1
Welcome and Announcements Kelly Cox
Director Support Groups & Senior Director Regional Community Workshops 2
Thank you to our sponsors!
3
March is Myeloma Action Month!
4
IMF REGIONAL COMMUNITY WORKSHOP – Tri-State Saturday March 19, 2022 - Agenda
10:00 AM - Welcome and Announcements Kelly Cox, Director Support Groups & Senior Director of Regional Community Workshops 10:05 AM - Myeloma 101 and Frontline Therapy Jonathan Kaufman, MD, Winship Cancer Institute, Emory University 10:40 AM - Q & A with Panel 10:55 AM – Myeloma Action Month Robin Tuohy, Vice President, Support Groups 10:55 AM – Meditation and Stretch Break 11:05 AM - Relapsed Therapy and Clinical Trials David Vesole, MD, PhD, FACP, The John Theurer Cancer Center at Hackensack University Medical Center 11:45 AM - How to Manage Myeloma Symptoms and Side Effects Daniel Verina, DNP, RN, MSH, ACNP-BC, Mount Sinai Hospital, IMF Nurse Leadership Board 12:05 PM - Q&A with Panel
5
Myeloma 101 and Frontline Therapy
Jonathan Kaufman, MD, Winship Cancer Institute, Atlanta, GA 6
MYELOMA 101 JONATHAN L. KAUFMAN, MD MARCH 19TH, 2022
TOPICS TO COVER
• What is Myeloma? • How do we stage myeloma? • How do we diagnose myeloma? • Treatment options • Role of autologous stem cell transplant
8
Epidemiology
• Men > Women • Blacks > Whites • Median age of diagnosis is 66 • 10% < 50, 2% <40 Normal
+
-
M-protein
+
-
Pathophysiology
• Recall the role of the normal plasma cell • Malignant plasma cell “dyscrasia” • Accumulation of plasma cells in the bone marrow
• These produce a single immunoglubulin (Ig) – monoclonal protein
• Sequelae relate to presence of plasma cells or interactions they induce via cytokines in microenvironment
The Plasma Cell
Carr and Rodak: Clin Hematol Atlas
Immunoglobulins
Heavy Chain
Light Chain
-IgG
-kappa
-IgA
-lambda
-IgM -IgD -IgE
Molecular progression
Normal plasma cell
MGUS
Translocations Infection Inflammation
Asymptomatic Myeloma
Active Myeloma
ras & p53 mutation c-myc dysregulation Bone resorption Angiogenesis
Aggressive Myeloma
Del 13 Secondary translocations
SPECTRUM OF PLASMA CELL DISORDERS
MGUS
M-protein < 3 g/dL Clonal plasma cells in marrow <10 % No MDE
Smoldering Myeloma
M-protein ≥ 3 g/dL (serum) or ≥ 500 mg/24 hrs (urine) and/or Clonal plasma cells in marrow >10 % No MDE
Multiple Myeloma
Clonal plasma cells ≥ 10% or ≥ 1 biopsyproven plasmacytoma MDE
15
DIAGNOSTIC CRITERIA
Revised International Myeloma Working Group (IMWG) Criteria for the Diagnosis of Multiple Myeloma
16
LIVING WITH MYELOMA
An estimated 128,969 people in the US are living with, or in remission from, myeloma. There is currently no cure for myeloma, but there are very effective treatments that help patients feel well and live longer.
17
RISK FACTORS
The exact cause of myeloma is not known. Some factors may increase the risk: • Age: Most people who develop myeloma are older than 50. • Sex: More men than women develop myeloma. • Race: Blacks have more than twice the age-adjusted incidence rate of myeloma than whites. • History of monoclonal gammopathy of unknown significance (MGUS) • Environmental factors, such as exposure to radiation or certain kinds of chemicals
18
DIAGNOSING MYELOMA • Blood and urine tests • Bone marrow tests o Bone marrow aspirations o Bone marrow biopsy • Cytogenetic analysis o FISH • Next-Generation Sequencing (NGS) • Imaging Tests o Bone/skeletal survey o MRI o PET-CT scan 19
MONOCLONAL PROTEINS
Monoclonal protein (“M protein”) is an antibody found in large amounts in the blood or urine of people with myeloma. Monoclonal proteins can be either intact monoclonal immunoglobulins or immunoglobulin light chains (Bence Jones proteins) found in the blood and/or urine. Measuring the amount of M protein can tell the severity of the myeloma. A special test to check for light chains is called a serum free light chain test.
20
STAGING • Oncologists now routinely use the Revised International Staging System (R-ISS) which calculates the myeloma stage by measuring: • • • •
Blood Beta 2 macroglobulin Blood albumin Blood LDH Bone marrow Cytogenetics
• The results from these tests allow the doctor to classify the patient’s myeloma as stage I, stage II, or stage III disease. • Unlike other cancers, stage doesn’t have to do with how the cancer has spread in the body. But it does give information about how aggressive the myeloma is. • Approximately, 82% of R-ISS I patients are alive 5 years after diagnosis, 62% of R-ISS II patients are alive 5 years after diagnosis, and 40% of R-ISS III are alive 5 years after diagnosis.
21
HOW OFTEN TO DO TESTING?
• Serum protein electrophoresis and immunofixation, Immunoglobulins, CBC, CMP, Free light chains: monthly • Urine protein electrophoresis and immunofixation : At diagnosis and then varies per patient • Radiology Imaging: At diagnosis, when clinically indicated, to confirm complete remission. • Bone marrow biopsy:
• At diagnosis • At relapse • To confirm complete remission 22
TREATMENT PLANNING Factors considered when determining a treatment plan include: • Stage • The general health of the patient • Patient preferences • The presence of other significant diseases • The presence of kidney disease • Other findings that influence the patient’s tolerance to treatment • The risk of treatment-induced complications • Whether treatment is required • Which treatment approach to take • How myeloma has affected the body 23
Managing myeloma: the components Transplant Eligible Patients
Transplant Ineligible patients
Consolidation
Maintenance
Initial Therapy
Treatment of Relapsed disease Consolidation/ Maintenance/ Continued therapy
Supportive Care
TREATMENTS FOR MYELOMA
Treatments for myeloma include: •
Combination drug therapy
•
High-dose chemotherapy with stem cell transplant
•
Radiation therapy for local disease or bone pain
•
Watch-and-wait approach (smoldering myeloma/MGUS)
•
New and emerging drug therapies (as part of clinical trials)
•
Supportive care
25
DRUG THERAPY FOR MYELOMA
• Drug therapy for myeloma has led to sustained remissions in some patients. • Temporary cessation or significant slowing of the disease may occur for a time. • Long periods of complete remission are being seen more often as newer, more effective drugs are developed. • Drugs are given orally, by intravenous injection, or injection under the skin.
