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

Welcome and Announcements

Kelly Cox, Director Support Groups & Senior Director Regional Community Workshops 2

Thank you to our sponsors!

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Southern US REGIONAL COMMUNITY WORKSHOP Saturday October 2, 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 Siddhartha Ganguly, MD, FACP, Houston Methodist, Houston, TX 10:35 AM - Q & A with Panel 10:50 AM - Stretch Break 11:00 AM - Relapsed Therapy and Clinical Trials Rafat Abonour, MD, Indiana University School of Medicine, Indianapolis, IN 11:30 AM - Q & A with Panel 11:45 AM - How to Manage Myeloma Symptoms and Side Effects Ann McNeill, RN, MSN, APN, John Theurer Cancer Center at HMH, Hackensack, NJ IMF Nurse Leadership Board 12:05 PM - Q&A with Panel 7

Myeloma 101 and Frontline Therapy Siddhartha Ganguly, MD, FACP Houston Methodist, Houston, TX

Myeloma 101 and Frontline Therapy International Myeloma Foundation Southern Regional Community Workshop Siddhartha Ganguly, MD, FACP Section Chief, Division of Hematology Houston Methodist Hospital and Cancer Center Affiliate, Weil Cornell School of Medicine Adjunct Professor, Baylor College of Medicine Houston, TX

Multiple Myeloma: A cancer of our Immune System

Marty Feldman

Earliest Evidence of Myeloma

Sarah Newbury, the first reported patient with multiple myeloma

“The bones had a red grumous matter.” (Thick and lumpy, as clotting blood) Kyle RA, Rajkumar SV. Multiple myeloma. Blood. 2008 Mar 15;111(6):2962-72.

Myeloma Survival By Decades

Advances in Treatment of Multiple Myeloma

Diagnosis & Risk Stratification

SCT ineligible

SCT eligible

Stages of Myeloma Treatment Induction

Consolidation

Maintenance

Induction followed by continuous therapy

Tumor Burden

Treatment response and Minimal Residual Disease

Questions in Induction / Transplant • • • • • • •

2 drugs, 3 drugs or 4 drugs? Which 3 drugs – steroids + PI + IMID vs others Fourth drug if added: Monoclonal Antibody Role of transplant Maintenance After transplant Can we stop maintenance How close are we to Cure for Myeloma

SWOG 0777 Trial: Is a Three Drug Therapy (VRd) Better than Two (Rd)? Overall Survival (OS)

Progression Free Survival (PFS) 100%

Median Events/N in months VRd 137/242 43 (39, 52) Rd 166/229 30 (25, 39)

80%

Median Deaths/N in months VRd 76/242 75 (66, .) Rd 100/229 64 (56, .)

100% 80%

60%

40%

Log-rank P value = 0.0018 (one sided)* HR = 0.712 (0.560, 0.906)* *Stratified

20% 0% 0

24 48 Months from Registration

HR = 0.709 (0.516, 0.973)* Log-rank P value = 0.0250 (two sided)*

20%

*Stratified

0% 72

48 Months from Registration

• 3 drug regimens: Better responses but more/greater severity AEs (esp. neuropathy) • Clinicians should manage AEs proactively to keep patients on therapy HR = hazard ratio; Rd = lenalidomide, dexamethasone; VRd = bortizomid, lenalidomide, dexamethasone Durie B et al. ASH 2015 #25.

Daratumumab: Mechanism of Action • Human CD38 IgGκ monoclonal antibody • Direct and indirect antimyeloma activity1-5 • Depletes CD38+ immunosuppressive regulatory cells • Promotes T-cell expansion and activation5 5

1. Lammerts van Bueren J, et al. Blood. 2014;124:Abstract 3474. 2. Jansen JMH, et al. Blood. 2012;120:Abstract 2974. 3. de Weers M, et al. J Immunol. 2011;186:1840-8. 4. Overdijk MB, et al. MAbs. 2015;7:311-21. 5. Krejcik J, et al. Blood. 2016. Epub ahead of print.

