IMF Virtual Regional Community Workshop (RCW) - East South Central

Welcome and Announcements Kelly Cox

Director Support Groups & Senior Director Regional Community Workshops 2

Thank you to our sponsors!

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IMF REGIONAL COMMUNITY WORKSHOP August 6, 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 Craig Cole, MD, Michigan State University 10:40 AM - Q & A with Panel 10:55 AM – Meditation and Stretch Break 11:05 AM - Relapsed Therapy and Clinical Trials Jesús G. Berdeja, MD, Sarah Cannon Research Institute 11:45 AM - How to Manage Myeloma Symptoms and Side Effects Patricia Mangan, RN, MSN, APRN-BC, University of Pennsylvania, IMF Nurse Leadership Board 12:05 PM - Q&A with Panel

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Myeloma 101 and Frontline Therapy Craig Cole, MD Michigan State University 5

The Application of Science: Multiple Myeloma 101 and Frontline Therapy International Myeloma Foundation Regional Community Workshop Saturday August 6th, 2022

Craig Emmitt Cole, M.D.

Assistant Professor Director of Clinical Research Department of Internal Medicine Division of Hematology/Oncology; Hematology Section Michigan State University College of Human Medicine Karmanos Cancer Institute

Today’s Discussion 

How common is multiple myeloma



Spectrum of plasma cell disorders



Diagnosis of myeloma and labs



Staging and risk stratification



The Science behind the treatments!



Up front therapy strategies: induction, transplant, and maintenance



Bone support



“New Stuff” 4 drug induction therapy



Perspectives in the advancement of myeloma science and survival

Multiple Myeloma Fast Facts Multiple Myeloma 2nd most common blood 34,920 new cancer cases of 138,415 myeloma in 2021U.S. patients

living with myeloma in 2021

Myeloma is most frequently diagnosed in people 65 to 74 years oldBlack Incidence: 14.1/100,000 White Incidence: 6.1/100,000 Leukemia & Lymphoma Society. Facts and Statistics. http://www.lls.org/facts-and-statistics/facts-and-statistics-overview#Myeloma.

SEER Cancer Stat Facts: Myeloma. National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/statfacts/html/mulmy.html

North American Association of Central Cancer Registries (NAACCR), 2021 http://www.naaccr.org/DataandPublications/CINAPubs.aspx

Common Symptoms Multiple Myeloma

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

Low Blood Counts • Anemia is present in 60% at diagnosis • May lead to anemia and infection

Weakness Fatigue Infection

Decreased Kidney Function • Occurs in over half of myeloma patients

Weakness

Bone Damage • Affects 85% of patients • Leads to fractures

Bone pain

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

Loss of appetite Weight loss

C: Calcium elevation (>11 mg/dL) R: Renal- low kidney function; (serum creatinine >2 mg/dL) A: Anemia –low red blood count (Hb <10 g/dL) B: Bone disease (≥1 lytic lesions on skeletal radiography, CT, or PET-CT) Campbell K. Nurs Times. 2014;110:12.

Spectrum of Plasma Cell Disorders and Myeloma MGUS Monoclonal Gammopathy of Uncertain Significance

M protein under 3 g/dL AND Plasma cells in Bone Marrow <10% AND No CRAB or “SLiM” high risk features

Smoldering Myeloma M protein over 3 g/dL (serum) or over 500 mg/24 hrs (urine) AND Plasma cells in Bone Marrow 10%–60% AND No CRAB or “SLiM” high risk features

High Risk Smoldering

Multiple Myeloma

M protein over 2 g/dL AND Plasma cells in Bone Marrow 20%–60% AND Free Lt Chain Ratio >20

Malignant Plasma cells seen on any biopsy (usually bone marrow) AND ≥1 “CRAB” feature

“Evolving type”SMM Increase >10% protein w/in 6mo AND No CRAB or “SLiM” high risk features

1% risk of progression/year to multiple myeloma or related conditions

10% risk of progression/year to active myeloma

>46% risk of progression in 2 yr to active myeloma

Observation Clinical Trials

Observation Clinical Trials

Close Observation Clinical Trials ?? Treatment??

C: Calcium elevation (>11 mg/dL) R: Renal- low kidney function; (serum creatinine >2 mg/dL) A: Anemia –low red blood count (Hb <10 g/dL) B: Bone disease (≥1 lytic lesions on skeletal radiography, CT, or PET-CT)

OR have >1 SLiM ‘high risk” features:

S: >60% Plasma Cells on Bone Marrow biopsy Li: Serum light chain ratio >100 M: >1 lytic lesions on MRI (or PET/ CT scan)

Front Line Treatment Clinical Trials

Diagnosing Myeloma: Learn Your Labs!

CBC

• Number of red blood cells, white blood cells, and platelets

CoMP

• Measure levels of albumin, calcium, and creatinine. Assess function of kidney, liver, and bone status (alkaline phosphatase) and the extent of disease.

Beta2 MicroG

• Determine the level of a protein that indicates the presence/extent of MM and kidney function: USED FOR STAGE

LDH

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

Lactate

Dehydrogenase

Serum Protein EP

• Detect the presence and level of M protein = how much myeloma

Immuno Fixation

• Identify the type of abnormal antibody proteins: IgG, IgA, κ,or λ

Serum FreeLight Chain

• Freelite test measures free light chains (kappa or lambda) in blood = how much myeloma

Urine Protein EP

• Detect Bence-Jones proteins (otherwise known as myeloma light chains) in urine (present or not present)

24-hr Urine Analysis

• Determine the presence and levels of M protein and Bence Jones protein in the urine = how much myeloma

Serum Protein EP

Monoclonal protein

• Detect the presence and level of M protein = how much myeloma Treatment

IgG Kappa M-Protein

Treatment

Serum FreeLight Chain

IgG Kappa M-Protein

• Freelite test measures free light chains (kappa or lambda) in blood = how much myeloma

Kappa Lt. Chain Kappa MM Lt. Chain

Positive Kappa Normal Monoclonal Serum Light Chains Lambda Lt. Chain

Ratio: Ratio: Ratio: >100 11

Types of Monoclonal Protein (M Protein) in Multiple Myeloma

Intact immunoglobulin • For example: • IgG+kappa • IgG+lambda • IgA+kappa • IgA+lambda • etc…

• 80% of myeloma cases

Light chain only

Non-secretory

• Also known as Bence Jones protein

• No monoclonal protein present

• 18% of all myeloma cases

• Less than 3% of cases of multiple myeloma

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

Diagnosis of Multiple Myeloma ●

●

Conventional X-rays reveal punched-out lytic lesions, osteoporosis, or fractures in 75% of patients.

FDG PET/CT appears to be more sensitive (85%) than skeletal survey for the detection of small lytic bone lesions.

• Diagnosis is confirmed with bone marrow demonstrating greater than 10% involvement by malignant plasma cells with either CRAB or SLiM

Malignant Plasma cells seen on biopsy AND ≥1 “CRAB” feature C: Calcium elevation (>11 mg/dL) R: Renal- low kidney function; (serum creatinine >2 mg/dL) A: Anemia –low red blood count (Hb <10 g/dL) B: Bone disease (≥1 lytic lesions on skeletal radiography, CT, or PET-CT)

OR have >1 SLiM ‘high risk” features: S: >60% Plasma Cells on Bone Marrow biopsy Li: Serum light chain ratio >100 M: >1 lytic lesions on MRI (or PET/ CT scan)

Kyle RA et al. Mayo Clin Proc Jan;78(1): 2003. Nanni C et al. European Journal of Nuclear Medicine and Molecular Imaging Vol. 33:2006 Dimopoulos MA, et al. Leukemia. 2009

Staging Myeloma: The Importance of Genomic Testing

Conventional cytogenetic analysis (karyotyping) Myeloma Cell

Chromosome FISH (fluorescence in situ hybridization)

DNA

Advances • Genetic expression profiling [GEP] • Whole-genome/ whole-exome sequencing • Plasma cell next generation sequencing

Staging Myeloma: FISH helps to Assign Risk in Myeloma Risk Category Findings on Chromosome (FISH) Analysis Results in the Bone marrow

High Risk FISH:

• Deletion 17th chromosome • Gain of chromosome 1q • Translocation 4 and 14 • Translocation 14 and 16 • Translocation 14 and 20 NGS: p53 mutation (on chrom 17)

Standard Risk FISH:

• Hyperdiploid: More than 1 pair of chromosomes (Trisomies) • Translocation 11 and 14 • Translocation 6 and 14 • Others • Normal

• Double Hit Myeloma: 2 high risk genetic abnormalities • Triple Hit Myeloma: 3 or more high risk genetic abnormalities *Based on the Updated Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) Consensus Guidelines 2013 Mikhael JR et al. Mayo Clin Proc. 2013;88:360.