26
STEM CELL TRANSPLANTATION (SCT) • Sometimes called bone marrow transplant. • Stem cells are the seeds that can grow a new bone marrow. They are usually collected from the blood. Sometimes they are collected from the bone marrow. • Most common type is autologous stem cell transplant, where stem cells come from the myeloma patient. The purpose is to give a high dose of chemotherapy to clear out myeloma cells, and then use a patient’s stem cells to help the bone marrow recover more quickly from the chemotherapy. • The purpose is to give a patient a new bone marrow and immune system which will prevent myeloma from growing.
27
STEM CELL TRANSPLANTATION, CONT.
Factors that influence whether transplant is an option: •
Patient’s age/performance status
•
Ability to tolerate intensive treatment
•
Patient’s health, including possible co-morbidities, tobacco or drug use
•
Alternative treatment options
•
Weighing of risks versus benefits
28
STEM CELL COLLECTION Peripheral Stem Cell Collection - Done in the outpatient clinic, not a surgery or procedure - Use self-administered growth factor injections to rev up the marrow and cause stem cells to move out of the marrow into the peripheral bloodstream - Using a central venous catheter and an apheresis machine, these stem cells are filtered out of your blood and then sent for processing and frozen until the day of transplant - Common side effects: • Feeling cold • Experiencing electrolyte abnormalities • Fatigue • Headache • Nausea
WINSHIP CANCER INSTITUTE OF EMORY UNIVERSITY
NCI Designated Comprehensive Cancer Center
PERIPHERAL STEM CELL COLLECTION
WINSHIP CANCER INSTITUTE OF EMORY UNIVERSITY
NCI Designated Comprehensive Cancer Center
CONDITIONING The conditioning regimen is the chemotherapy you receive prior to infusion of stem cells
Chemotherapy called Melphalan, which is given at a high dose that is effective at killing myeloma cells as well as normal blood cells Administered through you PICC line that is placed prior to transplant Common side effects:
GI toxicity: mucositis (mouth ulcers), nausea, vomiting, abdominal pain/cramping and diarrhea Hair loss Low blood counts Almost all patients will require blood and platelet transfusion at some point during their transplant course Low WBC count places you at increased risk of infection. Patient are started on prophylactic antibiotics to try to prevent infection and monitored closely for fevers
WINSHIP CANCER INSTITUTE OF EMORY UNIVERSITY
NCI Designated Comprehensive Cancer Center
STEM CELL INFUSION Occurs in your hospital room Infusion through you PICC line just like a unit of blood or platelets – not a surgery or procedure 30 min-1 hour Pre-medications and monitored for reaction to the product (fevers, chills, hives, chest pain etc)
WINSHIP CANCER INSTITUTE OF EMORY UNIVERSITY
NCI Designated Comprehensive Cancer Center
AWAITING ENGRAFTMENT A few days following chemotherapy, blood counts will start to drop This the period of time where patients are feeling the side effects of chemotherapy (GI toxicities) and are at most risk of infection Most patients will require blood and platelet transfusions Remain inpatient during this time so that we can rapidly address medical needs (IVF, electrolytes, treatment for nausea/diarrhea, transfusions, antibiotics etc) Wait for neutrophil count (bacteria-fighting WBC), platelet count and red blood cell count to be at safe levels (engraftment) prior to discharge home from the hospital Occurs 10-14 days on average following stem cell infusion
WINSHIP CANCER INSTITUTE OF EMORY UNIVERSITY
NCI Designated Comprehensive Cancer Center
TIMELINE
Melphalan Stem cells Engraftment -2 -1 0 +1 +2 +3 +4 +5 +6 +7 +8 +10-14 • Every day prior transplant is marked with (-) and days following transplant with a (+) • Day -1 = Day of rest; Allows time for chemo to be excreted from the body so it does not damage new stem cells
WINSHIP CANCER INSTITUTE OF EMORY UNIVERSITY
+9
NCI Designated Comprehensive Cancer Center
Managing myeloma: the components Transplant Eligible Patients
Transplant Ineligible patients
Consolidation
Maintenance
Initial Therapy
Treatment of Relapsed disease Consolidation/ Maintenance/ Continued therapy
Supportive Care
Individualizing Care
• Important Factors: • Age • High Risk cytogenetics • Renal disease • Convenience/location • Counts • Steroid “status” • Previous therapy • PATIENT PREFERENCE
Supportive Care
• Remember we treat the patient, not the disease… • Bone Disease • Fatigue and Anemia • Infections • Overall Quality of Life
Well Being Cancer Care “Evolution” 1. Survival 2. Pain 3. Nausea & Vomiting 4. Energy & Quality of Life Exercise Program Patient Advocacy Support Group Fund Raising
Conclusions • • • • •
MGUS is a common condition that must be appropriately managed, including risk stratifying patients Multiple Myeloma is an uncommon condition but must be considered Stem cell transplant is still the standard of care in myeloma in eligible patients Newer agents are showing outstanding results that will likely further improve the overall survival of patients with myeloma Although the mainstay of treatment is directed at the cancer itself, considerations must be given to supportive care and quality of life
40
Relapsed Therapy and Clinical Trials David Vesole, MD, PhD, FACP, The John Theurer Cancer Center, Hackensack, NJ 41
IMF Regional Community Workshop Management of relapsed Multiple Myeloma & Clinical Trials: The Future is BRIGHT!