MAIA Trial: Dara/Rev/Dex vs Rev/Dex

Key eligibility criteria: • Transplantineligible NDMM • ECOG 0-2 • Creatinine clearance mL/min

≥30

1:1 Randomization

D-Rd (n = 368) Daratumumab (16 mg/kg IV)a Cycles 1-2: QW Cycles 3-6: Q2W Cycles 7+: Q4W until PD R: 25 mg PO daily on Days 1-21 until PD d: 40 mgb PO or IV weekly until PD

Rd (n = 369) R: 25 mg PO daily on Days 1-21 until PD d: 40 mgb PO or IV weekly until PD

Primary endpoint: • PFS Key secondary endpointsc: • ≥CR rate • ≥VGPR rate • MRD-negative rate (NGS; 10–5) • ORR • OS • Safety

Cycle: 28 days

• Phase 3 study of D-Rd vs Rd in transplant-ineligible NDMM (N = 737)

Facon et al, ASH 2018

Facon T et al. N Engl J Med 2019;380:2104-2115

GRIFFIN (NCT02874742): Randomized D- RVD vs RVD followed by Transplant

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

1:1 Randomization

Key eligibility criteria:

Induction: Cycles 1-4

Consolidation: Cycles 5-6c

Maintenance: Cycles 7-32d

D-RVd

D-R

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

T R A N S P L A N T

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

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 Cycle 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 Cycle 10+

21-day cycles

28-day cycles

21-day cycles

Stem cell mobilization with GCSF ± plerixaforb

Endpoints & statistical assumptions Primary endpoint: sCR (by end of consolidation); 1-sided alpha of 0.1 80% power to detect 15% improvement (50% vs 35%), N = 200

Secondary endpoints: MRD (NGS 10–5), CR, ORR, ≥VGPR

Primary Endpoint: sCR by the End of Consolidationa •

Post-consolidation depth of responsea

Primary endpoint met at pre-set 1-sided alpha of 0.1 

sCR by end of consolidation − 42.4% D-RVd vs 32.0% RVd

60 50 40

80 70 60 50

42.4

32.0

20 10 0

D-RVd (n = 99)

RVd (n = 97)

≥CR: 51.5% ≥VGPR: 90.9%

42.4

9.1

40 30

ORR = 91.8%

sCR: 1-sided P = 0.068b

sCR

ORR = 99.0%

100

Patients (%)

ORR: 2-sided P = 0.0160b

− Odds ratio, 1.57; 95% CI, 0.87-2.82; 1-sided P = 0.068b 100 90

VGPR

39.4 8.1 D-RVd (n = 99)

sCR: 1-sided P = 0.068b

32.0 10.3 30.9

18.6 RVd (n = 97)

PR, partial response. aIncluded patients in the response-evaluable population (all randomized patients with a confirmed diagnoses of MM, measurable disease at baseline, received ≥1 dose of study treatment, and had ≥1 post-baseline disease assessment). bP values were calculated with the use of the Cochran–Mantel–Haenszel chi-square test. A 1-sided P value is reported for sCR; for all other responses, 2-sided P values not adjusted for multiplicity are reported.

≥CR: 42.3% ≥VGPR: 73.2%

Continuous Rd Len + LoDex Lenalidomide 25 mg Days 1-21/28 LoDex 40 mg Days 1, 8, 15, 22/28

N = 1623 Randomized 1:1:1

Rd18 Len + LoDex Lenalidomide 25 mg Days 1-21/28 LoDex 40 mg Days 1, 8, 15, 22/28

18 cycles (72 wks)

MPT Mel + Pred + Thal 12 cycles Melphalan 0.25 mg/kg Days 1-4/42 Prednisone 2 mg/kg Days 1-4/42 Thalidomide 200 mg Days 1-42/42

12 cycles (72 wks)

•

Primary endpoint: PFS of continuous Rd vs MPT

•

Secondary endpoints: OS, response, DoR, TTR, TTF, time to second-line therapy, QoL, safety

Benboubker L, et al. N Engl J Med. 2014;371:906-917.

Until disease progression

RD (continuous or 18 ms) vs. MPT

Benboubker et al, N Engl J Med 2014;371:906-17.

Autologous Transplantation Improves Progression Free Survival Even in the Era of Novel Drugs

EMN02/HO95 MM Trial: Study Design

Adult pts 18 - 65 yrs with symptomatic, newly diagnosed MM (N = 1192)

CTX 2-4 g/m2 + G-CSF + PBSC collection

VMP x 4, 42-day cycles: V: 1.3 mg/m2 Days 1, 4, 8, 11, 22, 25, 29, 32 M: 9 mg/m2 Days 1-4 P: 60 mg/m2 Days 1-4 (n = 497)

HDM x 1-2 courses: M: 100 mg/m2 + Single (n = 488) or double (n = 207) ASCT (n = 695)

Randomization 2

Induction: VCD* x 3-4 21-day cycles

Randomization 1

1:1 (centers with single ASCT policy) 1:1:1 (centers with double ASCT policy) Stratified by ISS I vs II vs III

VRD† x 2, 28-day cycles consolidation therapy Lenalidomide 10 mg daily Days 1-21/28 No consolidation therapy

*Bortezomib 1.3 mg/m2 twice weekly, cyclophosphamide 500 mg/m2 Days 1-8, dexamethasone 40 mg day of and day after bortezomib. †Bortezomib 1.3 mg/m2 twice weekly, lenalidomide 25 mg Days 1-21, dexamethasone 20 mg Days 1, 2, 4, 5, 8, 9, 11, 12.