Revised International Staging System for Multiple Myeloma From International Myeloma Working Group

Stage 1

Stage 2

β2-microglobulin under 3.6 mg/L Normal

Lactate Dehydrogenase (LDH) AND

Stage 3 β2-microglobulin over 5.5 mg/L

Does not meet Criteria for Stage 1 or 3

NO High Risk Cytogenetics (FISH)

HIGH

Lactate Dehydrogenase (LDH) AND/OR High Risk Cytogenetics (FISH)

Deletion 17thchromosome Translocation 4th and 14th Translocation 14th and 16th Translocation 14th and 20th

*Based on the Updated Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) Consensus Guidelines 2013 Mikhael JR et al. Mayo Clin Proc. 2013;88:360.

Palumbo et al. JCO. September 10, 2015 vol. 33 no. 26 2863-2869

So…..

How do we treat

Multiple Myeloma

Immunomodulatory Drugs (IMiDs):

Thalomid(Thalidomide), Revlimid(Lenalidomide), Pomalyst(Pomalidomide)

Proteasome Inhibitors (Pis): Velcade(Bortezomib), Ninlaro(Ixazomib), Kyprolis(Carfilzomib)

Antibodies Against Myeloma (Immunotherapy): Darzelex (Daratumumab), Sarclisa(Isatuximab), Empliciti(Elotuzumab)

IMiDs for Multiple Myeloma How does it work?-SCIENCE! • Direct inhibition of DNA synthesis of myeloma cells.

IMiDs for Multiple Myeloma VEGF bFGF

How does it work?-SCIENCE! • Direct inhibition of DNA synthesis of myeloma cells.

• Inhibition of blood vessel synthesis in the bone marrow.

IMiDs for Multiple Myeloma How does it work?-SCIENCE! • Direct inhibition of DNA synthesis of myeloma cells.

• Inhibition of blood vessel synthesis in the bone marrow.

• Inhibition of adhesion between the myeloma and bone marrow stromal cells.

IMiDs for Multiple Myeloma How does it work?-SCIENCE!

IL-6 IL-1β TNF-α

• Direct inhibition of DNA synthesis of myeloma cells.

• Inhibition of blood vessel synthesis in the bone marrow.

• Inhibition of adhesion between the myeloma and bone marrow stromal cells.

• Inhibition of the release of the cytokines IL-6, TNF-α, and IL-1β.

IMiDs for Multiple Myeloma How does it work?-SCIENCE! • Direct inhibition of DNA synthesis of myeloma cells.

• Inhibition of blood vessel synthesis in the bone marrow.

• Inhibition of adhesion between the myeloma and bone marrow stromal cells.

• Inhibition of the release of the cytokines IL-6, TNF-α, and IL-1β.

• Activation of the body’s natural killer cells (T-cells) which attack the myeloma cells.

Rise of the IMiD Biologic Therapies

 

Revlimid is felt to be 50 to 2000 more potent than thalidomide.



Phase 2 trial 91% new myeloma achieved responses with Lenalidomide plus dexamethasone.





Pomalyst and dexamethasone given to multi-refractory myeloma with response rates of 35 to 65%.



Combination of pomalidomide, bortezomib, and dexamethasone in relapsed MM response rates of 72%.

O O

H N O

N Lenalidomide O O N

2013 FDA approves Pomalidomide.





Thalidomide

O

1990s, several thalidomide analogs were synthesized to increase efficacy and minimize toxicity.

2006 FDA approves Lenalidomide (Revlimid).



NH2 Pomalidomide

Iberdomide (CC-220) is the newest in the class and is now in clinical trials CELMODs are the next class of IMiD with CC92480 drug more potent than iberdomide Blood. 2005;106:4050-4053. Blood. 2013 Jan 14. [Epub ahead of print]. Exp Hematol Oncol. 2012; 1: 27; J Clin Oncol. 2009;27(30):5008-5014.

H N O

Rise of the Proteasome

Proteasome

R Vij et al. Br J Haem, June 2012. ; MOREAU et al. BLOOD, AUG VOL 120(5 ); 2012

Rise of the Proteasome

Proteasome

R Vij et al. Br J Haem, June 2012. ; MOREAU et al. BLOOD, AUG VOL 120(5 ); 2012

Rise of the Proteasome Pi Proteasome

R Vij et al. Br J Haem, June 2012. ; MOREAU et al. BLOOD, AUG VOL 120(5 ); 2012

Rise of the Proteasome • Bortezomib(velcade) approved by the FDA in 2003 in patients with relapsed refractory myeloma.

• Several phase 2 trials in newly diagnosed myeloma with bortezomib-dexamethasone induction. o

Responses 66% to 90%, including 15% to 21% Complete Responses!

Bortezomib(Velcade)

• 2012 FDA approves Carfilzomib(Kyprolis); secondgeneration irreversible Proteasome inhibitor •

In refractory myeloma with 48% response rates. Higher in combination!

• Ixazomib (Ninlaro) is new oral boronated reversible proteasome inhibitor currently approved by the FDA in 11/2015.

Carfilzomib(Kyprolis)

Ixazomib (Ninlaro)

R Vij et al. Br J Haem, June 2012. ; MOREAU et al. BLOOD, AUG VOL 120(5 ); 2012; Blood. 2014;124(7):1047–1055

Targets on the Myeloma Cell Surface and Therapeutic Antibodies Bi-Specific Antibodies CAR-T

Bi-Specific Antibodies CAR-T GPRC5D

FcRH5

SLAMF7

CD38

Antibody Drug Daratumumab and Darzalex Faspro Isatuximab TAK-079 MOR202

Antibody Drug Elotuzumab Bi-Specific Antibodies

BCMA

Immune Therapies Belantamab Ide-cel CAR-T Cilta-cel CAR-T Bi-Specific Antibodies Other CAR-Ts

Manufactured Antibody Targeting of Myeloma Antibody and Immune System Attack

Increase production of cytoxic macrophages

Macrophages Good Guys

Natural Killer Cell Good Guys

Manufactured Anti-Myeloma Myeloma Antibody surface targets

Antibody Receptor

Complement Protein Attack Myeloma Cells

Attacking the Myeloma Cell Biology

Complement Proteins

Inhibition of adhesion between the myeloma and bone marrow stromal cells

Tools of the Trade for Frontline Therapy Standard Drug Overview

Class

Drug Name

IMiD immunomodulatory drug

Abbreviation

Revlimid (lenalidomide)

R or Rev

Thalomid (thalidomide)

T or Thal

Chemotherapy Steroids

Monoclonal Antibodies

Oral

Kyprolis (carfilzomib)*

C or K or Car

Intravenous (IV) or subcutaneous injection (under the skin)

Ninlaro (ixazomib)*

N or I

Oral

Cytoxan (cyclophosphamide)

