Accelerating Toward Curing Myeloma: New Data, New Agents, and Evolving Treatment Paradigm

This activity is provided by the Annenberg Center for Health Sciences at Eisenhower and developed in partnership with Clinical Care Options, LLC and the International Myeloma Foundation.

Accelerating Toward Curing Myeloma: Emerging Data, New Agents, and an Evolving Treatment Paradigm Friday, December 4, 2020 11:00 AM Pacific Time

This program is supported by educational grants from Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Karyopharm, and Oncopeptides.

Friday Satellite Symposium on Accelerating Toward Curing Myeloma: Emerging Data, New Agents, and an Evolving Treatment Paradigm, preceding the 62nd ASH Annual Meeting and Exposition.

Program Chair and Moderator Brian G.M. Durie, MD

Medical Director, AMyC Co-Chair Myeloma Committee, SWOG Chairman, International Myeloma Foundation Specialist in Multiple Myeloma and Related Disorders Cedars-Sinai Outpatient Cancer Center Los Angeles, California Brian G.M. Durie, MD, has disclosed that he has received consulting fees from Amgen, Celgene/Bristol-Myers Squibb, Janssen, and Takeda and fees from nonCME/CE services from Amgen.

Faculty Shaji Kumar, MD

Department of Hematology Mayo Clinic Rochester, Minnesota Shaji Kumar, MD, has disclosed that he has received funds for research support from AbbVie, Bristol-Myers Squibb, Celgene, Genentech, Janssen, MedImmune, Oncopeptides, Takeda, and TeneoBio and consulting fees from AbbVie, BristolMyers Squibb, Celgene, Genentech, Janssen, Oncopeptides, and Takeda.

Faculty Thomas G. Martin, MD

Clinical Professor of Medicine Associate Director, Myeloma Program University of California, San Francisco Medical Center San Francisco, California Thomas G. Martin, MD, has disclosed that he has received consulting fees from GlaxoSmithKline and funds for research support from Amgen, Janssen, and Sanofi.

Faculty Philippe Moreau, MD

Professor of Clinical Hematology Head, Hematology Department University Hospital HĂ´tel-Dieu Nantes, France Philippe Moreau, MD, has disclosed that he has received consulting fees from AbbVie, Amgen, Celgene, Janssen, and Sanofi.

Faculty S. Vincent Rajkumar, MD

Edward W. and Betty Knight Scripps Professor of Medicine Mayo Clinic Rochester, Minnesota S. Vincent Rajkumar, MD, has no relevant conflicts of interest to disclose.

Faculty JesĂşs F. San-Miguel, MD, PhD

Director of Clinical and Translational Medicine Universidad de Navarra Pamplona, Spain JesĂşs F. San-Miguel, MD, PhD, has disclosed that he has received consulting fees from AbbVie, Amgen, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Karyopharm, Merck Sharpe & Dohme, Novartis, Roche, Sanofi, and Takeda.

Symposium Format Each topic discussion will include the following:  Case presentation with interactive polling question(s) for the audience  Presentation by faculty  Second audience vote on case question(s)  Panel discussion with expert recommendations  Audience question and answer session

Polling and Questions: Online Participants  How to Vote ‒ When a new poll pops up on your screen, click VOTE next to your answer ‒ Unanswered polls will appear in the Polling window on the left side of your screen until answered

 Asking a Question ‒ Type in questions for the faculty on the left side of the screen in the Questions window

First, A Few Quick Polling Questions…

Poll 1: Which of the following best describes your role on the oncology care team?

1. Physician 2. Physician assistant 3. Nurse practitioner 4. Pharmacist 5. Allied health professional

Poll 2: Which of the following best describes your specialty?

1. Hematology 2. Hematology/oncology 3. Medical oncology 4. Primary care 5. Pharmacy 6. Translational science

Poll 3: Which clinical setting best describes your practice?