• •

Primary endpoint: PFS from R1 and R2 Secondary endpoints: response, OS from R1 and R2, toxicity, QoL

Cavo M, et al. ASCO 2016. Abstract 8000.

Slide credit: clinicaloptions.com

EMN02/HO95 MM Trial: Efficacy Outcome

HR (95% CI; P Value)

VMP

ASCT

Overall population, n  Median, mos  3 yr, %

497 44 57.5

695 NR 66.1

Standard-risk cytogenetics, n  Median, mos  3 yr, %

220 46 69.6

290 NR 76.6

0.68 (0.47-0.98; .034)

High-risk cytogenetics, n

181 32 43.2

292 42 55.2

0.69 (0.52-0.92; .010)

(n = 451)

(n = 641)

73.8

85.5

< .001

PFS

 Median, mos  3 yr, % Response  VGPR or better, %

0.73 (0.59-0.90; .003)

• Median follow-up: 26 mos (range: 19-37 mos) Cavo M, et al. ASCO 2016. Abstract 8000.

Slide credit: clinicaloptions.com

EMN02/HO95 MM Trial: Conclusions • Upfront ASCT significantly prolonged PFS vs VMP in pts with newly diagnosed MM – Benefit seen in overall population and in high- and low-risk cytogenetic subgroups • Upfront ASCT significantly improved response (VGPR or better) vs VMP • In the era of novel agent-based therapy, upfront HDM and ASCT remains a standard of care for younger, fit pts with newly diagnosed MM Cavo M, et al. ASCO 2016. Abstract 8000.

Slide credit: clinicaloptions.com

Early versus Delayed Transplant

“My doctor told me my Myeloma is in good remission.

Should I go for transplant now, or Harvest and Hold Stem Cells and consider transplant only when the disease progresses?”

IFM/DFCI 2009 Phase 3 Study Newly Diagnosed MM (aHCT candidates; n= 1000) Randomize RVD x 3

Induction

RVD x 3

CY (3g/m2) MOBILIZATION

Collection

CY (3g/m2) MOBILIZATION

Goal: 5 x106 cells/kg

Melphalan 200mg/m2 + ASCT RVD x 2 Lenalidomide

Goal: 5 x106 cells/kg

Consolidation

RVD x 5

Maintenance IFM: for 1 year USA: until progression

Lenalidomide

USA group will increase to 660 patients from 300, IFM at700 RVD=Lenalidomide, Bortezomib, Dexamethasone. Cy=Cyclophosphamide, Courtesy P Richardson

SCT at relapse

IFM 2009: PFS (9/2015) Median 4 y FU 10 0

HDT

no H D T

P a tie n t s ( % )

80 70 60 P < 0 .0 0 1

50 40 30 20 10 0 0

15 3 12 8

27 24

M o n th s o f f o llo w - u p N a t ris k HDT no H D T

35 0 35 0

309 296

2 61 2 28

Attal M. et al

IFM 2009: Conclusions • This second interim analysis demonstrates that transplantation : – Is associated with an acceptable Transplant Related Mortality: 1.4%. – Is associated with an improved 4-year PFS (47% vs 35%, p<0.001). • A longer follow up is required to draw conclusions concerning OS – The 4-year survival is high in both arms (80% vs 83%). – Even in the era of new drugs, transplantation remains the standard of care.