C

Alkeran or Evomela (melphalan)

M or Mel

Decadron (dexamethasone)

Dex or D or d

Prednisone

P

Velcade (bortezomib) Proteasome inhibitor

V or Vel or B

Administration

Daratumumab (Darzalex)

Dara

*In Clinical Trials/ not FDA approved

Oral or intravenous

Oral or intravenous Intravenous (IV) or subcutaneous injection (under the skin)

Treatment Sequence and Regimens for Active Myeloma Frontline treatment Induction • • • • • • • • • •

Velcade/Revlimid/Dex:(VRD) Velcade/Thalomid/Dex:(VTD) Velcade/Cytoxan/Dex:(CyBorD) Darzalex/Revlimid/Dex:(DRD) Darzalex/Velcade/Melphalan/Dex Darzalex/Velcade/Thalidomide/Dex Kyprolis/Revimid/Dex(KRD) Darzalex/Velcade/Revlimid/Dex: Dara-RVD Ninlaro/Revimid/Dex(IRD) Clinical trials

Maintenance

Consolidation • •

•

Stem Cell Transplant Continue Induction

Clinical trial

Maintenance • • • • • •

Revlimid Velcade Ninlaro Observation Thalidomide Clinical trial

Relapsed Rescue

Dara+Pomalyst+Dex Kyprolis+Pomalyst+Dex Cytoxan+Pomalyst+Dex Ninlaro+Pomalyst+Dex Elo+Pomalyst+Dex Elo+Thaliomide+Dex Dara+Kyprolis+Dex Kyprolis+Revlimid+Dex Elo+Revlimid+Dex Dara+Revlimid+Dex Dara+Velcade+Dex Elo+Velcade+Dex Panobinostat+thalidomide+ velcade+dex Cytoxan+Kyprolis+Thalidomide+dex 4 drug therapies of novel agents

Ninlaro+Cytoxan+Dex Velcade+ Cytoxan+Dex Velcade+ Pomalyst+Dex Chemotherapy Selinexor+Dex Isatuximab(Sarclisa)+ Pomalyst+Dex Darzalex Faspro (under skin) (FDA approved May 1, 2020) Belantamab mafodotin (FDA approved 8/5/2020) Ide-cel CAR-T (FDA approved 3/26/2021) Cilta-cel CAR-T (FDA approved 2/28/2022)

CLINICAL TRIALS!

National Comprehensive Cancer Network. The NCCN Clinical Practice Guidelines in Oncology Multiple Myeloma (Version 1.2020). http://www.nccn.org/. Accessed September 6 2020

Newly Diagnosed MM Not Transplant Candidate

Transplant Candidate

Preferred Standard Risk

High Risk Velcade/Revlimid/Dex (VRD) or Dara-Revlimid Dex (Dara-Rd) 9 to 12 cycles

Velcade Based Maintenance of VRD or Continued Dara-Rd Maintenance

VRD-light or Dara-RD Others: D-VMP,D-VTD,RD 9 to 12 cycles Revlimid Maintenance or Continued DaraRd Maintenance

High Risk

Standard Risk

Dara-VRD x 4 cycles Other: KRD

VRD x 4 cycles Other: Dara-VRD

Early Auto SCT ?Tandem SCT Velcade (PI) Based Maintenance Continued Dara-Rd Maintenance

Early Auto SCT

Delayed Transplant Collect & store Continue VRd x8

Revlimid Maintenance +/- Dara

Revlimid Maintenance +/- Dara

https://www.msmart.org/mm-treatment-guidelines Dispenzieri et al. Mayo Clin Proc 2007;82:323-341; Kumar et al. Mayo Clin Proc 2009 84:1095-1110; Mikhael et al. Mayo Clin Proc 2013;88:360-376. v18 //last reviewed June 2020

Disease Burden (# of myeloma cells)

Goals of Therapy: The Iceberg Model of Myeloma Symptomatic Myeloma >1 Trillion At diagnosis Partial response 50% reduction in M protein >1 Billion

>10 Million

1 myeloma cell in 100K to 1 million normal cells

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

Stem Cell Transplant: Fighting Myeloma with the Left Hook!

35

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

DESIGN

Consolidation

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

VRd cycles 2-3 (n = 357) VRd cycles 2-3 (n = 365)

Stem cell collection

Induction

ASCT: Melphalan 200 mg/m2 + Stem Cell Support (n = 310)

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 N Engl J Med. 2022 Jul 14;387(2):132-147. doi: 10.1056/NEJMoa2204925

Maintenance Until Progression

VRd cycles 4-8

R (n = 291)

VRd cycles 4-5

R (n = 289)

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

RESULTS

Parameter

RVd- No Transplant (n = 357)

RVD with Up Front Transplantation (n = 365)

Grade 3 or 4 toxicities (%)

78

94

OVERALL SURVIVAL at 5 years (%)

79.2

80.7

Median duration of Partial Response or better, mo

38.9

54.4

Negative MRD

39.8

79

P Value Is it Significant?

YES! P<0.001

• At a median follow-up of 76.0 months, the risk of disease YES! P<0.001 46.2 67.5 was 53% higher in the RVD-alone High group Risk Pts. Median to transplantation group (P<0.001) than time in the YES! P<0.001 17.1 55.5

All Pts. Median time to relapse (PFS), mos progression or death relapse (PFS), mos

N Engl J Med. 2022 Jul 14;387(2):132-147. doi: 10.1056/NEJMoa2204925

NO YES! .003

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

What to do After Transplant?

STaMINA: Phase III Study Design • • •

Revlimid Maintenance 10 mg/day for 3 cycles, then 15 mg/day* (n = 257)

RESULTS

New Dx NoMyeloma difference in time to relapse (PFS) or Overall Survival in After >2 Consolidation Melphalan who have standard risk patients two transplants, consolidation Revlimid Velcade 1.3 mg/m² IV Days 1, 4, 8, 11 cycles 200 mg/m² IV 15 mg Days 1-15 Maintenance Stem Cell induction Tx RVD therapy, or just straightDexamethasone toRevlimid maintenance first BMT 40 mg IV Days 1, 8, 15 after 10 mg/day for 3 cycles, Four cycles Transplant ASCT-eligible then 15 mg/day (n = 254) Straight to maintenance is the easiest! ≤ 70 yrs = 758) Second (Tandem) ? If(Nhigh risk patients benefit from two transplants Stem Cell Transplant

Induction regimens     

RVD CyBorD RD VD Others

Melphalan 200 mg/m² IV Second ASCT (n = 247)

Stadtmauer EA, et al. ASH 2016. Abstract LBA-1; Journal of Clinical Oncology 38, no. 15_suppl ( ASCO May 20, 2020) 8506-8506

Analysis of the Maintenance Revlimid (Lenalidomide) Trials • Data from 4 randomized trials of Revlimid (lenalidomide) maintenance vs. no maintenance – Involving a total of almost 2,000 multiple myeloma patients • The results of the analysis showed that Revlimid maintenance therapy is associated significant improvement in progression-free survival and a modest improvement in overall survival • Duration of maintenance is unknown

STaMINA Long-term Follow-up: Maintenance Therapy Time to elapse after transplant (PFS)  PFS benefit for lenalidomide continuation beyond 38 mos PFS 100

Continued Len

Probability (%)

80

P < .001

60

Stopped Len

40 20 0

0

12

24

36

Continued Len (n = 215)

Stopped Len (n = 207)

4 yrs

95.8 (92-98)

80.1 (74-85)

5 yrs

86.5 (81-90)

67.2 (60-73)

6 yrs

79.5 (73-84)

61 (54-67)

PFS, % (Range)

48

60

5-Yr PFS, % (Range)

Continued Len

Stopped Len

P Value

High risk

86.7 (77-95)

67.8 (52-79)

.2

Std risk

86.3 (80-91)

66.7 (58-74)

< .001

72

 Discontinuation of Revlimid maintenance at 3 years is not recommended because of the increased risk of disease progression Hari. ASCO 2020. Abstr 8506.