David H. Vesole, MD, PhD Co-Director, Myeloma Division Director, Myeloma Research John Theurer Cancer Center Hackensack University Medical Center Director, Myeloma Program Professor of Medicine, Hackensack Meridian School of Medicine and Georgetown University Medical School david.vesole@hmhn.org
What I aim to cover • An understanding of the treatment options available for patients when their myeloma comes back • How to navigate/understand the decision-making process on what that next treatment should be • What is new - but in our hands ready to use now • What the future holds – new therapies and trials
What is relapsed/refractory disease? • Relapsed: recurrence after a response to therapy • Refractory: progression despite ongoing therapy
Why do we care about what you had before? Darwinian evolution and in multiple myeloma – this is why combinations have been the key to success
Nizar J. Bahlis, Darwinian evolution and tiding clones in multiple myeloma, Blood, 2012, Copyright © 2021 American Society of Hematology
Johnnie B. • A 65-yr-old male with ISS stage 1 MM received Revlimid, Velcade and Dexamethasone induction therapy for 4 cycles followed by stem cell transplant. He declined Revlimid maintenance treatment and was in CR (M protein 0) for 3.5 yrs • He now presents with M protein of 0.6 g/dL and no anemia or other abnormalities on skeletal survey • 3 mos later, repeat testing shows M protein of 0.8 g/dL • 6 mos later, M protein is 0.9 g/dL with no changes in the other laboratory values • 9 mos later, M protein is 1.5 g/dL, moderate anemia
When to Consider Retreatment • Differences between biochemical relapse and symptomatic relapse need to be considered • Patients with asymptomatic rise in M protein can be observed to determine the rate of rise and nature of the relapse – Caveat: patients with known aggressive or high-risk disease should be considered for salvage even in the setting of biochemical relapse
• CRAB criteria are still listed as the indication to treat in the relapse setting C: Calcium elevation (> 11.5 mg/L or ULN) R: Renal dysfunction (serum creatinine > 2 mg/dL) A: Anemia (Hb < 10 g/dL or 2 g < normal) B: Bone disease (lytic lesions or osteoporosis)
Myeloma Drugs Approved Since 2000 Bortezomib Zoledronic acid
2000
Daratumumab Pomalidomide Ixazomib Elotuzumab
Liposomal doxorubicin Thalidomide Lenalidomide
2005
Carfilzomib
2010
Selinexor Daratumumab SC
Panobinostat Denosumab
2015
Melphalan flufenamide
Idecabtagene vicleucel
Isatuximab
2020
Belantomab mafodotin
2021
Cilta-Cel
2022
Possible Anti-Myeloma Regimens: So Many Choices! Pomalyst (pomalidomide)
Kyprolis (carfilzomib)
Darzalex (daratumumab)
Empliciti (elotuzumab)
Ninlaro (ixazomib)
Xpovia (selinexor
BCMAdirected
Dara Pom D
KD
Dara
Elo RD
Ixa
Selinexor
Ida-Cel (Abecma)
Car Pom D
KRD
Dara Pom
Elo PomD
Ixa Dex
BTZ Sel
Ixa Pom Dex
K Cy Dex
Dara Len
Elo BortD
IRD
Pom Sel
Bort Pom Dex
K Dara Dex
Dara Bort
Ixa Pom Dex
Dara Sel
Elo Pom Dex
Car Pano
Dara Carfil
Pom Cy Dex
Supportive care drugs should be integrated at diagnosis and throughout: ‒ Bone Modifying Agents (Zoledronic Acid, pamidronate and denosumab) ‒ Antivirals (acyclovir/valacyclovir)
Cilta-Cel (CARVYKTI) Belantamab mafodotin (Blenrep)
How do these drugs work? • Tell them to die steroids • Interfere with DNA replication chemo • Interfere with cellular dustbin PIs • Interfere with protein pathway IMIDs • Flag for destruction Mabs
Multiple factors drive treatment choice in relapsed/refractory MM Tolerance to prior therapies
Prior therapies received†
Time interval since last therapy
Side effects
Influential factors
Comorbidity e.g. renal impairment* Treatment availability
*Occurs in up to 50% MM patients. †Can repeat induction therapy where relapse occurs >6 months after treatment. PN, peripheral neuropathy; SCT, stem cell transplant.
Subtype e.g. t(4;14) Age
Previous SCT Pre-existing toxicities e.g. PN
Performance status
Moreau P, et al. Ann Oncol 2013;24 (Suppl 6):vi133–7; Lonial S. Hematology Am Soc Hematol Educ Program 2010;2010:303–9.
Patterns of Relapse / Implications • Indolent (=slow growth) – 1st – Slow and asymptomatic – Low /standard risk
Treatment implications Single agent / doublet Sequential versus combination therapies Emphasis on patient preference and convenience
• Aggressive (=FAST growth) – Multiple – Fast or symptomatic – High risk
Treatment implications Triplet or combination therapies Emphasis on efficacy
Factors to Consider in Treatment Selection DISEASE-RELATED • DOR to initial therapy • FISH/cytogenetics/genomics profile • • • •
PRIOR TREATMENT–RELATED Prior drug exposure Toxicity of regimen Mode of administration Previous SCT
• • • • •
PATIENT-RELATED Pre-existing toxicity Presence of other conditions Age General health Personal lifestyle and preferences
Treatment Considerations: Special Populations Patient Population
Considerations
Frail, elderly patients
Use standard 3-drug regimens with available dose reductions to improve tolerability Some would consider doublet therapy with Rd
Renal dysfunction
Consider RVd, with lenalidomide dose adjusted based on CrCl or RVd-Lite
Cardiac dysfunction
Avoid carfilzomib Use thromboprophylaxis with lenalidomide-based therapy
Peripheral neuropathy
Administer bortezomib SQ and use weekly dosing Consider induction with carfilzomib/len/dex (KRd) or ixazomib/len/dex (IRd)
Aggressive, high-risk disease
Consider induction with carfilzomib/len/dex (KRd)
Extramedullary disease and Associated with shorter survival rates, and considered as high-risk plasma cell leukemia Consider VTD-PACE and ASCT
Choosing Therapy for Patients With Relapsed/Refractory Multiple Myeloma Chosen 1st-line Therapy
Options for 2nd-line Therapy
Subsequent Therapy
Induction Therapy ± Consolidation → Len Maintenance Until PD
Daratumumab or Isatuximab + Pomalidomide/Dex Daratumumab or Isatuximab + Carfilzomib/Dex
Carfilzomib/ Cyclophosphamide/Dex Pomalidomide/ Cyclophosphamide/Dex
Carfilzomib/Pomalidomide/Dex Elotuzumab/Pomalidomide/Dex
Selinexor/ Bortezomib/Dex
Ixazomib/Pomalidomide/Dex
Belantamab Mafodotin
Pomalidomide/Cyclophosphamide/Dex
Ida-Cel; Cilta-Cel
Carfilzomib/Cyclophosphamide/Dex
Melphalan Flufenamide
Clinical trial should be considered for all eligible patients
Options at Relapse
How Do We Define & Measure Success? • Goals of therapy 1. 2. 3. 4.
