IMF Virtual Regional Community Workshop (RCW) - Florida by International Myeloma Foundation

Welcome and Announcements Kelly Cox

Director Support Groups & Senior Director Regional Community Workshops 2

Thank you to our sponsors!

FLORIDA REGIONAL COMMUNITY WORKSHOP Saturday November 20, 2021~ 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 Joseph Mikhael, MD, MEd, FRCPC, FACP, IMF Chief Medical Officer 10:40 AM - Q & A with Panel 10:55 AM – Meditation and Stretch Break 11:05 AM - Relapsed Therapy and Clinical Trials Ciara Freeman, MD, Moffitt Cancer Center, Tampa FL 11:45 AM - How to Manage Myeloma Symptoms and Side Effects Kathy Colson, RN, BSN, BS, IMF Nurse Leadership Board 12:05 PM - Q&A with Panel

Myeloma 101 and Frontline Therapy

Joseph Mikhael, MD, MEd, FRCPC, FACP, IMF Chief Medical Officer 7

Multiple Myeloma 101 and Frontline Therapy IMF Regional Community Workshop November 2021 Joseph Mikhael, MD, MEd, FRCPC Chief Medical Officer, International Myeloma Foundation Professor, Translational Genomics Research Institute (TGen) City of Hope Cancer Center

Objectives • Review the basics of blood and cancer • Define multiple myeloma and its key features • Highlight the approach to initial therapy for myeloma • Discuss the role of stem cell transplantation in myeloma

The Basics of Blood

• The blood is an “organ” made up of both cells and liquid “plasma” • Think of wine (red/white/rose) 1. Red Cells – carry Oxygen…trucks 2. White Cells – immune system…army 3. Platelets – help with clotting…ambulance

All produced in the blood factory = Bone Marrow

What is Cancer? • Simple definition: –

Identical, uncontrolled growth

• The body usually has a balance to allow cells to grow in the

right place for the right period of time – When that system is unbalanced, cancers grow – Ie, solid tissue (breast, colon…) or blood cells

• The “double whammy” of blood cancers is that they are the cells

meant to protect you • citizen crime vs military crime

What is Multiple Myeloma? Multiple Myeloma* is a blood cancer that starts in plasma cells of the spongy center of bones (bone marrow). – This is where stem cells mature into red blood cells, white blood cells, and platelets. – Myeloma cells are abnormal plasma cells that make an abnormal antibody called “M protein”. * Myeloma is NOT a bone cancer or skin cancer (melanoma), it is a type of blood cancer.

Multiple Myeloma Snapshot National MM Statistics 34,920 Estimated New Cases in 2021

12,410 Estimated Deaths in 2021

Trends in MM Natural History by Race MM Incidence

 Higher incidence in AA vs White patients: • 15.9 vs 7.5 cases per 100,000 per year

MM  Higher mortality in AA vs White patients: Mortality • 5.6 vs 2.4 MM deaths per 100,000

The Average Survival of patients with myeloma is IMPROVING! The expected survival is nearly 10 years for all patients, but still less than 5 years in patients with high risk disease

 5-year relative survival evolution from 1973 to 2005 MM • Survival for White patients increased Survival significantly from 26.3% to 35% • Survival for AA patients increased from 31% to 34.1%

Myeloma Is a Cancer of Plasma Cells • • •

Cancer of plasma cells Healthy plasma cells produce immunoglobulins G, A, M, D, and E Myeloma cells produce abnormal immunoglobulin “paraprotein” or monoclonal protein

FAST STATS 1.8% of all cancers; 17% of hematologic malignancies in the United States

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

Bone marrow of patient with multiple myeloma Image courtesy of American Society of Hematology Kyle et al. Mayo Clin Proc. 2003;78:21-33;

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

Diagnosis of multiple myeloma: Monoclonal immunoglobulin - both “heavy” and ”light” chains

Multiple Myeloma Typically Preceded by Premalignant Conditions Premalignant

Condition

(Monoclonal Gammopathy of Undetermined Significance)

SMM1-5,8

(Smoldering Multiple Myeloma)

Active Multiple Myeloma6-8

<10%

10%-60%

>10%

None

Yes

~1% per year

~10% per year

Not Applicable

No; observation

Yes for high risk*; No for others

Yes

MGUS1-4

Clonal plasma cells in bone marrow Presence of Myeloma Defining Events Likelihood of progression Treatment

Malignant

* In clinical trial (preferred)

or offer treatment for those likely to progress within 2 years

1. Kyle RA, et al. N Engl J Med. 2007;356:2582-90. 2. International Myeloma Working Group. Br J Haematol. 2003;121:749-57. 3. Jagannath S, et al. Clin Lymphoma Myeloma Leuk. 2010;10(1):28-43.

4. Kyle RA, et al. Curr Hematol Malig Rep. 2010;5(2):62-69. 5. Mateos M-V, et al. Blood. 2009;114:Abstract 614. 6. Durie BG, Salmon SE. Cancer. 1975;36:842-854.

7. Durie BG, et al. Leukemia. 2006;20(9):1467-1473. 8. Rajkumar SV, et al. Lancet Oncology 2014; 15:e538e548.

2014 IMWG Active Myeloma Criteria: Myeloma-Defining Events Clonal bone marrow ≥10% or bony/extramedullary plasmacytoma AND any one or more Myeloma-Defining Events

Calcium elevation R enal complications A nemia B one disease

Clonal bone marrow ≥60%

FLC

sFLC ratio >100

MRI

>1 focal lesion by MRI

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

Active Myeloma Not CRAB but now SLiM CRAB • S (60% Plasmacytosis) • Li (Light chains I/U >100) • M (MRI 1 or more focal lesion) • C (calcium elevation) • R (renal insufficiency) • A (anemia) • B (bone disease) Rajkumar SV, et al. Lancet Oncol. 2014;15:e538-e548.

More About the Common “CRAB” Symptoms Low Blood Counts • May lead to anemia and infection • Anemia is present in 60% at diagnosis

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

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

Multiple Myeloma diagnosis can be challenging

Fatigue

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

Anemia

A Call to Action: Facts About African Americans & Myeloma 1.