Bone Support & Control of Bone Pain Multiple myeloma can cause weakened areas in the bone called osteolytic lesions which can compress the spinal cord or cause bone destruction.

• Bone strengthening drugs: bisphosphonates (pamidronate & Zometa) or monoclonal antibodies (Xgeva) are given at diagnosis and continued for at least 2 years • Vitamin-D and Calcium supplements to help bone healing • Orthopedic support – Physical therapy, physical medicine consults, orthopedic/neuro surgery, radiation therapy, etc

• Minimally invasive procedures: kyphoplasty or vertebroplasty • Use of medication to control pain • Anticonvulsants and antidepressants for treat relieve pain from nerve damage or numbness

GRIFFIN Randomized Phase II: Dara-RVD vs. RVD in Newly Diagnosed Multiple Myeloma Randomized 1:1

Induction: Cycles 1-4

Transplant-eligible adults with Newly Diagnosed MM, with good performance status and kidney fxn (N = 207)

Dara-VRd in 21-day cycles (n = 104) VRd in 21-day cycles (n = 103)

A S C T

Consolidation: Cycles 5-6†

Maintenance: Cycles 7-32‡

Dara-VRd in 21-day cycles

Dara-R in 28-day cycles

D: 16 mg/kg IV D1 VRd: as in induction

VRd in 21-day cycles VRd: as in induction

 Primary endpoint: CR by end of consolidation Kaufman. ASH 2020. Abst.594; Voorhees PM etal. Blood. 2020 Aug 20;136(8):936-945.

D: as in consolidation Q4W or Q8W R: 10 mg PO D1-21 of C7-9 and 15 mg PO D1-21 of C10+§

R in 28-day cycles

R: 10 mg PO D1-21 of C7-9 and 15 mg PO D1-21 of C10+§

GRIFFIN Randomized Phase II: Dara-RVD vs. RVD in Newly Diagnosed Multiple Myeloma Response by End of Consolidation

sCR CR VGPR PR

Depth of Response

1-sided P = .016 ORR = 99.0%

100

Patients (%)

80 60 40

≥ CR: 51.5% ≥ VGPR: 90.9%

20 0

 Median follow-up: 13.5 months

ORR = 91.8%

42.4

32.0

9.1

10.3

39.4 8.1

Dara-VRd (n = 99)

30.9 18.6

VRd (n = 97)

≥ VGPR: 73.2%

≥ CR: 42.3%

GRIFFIN 2-Yr Maintenance Phase Update: Response

Estimated 36-month PFS rates were 88.9% for D-RVd and 81.2% for RVd Laubach. ASH 2021. Abstr 79.

GRIFFIN 2-Yr Maintenance Phase Update: PFS

Where We Are Going…4-Drug Induction for Newly Diagnosed Myeloma Study

No. of Phase of patients study

Dara-VMP vs VMP Dimopoulos MA, 2018

706

Phase III

Dara-IRD Kumar 2019

40

Phase II

Dara-RVD vs RVD followed by ASCT Voorhees 2020

D-RVD: 99 RVD: 97

Phase III

Dara-CVD Yimer 2018

87 NDMM (101 total)

Phase II

Dara-KRd Costa 2019 -------------------Landgren 2021

38 ----41

Phase II

Isatuximab-RVD Ocio 2018

22

Phase I

Isatuximab-KRD for high-risk MM Abstract S204. EHA 2020

46

Efficacy Data

Safety Data

72.9% CR+ = 45.1% Median PFS (at 27.8 months) = NR

Grade 3 or 4 TEAEs = 23.7%

CR = 11% VGPR = 47% PFS = 97.5% ORR = 95%

Grade ≥3 AEs = 42%

ORR: DVRD=99.0% vs VRD=91.8%;

Serious AEs were reported in 39 (39.4%) patients in the D-RVd group and 52 (51.0%) in the RVd group

ORR = 90.9% sCR = 22.3% VGPR = 27.7% PR = 18.0% ≥VGPR =

22 mo sCR: DVRD 62.6% vs RVD 45.4% MRD negativity DRVD 51.0% vs RVD 20.4% 24-mo PFS DRVD 95.8% RVD 89.8% ≥VGPR = 56% CR = 9% ORR = 81% 12-month PFS = 87% OS = 99% ORR = 100%; ≥VGPR = 92% after induction CR/sCR = 91% before BMT; MRD negative 65% at best response

ORR = 100%; ≥VGPR = 95% after induction; PFS was 98%MRD

Grade 3/4 AEs: neutropenia (n=7), infection (n=6), insomnia (n=4), hyperglycemia (n=2), rash (n=2)

ORR = 93% MRD negativity = 38.5% sCR = 7.14% VGPR =

Grade ≥3 AEs = 46%

--------------------------------------------------

negative 71% at 20.3 months follow-up

Phase II

Grade ≥3 AEs = 56%

71.43% CR = 7.14% 7.5 mo PFS = 100%

ORR = 100%, with PR=10%, VGPR=44% and CR=46%; 20 of 33 pts were MRD negative in ASCT eligible arm

Grade 3/4 AE: neutropenia 34%, anemia10%, thrombocytopenia 14%, hypertension 12%, infection 8%

It’s important to know…

What are YOUR goals of therapy How to read your M-protein level What is your MM risk/ stage What are your therapy options What is your response to tx Know what side effects to expect so you can report them Who is on your care team Obtain a second opinion Ask about clinical trials

M-Protein

IgG Kappa M-Protein

Advancements in Survival of Multiple Myeloma 138,451 124,483

• With new biology-based medication 3 and 4 drug regimens the response rates are now >98% • We have had 31 drugs and tx indications FDA approvals for myeloma 2015-2022!

74,814

• With novel therapies are used at diagnosis, survival has improved dramatically From 3.8 years to >8 years!  The 10yr relative survival rate has nearly doubled since in the past 20 years 

Myeloma is not curable…yet.

But is survivable now!

54,963

2019

2021

2011

2004

People in the United States living or in a Remission from Multiple Myeloma

Blood (ASH Annual Meeting Abstracts) 2011 118: Abstract 5070; Blood Advances, 2017 Vol1(4);p282-287.

colecrai@msu.edu

52

Relapsed Therapy and Clinical Trials Jesús G. Berdeja, MD Sarah Cannon Research Institute 53

Relapsed Therapy and Clinical Trials Jesús G. Berdeja, M.D. Director of Myeloma Research Sarah Cannon Research Institute Nashville, TN, USA

CONFIDENTIAL – Contains proprietary information.

Not intended for external distribution.

Disclosures •

Consultant: [Bluebird, BMS, Celgene, CRSPR Therapeutics, Janssen, Kite, Legend, SecuraBio, Takeda]

•

Speaker’s Bureau: [none]

•

Grant/Research Support: [Abbvie, Acetylon, Amgen, Bluebird, BMS, C4 Therapeutics, CARsgen, Cartesian Therapeutics, Celularity, CRISPR Therapeutics, EMD Sorono, Fate Therapeutics, Genentech, GSK, Ichnos Sciences, Incyte, Janssen, Karyopharm, Lilly, Novartis, Poseida, Sanofi, Takeda, Teva, Zentalis]

•

Stock Shareholder: [none]

•

Honoraria: [none]

•

Full-time/Part-Time Employee: [none]

•

Other: [none]

55

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

• Relapsed: recurrence after a response to therapy • Refractory: progression despite ongoing therapy • Line of therapy: a change in treatment due to either progression of disease or unmanageable side effects o Note: initial (or induction) therapy + stem cell transplant + consolidation/ maintenance therapy = 1 line of therapy 56

Slide courtesy MMRF

Available Anti-Myeloma Agents: So Many Choices!