Improve quality of life Prevent complications Improve survival ? Functional cure
Some commonly used players for first relapse Proteosome inhibitor • Kyprolis (carfilzomib) • Ninlaro (ixazomib) • Return to Velcade (bortezomib)
IMiD
Antibodies
• Pomalyst (pomalidoide) • Revlamid (lenalidomide) – if not used already
• Darzalex (daratumumab) – if not used already • Sarclisa (isatuximab) • Empliciti (elotuzumab)
•
dexamethasone.
Main Targets for Immunotherapy Monoclonal antibodies
CAR T cells
Directly targeting myeloma cell markers
Overcoming immune suppression
Boosting myeloma-fighting T cells
Activating myelomaspecific immunity
Rodriguez-Otero P et al. Haematologica. 2017;102:423.
IMiDs, checkpoint inhibitors
Vaccines
B-Cell Maturation Antigen (BCMA) in Multiple Myeloma
• Expressed on late memory B-cells committed to plasma cell differentiation • BCMA plays a role in survival of long-lived plasma cells
Cho. Front Immunol. 2018;10:1821.
BCMA-Targeted Therapies Antibody–Drug Conjugates Belantamab mafodotin MEDI2228 CC-99712
BCMA
Myeloma cell
Bispecific T-Cell Engagers AMG 420 AMG 701 CC-93269 REGN5458 JNJ-64007957 PF-06863135 CAR T-Cell Therapies Idecabtagene vicleucel Ciltacabtagene autoleucel Orvacabtagene autoleucel P-BCMA-101 bb21217 ALLO-715
Belantamab Mafodotin (Blenrep®): A BCMA-Targeted Antibody Drug Conjugate Belantamab mafodotin
Fc region –Target specific of the Ab –Enhanced ADCC
ADC
• Humanized anti-BCMA antibody • Conjugated to a chemotherapy disrupting agent MMAF
BCMA lysosome
BCMA
X
Effector cell
MM cell
Tai. Blood. 2014;123:3128. Farooq. Ophthalmol Ther. 2020;9:889.
BCMA
ADCC
Multiple Myeloma Cell Death
Fc receptor
Mechanisms of action: 1. ADC mechanism 2. ADCC mechanism 3. Immunogenic cell death
Linker
–Stable in circulation
Drug
–MMAF (non-cell permeable, highly potent auristatin)
Belantamab Mafodotin for Relapsed/Refractory Multiple Myeloma • DREAMM-2: Open-label, randomized phase II trial in patients with Relapsed/Refractory Myeloma after ≥3 prior lines of therapy; refractory or intolerant to IMiDs, PIs, and CD38 2.5 mg/kg mAbs (N = 196)y Key Adverse Events Outcome
Median lines of therapy, n (range) Overall Relapse Rate Median Progression-free survival Median Overall Survival
2.5 mg/kg (n = 97) 7 (3–21) 31% 2.9 mos
Not reached
Approved for patients with relapsed/refractor myeloma who have received ≥4 previous therapies including an anti−CD-38 mAb, a PI, and an IMiD Lonial. Lancet Oncol. 2020;21:207.
(n = 95)
Grade 1/2 Keratopathy (eye damage) Grade 3/4 Keratopathy Thrombocytopenia Anemia Parameter, n (%)
41 (43%) 26 (27%) 19 (20%) 19 (20%) 2.5 mg/kg
Dose delay
51 (54%)
Dose reduction
28 (29%)
IMiD: immunomodulatory drug; mAb: monoclonal antibody; PI, protease inhibitor
Belantamab Mafodotin + Pomalidomide/Dexamethasone Outcome Overall Response Rate
Patients (n = 34) 88%
Complete Remission
14.7%
Very Good Partial Remission
52.9%
Partial Remission
20.6%
Median Progression-Free Survival NR (10.8-NR) (95% CI) • 9 patients discontinued treatment for Pom/Dex (n = 7), patient withdrawal (n = 1); grade 4 decreased visual acuity (n = 1) • Most frequent adverse events of any grade: corneal surface layer changes (75.7% ), low white counts (56.8%), low platelets counts (48.6%), decreasedTrudel. visual acuity ASH 2020. Abstr 725.
Ocular Adverse Events - Belantamab Mafodotin • BCMA not expressed in the cornea; ocular toxicity an off-target effect of belantamab mafodotin leading death of surface layer of corneal cells • With dose holds, majority of patients recover from keratopathy and visual changes • Dose holds may not affect response; 88% of patients maintained or deepened response with dose holds >63 days • Risk Evaluation and Mitigation Strategy (REMS) program, with ophthalmology evaluation prior to each dose of belantamab mafodotin Lonial. ASH 2020. Abstr 3224. Lonial. Lancet Oncol. 2020;21:207. Farooq. Ophthalmol Ther. 2020;9:889. Belantamab mafodotin PI. Cohen. SOHO 2020.
DREAMM-2: Outcomes due to Ocular Adverse Events Belamaf 2.5 mg/kg* n = 95 Keratopathy (MECs) 68/95 (72%) Symptoms (eg, blurred vision, dry eye) and/or a ≥2-line BCVA decline (better-seeing eye) 53/95 (56%) BCVA change to 20/50 or worse† 17/95 (18%) Discontinuation Due to corneal Adverse Event 3/95 (3%)
BCVA: best corrected visual acuity; KVA: keratopathy and visual acuity; MEC: microcyst-like epithelial changes epithelial changes
So – What about CAR T-Cell Therapy? Genetically modified T cells designed to recognize specific proteins on MM cells CAR T cells are activated once in contact with the MM cell and can destroy the MM cell
Chimeric antigen receptor
CAR T cell
CAR T cells can persist for long periods of time in the body CAR T cells are created from a patient’s own blood cells, but the technology is evolving to develop “off-the-shelf” varieties CAR, chimeric antigen receptor; MM, multiple myeloma CAR T-cell therapy is not yet FDA-approved for patients with MM.