Lenalidomide Maintenance After High-Dose Melphalan and Autologous Stem Cell Transplant in Multiple Myeloma: A Meta-Analysis of Overall Survival Michel Attal,1 Antonio Palumbo,2 Sarah A. Holstein,3 Valérie Lauwers-Cances,1 Maria Teresa Petrucci,4 Paul Richardson,5 Cyrille Hulin,6 Patrizia Tosi,7 Kenneth C. Anderson,5 Denis Caillot,8 Valeria Magarotto,9 Philippe Moreau,10 Gerald Marit,11 Zhinuan Yu,12 Philip L. McCarthy13

1Institut

Universitaire du Cancer , Toulouse-Oncopole, France; 2The Myeloma Unit, Department of Hematology, University of Turin, Turin, Italy; 3Roswell Park Cancer Institute, Buffalo, NY; 4University La Sapienza, Rome, Italy; 5Dana-Farber Cancer Institute, Boston, MA; 6Bordeaux Hospital University Center (CHU), Bordeaux, France; 7Seràgnoli Institute of Hematology and Medical Oncology, Bologna University, Bologna, Italy; 8Dijon University Hospital Center, Dijon, France; 9University of Torino, Torino, Italy; 10University Hospital Hôtel-Dieu, Nantes, France; 11Centre Hospitalier Universitaire, Bordeaux, France; 12Celgene Corporation, Summit, NJ; 13Blood and Marrow Transplant Program, Roswell Park Cancer Institute, Buffalo, NY

1.0

7-yr OS

Survival Probability

0.8 62% 0.6

50%

0.4 0.2

N = 1209

LENALIDOMIDE

CONTROL

NE (NE-NE)

86.0 (79.8-96.0)

Median OS (95% CI), mos

0.74 (0.62-0.89) .001

HR (95% CI) P value

0.0

Patients at risk

30 40 50 60 Overall Survival, mos

100

110

120

605 604

578 569

555 542

509 505

282 271

200 174

95 71

20 10

1 0

474 458

431 425

385 350

Risk Factors FISH Cytogenetics β2-microglobulin* PCLI Gene expression profile

Standard Risk (80%) (Expected OS: 6-7 Yrs)

High Risk (20%) (Expected OS: 2-3 Yrs)

t(11;14), t(6;14)

del(17p), t(4;14)* t(14;16), +1q21

Hyperdiploidy

Hypodiploidy del(13q)

Low (< 3.5 mg/L)

High (≥ 5.5 mg/L)

< 3%

High (≥ 3%)

Good risk

High risk

• Other high risk features:

− Extramedullary disease − Plasma cell leukemia − Plasmablastic morphology

Dispenzieri A, et al. Mayo Clin Proc. 2007;82:323-341. Kumar SK, et al. Mayo Clin Proc. 2009;84:1095-1110. Mikhael JR, et al. Mayo Clin Proc. 2013;88:360-376. NCCN. Clinical practice guidelines in oncology: multiple myeloma. v.1.2015. Chng WJ, et al. Leukemia. 2014;28:269-277.

VRd Maintenance After ASCT in High Risk Disease

•

45 patients received VRd maintenance after ASCT for 2 years − Bortezomib 1.3mg/m2 weekly − Lenalidomide 10mg d1-21 − Dexamethasone 40mg weekly.

High-risk Features

n (%)

Del 17p

19 (42)

Del 1p

9 (20)

T (4;14)

2 (5)

T (14;16)

5 (11)

PCL

11 (24)

Others (aggressive presentation)

7 (16)

> 1 Cytogenetic abnormalities

PFS: 32 months 3-year OS: 93% from: Nooka, AK, et al. Leukemia.2014 28,690-693

34 (75)

100 90 80 70 60 50 40 30 20 10 0

sCR% sCR+CR % ≥ VGPR % ORR % SD % PD %

Post-induction Response

Post-ASCT day 60 Response

Best Response

Phase III Study of Daratumumab + Lenalidomide (DL) or Lenalidomide (L) as Post-Autologous Stem Cell Transplant Maintenance Therapy in Patients with Multiple Myeloma (MM) Using Minimal Residual Disease to Direct Therapy Amrita Krishnan M.D., F.A.C.P./ Hari Parameswaran M.D.

R E G I S T R A T I O N *

R A N D O M I Z A T I O N

Lenalidomide

Lenalidomide+ Daratumumab

M R D A S S E S S M E N T

*Patients may register any time following induction therapy.

MRD Negative

MRD Positive

R A N D O M I Z A T I O N

Continue assigned maintenance therapy

Stop assigned maintenance therapy

Continue assigned maintenance therapy

Relative survival ratio

Usmani et al; Leukemia 2013

Take Home Message • 10-15% patients with Myeloma may be cured by modern treatment; Future may yield more • Early and upfront transplantation is the standard of care • Hence, early referral to a transplant center should also be the standard • Risk stratification, personalized medicine and Immunotherapy holds promise for future

Progress

1950’s

1960’s

1980’s to Today

The Future?