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

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

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

African Americans are less likely to receive the three T’s: Transplant, Triplets and Trials

Survival improvements have not been equal across race – for every 1.3 years of life gained in whites, it was only 0.8 in blacks

African Americans have biologic differences and achieve equal or better outcomes when they receive therapy 21

Learn Your Labs Counts the number of red blood cells, white blood cells, and platelets Measures levels of albumin, calcium, and creatinine to assess kidney and liver functions, bone status ,and the CoMP extent of disease

CBC

Beta2 MicroG

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

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

Lactate Dehydrogenase

Serum Protein EP

Detects the presence and level of M protein = how much myeloma Identifies the type of abnormal antibody proteins: IgG, IgA, IgM

Immuno Fixation Serum Free Light Chain

Measures myeloma free light chains (kappa or lambda) in blood = how much myeloma

Urine Protein EP

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

24-hr Urine Analysis

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

Myeloma Stage:

Staging refers to the degree to which the cancer has progressed

Stage 1

Stage 2

Stage 3

β2-microglobulin under 3.6 mg/L

β2-microglobulin Between 3.5 & 5.4mg/L

β2-microglobulin over 5.5 mg/L

Normal

Lactate Dehydrogenase (LDH) AND

NO High Risk Cytogenetics (FISH)

HIGH

NO High Risk Cytogenetics (FISH)

Lactate Dehydrogenase (LDH) AND/OR High Risk Cytogenetics (FISH) Deletion 17thchromosome Translocation 4th and 14th Translocation 14th and 16th Translocation 14th and 20th

Treatment Planning Treatment Planning is the process of thinking about the treatment steps you can take with your doctor, based on your goals and preferences. Treatment decisions are based on: • The results of biomarker tests, cytogenetic (FISH) test, and the stage of multiple myeloma • Your values, goals, and preferences • Your age • Your health and symptoms (if you have kidney disease, heart disease, anemia, or other issues) • Your medical history and past treatments for multiple myeloma

How to Choose a Treatment Plan Age

Lifestyle Goals of Therapy

Patient Preference

Myeloma Symptoms

Tools of the Trade for Frontline Therapy Standard Drug Overview

Class

Drug Name

IMiD immunomodulatory drug

Revlimid (lenalidomide)

R or Rev

Thalomid (thalidomide)

T or Thal

Chemotherapy Steroids Monoclonal Antibodies

V or Vel or B

Administration Oral

Kyprolis (carfilzomib)

C or K or Car

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

Ninlaro (ixazomib)

N or I

Oral

Cytoxan (cyclophosphamide)

Alkeran or Evomela (melphalan)

M or Mel

Decadron (dexamethasone)

Dex or D or d

Prednisone

Daratumumab (Darzalex)

Dara

Velcade (bortezomib) Proteasome inhibitor

Abbreviation

Oral or intravenous Oral or intravenous Intravenous (IV)

Second/Expert Opinion • You have the right to get a second opinion. Insurance providers may require second opinions. • A second opinion can help you: – Confirm your diagnosis – Give you more information about options – Talk to other experts – Introduce you to clinical trials – Help you learn which health care team you’d like to work with, and which facility

General Principles of Initial Therapy 1. Frontline therapy has a significant impact on long term survival 2. We don’t “save the best for last” but use the best we have early on 3. We leverage combinations of drugs to best control the myeloma 4. We seek a DEEP and DURABLE response 5. We mix and match from the 3 major classes of drugs and add steroids: Proteasome Inhibitors Immunomodulatory Drugs Monoclonal Antibodies 6. We decide early on whether or not someone will have a stem cell transplant

Personalized Approach to Frontline Therapy Newly Diagnosed MM and Risk Stratified

Factors to be considered for ASCT Age, performance status (PS), comorbidities (R-MCI score, HCT-Cl) and organ function

ASCT Eligible

ASCT Ineligible

Treatment Algorithm in Frontline Newly Diagnosed MM

Not Transplant Candidate

VRd x 8-12 cycles followed by Len

Transplant Candidate VRd x 4 cycles

DRd

Early Auto SCT followed by Maintenance

*Based on CALGB 100104, S0777, IFM-2009, MAIA ¶ VTd/VCd if VRd not available Rajkumar SV. 2020

Collect & store Continue VRd x4 Maintenance Delayed Transplant

Transplant Eligible Key Questions: 1. Is Transplant still necessary? 2. What is the triplet combination? (VRD or KRD) 3. Should we switch to quadruplet combinations? (D-VRD, D-KRD or I-VRD, I-KRD)

IFM 2009 Study design 700 patients randomized stratified on ISS and FISH Arm A – RVD alone 3 RVD

Arm B - Transplantation 3 RVD

PBSC collection (cyclophosphamide 3g/m2 and GCSF 10 μg/kg/d)

5 RVD

HD Melphalan 200 mg/m2 + ASCT 2 RVD

Lenalidomide maintenance 13 cycles (10-15 mg/d)

Remember that RVD is: Revlimid + Velcade + Dexamethasone RVd 21d cycles . Lenalidomide 25 mg/d: D1-D14 . Bortezomib 1.3 mg/m2 D1, D4, D8, D11 . Dexamethasone 20 mg/d: D1, D2, D4, D5, D8, D9, D11, D12

Primary endpoint = PFS Secondary endpoints . ORR, MRD . TTP . OS . Toxicity

M Attal et al, N Engl J Med 2017

Updated PFS (primary endpoint) Median follow up

89.8 months

This means that the average time to relapse is about 3 years for RVD and 4 years for RVD + Transplant Median PFS 47.3 months (Transplantation, arm B)

Median PFS 35 months (RVD alone, arm A) HR (95CI)

0.70 [0.59;0.83]

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

Median follow up

89.8 months

8y-OS 62.2% (Transplantation, arm B) 8y-OS 60.2% (RVD alone, arm A)

HR (95CI)

1.03 [0.8;1.32]

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

Carfilzomib, Lenalidomide and Dexamethasone (KRD) for Newly-Diagnosed, Transplant-Eligible Multiple Myeloma

Induction 4, 28-day cycles Len: 25 mg PO D1-21 CFZ*: 20/36 mg/m2 IV D1, 2, 8, 9, 15, 16 Dex: 40 mg PO D1, 8, 15, 22

Transplant

Consolidation

MEL 200 mg/m2

4, 28-day cycles Len: 25 mg PO D1-21 CFZ*: 36 mg/m2 IV D1, 2, 8, 9, 15, 16 Dex: 20 mg PO D1, 8, 15, 22

Jasielec, J, et al. Blood 2020; Epub ahead of print.

Maintenance 10, 28-day cycles Len: 25 mg D1 – 21 CFZ 36 mg/m2 D1, 2, 15, 16 Dex 20 mg D1, 8, 15, 22 →Lenalidomide monotherapy off protocol

Len maintenance until PD

Trial design

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

4x KCd

R1 1:1:1

4x KRd

mg/m2

K: 36^ d 1-2,8-9,15-16 R: 25 mg d 1-21 d: 20 mg. d 1-2,8-9,15-16,22-23

4x KRd

K: 36^ mg/m2 d 1-2,8-9,15-16 R: 25 mg d 1-21 d: 20 mg. d 1-2,8-9,15-16,22-23

MOBILIZATION

K: 36^ mg/m2 d 1-2,8-9,15-16 C: 300 mg/m2 d 1,8,15 d: 20 mg. d 1-2,8-9,15-16,22-23

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

4x KRd

K: 36 mg/m2 d 1-2,8-9,15-16 R: 25 mg d 1-21 d: 20 mg. d 1-2,8-9,15-16,22-23

4x KCd

K: 36 mg/m2 d 1-2,8-9,15-16 C: 300 mg/m2 d 1,8,15 d: 20 mg. d 1-2,8-9,15-16,22-23

4x KRd

K: 36 mg/m2 d 1-2,8-9,15-16 R: 25 mg d 1-21 d: 20 mg. d 1-2,8-9,15-16,22-23

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

R2 1:1

4x KRd

K: 36 mg/m2 d 1-2,8-9,15-16 R: 25 mg d 1-21 d: 20 mg. d 1-2,8-9,15-16,22-23

K: 36 mg/m2 d 1, 2, 15, 16 up to 2 years* R: 10 mg days 1-21, until progression or intolerance