Conventional Chemotherapy

Dexamethasone Prednisone

Steroids

IMiDs

Proteasome Inhibitors

mAbs

Newer Agents

CART

Melphalan (Alkeran)

Thalomid (thalidomide)

Velcade (bortezomib)

Empliciti (elotuzumab)

Xpovio (selinexor)

Abecma (Ide-cel)

Cytoxan (cyclophosphamide)

Revlimid (lenalidomide)

Kyprolis (carfilzomib)

Darzalex (daratumumab)

Blenrep (Belamaf)

Carvykti (Cilta-cel)

Doxil (liposomal doxorubicin)

Pomalyst (pomalidomide)

Ninlaro (ixazomib)

DCEP or DPACE Carmustine (BCNU) Bendamustine (Treanda) 57 IMiD, immunomodulatory drug; HDAC, histone deacetylase; mAb, monoclonal antibody.

HOW DO YOU CHOOSE? 58

Confronting Disease Relapse in Myeloma Attrition Rates

Median Response Duration (Mos)

Response Duration With Increasing Treatment[1] 12

100

10

90

8

70

61

60

6

50

4

38

40 30

2 0

95

80

20

15

10

First Second Third Fourth Fifth Treatment Regimen

59

% of Patients Reaching Line of Therapy

Kumar. Mayo Clin Proc. 2004;79:867.

Sixth

0

1

1st Line

2nd Line

3rd Line

Yong et al. BJH 175:252-264, 2016

4th Line

5th Line

• Age • PS/frailty • Comorbidities (HTN, CAD, CRF, DM, etc)

Patient Characteristics Pathophysiology

The Four Ps of Treatment Selection

Patient Preference • Goals of therapy • QOL issues • Oral vs IV, etc

60

• Risk status • Genetic Profile • Type of relapse

Prior Therapy • Type of prior Tx • Depth/duration of response • Toxicity from Tx

Treatment of Early Relapse: Revlimid (lenalidomide) still preferred POLLUX

ASPIRE

ELOQUENT-2

TOURMALINE-MM1

Treatment

DaraRd vs Rd

KRd vs Rd

Erd vs Rd

IxaRd vs Rd

PFS (mos)

44.5 v 17.5

26.1 v 16.6

19.4 v 14.9

20.6 v 14.7

0.44

0.69

0.73

0.74

HR

1. Dimopoulos. NEJM 375:1319, 2016. 2. Bahlis. ASH 2018, Abstr 1996 . 3. Stewart. NEJM 372:142, 2015. 4. Stewart. ASH 2017, Abstr 743.

5. Lonial. NEJM 373:621,2015. 6. Lonial. ASCO 2018, Abstr8040. 7. Moreau. NEJM 374:1621,2016;.

61

Treatment of Early Relapse: Proteasome inhibitor preferred CASTOR

ENDEAVOR

CANDOR

IKEMA

Treatment

DaraVd vs Vd

Kd vs Vd

DaraKd vs Kd

IsaKd vs Kd

PFS (mos)

16.7 v 7.1

18.7 v 9.4

NR v 15.8

NR v 19.2

0.31

0.53

0.63

0.53

HR

1. Palumbo. NEJM 375:754, 2016. 2. Lentzsch. ASCO 2017, Abstr 8036. 5. Dimopoulos. Lancet Oncol 17:27,2016.

6. Dimopoulos. Lancet 2020; 18;396:186-197. 7. Moreau. Lancet 2021; 19;397:2361-71.

62

Treatment of Relapse: Pomalidomide-based regimen preferred OPTIMISM

ELOQUENT

APOLLO

ICARIA

Treatment

PVd vs Pd

EloPd vs Pd

DaraPd vs Pd

IsaPd vs Pd

PFS (mos)

11.2 v 7.1

10.3 v 4.7

12.4 v 6.9

11.5 v 6.5

0.61

0.54

0.63

0.59

HR

1. Richardson. Lancet Oncol 20:781, 2019. 2. Dimopoulos. NEJM 379:1811,2018.

3. Dimopoulos. Lancet Oncol 2021;22(6):801-12. 4. Attal. Lancet 394:2096, 2019.

63

What we know - Lots of options

How does the evidence help me choose?

- Consistently Triplets have been found to be superior to doublets in randomized phase 3 trials - Treatment until progression or intolerance is the paradigm in the relapsed/refractory setting - Triplets in general perform better in pts with poor risk cytogenetics but do not overcome poor risk

64

What we don’t know - There are no head to head comparisons between triplets to help guide selections - The patient populations differ between studies and often don’t reflect the average US patient

Despite Progress in MM There Remains Need for New Tx The MAMMOTH study

1.0

• Retrospective study of 275 patients from 14 academic centers in the US who had MM refractory to anti-CD38 monoclonal antibodies (MoAB)

0.8

OS of patients who are refractory to CD38 MoAB according to refractoriness to different immunomodulatory agents or proteasome inhibitors

• Prior autologous stem cell transplantation = 72% Efficacy • mOS from T0 for the entire cohort: 8.6 months (95% CI 7.5–9.9) • At least one subsequent treatment regimen was given post T0 in 249 (90%) patients − ORR to first regimen after T0 = 31%

Proportion Surviving

• Median number of prior therapies = 4 (range 1–16) 0.6

0.4

Med OS 11.2 mos

0.2

− mPFS = 3.4 months − mOS = 9.3 months

Med OS 9.2 mos 0

65

Gandhi UH, et al. Leukemia. 2019;33(9):2266–2275.

Med OS 5.6 mos

0.0 10

20

Months

30

40

50

66

67

Antibody Drug Conjugates (ADCs) Antibody-delivery of toxic payload

Target

68

Payload

Belantamab mafodotin (GSK2857916) Four mechanisms of action: 1. ADC mechanism 2. ADCC mechanism 3. Immunogenic cell death 4. BCMA receptor signaling inhibition

Background 1 ADC

 Antibody  Humanized, afucosylated IgG1

BCMA BCMA

 Antibody-Target  Payload  MMAF (monomethyl auristatin-F)

4

Lysosome BCMA

2 ADCC Effector cell

BCMA

x

 BCMA

3

Fc receptor

Malignant plasma cell

Cell death 1Tai

YT, et al. Blood 2014;123(20):3128-38.

ADC, antibody-drug conjugate; ADCC, antibody-dependent cell-mediated cytotoxicity; BCMA, 69B-cell maturation antigen; IgG, immunoglobulin G; MMAF, monomethyl auristatin-F

Trudel et al. The Lancet Oncology. 2018 Dec 1;19(12):1641-53.

70

Belantamab mafodotin • FDA-approved August 2020 (this guideline published July 2020, so not included) for R/R MM after >4 prior therapies, including anti-CD38, PI, and IMiD Trial DREAMM1 DREAMM2

70

Phase

Patient population

N

Treatment arm(s)

ORR

Median PFS

1

R/R MM after ASCT, alkylators, PI, and IMiD

35

3.4 mg/kg belantamab mafodotin Q3W

60%

12 months

2.5 mg/kg belantamab mafodotin Q3W

31%

2.9 months

2

R/R MM after IMiD, PI, and anti-CD38

3.4 mg/kg belantamab mafodotin Q3W

34%

4.9 months

Trudel, Blood Cancer J 2019; Lonial, Lancet Oncol 2019.