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 Rafat Abonour, MD, Indiana University School of Medicine, Indianapolis, IN Q & A with Panel How to Manage Myeloma Symptoms and Side Effects Ann McNeill, RN, MSN, APN, John Theurer Cancer Center at HMH, Hackensack NJ IMF Nurse Leadership Board Q&A with Panel

Relapsed Therapy and Clinical Trials Rafat Abonour, MD

Indiana University School of Medicine, Indianapolis, IN 52

How Do I Treat Relapsed Multiple Myeloma? Rafat Abonour, M.D.

Harry and Edith Gladstein Professor of Cancer Research Professor of Medicine, Pathology and Laboratory Medicine Director, Multiple Myeloma, Waldenstrom's Disease and Amyloidosis Program Indiana University School of Medicine

When should we treat relapsed disease? • At biochemical relapse? • When myeloma protein starts rising! • When involved free light chain starts rising! • At Clinical relapse? • CRAB criteria (Anemia, kidney failure, high calcium or new bone disease) • Extramedullary disease (myeloma growing at tumors outsides the bone)

When should we treat relapsed disease? • We do not know, but we can speculate! • Most approved treatment in relapsed myeloma were based on biochemical relapse. • Some observations support better outcome when treating biochemical relapse: • Mayo clinic showed better overall survival when treating biochemical relapse (median PFS 125 vs 81 months)

Pros and Cons of treating Biochemical Relapse • Con: • 25% of biochemical relapse patients will have a smoldering course. No progression for 2 years. • Pros: • Median time between biochemical relapse and clinical symptoms is about 5-6 months. • If you do not get it right at first relapse you may not get it right at subsequent relapses

Response Duration Decreases with each relapse

Median response duration (months)

12 10 8 6 4 2 0 First

Second

Third

Fourth

Treatment Regimen

Fifth

Sixth

Genomic Heterogeneity Affects the Course of MM • Most patients with MM have multiple

distinct subclonal populations as a result of the expansion of genetically different myeloma cells; this causes intratumoral heterogeneity1 • MM is clonally heterogeneous at diagnosis and throughout treament2 • The genomic heterogeneity of MM contributes to treatment resistance and relapse3 • Wide variety of mutations found within •

a single patient may result in treatment resistance and refractory disease1,3,4 Furthermore, subclones continually mutate over time, including after treatment, which may contribute to resistance and result in disease progression1,5

1. Bolli N et al. Nat Commun. 2014;5:2997. 2. Walker BA et al. Leukemia. 2014;28(2):384-390. 3. Kyrtsonis M et al. Appl Clin Genet. 2010;3:41-51. 4. Keats JJ et al. Blood. 2012;120(5):1067-1076. 5. Abdi J et al. Oncotarget. 2013;4(12):2186-2207.

Evolution of Clonal Populations of Myeloma Cells4

Republished with permission of American Society of Hematology, from Keats JJ et al. Blood. 2012;120(5):1067-1076; via Copyright Clearance Center, Inc.

Clonal heterogeneity in English • Myeloma cells in each patients are a family of odds and aggressive members • The longer this family sticks around the odder and more aggressive it becomes • Family therapy is not going to work, you can not be politically correct here, eradicate them early. • This is making the case for early treatment and with combination regimen

Factors influencing the choice of therapy at Relapse

• Disease related • Regimen related • Patients related

Disease related Factors • Clinical features associated with relapse (elevated calcium, renal failure, anemia, bone lesions) • Expanding or new plasmacytomas or hyperviscosity • High-risk cytogenetics • Extramedullary disease or plasma cell leukemia • High ISS stage

Regimen-related Factors • Previous treatment and dose • Duration of prior response • Side effects, tolerability, and toxicity of prior treatment(s) and treatment combinations • Depth and duration of previous transplant

Patient-related Factors • Performance status, Frailty • Patient comorbidities • Transplant eligibility • Patient preference • Cost/socioeconomics

Currently available Anti-Multiple Myeloma Agents Steroids

Conventional Chemo

ImIDs

Proteasome Inhibitors

HDAC inhibitor

Immunologic approaches

XPO inhibitor

Prednisone

Melphalan

Thalidomide

Bortezomib

Panobinostat

Daratumumab (anti-CD38)

Selinexor

Dexamethasone

Cyclophosphamide

Lenalidomide

Carfilzomib

Isatuximab (anti-CD38)

Doxorubicin

Pomalidomide

Ixazomib

Elotuzumab (anti-CS1)

Belantamab

(anti-BCMA + MMAF)

DCEP/D-PACE

ABECMA

METRO28 Carmustine

Others: Venetoclax

Bendamustine

Melflufen

INDIANA UNIVERSITY SCHOOL OF MEDICINE

How does your oncologist decide what to do?