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

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

Francesca Gay

Progression-free survival KRd_ASCT vs. KRd12 vs. KCd_ASCT

KR vs. R

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

Median follow-up from Random 2: 37 months (IQR 33‒42) 1.00

0.75

0.69 0.56

0.50

0.51

0.25

KRd_ASCT vs. KCd_ASCT: HR 0.54, 95% CI 0.38-0.78, p<0.001 KRd_ASCT vs. KRd12: HR 0.61, 95% CI 0.43-0.88, p=0.0084 KRd12 vs. KCd_ASCT: HR 0.88, 95% CI 0.64-1.22, p=0.45

0.00 0

30 Months

Progression-free survival

1.00

0.75

0.65

0.50

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

0.00 0

20 Months

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

Francesca Gay

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

GRIFFIN: Randomized Phase • Phase 2 study of D-RVd versus RVd in transplant-eligible NDMM, 35 sites in the United States with enrollment between December 2016 and April 2018 Induction: Cycles 1-4

• Transplanteligible NDMM • 18-70 years of age • ECOG PS score 0-2 • CrCl ≥30 mL/mina

D-RVd

1:1 randomization

Key eligibility criteria:

D: 16 mg/kg IV Days 1, 8, 15 R: 25 mg PO Days 1-14 V: 1.3 mg/m2 SC Days 1, 4, 8, 11 d: 20 mg PO Days 1, 2, 8, 9, 15, 16

RVd

R: 25 mg PO Days 1-14 V: 1.3 mg/m2 SC Days 1, 4, 8, 11 d: 20 mg PO Days 1, 2, 8, 9, 15, 16 21-day cycles

Consolidation: Cycles 5-6c T R A N S P L A N T

D-RVd

D: 16 mg/kg IV Day 1 R: 25 mg PO Days 1-14 V: 1.3 mg/m2 SC Days 1, 4, 8, 11 d: 20 mg PO Days 1, 2, 8, 9, 15, 16

RVd

Maintenance: Cycles 7-32d D-R

D: 16 mg/kg IV Day 1 Q4W or Q8We R: 10 mg PO Days 1-21 Cycles 7-9; 15 mg PO Days 1-21 Cycles 10+

R: 25 mg PO Days 1-14 V: 1.3 mg/m2 SC Days 1, 4, 8, 11 d: 20 mg PO Days 1, 2, 8, 9, 15, 16

R: 10 mg PO Days 1-21 Cycles 7-9; 15 mg PO Days 1-21 Cycles 10+

21-day cycles

28-day cycles

Endpoints and statistical assumptions Primary endpoint:

sCR rate (by end of consolidation); 1-sided alpha of 0.1 80% power to detect 15% improvement (50% vs 35%), N = 200

Secondary endpoints:

Rates of MRD negativity (NGS 10–5), ORR, ≥VGPR, CR

Stem cell mobilization with G-CSF ± plerixaforb

ECOG PS, Eastern Cooperative Oncology Group performance status; CrCl, creatinine clearance; IV, intravenous; PO, oral; G-CSF, granulocyte colony-stimulating factor; Q4W, every 4 weeks; Q8W, every 8 weeks; NGS, next-generation sequencing; ORR, overall response rate; VGPR, very good partial response; CR, complete response. aLenalidomide dose adjustments were made for patients with CrCl ≤50 mL/min. bCyclophosphamide-based mobilization was permitted if unsuccessful. cConsolidation was initiated 60 to 100 days post transplant. dPatients who complete maintenance cycles 7 to 32 may continue single-agent lenalidomide thereafter. eProtocol Amendment 2 allowed for the option to dose daratumumab Q4W, based on pharmacokinetic results from study SMM2001 (NCT02316106).

Responses Deepened over Timea sCR, P = 0.0253b ≥CR, P = 0.0014b 100 90

Patients, %

12.1 7.1

≥CR: 19.2%

6.1

70 60 50

21.2

≥CR: 27.3%

52.5

≥CR: 51.5%

63.6

39.4 26.3

2.0 End of induction

12.1 End of ASCT

1.0

8.1

1.0

End of consolidation

D-RVd

14.1 3.0

1.0

12-months-ofmaintenance cutoff

14.4 5.2

≥CR: 19.6%

32.0

≥CR: 42.3%

≥CR: 60.8%

13.4

30.9 35.1

47.4

10.3

46.4

sCR CR VGPR PR SD/PD/NE

18.2

≥CR: 13.4%

43.3

≥CR: 81.8%

59.6

42.4

9.1

7.2 6.2

18.6 25.8

18.6

13.4

8.2

7.2

End of induction

End of ASCT

End of consolidation

12-months-ofmaintenance cutoff

RVd

• Results for end of induction, ASCT, and consolidation are based on a median follow up of 13.5 months at the primary analysis • Median follow up at 12-months-of-maintenance therapy cutoff was 27.4 months

Response rates and depths were greater for D-RVd at all time points PR, partial response. SD/PD/NE, stable disease/progressive disease/not evaluable. aData are shown for the response-evaluable population. bP values (2-sided) were calculated using the Cochran–Mantel–Haenszel chi-square test.

PFS and OS in the ITT Population •

Median follow-up = 27.4 months 12-month PFS ratea 96.9% 94.0% 80

94.5%

D-RVd

90.8%

40 20 0

97.9%

RVd

99.0%

100 80

% surviving

% surviving without progression

100

12-month OS ratea

24-month PFS ratea

24-month OS ratea 94.7%

RVd

93.3%

D-RVd

60 40 20

9 12 15 18 21 24 27 30 33 36 Months

No. at risk RVd 103 93 77 71 68 66 62 60 52 23 D-RVd 104 98 93 89 89 88 86 86 66 32

7 9

0 2

0 0

9 12 15 18 21 24 27 30 33 36 Months

No. at risk RVd 103 101 98 95 89 87 84 81 67 46 14 D-RVd 104 100 98 98 96 95 93 91 85 61 23

2 6

0 0

Median PFS and OS were not reached for D-RVd and RVd OS, overall survival. aKaplan‒Meier estimate.

MASTER: Phase 2 Study of Dara-KRd in TEMM

MRD assessment by NGS

Consolidation

Dara-KRd x 4

2nd MRD (-) (<10-5)

MRD→

Consolidation

MRD→

Dara-KRd x 4

AHCT

MRD→

Induction

Lenalidomide Maintenance

2nd MRD (-) (<10-5)

Treatment-free observation and MRD surveillance*

Dara-Based Quads: Depth of Response N

Post-Induction

Post-ASCT

Post-Consolidation

sCR

≥VGPR

sCR

≥VGPR

sCR

≥VGPR

MRD-

VTd

542

6.5%

56.1%

9.4%

67.4%

20.3%

78.0%

43%

D-VTd

542

7.4%

64.9%

13.4%

76.7%

28.9%

83.4%

62%

RVd

103

7.2%

56.7%

14.4%

66.0%

32.0%

72.9%

20.4%

D-RVd

104

12.1%

71.7%

21.2%

86.9%

42.4%

90.9%

51.0%

D-KRd

39%

91%

81%

100%

95%

100%

82%

Costa L, et al. ASH 2019. Moreau, P et al. Lancet 2019;394:29-38. Voorhees P, et al. ASH 2019.