Chimeric antigen receptor
Myeloma cell
What Is CAR T-Cell Therapy?
• A treatment strategy that engineers a patient’s T-cells to target and attack malignant cells; T-cells are a type of white blood cell, which are part of the immune system Apheresis Myeloma Cell Bridging therapy
17-22 days
CAR T-cell manufacturing
Viral vector 1
Binding domain
Lymphodepleting therapy CAR T-cell infusion
Aftercare and potential CAR T-cell AE management Feins. Am J Hematol. 2019;94:S3.
3 2
Signaling domain T-cell
Autologous CAR T-Cell Therapy: Underlying Principles Leukapheresis
Manufacturing
Collect patient’s white blood cells
Engineer T-cells Isolate and activate T-cells with CAR gene Tumor cell
Infusion Targeting element (BCMA)
Expand CAR T-cells
Spacer
Viral vector CARwith CAR engineered T-cell DNA
Transmembrane domain Costimulatory domain (eg, CD28 or 4-1BB) CD3𝛇𝛇 (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.
Infuse same patient with CAR T-cells
Activity BCMA
CAR T-Cell Treatment • Treatment can be given inpatient or outpatient1 – Institution policies – Patient risk factors • Approved fludarabine and cyclophosphamide for adults given on Days -5, -4, -3 prior to CAR T-cell infusion3-7 • Supportive care during chemotherapy includes IV fluids, antiemetics, prophylactic medication for infection8-11 • CAR T-cells are infused on Day 02 • Patients receive wallet card required by the FDA prior to infusion2 1. Brudno. Blood. 2016;127:3321. 2. Beaupierre. J Adv Pract Oncol. 2019;10(suppl 3):29. 3. Axicabtagene ciloleucel PI. 4. Brexucabtagene autoleucel PI. 5. Idecabtagene vicleucel PI. 6. Lisocabtagene maraleucel PI. 7. Tisagenlecleucel PI. 8. Neuss. J Oncol Pract. 2013;9(2 suppl):5s. 9. Alakel. Onco Targets Ther. 2017;10:597. 10. Rao. Am Health Drug Benefits. 2012;5:232. 11. MDACC. IEC therapy toxicity assessment and management (also known as CARTOX) – adult. Approved September 15, 2020.
Cytokine Release Syndrome • Systemic inflammatory response that can occur as CAR T-cells activate and expand1 • Median time to onset: 1-5 days2-6 • Signs/symptoms7 – Fever – Constitutional symptoms (flulike symptoms) – Hypotension (low blood pressure) – Hypoxia (low oxygen in tissues) – End organ dysfunction
• Infectious workup7 • Treatment7: – supportive care – Tocilizumab – steroids • Tocilizumab: humanized monoclonal antibody against IL-6R7 – Rapid reversal of life-threatening CRS symptoms
1. Adkins. J Adv Pract Oncol. 2019;10(suppl 3):21. 2. Axicabtagene ciloleucel PI. 3. Brexucabtagene autoleucel PI. 4. Idecabtagene vicleucel PI. 5. Lisocabtagene maraleucel PI. 6. Tisagenlecleucel PI. 7. Lee. Blood. 2014;124:188.
Immune Effector Cell–Associated Neurotoxicity Syndrome (ICANS) • Median onset 2-8 days, can occur in the absence of CRS or concurrently16
• Signs/symptoms7 – Aphasia (difficulty speaking) – Altered or loss of consciousness – Cognitive impairment – Motor weakness – Seizures – Cerebral edema (fluid around the brain)
• Evaluation8,9 – CT scan head/brain MRI – Lumbar puncture – Infectious workup – EEG – Consider Neurology consultation • Treatment: supportive care, steroids, seizure prophylaxis and precautions9
1. Adkins. J Adv Pract Oncol. 2019;10(suppl 3):21. 2. Axicabtagene ciloleucel PI. 3. Brexucabtagene autoleucel PI. 4. Idecabtagene vicleucel PI. 5. Lisocabtagene maraleucel PI. 6. Tisagenlecleucel PI. 7. Gust. Cancer Discov. 2017;7:1404. 8. Lee. Biol Blood Marrow Transplant. 2019;25:625. 9. MDACC. IEC therapy toxicity assessment and management. 2020.