This is a very short menu

How does your oncologist decide what to do? This is not a very short menu

GREAT NEWS WE HAVE OPTIONS

BAD NEWS YOUR DOCTOR MAY GET CONFUSED

Mayo Practical Approach- First Relapse

Mayo Practical Approach- 2nd/ later Relapse

6 9

Combination is Better. Multicenter, randomized (1:1), open-label, active-controlled, phase 3 study

DRd (n = 286) Key eligibility criteria • RRMM • ≥1 prior line of therapy • Prior lenalidomide exposure, but not refractory • Creatinine clearance ≥30 mL/min

Stratification factors

R A N D O M I Z E

1:1

Daratumumab 16 mg/kg IV • Qw in Cycles 1 to 2, q2w in Cycles 3 to 6, then q4w until PD R 25 mg PO • Days 1 to 21 of each cycle until PD d 40 mg PO • 40 mg weekly until PD

Rd (n = 283) R 25 mg PO • Days 1 to 21 of each cycle until PD d 40 mg PO • 40 mg weekly until PD

• No. of prior lines of therapy • ISS stage at study entry

Cycles: 28 days

Primary endpoint • PFS Secondary endpoints • TTP • OS • ORR, VGPR, CR • MRD • Time to response • Duration of response Statistical analyses • Primary analysis: ~177 PFS events

• Prior lenalidomide

Pre-medication for the DRd treatment group consisted of dexamethasone 20 mg,a acetaminophen, and an antihistamine ISS, international staging system; DRd, daratumumab/lenalidomide/dexamethasone; IV, intravenous; qw, weekly; q2w, every 2 weeks; q4w, every 4 weeks; PD, progressive disease; R, lenalidomide; PO, oral; d, dexamethasone; Rd, lenalidomide/dexamethasone; PFS, progression-free survival; TTP, time to progression; OS, overall survival; ORR, overall response rate; VGPR, very good partial response; CR, complete response; MRD, minimal residual disease. aOn daratumumab dosing days, dexamethasone 20 mg was administered as pre-medication on Day 1 and Day 2.

% surviving without progression

POLLUX updated analysis: PFS (time without relapse is much better with 3 drugs....) Progression-free survivala

100

30-month PFSb

58%

DRd Median: not reached

35%

Rd Median: 17.5 months

20 0

No. at risk Rd DRd

HR 0.44; 95% CI, 0.34-0.55; P <0.0001 0

12 15 18 21 24 27 30 33 36 39 42 Months

283 249 206 181 160 143 126 111 100 89 80 36 286 266 249 238 229 214 203 194 183 167 145 67

5 16

1 2

0 0

Median follow-up: 32.9 months (range, 0 - 40.0 months) 56% reduction in risk of progression/death for DRd versus Rd HR, hazard ratio; CI, confidence interval. aExploratory analyses based on clinical cut-off date of October 23, 2017; bKaplan-Meier estimate.

Dimopoulos MA, et al. Presented at ASH 2017 (Abstract 739), oral presentation.

Time From Last Line of Therapy to Study Treatment of > or ≤12 Months >12 Months: Late relapses 18-month PFSa

100

% surviving without progression

83% 80

DRd

60%

Rd 40

HR: 0.37 (95% CI: 0.23-0.61; P <0.0001) 0

139 133

123 127

111 122

No. at risk Rd >12 DRd >12

149 140

12 15 Months

103 118

26 44

4 9

0 1

0 0

88 109

DRd is superior to Rd regardless of time since last therapy aKaplan-Meier

estimate. population.

bResponse-evaluable

Moreau P, et al. Presented at ASH 2016 (Abstract 1151), oral presentation

Isatuximab: CD38 antibody 100

PFS (%)

80 60 40 20

Median PFS, mos Isatuximab-Pd Pd 11.53 6.47

0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 No. at risk Mos 314 1 Isa-Pd 154 129 106 89 81 52 153 80 105 63 51 17 33 5 0 Pd

HR: 0.596 (95% CI: 0.4360.814); P = .001

PFS HR (95% CI)  Len refractory: 0.59 (0.43-0.82)  Len refractory in last line: 0.50 (0.340.76)  Len / PI refractory: 0.58 (0.40-0.84)