196

Ocular toxicities of belantamab mafodotin • Patients should receive pre-treatment eye exam • Symptoms may include dry eyes, blurred vision, changes in vision, and exam findings • 72% of patients on trials had keratopathy on exam • Around 50% of patients on clinical trials reported significantly worsening vision symptoms • Management approaches: o Belantamab mafodotin dose reductions o Supportive care, like lubricating eye drops 71

Popat, ASH 2020 #2278; Lonial, ASH 2020 #3224

YOU THOUGHT YOU KNEW CARS…

72

CAR T-Cell Structure

Tumor antigen–binding domain

VH VL

Tumor cell

Viral vector 1

Fusion protein  T-cell costimulatory receptor signaling domain

Binding domain

T-cell

 TCRζ activation domain

3 2

Signaling domain T-cell

BCMA-directed CAR T-cell  Comprising a BCMA antigen–binding domain, a costimulatory domain (generally CD28 or 4-1BB), and CD3-ζ signaling domain Bruno. Haematologica. 2021;106: 2054. Morgan. Biomedicines. 2016;4:9.

Slide credit: clinicaloptions.com

CAR T Cells: Mechanism of Action Tumor cell

T cell Expression of CAR

CAR enables T cell to recognize tumor cell antigen

Viral DNA Insertion

Antigen

Tumor cell apoptosis CAR T cells multiply and release cytokines 74

CAR T-Cell Therapy Patient Journey 4 Infusion

Apheresis 1

Patient must be recovered from any toxicity incurred from bridging therapy before starting lymphodepletion

3 Lymphodepletion

Patients go to the CAR T center or local apheresis center

(Manufacturing) 2 Patients return home 10 - 28 Days 75

Timeline varies by manufacturer

Standard of care therapy is permitted until CAR T cells are ready for infusion

FDA-Approved BCMA-Targeted CAR T-Cell Therapies for Multiple Myeloma

76

BCMA-Targeted Therapy

Indications

ABECMA® (Idecabtagene vicleucel)

 Adults with R/R multiple myeloma after ≥4 prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal Ab

CARVYKTI™ (Ciltacabtagene autoleucel)

 Adults with R/R multiple myeloma after ≥4 prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal Ab

Idecabtagene vicleucel PI. Ciltacabtagene autoleucel PI.

Phase II KarMMA: Idecabtagene Vicleucel (Ide-cel) in Relapsed/Refractory MM Lentiviral vector

Patients with R/R MM and ≥3 prior regimens each with ≥2 consecutive cycles, prior IMiD, PI, and anti-CD38 mAb, and refractory to last therapy

by IMWG criteria (N = 158)

Tumor Cell Tumor binding domain Signaling domains

T-cell

Leukapheresed n = 140

Idecabtagene CAR design MND SP Promoter

Anti-BCMA scFv Tumor-binding domain

CD8

4-1BB

CD3 ζ

Linker Signaling domains

Anderson. ASCO 2021. Abstr 8016. Munshi. NEJM. 2021;384:705.

Idecabtagene vicleucel (n = 128) 150 x 106 CAR T-cells (n = 4) 300 x 106 CAR T-cells (n = 70) 450 x 106 CAR T-cells (n = 54) Median Follow-Up, mo 150 x 106 CAR T-cells: 18.0 300 x 106 CAR T-cells: 15.8 450 x 106 CAR T-cells: 12.4 Total: 24.8



Primary endpoint: ORR



Secondary endpoints: CRR, safety, DoR, PFS, OS, PK, MRD, QoL, HEOR



Exploratory endpoints: immunogenicity, BCMA expression/loss, cytokines, Tcell immunophenotype, GEP in BM

Baseline characteristics:  High-risk cytogenetics: 35%  Extramedullary disease: 39%  Median no. of prior therapies: 6 (range: 3-16)  Triple refractory: 84%

Slide credit: clinicaloptions.com

KarMMa - Best Overall Response 100

Response, %

80

CR/sCR and MRD-negative CR/sCR and MRD not evaluable VGPR ORR=69% PR 24

60

ORR=50% 40

20

25

CRR 25%

25

4 14

ORR=82% ORR=73%

28

CRR 29%

CRR 39% 11 26

26 17

26

CRR 33% 7 20

21

0

CAR+ T cells:

• • • 78

150 × 10⁶ (n=4)

300 × 10⁶ (n=70)

450 × 10⁶ (n=54)

Ide-cel Treated (N=128)

Median time to first response of 1.0 mo (range, 0.5−8.8); median time to CR of 2.8 mo (range, 1.0−11.8) Median follow-up of 13.3 mo across target dose levels MRD-negative in all pts in ≥CR was 26% (79% in evaluable pts for MRD and in in ≥CR)

Munshi et al. NEJM 2021;384:705-16.

78

KarMMa: PFS and OS With Ide-cel PFS by Prior Lines of Therapy

Median, Mo (95% CI) 3 8.6 (2.9-12.1) ≥4 8.9 (5.4-11.6) All Ide-cel treated 8.6 (5.6-11.6)

1.0 0.8 0.6 0.4 0.2 0

0 2

0.8

0 2 2

24 mo-OS: 51%

0.4 0.2 0

0 3 3

18-mo OS: 65%

0.6

4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 0 Mo Patients at

Patients at Risk, n 3 15 13 11 9 8 5 5 2 2 2 2 2 2 1 ≥4 113 89 73 62 56 51 41 33 31 25 22 19 10 9 All ide-cel 128 102 84 71 64 56 46 35 33 27 24 21 12 10 treated

Median, Mo (95% CI) 3 22.0 (10.0-NE) ≥4 25.2 (19.9-NE) All Ide-cel treated 24.8 (19.9-31.2) 12-mo OS: 78%

1.0 OS Probability

PFS Probability

OS by Prior Lines of Therapy

Risk, n 3 15 0 ≥4 113 0 All ide-cel 138 treated

3

6

9

14 106 120

13 94 107

13 87 100

12 15 18 21 24 27 30 33 36 Mo 10 80 90

8 71 79

7 65 72

7 52 59

5 43 48

2 24 26

0 14 14

0 1 1

0 0

 Update at ASCO 2021 with median f/u of 24.8 mo Anderson. ASCO 2021. Abstr 8016.

Slide credit: clinicaloptions.com

KarMMa: PFS by Dose and Best Response PFS by Target Dose

Median, Mos (95% CI) 150 x 106 2.8 (1.0-NE) 300 x 106 5.8 (4.2-8.9) 450 x 106 12.1 (8.8-12.3)

0.8

1.0 Probability of DoR

PFS Probability

1.0

0.6 0.4 0.2 0

DoR by Best Response

0

2

4

6

Patients at Risk, N 150 x 106 4 2 300 x 106 70 56 450 x 106 54 44

8 10 12 14 16 18 20 22 Mos

1 42 40

1 33 36

1 29 34

1 24 31

1 17 17

1 14 4

1 11 1

1 7 0

1 2 0

PFS may be dose dependent median PFS 12 mos at 450x106 CAR+ T cells Munshi. ASCO 2020. Abstr 8503.