BCMA CARTs: Summary - ASH 2020 and ASCO 2021 Patients Median prior regimens Triple refractory, % CAR-T dose
CARTITUDE-11 Cilta-cel Phase 1/2
CRB-4012 Ide-cel Phase 1
KarMMa3,4 Ide-cel Phase 2
LUMMICAR-25 Zivo-Cel Phase 1b
97
62
128
20
PRIME6 P-BCMA101 Phase 1/2 55
6
6
6
5
8
5
87.6% 0.71×106 (range 0.50.95×106) 97.9% 80.4% 66%@ 18m 94.8% 5.4%
69.4%
84.0%
85%
60%
95% (exposed)
50, 150, 450 and 800 x 106
150, 300, 450 x106
1.5-1.8/2.5-3.0 x108
0.75-15 x106
1.0-3.0 x105
75.8% 38.7% 8.8m 75.8% 6.5%
50%/69%/81% 25%/29%/39% 8.8m (12m @450ml) 50%/76%/96% 0/6%/6%
94.0% 25%
67%b NR
94.7% 84.2%
77%/83%a 0%
17% 0%
95% 11%
35.5%
0/17%/20%
15%/17%a
3.8%
0%
1.6%
0/1%/6%
8%/0a
3.8%
0%
ORR CR/sCR PFS CRS, all grades CRS, grade 3/4 Neurotoxicity, 20.6% all grades Neurotoxicity, 10.3% a1.5-1.8/2.5-3.0 x108 dose, b0.75x106 dose grade 3/4
GC012F7 Dual CAR-T BCMA+CD19 19
BCMA, B-cell maturation antigen; CAR-T, chimeric antigen receptor T-cell therapy; CRS, cytokine release syndrome; NR, not reported 1. Usmani et al., ASCO 2021: Abstract 8005; 2. Lin et al., ASH 2020: Abstract 131; 3. Anderson et al., ASCO 2021: Abstract 8016; 4. Munshi. NEJM. 2021;384:705. 5. Kumar et al., ASH 2020: Abstract 133; 6. Costello et al., ASH 2020: Abstract 134; 7. Jiang et al., ASCO 2021: Abstract 8014
... And Abecma and Carvykti are born!!! Median follow-up: 24.8 months FDA Approval on March 26, 2021 and February 28, 2022 Dose, x 10^6 CAR-T cells
450 (N=54) Total (N=128) CR Patients First cell-based gene therapies for the treatment of R/R MM
Median DOR: 21.5 mo
Progression on/after > 4 lines of therapy including an immunomodulatory agent, ORR 44 (81%) inhibitor, 94and (73%) Median PFS: 22.4antibody mo a proteasome an anti-CD38 monoclonal CR/sCR
21 (39%)
42 (33%)
12.2
8.6
Responses in difficult to treat patients
Manufacturing limitations: facilities must be cleared by FDA and low supply for the gene vector,10.9 which has strict specifications Median 11.3 High tumor burden, ORR: 71% DOR
Median PFS
Munshi NC et al. NEJM 2021; 384 (8): 705-716 Anderson LD et al. IMW 2021. Abstract OAB27 Anderson LD et al. ASCO 2021. Abstract 8016
Extramedullary disease, ORR: 70% R-ISS-III, ORR: 48%
Bispecific and Trispecific Antibodies
Data With Anti-BCMA Bispecific Antibodies Promising responses in patients with ”triple-class exposed” CR disease, with associated CRS toxicities VGPR 100 N=9
N=6
Response rate (%)
80
N = 22
PR
N = 15
83%
73%
N=8
60
80%
N = 20
70%
40
23%
0
CC93269
Teclistimab
17%
AMG 701
13%
REGN5458 TNB-383B
Elranatamab
Nearly all patients had prior anti-CD38 antibody across trials. 1. Costa. EHA 2020. Abstr S205. 2. Garfall. ASH 2020. Abstr 180. 3. Harrison. ASH 2020. Abstr 181. 4. Madduri. ASH 2020. Abstr 291. 5. Rodriguez. ASH 2020. Abstr 293. 6. Bahlis. ASCO 2021. Abstr 8006.
77%
N = 85
N = 22 64%
65%
20
3% CC- Teclistimab 93269
N = 58 39%
AMG 701
REGN5458 TNB-383B
CC- Teclistimab 93269
Elranatamab
N = 30 20% N = 49
N = 30
73%
45%
Grade 1-2 neurotoxicity only
N = 22 3%
N = 30
9%
10
0
Grade 3+ CRS Grade 1-2 CRS
N = 49
40
30
30%
20
60
0
62%
44%
N = 30
20
Neurotoxicity rate (%)
•
CRS rate (%)
80
N = 85 AMG 701
12%
N = 58 REGN5458 TNB-383B
Elranatamab
Summary of Bispecific Antibodies in R/R MM Drug
Target
Median prior lines, n
Dosing
ORR, %
CRS, %
Neurotoxicity, %
Notes
65 @ RP2D (70 @ other IV/SC doses)
70 @ RP2D (no grade 3)
2.5 @ RP2D (0 in other SC doses)
SC dosing! Q3W, allowed for CrCl 30
Teclistamab1 (n = 40 RP2D)
BCMA
5 (2-11)
SC QW for RP2D
TNB-383B2 (n = 58, 15)
BCMA
6 (3-15)
Q3W
80 @ higher doses (n = 15)
45 (no grade 3)
0
REGN-54583 (n = 49, 8)
BCMA
5
Q2W
63 @ highest doses (n = 8)
39 (no grade 3)
12
Pavurutamab/ AMG-7014 (n = 85, 6)
BCMA
6 (2-25)
QW
83 @ most recent doses (n = 6)
64 (9% grade 3)
3.8
Elranatamab5 (n = 30)
BCMA
8 (3-15)
SC weekly
70 @ ≥215 μg/kg
73
20
SC dosing!
6 (2-17)
SC weekly RP2D: 450 μg/kg
53.3 all SC doses (70.0 @ RP2D)
67 all SC (73 @ RP2D) (3% grade 3 @ RP2D)
4.9 all SC (7 @ RP2D)
SC dosing! 16% of pts @RP2D had prior BCMA tx Some grade 3 skin rash, oral toxicity, back pain
28
21% with prior BCMA tx
Talquetamab6 (n = 82 all SC, 30 RP2D)
GPRC5D
53, higher doses 76 FcRH5 6 (2-15) Q3W 61, highest dose (n = 18) (2% grade 3) 1. Usmani. Lancet. 2021;398:665. 2. Rodriguez. ASH 2020. Abstr 293. Madduri. 2020. 633. in prior ASH BCMA (nAbstr = 8)291.
Cevostamab7 (n = 53, 34)
4. Harrison. ASH 2020. Abstr 181. 5. Bahlis. ASCO 2021. Abstr 8006. 6. Berdeja. ASCO 2021. Abstr 8008. 7. Cohen. ASH 2020. Abstr 292.
CAR’s vs BiTE’s – Apples vs Oranges? Advantages with CAR T cells
Advantages with BiTE’s & BsA’s
Achieves deep durable responses in heavily –treated MM patients
Achieves deep durable responses in heavily –treated MM patients
Manageable acute toxicities (CRS & ICANS)
Manageable acute toxicities (CRS & ICANS)
Single infusion – period of response OFF ALL THERAPY!
Off-the-shelf availability Amenable to flexible dosing strategies
Disadvantages with CAR T cells
Disadvantages with BiTE’s & BsA’s
Production causes treatment delays
Requires repetitive administration
Unable to stop and restart treatment Fitness of collected T cells impacts response
Clinical Trials as an Option
• ALWAYS ask your doctor whether a clinical trial is potentially available • Promising therapies in development – Venetoclax* – Iberdomide, CC-480 – BITEs – Other CAR-T cell therapies – Many, many others….