Transplant Eligible Key Questions: 1. Is Transplant still necessary? YES, it seems that it still helps with DEPTH and DURATION of response 2. What is the triplet combination? (VRD or KRD) Both are legitimate, we tend to use VRD more but KRD in certain patients 3. Should we switch to quadruplet combinations? (D-VRD, D-KRD or I-VRD, I-KRD) It is still early, but is clearly promising and will come soon…

Transplant Ineligible • Key Questions: 1. Are triplets better than Doublets? (VRD vs RD and DRD vs RD) 2. How long should patients be treated? 3. How can we make these combinations more tolerable?

VRd vs Rd: SWOG S0777 Data

3-Drug Regimen as Initial Induction Treatment-naive MM without intent for immediate ASCT* (N = 525)

VRd†: Bortezomib Lenalidomide Dexamethasone (n = 264)

Rd Primary endpoint: PFS

Eight 21-day cycles

Rd: Lenalidomide Dexamethasone (n = 261)

Stratifications: ISS; intent to transplant at progression

Rd Len: 25 mg PO Until progression

Six 28-day cycles

VRd

HR; P Value

Median PFS, mo

0.712; .0018 (1sided)

Median OS, mo

0.709; .025 (2-sided)

VRd showed better PFS in patients with high- or standard-risk vs Rd‡

• • •

*All patients received aspirin (325 mg/d). †Patients received HSV prophylaxis. ‡High-risk cytogenetics included: t(4;14), t(14;16), or del(17p); preliminary data from 316 patients. Durie BG, et al. Lancet. 2017;389:519-527.

Overall Survival By Assigned Treatment Arm 100%

|| |

| |

80%

| |

OS (%)

|| | || |

60%

|||

|||||||||| ||| ||||||||| |||| ||||||||| |||||||| ||||||||||||||| ||| ||| |

40%

20%

Rd VRd

Deaths / N 125/225 102/235 *P-value = 0.0114

|||||||| | ||| ||||||||| || || |||| |||||||| | ||| || || |

||| || || |||||||||| |||||| || || | ||||||||| |||||| | | || | |||| ||| |

Median in Months 68.90 (58.41, 86.18) . (79.90, . )

225 (0) 209 (1) 189 (3) 166 (3) 144 (4) 123 (5) 97 (15) 53 (51) 25 (76) 235 (0) 220 (2) 204 (3) 194 (4) 172 (7) 155 (9) 125 (20) 60 (76) 26 (107) 24

| ||||||||| ||| | | | | | ||| |

Months from Registration

Durie BG, et al. Blood. 2015;126: Abstract 25. Durie BG, et al. Lancet. 2016 Dec 22 [Epub ahead of print].

VRD is a Standard of Care in Myeloma for Both Eligible and Ineligible Patients • However, the regimen is limited by the shorter use of bortezomib – Study design called for 8 cycles but median was 6 cycles – Most common cause of discontinuation was neuropathy

• Mounting evidence supports continuous therapy in transplant ineligible patients • It would be ideal if we could combine effective and well tolerated agents to treat with a combination for longer… • There is also a need to consider alternatives when patients have pre-existing neuropathy

The ENDURANCE Trial Multicenter, randomized (1:1), open-label, phase 3 study (N = 1087)

VRd

Key Eligibility Criteria Standard risk disease

R A N D O M I Z E 1

Twelve 21-day cycles = 36 weeks V 1.3 mg/m2 IV/SC days 1, 4, 8 and 11 of cycles 1 – 8, days 1 and 8 of cycles 9 – 12 R days 1-21 cycles 1 – 14 d days 1, 2, 4, 5, 8, 9, 11 and 12 cycles 1 – 8, days 1, 2, 8 and 9 of cycles 9 – 12

KRd

Nine 28-day cycles = 36 weeks K 27 mg/m2 days 1, 2, 8, 9, 15 and 16 R days 1-21 d days 1, 8, 15 and 22

ClinicalTrials.gov identifier: NCT01863550

R A N D O M I Z E 2

4-week cycles x 24 Len days 1 – 21

4-week cycles until PD or unacceptable Toxicity Len days 1 – 21

1o Endpoint #1 • PFS 1o Endpoint #2 • OS

ENDURANCE: PFS

Progression-Free Survival (%)

100

• 2nd interim analysis of PFS (Jan 2020): 298 PFS events (75% of 399 planned)

• Median (95% CI) estimated follow up of 15 (13-18) months • For patients >/= 70 years, median PFS(95% CI) for VRd = 37 (29-NE) and KRd = 28 (24-36) months

Median (95% CI) PFS: VRd=34·4 (30·1-NE); KRd=34·6 (28·8-37·8) months HR (KRd/VRd) = 1·04 (95% CI, 0·83-1·31); P=0·742

0 0

Time from Randomization (Months) KRd VRd

545 542

401 377

252 243

187 183

Numbers at Risk 127 83 59 114 73 43

38 31

Kumar, S, et al. ASCO 2020.

25 26

13 14

3 0

• With censoring at SCT or alternative therapy: Median PFS (95% CI) for VRd = 31·7 (28·5-44·6) and KRd = 32·8 (27·2-37·5) months

MAIA – DRD vs RD Study Design ‒

Patients were enrolled in MAIA from March 2015 through January 2017

Key eligibility criteria • TIE NDMM • ECOG PS score 0-2 • CrCl ≥30 mL/min

1:1 randomisation

D-Rd

D: 16 mg/kg IV QW Cycles 1-2, Q2W Cycles 3-6, then Q4W thereafter until PD R: 25 mg PO Days 1-21 until PD da: 40 mgb PO or IV Days 1, 8, 15, 22 until PD

R: 25 mg PO Days 1-21 until PD d: 40 mg PO Days 1, 8, 15, 22 until PD

End-oftreatment visit (30 days after last dose)

Primary endpoint • PFS Longterm follow-up

Key secondary endpoints • OS • PFS2 • ORR • CR/sCR rate • MRD (NGS; 10–5)

Cycles: 28 days

MAIA is a multicentre, randomised, open-label, active-controlled, phase 3 study of D-Rd versus Rd alone in patients with NDMM who are transplant ineligible TIE, transplant-ineligible; ECOG PS, Eastern Cooperative Oncology Group performance status; CrCl, creatinine clearance; IV, intravenous; QW, once weekly; Q2W, once every 2 weeks; Q4W, once every 4 weeks; PD, progressive disease; PO, oral; ORR, overall response rate; CR, complete response; sCR, stringent complete response; MRD, minimal residual disease; NGS, next-generation sequencing; BMI, body mass index. aOn days when DARA is administered, dexamethasone will be administered to patients in the D-Rd arm and will serve as the treatment dose of steroid for that day, as well as the required pre-infusion medication. bFor patients >75 years of age or with BMI <18.5 kg/m2, dexamethasone was administered at a dose of 20 mg QW.

