (95% CI: 67.6–88.2)
Overall median DOR
(95%
14.9–NE)
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)
187
AEs ≥20%, n (%) Any Grade Grade 3/4 Hematologic Neutropenia 117 (70.9) 106 (64.2) Anemia 86 (52.1) 61 (37.0) Thrombocytopenia 66 (40.0) 35 (21.2) Lymphopenia 57 (34.5) 54 (32.7) Nonhematologic CRS 119 (72.1) 1 (0.6) Diarrhea 47 (28.5) 6 (3.6) Fatigue 46 (27.9) 4 (2.4) Nausea 45 (27.3) 1 (0.6) Pyrexia 45 (27.3) 1 (0.6) Injection site erythema 43 (26.1) 0 (0) Headache 39 (23.6) 1 (0.6) Arthralgia 36 (21.8) 1 (0.6) Constipation 34 (20.6) 0 (0) Cough 33 (20.0) 0 (0)
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.
Raje N, et al. ASH. 2022:
abstract 158.
T P 5 3 K R A S N R A S
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
Chari A, et al. Blood. 2022;140 (suppl 1): 384-387.
responders
each group. QW =
Timing, mos 405 μg/kg SC QW n = 143 800 μg/kg SC Q2W n = 15 Median follow-up, mos (range) 14.9 (0.5–29.0). 8.6 (0.2–22.5) Median time to first response*, mos (range) 1.2 (0.2–10.9) 1.3 (0.2–9.2) Median time to best response*, mos (range) 2.2 (0.8–12.7) 2.7 (0.3–12.5) ORR 0 20 40 60 80 100 14.7 15.9 25.9 24.8 9.8 12.4 23.8 20.0 74.1% (106/143) 73.1% (106/145) ≥VGPR: 59.4% 405 μg/kg SC QW 800 μg/kg SC Q2W P a ti e n t s ( % ) ≥VGPR: 57.2% 100% 80% 60% 40% 20% 0% Data cut-off 9/12/2022 ⍭Investigational, not FDA-approved
*Calculated from n =106
in
weekly.
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
Chari
et al. Blood. 2022;140
1 9 0% 20% 40% 60% 80% 100%
A,
P a ti e n t s , n
( % )
405 μg/kg SC QW 800 μg/kg SC Q2W (n = 143) (n = 145) 79.0 % 72.4 %
Bispecific Antibodies: >20% Activity
*Based on a recent sampling
Myeloma cell target Bispecific agent Patients responding* BCMA Teclistamab 63% BCMA REGN5458 73% BCMA Elranatamab 73% BCMA TNB383B 60% BCMA CC93269 89% BCMA AMG701 83% GPRC5D Talquetamab 70% FCRH5 Cevostamab 55%
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
CAR T-cell therapy Bispecific antibody Approved product Abecma, Carvykti Tecvayli Efficacy ++++ +++ How given One-and-done IV or SC, weekly to every 3 weeks until progression Where given Academic medical centers Academic medical centers Notable adverse events CRS and neurotoxicity CRS and neurotoxicity Cytokine release syndrome +++ ++ 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
Induction Consolidation Front line treatment Post consolidation Maintenance Rescue Relapsed New
++++++++ Now
Lenalidomide Carfilzomib Pomalidomide Selinexor Panobinostat Daratumumab Ixazomib
Clinical Trials
196
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
200
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 I
Phase II
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
208
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
209
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
210
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
212
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
Considering Entering a Clinical Trial?
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
216
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