• www.clinicaltrials.gov • Myeloma Matrix 2.0
*FDA
approved for a non-MM indication therapy not yet FDA approved
†Experimental
In summary, tools are multiplying! Survival is improving
Nishida, H. Cancers, 2021. 13(11): p. 2712.
The future is bright!!! What next? • Trials to look at optimizing therapy – deeper responses, fewer drugs, stopping treatment • How can we achieve more for less? • Remissions that LAST • Patients OFF therapy • Looking for that elusive cure….
Thank you!!!
How to Manage Myeloma Symptoms and Side Effects
Daniel Verina, DNP, RN, MSH, ACNP-BC, IMF Nurse Leadership Board 86
March 19, 2022
LIFE IS A CANVAS, YOU ARE THE ARTIST Daniel Verina DNP, RN, MSN, ACNP-BC Mount Sinai Medical Center New York City, NY
Patient Education Slides 2021
FRAMING YOUR CARE Know your care team, Shared Decision Making & Reliable Resources
You are central to the care team
Pharmacist
CARE TEAM COLLAGE General Hem/Onc Myeloma Specialist
Communicate with your team • Myeloma is a chronic disease • Understand the roles of each
team member and who to contact for your needs • Participate in support network
Be empowered • Ask questions, learn more • Participate in decisions • Know your history –
Myeloma ManagerTM Personal Care AssistantTM
Primary Care Provider (PCP)
You and Your Caregiver(s) Support Network
Subspecialists Allied Health Staff
89
SHARED DECISION-MAKING Be empowered to be part of the treatment decision-making • Ask for time to consider options (if needed/appropriate) • Understand options; consider priorities • Use reliable sources of information • Use caution considering stories of personal
experiences • Consider your goals/values/preferences • Get a 2nd opinion, Meet with a Myeloma expert
• Express your goals/values/preferences; create a
dialog
• My top priority is [goal/value]; additional [preferences] are also important. • I think [treatment] may be a good choice given my priorities… What do you think?
• Arrive at a treatment decision together
Data From Research
HCP Clinical Experience TREATMENT DECISION
Your Preference Philippe Moreau. ASH 2015.
90
COLOR WHEEL OF TREATMENT
Treatment options, side effects, symptom management, & supportive care
GALLERY OF GOALS MYELOMA TREATMENT • Rapid and effective disease control • Durable disease control • Minimize side effects • Allow for good quality of life
SUPPORTIVE THERAPIES • Prevent disease- and treatmentrelated side effects • Optimize symptom management • Allow for good quality of life
• Improved overall survival
DISCUSS GOALS AND PRIORITIES WITH YOUR HEALTHCARE TEAM 92
MANAGING MYELOMA: THE BIG PICTURE Transplant Eligible Patients
Transplant Ineligible patients
Everyone
Transplant Consolidation
Maintenance
Initial Therapy
Treatment of Relapsed disease Consolidation/ Maintenance/ Continued therapy
Supportive Care
93
SHADES OF “AUTO” STEM CELL TRANSPLANT (ASCT) • There are no black and white answers to deciding to undergo a transplant • Undergoing transplant is a commitment for both you and your care partner • Understanding the process will help bring to focus elements needed to decide if/when to undergo transplant
Clinical Experience
Data from Research DECISION
Patient Preference
Adapted from Philippe Moreau, ASH 2015
(WHEN) IS TRANSPLANT RIGHT FOR ME?
Current studies continue to support early autologous transplant Commitment: Quality of life must be considered when deciding timing Allogeneic transplant not recommended as initial therapy
Upfront autologous transplant remains the standard of care for transplant-eligible patients. Miceli T, et al. Clin J Oncol Nurs. 2013;17(6)suppl:13-24. Kaufman GP, et al. Leukemia (2016) 30, 633-639.
TRANSPLANT BY NUMBER
•Duration: Approximately 2 weeks •Location: Transplant Center
• High Dose Chemotherapy, stem cell infusion • Supportive Care • Engraftment
• Duration: Approximately 3-4 weeks • Location: Transplant Center
POST-TRANSPLANT
PHASE 3
•Measuring treatment response •Determining Transplant Eligibility •Insurance authorization •Collecting stem cells
TRANSPLANT
PHASE 2
PHASE 1
ELIGIBILITY
• Restrengthening • Appetite recovery • “Day 100” assessment • Begin maintenance therapy • Duration: Approximately 1012 weeks • Location: HOME!
CARE PARTNER SUPPORT Care partner support is essential for the entire transplant process. Phase 1: Sedated procedures; Education sessions; Phase 2: Some transplant centers allow for outpatient transplant management as long as a care partner is present to assist with daily activities, medication management and alert the medical team of changes Phase 3: Continued support and assistance is often needed in the early days after returning home. Less assistance will be needed as time and healing go on. Care partner can be one person or a rotation of many people.
PATIENT-REPORTED SYMPTOMS A meta-analysis identified the most common patient-reported symptoms and impact on QOL, and were present at all stages of the disease. Symptoms resulted from both myeloma disease and treatment, including transplant, and were in these categories:
Physical
Psychological
• Fatigue
• Depression
• Constipation
• Anxiety
• Pain
• Sleep Disturbance
• Neuropathy
• Decreased Cognitive Function
• Impaired Physical Functioning • Sexual Dysfunction
Ramsenthaler, et al. 2016. https://doi.org/10.1111/ejh.12790.
Financial • Financial burden (80%) • Financial toxicity (43%)
• Decreased Role & Social Function
98
GI SYMPTOMS: PREVENTION & MANAGEMENT Diarrhea may be caused by medications and supplements • • • •
Laxatives, antacids with magnesium Antibiotics, antidepressants, others Milk thistle, aloe, cayenne, saw palmetto, ginseng Sugar substitutes in sugar free gum
Avoid caffeinated, carbonated, or heavily sugared beverages Take anti-diarrheal medication • Imodium®, Lomotil®, or Colestid if recommended • Fiber binding agents – Metamucil®, Citrucel®, Benefiber® • Welchol® if recommended
Physical
Constipation may be caused by • Opioid pain relievers, antidepressants, heart or blood pressure medications, others • Supplements: Calcium, Iron, vitamin D (rarely), vitamin B-12 deficiency
Increase fiber • Fruits, vegetables, high fiber whole grain foods • Fiber binding agents – Metamucil®, Citrucel®, Benefiber®
Fluid intake can help with both diarrhea and constipation, and good for kidneys. Discuss GI issues with health care providers to identify causes and make adjustments to medications and supplements.