Updated PFS (progression free survival) 60-month PFS rate % surviving without progression

100 80 52.5%

D-Rd: median, NR

28.7%

Rd: median, 34.4 months 20 0

HR, 0.53; 95% CI, 0.43-0.66; P <0.0001 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66 69 Months

No. at risk Rd 369 333 307 280 255 237 220 205 196 179 172 155 146 133 123 113 105 94 63 36 12 4 D-Rd 368 347 335 320 309 300 290 276 266 256 246 237 232 222 210 199 195 170 123 87 51 17

2 5

0 0

• D-Rd continued to demonstrate a significant PFS benefit, with median PFS not reached with D-Rd • These data provide a new PFS benchmark in patients with NDMM who are transplant ineligible NR, not reached; CI, confidence interval.

Overall Survival 60-month OS rate 100

% surviving

66.3% D-Rd: median, NR

53.1%

Rd: median, NR

40 20 0

HR, 0.68; 95% CI, 0.53-0.86; P = 0.0013 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66 69 72 Months

No. at risk Rd 369 351 343 336 324 317 308 300 294 281 270 258 251 241 232 223 213 183 134 85 42 14 5 D-Rd 368 350 346 344 338 334 328 316 305 302 297 286 280 273 266 255 249 228 170 118 63 22 6

1 1

0 0

D-Rd demonstrated a significant benefit in OS, with a 32% reduction in the risk of death, in patients with NDMM who are transplant ineligible

Transplant Ineligible • Key Questions: 1. Are triplets better than Doublets? (VRD vs RD and DRD vs RD) YES, this has been a consistent trend, but it has to be matched to the patient as some may still receive a doublet 2. How long should patients be treated? In general, the longer the better – but hopefully we will develop stopping rules in the future 3. How can we make these combinations more tolerable? Using drugs that impair quality life LESS is critical…

Conclusions in Transplant Ineligible Patients • There is more overlap than ever between therapies for transplant eligible and transplant ineligible patients • Although ASCT remains the standard of care, use is likely to decline in patients who are 65-75 or with significant comorbidities • Continuous therapy has resulted in better outcomes • The balance of toxicity and efficacy is particularly important in this population • My approach is to select 2 agents from the 3 Novel Classes (PIs, IMiDs and MoAbs) – I favor DRD in standard risk patients – I favor VRD in high risk patients

• DRD is more easily delivered and feasible • D-VRD may well be a future standard of care

Pillars of Myeloma Treatments • Doxorubicin, Panobinostat, Steroids

Belantamab mafodotin

Bispecific T Cell Engagers? Proteasome Inhibitors

Immunomodulatory

Bortezomib Carfilzomib Ixazomib

Thalidomide Lenalidomide Pomalidomide

Selinexor Monoclonal Antibodies Daratumumab Elotuzumab

• Others?

• Steroids • Elotuzumab

Isatuximab

CAR T Cell Therapy

Alkylators Melphalan, Cyclophosphamide Melphalan flufenamide

• Other Conventional Chemo (Bendamustine, DPACE…)

CAR, chimeric antigen receptor; DPACE, dexamethasone, cisplatin, doxorubicin, cyclophosphamide; etoposide

Options of Therapy for Myeloma – Current Induction therapy

ASCT eligible

Bortezomib-Lenalidomide-Dex OR Carfilzomib-Lenalidomide-Dex

OR Daratumumab-Lenalidomide-dexamethasone

ASCT (melphalan)

OR Doublets (rarely)

Lenalidomide Maintenance First relapse

Second Relapse

Third+ Relapse

non-ASCT eligible Bortezomib-Lenalidomide-Dex

Lenalidomide Maintenance

Daratumumab-Pomalidomide-Dex Daratumumab-Carfilzomib-Dex Daratumumab-Lenalidomide-Dex Daratumumab-Bortezomib-Dex Isatuximab-Pomalidomide-Dex Selinexor-Bortezomib-Dex Isatuximab-Carfilzomib-Dex Carfilzomib Based Combination – Pomalidomide or Cyclophosphamide Pomalidomide Based Combination – Isatuximab or Elotuzumab Selinexor-Dex Belantamab mafodotin Melphalan-Flufenamide CAR T Cell Therapy

ASCT, autologous stem cell transplant; CAR, chimeric antigen receptor

Options of Therapy for Myeloma – Current Induction therapy

ASCT eligible Daratumumab or Isatuximab + Bortezomib-Lenalidomide-Dex OR Carfilzomib-Lenalidomide-Dex CAR T Cell?

First relapse

Second Relapse

Third+ Relapse

non-ASCT eligible Bortezomib-Lenalidomide-Dex OR Daratumumab-Lenalidomide-dexamethasone

ASCT (melphalan)

OR Doublets (rarely)

Lenalidomide Maintenance

CAR T Cell? Bispecific Antibodies? Other combos with Selinexor Belantamab

Lenalidomide Maintenance

Daratumumab-Pomalidomide-Dex Daratumumab-Carfilzomib-Dex Daratumumab-Lenalidomide-Dex Daratumumab-Bortezomib-Dex Isatuximab-Pomalidomide-Dex Selinexor-Bortezomib-Dex Isatuximab-Carfilzomib-Dex

Carfilzomib Based Combination – Pomalidomide or Cyclophosphamide Pomalidomide Based Combination – Isatuximab or Elotuzumab Selinexor-Dex Belantamab mafodotin Melphalan-Flufenamide CAR T Cell Therapy

ASCT, autologous stem cell transplant; CAR, chimeric antigen receptor

The Evolution of Myeloma Therapy

Now

VD Rev/Dex CyBorD VTD VRD SCT KRD Tandem ASCT (?) D-VMP DRD Front line treatment

Induction

New

D-VRD Isa-VRD D-KRD Isa-VRD

Nothing Thalidomide? Bortezomib Ixazomib Lenalidomide Combinations Maintenance

Consolidation

Post consolidation

“more” induction?

Daratumumab? Carfilzomib? Lenalidomide + PI

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

Panobinostat Bortezomib Lenalidomide Daratumumab Ixazomib Carfilzomib Pomalidomide Elotuzumab Isatuximab Selinexor Belantamab mafodotin Melphalan flufenamide CAR T Cell Therapy Relapsed

Rescue

Bispecific/Trispecific Antibodies Cell Modifying Agents Venetoclax? PD/PDL-1 Inhibition? Multiple small molecules ++++++++

IMF Global Presence Primary Goal is to cure Myeloma Imaging

Iceland Early disease Full sequencing

Mayo

Central Platform

Pipeline trials

ACCESS to Novel Agents worldwide

CLIA lab NGF

Cure Trial

Germany

Retrospective studies

Spain Immune monitoring

NEWLY CREATED LATIN AMERICAN MYELOMA NETWORK!