• Phase III ICARIA-MM: Isatuximab + Pom/Dex vs Pom/Dex in R/R MM • Phase III IKEMA IsaKD vs KD • FDA approved isatuximab in combination with pomalidomide or carfilzomib

INDIANA UNIVERSITY SCHOOL OF MEDICINE

Anti-Multiple Myeloma Novel Immunotherapeutic Agent Structures Antibody Drug Conjugate

T-Cell Bispecific Antibody

T-Cell Trispecific Antibody

Designed ankyrin repeat proteins (DARPins)

Lancman, et al. ASH 2020.

INDIANA UNIVERSITY SCHOOL OF MEDICINE

Comparison of Novel Immunotherapeutic Approaches Pros

Chimeric antigen receptor T cells (CAR-T)

Unprecedented ORR including MRD neg in heavily pre-treated patients One time intervention; long chemo holiday resulting in median PFS ~1 year

Cons

Manufacturing time makes impractical for patients with aggressive/rapidly progressing disease Requires complex infrastructure – stem cell lab, RN/ ICU/ER training – thus restricted to accredited centers CRS ? role in frail elderly Impact of bridging chemo on remission duration Low WBC and plts post CAR-T Cost given relapses even in MRD neg patients; mgmt. challenging especially if soon after flu/cy given impact on T cells

Bispecific antibodies

Antibody-drug conjugates

Off the shelf

Deep responses

Encouraging response rates

Limited severe CRS - ? Safety in frail elderly

1 hour infusion every 3 weeks

Can be given in community settings after 1st cycle ? Need for admissions with initial doses until CRS risk low Dosing/schedule to be determined Need for continuous treatment until progression

No CRS, can be given in community settings Ocular toxicity – requires close collaboration with opthamology & impact on pt quality of life Thrombocytopenia Need for continuous treatment until progression

Toxicities require further study – Modest ORR and PFS in triple infections, neurotoxicty class/penta refractory

Lancman, et al. ASH 2020.

BCMA (B-cell maturation antigen) • Receptor for BAFF and APRIL • Expressed on mature B cell subsets, PC’s, and plasmacytoid DC’s • Maintains plasma cell homeostasis • BCMA-/- mice have normal B cell #s, impaired PC survival

Hengeveld et al Bl Cancer J 2015 ; Maus, June, Clin Can Res 2013

Belantamab Mafodotin: BCMA-Targeted ADC Four mechanisms of action:

• Belantamab mafodotin (GSK2857916): Humanized, afucosylated, IgG1 BCMA-targeted ADC that neutralizes soluble BCMA

1. 2. 3. 4.

• Preclinical studies demonstrate selective, potent activity

Afucosylation Linker

–Enhanced ADCC –Stable in circulation

Tai. Blood. 2014;123:3128. Trudel. Lancet Oncol. 2018;19:1641. Trudel. Blood Cancer J. 2019;9:37.

BCMA BCMA 4

Lysosome

4 BCMA

–MMAF (non–cell-permeable, highly potent auristatin)

ADC

Belantamab Mafodotin Cytotoxic agent

ADC ADCC Immunogenic cell death BCMA receptor signaling inhibition

Malignant plasma cell

Cell death

Fc receptor

BCMA

ADCC Effector cell

Belantamab Mafodotin

BCMA Antibody Drug Conjugates Study Phase Treatment (All are IV q 3wk)

Patients Median prior lines Triple-class refractory ORR % PFS

DREAMM-1

DREAMM-2

DREAMM-4

DREAMM-6

MEDI2228

I/II

Belamaf dose escalation, expansion 3.4 mg/kg

Belamaf 2.5 or 3.4 mg/kg

Belamaf 2.5 or 3.4 mg/kg + pembrolizumab

Belamaf 2.5 mg/kg + bortezomib-dex

MEDI2228 (BCMAIg-DNA crosslinking pyrrolobenzodiaze pine (PBD) dimer )

n=35

n=196

n=13

n=18

n= 82

6-7

8/ 5

range 2-11

37%

100%

NR (100% exposed)

60% (38.5% if prior dara exposure)

31% / 34%

67% / 14%

78%

61% (25/41) (0.14 mg /kg)

12 months (6.8 months if prior dara)