1. Academic 2. Cancer center 3. Hospital or health system-owned 4. Physician owned 5. Federal government owned (eg, Veterans Affairs hospitals) 6. Research

Poll 4: If you are a practicing clinician, how many patients with multiple myeloma do you provide care for in a typical month?

1. < 5 2. 5-10 3. 11-15 4. 15-20 5. > 20

Agenda  Early Treatment for High-Risk Smoldering MM: Going for a Cure?

Shaji Kumar, MD  Individualized Approaches to Frontline Treatment Selection Philippe Moreau, MD  Managing the Patient With Relapsed Disease After ≥ 1 Lines of Therapy Jesús F. San-Miguel, MD, PhD  Understanding the Different Anti-BCMA Therapies Thomas G. Martin, MD  Future Directions and Key Studies from ASH 2020 S. Vincent Rajkumar, MD  Proposed 2021 Treatment Algorithms for MM

Early Treatment for High-Risk Smoldering MM: Going for a Cure?

Shaji Kumar, MD

Mark and Judy Mullins Professor of Hematological Malignancies Chair, Myeloma, Amyloidosis, Dysproteinemia Group Department of Hematology Mayo Clinic Rochester, Minnesota

Disclosures Shaji Kumar, MD, has disclosed that he has received funds for research

support from AbbVie, Bristol-Myers Squibb, Celgene, Genentech, Janssen, MedImmune, Oncopeptides, Takeda, and TeneoBio and consulting fees from AbbVie, Bristol-Myers Squibb, Celgene, Genentech, Janssen, Oncopeptides, and Takeda.

Patient Scenario  A 56-year-old woman was noted to have elevated total protein during routine evaluation and underwent additional testing ‒ Hb: 13.2 g/dL ‒ Serum calcium: 9.2 mg/dL, creatinine: 0.8 mg/dL, LDH: normal, B2M: 3.7 mg/dL ‒ SPEP: 2.3 g/dL M spike (IgG kappa), serum FLC – kappa 40 mg/dL, lambda 1.2 mg/dL, k:l ratio 33

 Bone marrow biopsy showed 40% plasma cells, FISH shows t(4;14)  Whole body low-dose CT negative for lytic lesions  MRI spine shows marrow heterogeneity, no lesions

Presurvey 1: In your current practice, what would you recommend next for this patient?

1. Continue observation and repeat testing in 6 months 2. Continue observation and repeat testing in 2 months 3. Start treatment with lenalidomide/dexamethasone 4. Start treatment with bortezomib/lenalidomide/dexamethasone with plans for an ASCT after 4 cycles 5. Enroll in a clinical trial 6. Uncertain

Expert Recommendations Expert Recommendations Brian G.M. Durie, MD Shaji Kumar, MD Thomas G. Martin, MD Philippe Moreau, MD S. Vincent Rajkumar, MD JesĂşs San-Miguel, MD

Enroll in a clinical trial Enroll in a clinical trial Enroll in a clinical trial Enroll in a clinical trial Start treatment with lenalidomide/dexamethasone Start treatment with VRD, with plans for ASCT

Smoldering Myeloma

Kyle. NEJM. 1980;302:1347.

Smoldering Myeloma

Kyle. NEJM. 1980;302:1347.

Smoldering Myeloma

Kyle. NEJM. 1980;302:1347.

Why Have We Not Been Treating SMM? 1. Patients are asymptomatic 2. We do not know who will get myeloma 3. Treatments are toxic and have limited efficacy 4. No evidence to suggest that it improves survival

Why Have We Not Been Treating SMM? 1. Patients are asymptomatic

First symptom may be catastrophic

2. We do not know who will get myeloma 3. Treatments are toxic and have limited efficacy 4. No evidence to suggest that it improves survival