Smith LC, et al. CJON.2008;12(3)suppl:37-52. Faiman B. CJON. 2016;20(4):E100-E105. Miceli, T. et al. (2021). Cancer Treatment and Res Com, 100476.
99
PAIN: PREVENTION AND MANAGEMENT
Physical
Pain can significantly compromise quality of life Sources of pain include bone disease, neuropathy and medical procedures Management • Prevent pain when possible • Bone strengtheners to decrease fracture risk; anti viral to prevent shingles; sedation before procedures
• Interventions depends on source of pain • May include medications, physical therapy, surgical intervention, radiation therapy, etc
• Complementary therapies • Mind-body, meditation, yoga, supplements, acupuncture, activity, etc
Faiman B, et al. CJON. 2017;21(5)suppl:19-36. Miceli, T. et al. (2021). Cancer Treatment and Res Com, 100476.
Tell your health care provider about any new bone pain or chronic pain that is not adequately controlled
100
PERIPHERAL NEUROPATHY MANAGEMENT Peripheral neuropathy: damage to nerves in extremities (hands, feet, or limbs) • • • • • •
Numbness Tingling Prickling sensations Sensitivity to touch Burning and/or cold sensation Muscle weakness
Physical
Prevention / Management: • Bortezomib once-weekly or subcutaneous administration • Massage area with cocoa butter regularly • Supplements:
• B-complex vitamins (B1, B6, B12) • Folic acid, and/or amino acids but do not take on day of Velcade® (bortezomib) infusion
• Safe environment: rugs, furnishings, shoes
If PN worsens, your HCP may: Report symptoms of peripheral neuropathy early to your health care provider; nerve damage from PN can be permanent if unaddressed
• Change your treatment • Prescribe oral or topical pain medication • Suggest physical therapy
Faiman B, et al. CJON. 2017;21(5)suppl:19-36. Tariman, et al. CJON.2008;12(3)suppl:29-36. Miceli, T. et al. (2021). Cancer Treatment and Res Com, 100476.
101
Physical symptoms impact mental well being. All can affect quality of life and relationships.
FATIGUE, ANXIETY & DEPRESSION
• Fatigue is the most common reported symptom (98.8%) Sources include anemia, pain, reduced activity, insomnia, treatment toxicity, bone marrow suppression
Physical Psychological
• Anxiety reported in >35% • Depression nearly 25% Financial concerns, disease progression, end-of-life, and change in social and sexual function were highlighted sources
Often, people do not share these symptoms with their provider. Talk to your provider about symptoms that are not well controlled or thoughts of self harm. Help is available. Ramsenthaler, et al. 2016. https://doi.org/10.1111/ejh.12790. Catamero D et al. CJON. 2017; 21(5)suppl:7-18.
102
REST AND RELAXATION CONTRIBUTE TO GOOD HEALTH 🐑🐑 Adequate rest and sleep are
essential to a healthful lifestyle
Short and disturbed sleep increase risk of • Heart related death • Increase anxiety • Weaken immune system • Worsened pain • Falls and personal injury
🐑🐑 Things that can interfere with sleep • Medications : steroids, stimulants, herbal
supplements, alcohol • Psychologic: fear, anxiety, stress • Physiologic: sleep apnea, nocturia, pain, inactivity, heart issues Rod NH et al 2014. PloS one. 9(4):e91965; Coleman et al. 2011. Cancer Nurs. 34(3):219-227. National Sleep Foundation. At: http://sleepfoundation.org/ask-the-expert/sleep-hygiene
Psychological
🐑🐑 Sleep hygiene is necessary for
quality nighttime sleep, daytime alertness
• Engage in exercise but not too near • • • • • •
bedtime Increase daytime natural light exposure Avoid Daytime napping Establish a bedtime routine - warm bath, cup of warm milk or tea Associate your bed ONLY with sleep Sleep aid may be needed Avoid before bedtime: • Caffeine, nicotine , alcohol and sugar • Large meals and especially spicy, greasy foods • Computer screen time
Mustian et al. Journal of clinical Oncology. Sep 10 2013;31(26):3233-3241. Stan DL, et al. Clin J Oncol Nurs. Apr 2012;16(2):131-141. Zeng Y et al., Complementary therapies in medicine. Feb 2014;22(1):173-186.
103
Manage stress
HEALTHFUL LIVING STRATEGIES: PREVENTION
• Rest, relaxation, sleep hygiene • Mental health / social engagement • Complementary therapy
Maintain a healthy weight • Nutrition • Activity / exercise
Preventative health care • Health screenings, vaccinations • Prevent falls, injury, infection • Stop smoking
Physical Psychological
Maintain renal health • Myeloma management • Hydration • Avoid renally-toxic medications – Dose adjust to renal function • Diabetes management
Protect your bones • Nutrition, Calcium + D supplement • Weight-bearing activity / walking • Bone strengthening agents
• Dental care
“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. Miceli, T. et al. (2021). Cancer Treatment and Res Com, 100476. 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.
104
Financial
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
Contact the Social Services department at your hospital or clinic to talk to a social worker for assistance.
Funding and assistance may be available • • • •
Federal programs Pharmaceutical support Non-profit organizations Websites: • • • • • • •
Medicare.gov SSA.gov LLS.org Rxassist.org NeedyMeds.com HealthWellFoundation.org Company-specific website
105
YOU ARE NOT ALONE
Audience Q&A with Panel
• Open the Q&A window, allowing you to ask questions to the host and panelists. It will be sent to our moderator and panelists for discussion. • If you have a question that does not get answered today, you can contact our Infoline at 800-452-CURE (2873) US & Canada, 1-818-4877455, or email infoline@myeloma.org.
107
108