Family Studies

Asian Trials Network Blood monitoring

Singapore

Single cell resistance analyses Blood DNA mutational analyses Clinical trial assessment

Patients Providers Countries Industry Myeloma Community

Centralized NGF/risk assessment

Australia

THANK YOU! Joseph Mikhael, MD, MEd, FRCPC Professor, Translational Genomics Research Institute (TGen) City of Hope Cancer Center Chief Medical Officer, International Myeloma Foundation Director of Myeloma Research and Consultant Hematologist, HonorHealth Research Institute jmikhael@myeloma.org

Audience Q&A with Panel

• Open the Q&A window, allowing you to ask questions to the host and panelists. They can either reply to you via text in the Q&A window or answer your question live. • If the host answers live, you may see a notification in the Q&A window. • If the host replies via the Q&A box – you will see a reply in the Q&A window.

We will begin with a 5-minute mindful meditation and then go into a 5-minute break For more guided audio and video meditations, and guided yoga, please visit our website: https://wellness.myeloma.org/mind-body/ Meditation is led by Kelley Sidorowicz, IMF Regional Director, Support Groups

Welcome Back!

Agenda After the Break Relapsed Therapy and Clinical Trials Ciara Freeman, MD, Moffitt Cancer Center, Tampa FL How to Manage Myeloma Symptoms and Side Effects Kathy Colson, RN, BSN, BS, IMF Nurse Leadership Board

Relapsed Therapy and Clinical Trials Ciara Freeman, MD, Moffitt Cancer Center, Tampa FL 67

IMF Regional Community Workshop Tampa November 20, 2021 Management of relapsed Multiple Myeloma & Clinical Trials: The Future is BRIGHT!

Dr Ciara Freeman, MD PhD MSc Moffitt Cancer Center Tampa. FL

MMWG Moffitt Myeloma Working Group

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 open here in Tampa MMWG Moffitt Myeloma Working Group

What is relapsed/refractory disease? • Relapsed: recurrence after a response to therapy • Refractory: progression despite ongoing therapy

MMWG Moffitt Myeloma Working Group

Pathway for the treatment of transplant eligible NDMM. NDMM

Transplant eligible: Stem Cell Collection

Induction

HDM-ASCT Maintenance

Until progression or toxicity

x6 (4-8) cycles

Induction x8-12 cycles (Collection and storage of stem cells should be attempted as above)

Transplant ineligible: Dara plus+ (DRd, DVd) or RVD-lite or CYBORD Most until tox or prog MMWG Moffitt Myeloma Working Group

71 71

Available Anti-Myeloma Agents: So Many Choices! IMiDs Thalomid (thalidomide)

Chemotherapy AnthraChemotherapy Proteasome cyclines Alkylators Inhibitors Velcade (bortezomib)

Revlimid (lenalidomide)

Kyprolis (carfilzomib)

Pomalyst (pomalidomide)

Ninlaro (ixazomib)

Adriamycin

Doxil (liposomal doxorubicin)

Steroids

Cytoxan (cyclophosphamide Dexamethasone ) Bendamustine

Melphalan

MMWG Moffitt Myeloma Working Group

Prednisone

mAbs Empliciti (elotuzumab) Darzalex (daratumumab) Sarclisa (isatuximab)

HDAC Inhibitors

Newer

XPO1 inhibitor Farydak (Xpovio/Selinex (panobinostat) or) Zolinza (vorinostat)

BCMA-targeting antibody drug conjugate (Belanatamab mafodotin) BCMA CAR-T cells (ide-cel

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

MMWG Moffitt Myeloma Working Group

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

Multiple combinations possible So Many Choices! Pomalidomide

Carfilzomib

Daratumumab

Elotuzumab

Ixazomib

Panobinostat

Dara Pom D

Dara

Elo RD

Ixa

Pano VD

Car Pom D

KRD

Dara Pom

Elo PomD

Ixa Dex

Car Pano Dex

Ixa Pom Dex

K Cy Dex

Dara Len

Elo BortD

IRD

Len Pano

Bort Pom Dex

K Dara Dex

Dara Bort

Elo Pom Dex

Car Pano

Dara Carfil

Ixa Pom Dex

Pom Cy Dex

MMWG Moffitt Myeloma Working Group

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

MMWG Moffitt Myeloma Working Group

OR- a more personalized approach – EMMA Translating Ex vivo drug screening to direct clinical utility.

0.5-2 million CD138Selected cells

31-127 drugs simultaneously

31-127 in silico clinical trials -simultaneously

Figure X. Ex vivo Mathematical Malignancy Advisor (EMMA) facilitates testing of 31-127 drugs or drug combinations in myeloma patient specimens in the context of the tumor microenvironment.

Khin et al Cancer Res 2015; Silva et al Cancer Res 2017; Zhao et al Nat Comm 2017

MMWG Moffitt Myeloma Working Group

Options at First Relapse

MMWG Moffitt Myeloma Working Group

Some commonly used players 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)

• And probably some dexamethasone. • It’s like parsley.

Beyond the treatment itself… Proteasome Inhibitors

Monoclonal Antibodies

IMiDs

HDAC Inhibitors

• Peripheral neuropathy occurs less often when subcutaneous or once-weekly dosing is used for Velcade • Other peripheral neuropathy prevention: − Vitamins and other supplements* − Certain medications such as gabapentin, pregabalin, duloxetine, opioids (methadone) − Acupuncture − Physical therapy − Shingles-prevention pills − Blood thinners

• Blood thinners • L-glutamine for cramps • GI toxicity: avoid dairy; fibers (Metamucil); Imodium; colestipol; cholestyramine; dose reduction • Sleep hygiene, regular exercise, dose reduction for fatigue

• Pre- and post-medication for infusion reactions • Antibiotic prophylaxis (levoflox or septra) for some

• Anti-diarrheal medication • Baseline EKG prior to starting medication

How Do We Define & Measure Success? • Goals of therapy 1. 2. 3. 4.

Improve symptoms Prevent complications Improve survival ? Functional cure

MMWG Moffitt Myeloma Working Group

Depth of Response and Outcome in MM

MMWG Moffitt Myeloma Working Group

Options at Second Relapse and Beyond

MMWG Moffitt Myeloma Working Group

Relapsed MM Management. Phase III (& II†) trials have helped to define salvage therapy for RRMM: -1-3 prior lines:         

ASPIRE: TOURMALINE: ELOQUENT-2: CASTOR: POLLUX: OPTIMISMM: CANDOR: Bellini: LYNX:

- “>3” prior lines: KRd vs Rd IRd vs Rd ERd vs Rd DVd vs Vd DRd vs Rd PVd vs Vd DKd56 vs Kd56 VenVd vs Vd D(sq)Kd vs Kd* (*prior IV Dara)

 ENDEAVOR:  ARROW:

 ELOQUENT-3†:  ICARIA:

EPd vs Pd IsaPd vs Pd

 DREAMM-1:

BM**

 DREAMM-3:  STORM†:  STOMP†:  CC-220†:  Melflufen:

(**Belantamab mafodotin)

BM** vs Pd XpD (Seli) PXpD, DXpD Iber/dex

Kd56 vs Vd Kd qw vs Kd 2x/wkz

What about the newer kids on the block? ADCs/Seli/CARs

Antibody-Drug Conjugates (ADCs) in MM ADCs can selectively target and deliver drugs to myeloma cells – Belantamab Mafodotin

2 Endocytosis

Components • Antibody • Stable linker • Toxin

1 Binding

MMWG Moffitt Myeloma Working Group

BCMA 3 Lysosomal degradation

BCMA ADC conjugate

Myeloma cell 4 Toxin activation  cell death

Myeloma cell dying

Small molecule inhibitors of nuclear export (SINE) • Selinexor (XPOVIO) --> XPO1 inhibitor • Theodoropoulos et al Oncology, 2020. 15(6): p. 697-708.