Why Have We Not Been Treating SMM? 1. Patients are asymptomatic

First symptom may be catastrophic

2. We do not know who will get myeloma We have better risk stratification systems

3. Treatments are toxic and have limited efficacy 4. No evidence to suggest that it improves survival

Why Have We Not Been Treating SMM? 1. Patients are asymptomatic

First symptom may be catastrophic

2. We do not know who will get myeloma We have better risk stratification systems

3. Treatments are toxic and have limited efficacy We have highly effective therapies

4. No evidence to suggest that it improves survival

Why Have We Not Been Treating SMM? 1. Patients are asymptomatic

First symptom may be catastrophic

2. We do not know who will get myeloma We have better risk stratification systems

3. Treatments are toxic and have limited efficacy We have highly effective therapies

4. No evidence to suggest that it improves survival We have phase III trials now

Progression By Risk Group 100

Probability of progression (%)

90

Characteristics included in the model:

High-risk group

80 70

Intermediate-risk group

60 50

Low-risk group

40 30

Serum M Spike: > 2g/dL FLC Ratio: > 20 BMPC: > 20%

20 10 0

0

2

4

6

8

10

12

14

16

18

Time to progressions (years)

Risk Stratification Groups

Number of risk factors

Hazard Ratio (95% CI) Versus Low-risk group

Risk of Progression at 2 years

Number of patients

Low-risk group

0

Reference

5%

424 (37%)

Intermediate-risk group

1

2.25 (1.68 to 3.01)

17%

312 (27%)

2-3

5.63 (4.34 to 7.29)

46%

415 (36%)

High-risk group

San Miguel. ASCO 2019. Abstr 8000. Mateos Blood Cancer J. 2020;10:102.

Risk Score to Predict Progression Risk At 2 Years Score 0 2 3 5 0 3 4 0 2 3 5 6 2

100 High-risk group >12 80

% with progression

Risk Factor FLC Ratio 0-10 (ref) > 10-25 > 25-40 > 40 M protein (g/dL) 0-1.5 (ref) > 1.5-3 >3 BMPC% 0-15 (ref) > 15-20 > 20-30 > 30-40 > 40 FISH abnormality

Intermediate-risk group (9-12) Low-intermediate-risk Group (5-8)

60

40 Low-risk group (0-4) 20

0

0

6

12

18

24

30

36

42

48

54

60

Months

# at Risk 0-4

241

238

229

213

194

175

153

117

100

76

63

5-8

264

256

229

197

174

145

118

91

73

53

44

9-12

133

119

98

73

59

47

33

26

20

14

13

>12

51

41

29

21

14

9

7

5

2

2

2

San Miguel. ASCO 2019. Abstr 8000. Mateos Blood Cancer J. 2020;10:102.

Risk Stratification Groups

Hazard Ratio (95% CI) Versus Low-risk group (censored 2 year)

0-4

Reference

5-8

7.56 (3.77 to 15.2)

9-12

17.3 (8.63 to 34.8)

> 12

31.9 (15.4 to 66.3)

Total Risk Score

2-year Progression n (%)

0-4

9 / 241 (3.7%)

5-8

67 / 264 (25.4%)

9-12

65 / 133 (48.9%)

> 12

37 / 51 (72.6%)

Phase III QuiRedex: Lenalidomide/Dex vs Observation Len-Dex vs Observation (n = 119) Median f/u: 10,8y

Len-dex, TTP: 9 yrs

Observation, TTP: 2.1 yrs

HR: 0.27 (95%CI: 0.16-0.42), P < .0001

Len-dex, OS NR

Observation, OS: 7.8 yrs 46% reduction in the risk of death

HR: 0.54 (95%CI: 0.30-0.90), P < .034

Caveat: No advanced imaging ï&#x192; many patients may have had active myeloma Mateos. NEJM. 2013.

Mateos. Lancet Oncology 2016.

Mateos. EHA 2020. Abstr EP950.

Phase III QuiRedex with Len/Dex vs Observation: OS From Progression To Active Disease Median follow-up: 10.8 years

Len-dex, median OS: 6.4 yrs

Observation, median OS: 4.7 yrs

Early treatment does not induce more resistant relapses Mateos. EHA 2020. Abstr EP950.