2.9 / 4.9 months

AEs- all grade (gr3+) Keratopathy 52% (3%) 70% (27%)/ 75% (21%) 67% (33%) 100% (56%) Thrombocytopenia 63% (35%) 35% (20%)/ 58% (34%) 67% (61%) Anemia 28% (17%) 24% (20) / 37% (25%) 50% (0%) Infusion reaction 12% (3%) 21% (3%) / 16% (1%) 17% (0%) Phase 3 DREAMM studies recruiting: 3: Blmf vs Pd, 7: BlmfVd vs DVd, 8: BlmfPd vs VPd Other

0% 32% (NR)

Photophobia 54% Dry eye 20% Rash (29%) Trudel, et al. Blood Cancer J 2019; Lonial, et al. Lancet Oncol 2019; Nooka, et al. Hematology Reports 2020;; Popat, et al. ASH 2020; Kumar, et al. ASH 2020 Pleural eff (20%)

Rapid response in highly resistant myeloma

Best therapy for Relapse • • • • •

Not all relapses are the same. Combination therapies provide better outcomes. Available drugs and combinations are increasing. The optimal therapy is the one based on your needs. We need to get it right at first relapse.

Audience Q&A with Panel

How to Manage Myeloma Symptoms and Side Effects Ann McNeill, RN, MSN, APN

John Theurer Cancer Center at HMH, Hackensack NJ, IMF Nurse Leadership Board

Be the Commander of Your Galactic Journey: Navigating the Journey Ann McNeill, RN, MSN, APN John Theurer Cancer Center at HMH, NJ

Regional Community Workshop October 2, 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

Explore Treatment Options & Plan Your Course Drug class Proteosome inhibitor Immuno-modulatory agent Monoclonal antibody Antibody-drug conjugate Nuclear export inhibitor

Anthracycline

Alkylating agents Alkylator conjugate

HDACi CAR T Many

Navigating the Journey

Myeloma therapies Common combinations Bortezomib (SQ) VRD, Vd Carfilzomib KRd, Kd, K Ixazomib IxRd Pomalidomide Pd, DPd, EPd Lenalidomide VRD, Rd HCP Data Clinical From Thalidomide Dara + VTd Research Daratumumab DRd, DVd, DPd, D-VMP Experience Elotuzumab ERd, EPd TREATMENT Isatuximab-irfc IsaPd DECISION Belantamab mafodotin Bela montherapy Selinexor Sel + d, Sel + Vd Liposomal doxorubicin BRd, BVd Cyclophosphamide PCd, VTD-PACE Your Melphalan MVP, MPT Preference Melphalan flufenamide Melphalan flufenamide + dex Panobinostat Panobinostat + Vd Philippe Moreau. ASH 2015. Abecma Clinical trials are always an option

Bela = belantamab C = cyclophosphamide; D = daratumumab; d = dexamethasone; E = elotuzumab; HDACi = histone deacytlase inhibitor; Isa = Isatuximab; Ix = ixazomib; K = carfilzomib; P = pomalidomide; R = lenalidomide; Sel = Selinexor; SQ = subcutaneous; V = bortezomib Faiman B, et al. J Adv Pract Oncol. 2016;2016:7(suppl 1):17-29. Philippe Moreau. ASH 2015; Prescribing information.

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 This Photo by Unknown Author is licensed under CC BY-SA

Major Tom to Ground Control… Communicating Effectively with Your Crew Prepare for Your Away Mission

Achieve Your Appointment

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

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

Navigating the Journey

Navigate Home • Communicate with other members of your health care crew (pharmacist, others) • Take your medications as directed • Follow up with members of your heath care crew

A Tool to Help You Discuss Your Treatment With Your Healthcare Team

Navigating the Journey

Take Time to Consider Your Preferences Before an Appointment Ask Important Questions at Your Appointments • •

What Can I Expect Now? What Can I Expect In the Future?

Have these conversations… • • • •

Whenever your treatment stops working Whenever you start a new treatment Whenever there is a change in your life priorities Whenever you have a question or concern Available in the IMF Resources or at myeloma.org

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 92

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 affect 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.

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)

Constellation of Symptoms

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.

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

IMF has many resources to help you learn

Videos

Website: http://myeloma.org

eNewsletter: Myeloma Minute

Download or order at myeloma.org

IMF Webinars

You are Not Alone

Questions?

100

Audience Q&A with Panel

101

Workshop Video Replay & Slides As follow up to today's workshop, we will have the speaker slides and a video replay available. These will be provided to you shortly after the workshop concludes.

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Thank you to our sponsors!

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