MMWG Moffitt Myeloma Working Group

RRMM: Triple class refractory and penta-refractory MM are characterized by poor outcomes. MAMMOTH study Next line of Tx:

New approvals in triple class refractory:

ORR: Triple class refractory: 31% Penta refractory: 30% Median PFS: Triple class refractory: 3.4 mo Median OS: Triple class refractory: 9.3 mo Penta refractory: 5.6

Selixenor/ Dex* Belantamab mafodotin Melphalan flufenamide

ORR

mPFS (mo)

mOS (mo)

26%

3.7

8.6

2.8

13.5

4.2

11.2

31% 26%

*approved for penta refractory patients.

Monoclonal Antibodies in Multiple Myeloma: Outcomes after Therapy Failure the MAMMOTH study Gandhi et al Leukemia 2019; Chari et al NEJM 2019; Lonial Lancet Onc 2020; Lonial et al ASCO abt 436; Richardon et al JCO 2021

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

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

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

Ide-cel (Abecma): ORR 73%, ≥ 33% CR+sCR

Overall Minimal Residual Disease (MRD) negative: 26% ORR: Overall Response Rate, ≥ Partial Response Munshi NC et al. NEJM 2021; 384 (8): 705-716

MMWG Moffitt Myeloma Working Group

 ... And Abecma is born!!!

Median follow-up: 24.8 months  FDA Approval on March 26, 2021

Dose, x  10^6 CAR-T cells

First gene 450cell-based (N=54) Totaltherapy (N=128)for the CRtreatment Patients of R/R MM

 Median DOR: 21.5 mo  Progression on/after > 4 lines of therapy including an immunomodulatory agent, a proteasome an anti-CD38 monoclonal antibody ORR 44 (81%) inhibitor, 94and (73%)  Median PFS: 22.4 mo

21 (39%) 42 (33%) CR/sCR Manufacturing limitations: facilities must be Responses cleared byinFDA andtolow supply for difficult treat patients the Abecma gene vector, which has strict specifications Median DOR

11.3

Median PFS

12.2

10.9

 High tumor burden, ORR: 71%

 Moffitt has had more manufacturing slots than other center to ORR: date 70%  Extramedullary disease, 8.6

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 MMWG Moffitt Myeloma Working Group

 R-ISS-III, ORR: 48%

One approved – more to come! Common Observations of CAR T-Cell Therapy Studies

All patients were very heavily pretreated, with some having received on average at least 6 prior therapies. Many patients on the trials were considered tripleclass refractory.

All have similar side effects, causing cytokine release syndrome (CRS), neurotoxicity, and low blood counts, but all at varying degrees.

Most patients respond very well to treatment, but also to varying degrees.

Clinical Trials as an Option

• ALWAYS ask your doctor whether a clinical trial is potentially available • Promising therapies in development – Venetoclax* – BITEs – Other CAR-T cell therapies – Many, many others….

• www.clinicaltrials.gov • Myeloma Matrix 2.0 MMWG Moffitt Myeloma Working Group

*FDA

approved for a non-MM indication therapy not yet FDA approved

†Experimental

Bispecific Antibodies and Bispecific T-Cell Engagers (BiTEs) Bispecific antibody

Bispecific antibodies can target two cell surface proteins at the same time

Bispecific T-cell engager (BiTE)

BCMA-bispecific antibody

BCMA-bispecific T-cell engager

T cell

CD3

BCMA Myeloma cell

T cell

T cell toxin

Adapted from Cho S-F et al. Front Immunol. 2018;9:1821.

BCMA Myeloma cell T cell toxin

Myeloma cell dying

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

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

MMWG Moffitt Myeloma Working Group

100

A snapshot of MM Clinical Trials at Moffitt •

High risk smoldering myeloma: –

•

Newly Diagnosed MM – –

•

ASCENT Dara+KRD for high risk smoldering Phase 2: daratumumab based response adapted therapy for older adults with NDMM Phase 2: KARMMA 4 for HR MM (coming soon)

HDM-ASCT and maintenance – – –

Phase 1: HDM-ASCT + Selinexor Phase 1-2: Panobinostat maintenance (enrollment complete). Phase 3: Lenalidomide daratumumab vs lenalidomide maintenance

• Cellular Immunotherapy: – –

•

Phase 1: NY-ESO & MAGE A3 TCR cell therapy Phase 1-3: BCMA CAR-T - Bluebirds and CARSGEN

Relapsed and/or Refractory MM: – – – – – –

MMWG

Phase 2: Elotuzumab + Lenalidomide for patients with biochemical progression Phase 1: CB-839 a novel glutaminase inhibitor and carfilzomib Phase 1/2 : venetoclax daratumumab dex for early relapse for patients with t(11;14) MM Phase 1: A bi-specific T cell engager(Regn 5458) for RRMM Phase ½: CC92480 a novel cell mod (IMID) in various combination (coming soon) Phase 1: Ixazomib and pevonedistat for RRMM Moffitt Myeloma Working Group

101

Can early detection and interception be adopted in MM? The PROMISE study: 1. To determine the prevalence of MGUS in a high-risk population

2. Determine clinical/genomic alterations present in these high- risk individuals

3. Determine clinical genomic and

immune predictors of progression from MGUS to MM

https://www.enroll.promisestudy.org/ Adapted from Irene Ghobrial

MMWG Moffitt Myeloma Working Group

102

PROMISE: Nation wide study of MM screening and prevention Genetics and Genomics

Screen 30,000 High-Risk Individuals

Viktor Adalsteinsson

Gad Getz

Develop novel biomarkers for diagnosis

Irene Ghobrial

Epidemiology

Tim Rebbeck

Screen Negative 26,100

Screen Positive 3,900

Accept Prospective Terms Follow-Up

Catherine Marinac Bone Marrow Niche

Lorelei Mucci

Ivan Borrello

Establish new risk stratification tools

Irene Ghobrial

Generate new tools to prevent Receive Schedule Imaging and Therapeutics Receive disease progression Blood Kit Blood Draw Results

Jeremiah Johnson

Irene Ghobrial

Adapted from Irene Ghobrial MMWG Moffitt Myeloma Workinghttps://www.enroll.promisestudy.org/ Group

103

In summary, tools are multiplying! Survival is improving

Nishida, H. Cancers, 2021. 13(11): p. 2712.

MMWG Moffitt Myeloma Working Group

104

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….