0 0

0.8

Median, Mos (95% CI) CR/sCR 20.2 (12.3-NE) VGPR 11.3 (6.1-12.2) PR 5.4 (3.8-8.2) Nonresponders 1.8 (1.2-1.9)

0.6 0.4 0.2 0

0

CR/sCR 42 VGPR 25 PR 27 Nonresponders 34

2

4

6

42 25 16 8

42 22 10 83

40 20 9 70

8 10 12 14 16 18 20 22 Mos 39 16 5 64

37 14 1 56

26 8 0 35

16 3 0 19

11 2 0 13

8 0 0 8

1 0

0 0

4

0

DOR improves with depth of response median DOR 20.2 mos in pts with CR/sCR

CARTITUDE-1: Ciltacabtagene Autoleucel for R/R MM Binding Domains

VHH



Single-arm, open-label phase Ib/II trial Patients with R/R MM per IMWG and ≥3 prior regimens or double refractory to IMiD and PI and had received IMiD, PI, and anti-CD38 mAb (N = 113)

VHH

Lymphodepletion n = 101 4-1BB CD3z

 

Contains 2 BCMA-targeting single-chain antibody designed to confer avidity



Identical to the CAR construct used in the LEGEND-2 study

Berdeja. Lancet. 2021;398:314. Martin. JCO. 2022;[EPub]

Ciltacabtagene autoleucel (n = 97) Target 0.75 x 106 CAR T-cells (range 0.5-1 x 106) Median administered dose: 6 0.71 x 10 (0.51 – 0.95 x 106) CAR+ viable T cells/kg Primary endpoints: Phase Ib: AEs; phase II: ORR

Baseline characteristics:  High-risk cytogenetics: 23.7%  Extramedullary disease: 13.4%  Median no. of prior therapies: 6 (range: 3-18)  Triple refractory: 87.6%

Slide credit: clinicaloptions.com

Ciltacabtagene Autoleucel for R/R MM (CARTITUDE-1): Responses  sCR rates deepened over time

ORR* by IRC: 97.9%

100

‒ 67% at median 1-yr follow-up ‒ 83% at median 2-yr follow-up

Patients (%)

80 60

sCR: 82.5%

82.5%

≥VGPR: 94.9%

40 20 0

3.1%

Best response =

 Median time to best response: 2.6 mo (range: 0.9-17.8)  Median time to ≥CR: 2.9 mo (range: 0.9-17.8)

12.4% sCR

 Median time to first response: 1 mo (range: 0.9-10.7)

 Median DoR: NE (range: 23.3-NE) VGPR

PR

 No patient had CR or SD as best response *ORR assessed by independent review committee.

Martin. JCO. 2022;[Epub].

Slide credit: clinicaloptions.com

Ciltacabtagene Autoleucel for R/R MM (CARTITUDE-1): PFS and OS PFS

100

27-mo PFS: 64.2% (95% CI: 51.9-74.1) Median PFS: NR

60 27-mo PFS: 54.9% (95% CI: 44.0-64.6) Median PFS: NR (95% CI: 24.5 mo-NE)

40 20 0

3

6

9 12 15 18 21 24 27 30 33 36 39 42 Mo

Patients at Risk, n All Patients 97 95 85 77 74 67 64 63 57 27 17 sCR patients 80 80 78 73 71 64 62 61 55 27 17 Martin. JCO. 2022;June 4:[Epub].

60 27-mo OS: 70.4% Median OS: NR (95% CI: 14.62 mo-NE)

40 20

All Patients sCR patients

0

80

OS (%)

PFS (%)

80

OS

100

3 3

1 1

1 1

0 0

0

0

3

6

9 12 15 18 21 24 27 30 33 36 39 42 Mo

Patients at Risk, n 97 96 91 88 85 81 79 77 71 42 22

6

2

1

0

Slide credit: clinicaloptions.com

Corneal toxicity

NEW TYPES OF SIDE EFFECTS (TOXICITY)

• Seen with ADCs, specific to the payload used • Usually reversible if identified early and drug stopped or dose reduced • Requires close ophthalmology evaluation Cytokine Release Syndrome (CRS) • Seen with CART and Bispecific TCE • Similar to symptoms associated with infections (fever, body aches, headaches, blood pressure changes, etc) • Mostly low level but can be severe, including fatal • Requires prompt intervention if develops • Usually responds to tocilizumab and/or steroids Neurotoxicity • • • • •

84

Seen with CART and Bispecific TCE Usually mild and requires no intervention Can be severe and lead to longer lasting effects Requires prompt intervention if develops Usually responds to steroids

TAKE HOME POINTS • In general, treat to maximum response, balancing toxicity • In general triplets should be chosen over doublets in all lines of therapy o Quads already in the frontline setting and possibly coming in the relapsed setting

• In the relapsed setting:

o Many options but no head to head comparisons of triplets o No good data on optimal sequence

o Use the four Ps to help choose individualized next best option

• Very exciting new therapies here which will change the treatment paradigm over the next few years • Very important to participate in clinical trials 85

Participation in a Clinical Trial

86

Major Cancer Organizations • NCCN (National Comprehensive Cancer Network) • ASCO (American Society of Clinical Oncology) • ASH (American Society of Hematology) • ACS (American Cancer Society) o Recommend participation on clinical trials whenever possible at any stage of treatment o Not just as last resort

87

Phases of Clinical Trials

88

Why Clinical Trials?

• All major medical advances are developed through clinical trial testing • Safest way to test new drugs or new combinations of existing drugs • Best way to ensure results can be interpreted

89

Why clinical trials for you?

• Your participation may help others in the future • Way to access the newest treatments • Way to get more supervised care • Help advance medical care

90

What is involved for a patient on a clinical trial?

• The consent o No study procedure can be conducted without an informed consent o You can revoke consent at any time

• The screening process

o All studies have rigid inclusion and exclusion criteria that must be met to enroll

• The study o If all eligibility criteria are met, study treatment can commence o All study procedures are consider standard of care or specific to study

• After the study 91

How do you find out about clinical trials?

• Ask your treating hematologist/oncologist about any available trials

• Visit the NCI website

• Check with any academic medical centers close to your home

• For Sarah Cannon

• Contact support organizations o https://www.myeloma.org

92

o http://www.clinicaltrials.gov

o http://www.sarahcannon.com

93

94

How to Manage Myeloma Symptoms and Side Effects Patricia Mangan, RN, MSN, APRN-BC University of Pennsylvania, IMF Nurse Leadership Board 95

August 6, 2022

LIFE IS A CANVAS, YOU ARE THE ARTIST Patricia A. Mangan, RN, MSN, APRN-BC Abramson Cancer Center University of Pennsylvania

Patient Education Slides 2022

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 97

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

THE BRIGHT

&

DARK SIDE TO STEROIDS

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

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

(insomnia), fatigue

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

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

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

• Increased risk of

infections, heart disease • Muscle

weakness, cramping

• Increase in blood

pressure, water retention

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

hiccups, heartburn, ulcers, or gas

• Weight gain, hair

thinning/loss, skin rashes

• Increase in blood

sugar levels, diabetes

Rajkumar SV, Jacobus S, Callander NS, Fonseca R, Vesole DH, Williams ME, Abonour R, Siegel DS, Katz M, Greipp PR, Eastern Cooperative Oncology Group (2010) Lenalidomide plus highdose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial. Lancet Oncol 11(1):29–37.

King T, Faiman B. Steroid-Associated Side Effects: A Symptom Management Update on Multiple Myeloma Treatment. Clin J Oncol Nurs. 2017 Apr 1;21(2):240-249. doi: 10.1188/17.CJON.240249. PMID: 28315528.

99

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

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

Physical

Constipation may be caused by • 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.

100

PAIN PREVENTION AND MANAGEMENT

Physical

Pain can significantly compromise quality of life Sources of pain include bone disease, neuropathy and medical procedures Management • Prevent pain when possible • Bone strengtheners to decrease fracture risk; anti viral to prevent shingles; sedation before procedures

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

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

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

101

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

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

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

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

Physical

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

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

• Safe environment: rugs, furnishings, shoes

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

102

FATIGUE, ANXIETY & DEPRESSION

Physical Psychological

All can affect quality of life and relationships

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

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

Often, people do not share these symptoms with their provider.

Talk to your provider about symptoms that are not well controlled or thoughts of self harm. Help is available.

Ramsenthaler, et al. 2016. https://doi.org/10.1111/ejh.12790. Catamero D et al. CJON. 2017; 21(5)suppl:7-18.

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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 • Psychologic: fear, anxiety, stress • Physiologic: sleep apnea, heart issues, pain Rod NH et al 2014. PloS one. 9(4):e91965; Coleman et al. 2011. Cancer Nurs. 34(3):219-227.

National Sleep Foundation. At: http://sleepfoundation.org/ask-the-expert/sleep-hygiene

Psychological

🐑🐑 Sleep hygiene is necessary for

quality nighttime sleep, 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.

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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

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INFECTION CAN BE SERIOUS FOR PEOPLE WITH MYELOMA Multiple myeloma

Treatment

Immune dysfunction

General Infection Prevention Tips • Good personal hygiene (skin, oral) • Environmental control (wash hands, avoid crowds and sick people, etc)

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

• Growth factor (Neupogen [filgrastim]) • Immunizations (NO live vaccines) • Medications (antibacterial, antiviral)

Brigle K, et al. Clin J Oncol Nurs. 2017;21(5)suppl:60-76. Faiman B, et al; IMF Nurse Leadership Board. Clin J Oncol Nurs.

2011;15(Suppl):66-76. Miceli TS, et al. Clin J Oncol Nursing. 2011;15(4):9-23.

ASH Website. COVID-19 Resources. Accessed January 30, 2022. https://www.hematology.org/covid-19/covid-19-and-multiple-myeloma

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HEALTHFUL LIVING STRATEGIES: KEEP ACTIVE Do Keep a log or journal of your activity • Notify your healthcare provider about sudden onset of pain, progressive weakness, headaches, blurred vision, numbness, and tingling •

•

Dehydration can lead to low blood pressure, falls

Movement therapies can reduce stress, promote sleep Yoga, Pilates, Tai Chi Shown to improve sleep and sleep quality, • Improved quality of life & mood •

Do Not: Overdo it • Force exercise • Try things without discussing with provider • Consider weight lifting limits •

Myeloma bone disease may affect your ability to do certain movement activities.

Review your activity interests with your health care provider!

Boullosa DA, et al., Jul 2013;45(7):1223-1228.

Faiman B et al., Clinical Journal of Oncology Nursing. 2008;12(0):53-62; Rome S et al., Clin J Oncol Nurs. Aug 2011;15 Suppl:41-52.

Miceli T et al., Clinical Journal of Oncology Nursing. 2011;15:9-23; Coleman EA et al.,Oncol Nurs Forum. May 2008;35(3):E53-61.

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Stress during an infectious disease outbreak may sometimes cause the following: • Fear and worry about your own • • • • • •

health and the health of your loved ones Fear/worry about your financial situation or job, or loss of support services you rely on Changes in sleep or eating patterns Difficulty sleeping or concentrating Worsening of chronic health problems Worsening of mental health conditions Increased use of tobacco, and/or alcohol and other substances

CDC = Centers for Disease Control; COVID-19 = coronavirus 2019.

CDC website. How to Select, Wear, and Clean Your Mask. Accessed October 27, 2020.

MANAGING STRESS DURING A PANDEMIC Take care of your Mental Health

• •

Take breaks from watching, reading, or listening to news stories Take care of your body

– Take deep breaths, stretch, – – – –

• •

or meditate Try to eat healthy, well-balanced meals Exercise regularly Get plenty of sleep Avoid excessive alcohol and drug use

Make time to unwind Connect with others. While social distancing measures are in place, consider connecting online, through social media, or by phone or mail

SHARED DECISION-MAKING Be empowered to be part of the treatment decision-making • Ask for time to consider options (if needed/appropriate) • Understand options; consider priorities • Use reliable sources of information • Use caution considering stories of personal

experiences • Consider your goals/values/preferences

• Express your goals/values/preferences; create a

dialog

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

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

• Arrive at a treatment decision together

Data From Research

HCP Clinical Experience TREATMENT DECISION

Your Preference Philippe Moreau. ASH 2015.

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CLINICAL TRIALS: EARLY ACCESS TO PROMISING TREATMENTS Preclinical PHASE 1

PHASE 2

ANIMAL STUDIES FIRST INTRODUCTION OF AN INVESTIGATIONAL DRUG INTO HUMANS

• • •

Determine metabolism and PK/PD actions, MTD, and DLT Identify AEs Gain early evidence of effectiveness, studied in many conditions; typically, 20 to 80 patients; everyone gets agent

EVALUATION OF EFFECTIVENESS IN A CERTAIN TUMOR TYPE

• •

Determine short-term AEs and risks; closely monitored Includes up to 100 patients, typically

PHASE 3

GATHER ADDITIONAL EFFECTIVENESS AND SAFETY INFORMATION COMPARED TO STANDARD OF CARE

PHASE 4

APPROVED AGENTS IN NEW POPULATIONS OR NEW DOSE FORMS

• •

Placebo may be involved if no standard of care exists; 100s to several thousand patients Often multiple institutions; single or double blind

AE = adverse event; DLT = dose-limiting toxicity; MTD = maximum tolerated dose; PD = pharmacodynamics; PK = pharmacokinetics.

Faiman B, et al. Adv Pract Oncol. 2016;7:17-29.

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HOW TO FIND CLINICAL TRIALS

Clinicaltrials.gov https://clinicaltrials.gov/

IMF Infoline US & Canada 800-452 CURE (2873) Worldwide: 1-818-487-7455 infoline@myeloma.org

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CLINICAL TRIAL MYTHS: DISPELLING INACCURACIES MYTH: If I participate in a clinical trial, I might get a placebo, not active treatment MYTH: If I participate in a clinical trial, I can’t change my mind

• Phase 1 and 2, everyone gets active treatment • Phase 3 standard of care vs new regimen: often standard regimen with/without additional agent in MM trials • Patients can withdraw their consent for clinical trial participation at any time

MYTH: Patients (whatever demographic/ distance from clinic/etc) never participate in clinical trials so I won’t mention it

• Mention the option and give the patient the opportunity; implicit and explicit biases can limit participation • Some groups may need more information about clinical trials to feel comfortable with participation

MYTH: Clinical trials are dangerous because they have new medicines and practices

• Some risk is involved with every treatment, but medicines are used in clinical trials with people only after they have gone though testing to indicate that the drug is likely to be safe and effective for human use

MYTH: Clinical trials are expensive and not covered by insurance

• Research costs are typically covered by the sponsoring company • Standard patient care costs are typically covered by insurance • Check with clinical trial team/insurers; costs such as transportation, hotel may not be reimbursed and are paid by patient

MM = multiple myeloma.

PhRMA website. Accessed April 15, 2022. https://phrma.org/-/media/Project/PhRMA/PhRMA-Org/PhRMA-Org/PDF/A-C/CLINICAL-TRIALS-MYTH-FACTPRINT.pdf?hsCtaTracking=f6689b95-1626-40d9-8c87-c6b8d31600a4%7C35221aa8-d487-4db3-9416-b9c3c35e3bac.

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PREPARE FOR VISITS & CONSIDER TELEMEDICINE Come prepared: • Bring a list of current medications, prescribed and • • •

• •

over the counter Write down your questions and concerns. Prioritize them including financial issues Have there been any medical or life changes since your last visit?

Current symptoms - how have they changed (improved, worsened, stable)? Keep a symptom diary. Bring it along Communicate effectively: your health care team can’t help if they don’t know Know the “next steps”, future appointments, medication changes, refills, etc

IMF Telemedicine Tip Sheet. In development.

Check with your healthcare team – Is telemedicine an option?

Similar planning for “in-person” appointment PLUS: • What is the process and what technology is needed?

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

• Plan your location: quiet, well-lit location with strong wi-fi is best • Plan yourself: consider if you may need to show a body part and wear accessible clothing • Collect recent vital signs (blood pressure, temp, heart rate) self-serve blood pressure cuff is available at many pharmacies and for purchase

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

IMF TV Teleconferences

eNewsletter: Myeloma Minute

Download or order at myeloma.org

IMF InfoLine 1-800-452-CURE 9am to 4pm PST 114

YOU ARE NOT ALONE

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