MMWG Moffitt Myeloma Working Group

105

Acknowledgments: Our Patients, their families, and care-givers MMWG: Beth Finley-Oliver Melissa Alsina M.D. Christine Simonelli Rachid Baz M.D. Latoya Washington Jason Brayer M.D., Ph.D Samantha Seitzler Brandon Blue M.D. Leslie Lauersdorf William S Dalton Ph.D, M.D. Taiga Nishihori M.D. Hien Liu M.D. Doris Hansen M.D. Lionel Ochoa-Bayona M.D. Dr Kenneth Shain, M.D PhD Omar Castaneda Puglianini, M.D. Dr Frederick Locke, M.D Dr Marco D’Avila, M.D. PhD Chris Cubitt Ph.D. John Koomen Ph.D. Ariosto Silva PH.D Dung-Tsa Chen Ph.D. John Cleveland Ph.D

MMWG Moffitt Myeloma Working Group

Elyce Turba Mark Melody Sabrina Hasan Anna Niebrzydowski Alicin Roop Ann Nelson

Gabrial De Avilla Raghu Alugubelli

106

107

How to Manage Myeloma Symptoms and Side Effects

Kathy Colson, RN, BSN, BS, IMF Nurse Leadership Board

108

Be the Commander of Your Galactic Journey: Navigating the Journey Kathleen Colson, RN, BSN, BS Dana-Farber Cancer Institute Regional Community Workshop November 20, 2021

Patient Education Slides 2021

You are in the Commander’s Chair

All Crew Members are Needed for a Successful Journey

Navigating the Journey

• You and your Subspecialists

Primary Care Provider (PCP)

caregiver are the center

General Hem/Onc

• Understand the

different roles of your health care team

You and Your Caregiver(s)

Family/Support Network

Allied Health Staff

Myeloma Specialist

• Understand how they can help you

Be an Empowered Patient “Scotty, We Need More Power!”

Navigating the Journey

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

• Understand options - Use reliable sources of information - Use caution considering stories of personal experiences

• Create a dialogue • Express your goals/values/preferences • Arrive at a treatment decision together Available for download at myeloma.org 11

Preparation for Appointments in the COVID Era

Health in the COVID Era

Preparation

Appointment

Back Home

• Write down your questions and concerns including about COVID • Bring current medications and supplements • Any medical or life changes since your last visit? • Current symptoms - how have they changed?

• Remember your mask • Ask your most important questions first • Understand your treatment plan and next steps • Have a list of who to contact and when • Include a Caregiver for another “set of ears”

• Take precautions to stay healthy • Communicate with other members of your health care team (pharmacist, others) • Take your medications as directed • Follow up with members of your heath care crew

Consider Telemedicine Visits

Tune Up Health in the Your COVID Era Knowledge

• Check with your healthcare provider(s) to see if telemedicine is an option • Plan as if for an in-person appointment PLUS – Ask provider for telemedicine process (tips/info, how to make appt, if any copay needed, etc.) – Plan your labs: are they needed in advance? Do you need a script? – Plan your technology: smartphone or tablet with camera are preferred – Plan your location: strong wifi, quiet, well-lit location 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 – At the end of the visit: check future appointments (virtual or in-person), testing, medication refills

IMF Telemedicine Tip Sheet. In development.

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Infection Prevention & Treatment • Compromised immune function comes from multiple myeloma and from treatment • Good personal hygiene (skin, oral) • Environmental control (wash hands, avoid crowds and sick people, etc) • Growth factor (Neupogen [filgrastim]) • Immunizations (NO live vaccines) • Medications (antibacterial, antiviral)

Health in the COVID Era

Report fever of more than 100.4°F, shaking chills even without fever, dizziness, shortness of breath, low blood pressure to HCP as directed. Infection is serious for myeloma patients!

– New research: for patients receiving active myeloma therapy, levofloxacin 500 mg once daily for 12 weeks reduced infection (fevers, death) (ASH 2017 #903)

Brigle K, et al. CJON. 2017; 21(5)suppl:60-76.

Myeloma and Treatments Both Contribute to How You Feel

Constellation of Symptoms

Myeloma cells in excess can cause symptoms

Treatments for myeloma kill myeloma cells but can cause symptoms

• • • •

Calcium elevation Renal dysfunction Anemia Bone pain

• Fatigue • Infection • Other symptoms

Myelosuppression Peripheral neuropathy Diarrhea Fatigue

• Deep vein thrombosis • Infection (eg, shingles) • Other symptoms

How You Feel 11

What Happens if Symptoms Are Not Managed Effectively? Poorly managed symptoms can lead to... • Anxiety • Depression • Social isolation • Missed doses • Reduced treatment efficacy • Reduced quality of life

Constellation of Symptoms

Discuss how you feel with your team... • Keep a symptom diary; discuss with team • Many options but your team cannot help if they don’t know • Express your priorities – Fatigue is common concern but making the right treatment decision is higher priority for most

Faiman, B. CJON. 2017, 21(5)suppl 3-6. Faiman, B. et al 2017. Patient Reported Symptoms, Concerns and Provider Intervention in Patients with Multiple Myeloma

Steroid Side Effects and Management Steroid Side Effects • Irritability,

mood swings, depression

• Blurred vision, cataracts • Flushing/sweating

• Difficulty sleeping

• Stomach bloating,

• Increased risk of

• Weight gain, hair

(insomnia), fatigue

infections, heart disease • Muscle weakness, cramping

hiccups, heartburn, ulcers, or gas thinning/loss, skin rashes

• Increase in blood

sugar levels, diabetes

Constellation of Symptoms

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

Steroids help kill myeloma cells. Do not stop or adjust steroid doses without discussing it with your health care provider.

• Increase in blood pressure,

water retention

King T, Faiman B. CJON. 2017; 21(5)suppl:240-249. Faiman B, et al. CJON. 2008;12(3)suppl:53-63.

Fatigue, Depression, and Anxiety

Constellation of Symptoms

• All can effect quality of life and relationships • Sources include anemia, pain, reduced activity, insomnia, treatment toxicity, bone marrow suppression

Management

• Exercise (walking, yoga, etc) • Proper rest • Support (social network, support group, professional counseling, etc) • Prayer, meditation, spiritual support • Mindfulness-based stress reduction

• • • • •

Medications Massage, aroma therapy Supplements: ginseng Transfusion, if indicated Effective management of other symptoms

At least 70% of patients experience fatigue, but only 20% tell their provider. Let your provider know about symptoms that are not well controlled or thoughts of self harm. Catamero D et al. CJON. 2017; 21(5)suppl:7-18. Faiman, B. et al 2017. Patient Reported Symptoms, Concerns and Provider Intervention in Patients with Multiple Myeloma.

Peripheral Neuropathy (PN) Management • Peripheral neuropathy: damage to nerves in extremities (hands, feet, or limbs) – – – – – –

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

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

Constellation of Symptoms

• 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

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

Pain Prevention and Management

Constellation of Symptoms

• Pain can significantly compromise quality of life • Sources of pain include bone disease, neuropathy and medical procedures • Management – Prevent pain when possible • Bone strengtheners to decrease fracture risk; antiviral to prevent shingles; sedation before procedures – Intervention depends on source of pain – May include medications, activity, surgical intervention, radiation therapy, etc – Complementary and alternative medicine (supplements, acupuncture, etc)

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

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

Knowledge is Power You are not alone - IMF has many resources to help you

Website: http://myeloma.org

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Download or order at myeloma.org

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