Phase II/III E3A06: Lenalidomide vs Observation

HR = 0.28 [95% CI: (0.12-0.63)]; P = .0005

Median follow up: 35 months

Phase III PFS 1 year 2 year 3 year

Lonial. ASCO 2019. Abstr 8001. Lonial. JCO. 2020;38:1126.

Len 0.98 0.93 0.91

Obs 0.89 0.76 0.66

More questions than answers  If we treat, should we be treating like myeloma?  Or should it be a low intensity to delay progression?  Or should it be more aggressive to potentially cure the disease?  What is a good surrogate for cure?  When do we stop treatment?

Phase III EAA173: Daratumumab to Enhance Therapeutic Effectiveness of Lenalidomide in Smoldering Myeloma (DETER-SMM)

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

NCT03937635.

Daratumumab + Lenalidomide + Dex x 24 mo; Dex stops at 12 mo Lenalidomide + Dex x 24 mo; Dex stops at 12 mo

CR/PR/ Stable

Continue therapy For 2 years

Prog. anytime

Off Rx

Planned N = 288

CurativE StrAtegy for High-Risk Smoldering Myeloma (GEM-CESAR)

Phase II Trial Enrollment

Patients newly diagnosed with high-risk* smoldering MM (N = 90) Response Category, n (%) ORR, n (%)

Induction

Consolidation

6 x 28-day cycles

2 x 28-day cycles

Carfilzomib IV 20/36 mg/m2 D1, 2, 8, 9, 15, 16

Carfilzomib IV 20/36 mg/m2 D1, 2, 8, 9, 15, 16

High-dose melphalan 200 mg/m2 followed by ASCT

Lenalidomide 25 mg D1-21 Dexamethasone 40 mg D1, 8, 15, 22 Induction (n = 90)

Dexamethasone 40 mg D1, 8, 15, 22

HDM-ASCT (n = 83) High Risk (n = 55) Ultrahigh Risk (n = 28) 

85 (94)

82 (99)

54 (95)

28 (100)

≥ CR

37 (41)

53 (64)

35 (64)

18 (64)



VGPR

35 (39)

18 (22)

12 (22)

6 (21)



PR

13 (14)

11 (13)

7 (13)

4 (14)

Stable disease

1 (1)

1(1)

1 (2)

--

Progressive disease

2 (3)

--

--

--

27 (30)

47 (56)

32 (58)

15 (54)

Mateos. ASH 2019. Abstr 781.

24 x 28-day cycles

Lenalidomide 25 mg D1-21



MRD negative

Maintenance



Lenalidomide 10 mg D1-21 Dexamethasone 20 mg D1, 8, 15, 22

5 patients did not undergo ASCT: PD after induction (n = 2); ASCT mobilization failure (n = 2); patient decision (n = 1) PBSC mobilization after C 4 of induction: 93% successful with GCSF, 7% required plerixafor; mean CD34 cells collected: 4 x 106/kg and 11 patients required second mobilization

CurativE StrAtegy for High-Risk Smoldering Myeloma (GEM-CESAR) Outcomes including Consolidation & 1 year maintenance 77 patients completed induction, HDT-ASCT, consolidation, and 1 yr of maintenance Induction (KRd x 6) (n = 77)

HDT-ASCT (n = 77)

Consolidation (KRd x 2) (n = 77)

Maintenance (Rd x 1 Yr) (n = 77)

â&#x2030;Ľ CR

43

63

75

81

VGPR

43

24

18

13

PR

13

13

7

5

Progressive disease

--

--

--

1*

MRD negative

33

49

65

62

Response, %

*Biological progressive disease at end of maintenance, MRD positive.

Mateos. ASH 2019. Abstr 781.

CurativE StrAtegy for High-Risk Smoldering Myeloma (GEM-CESAR): PFS and OS 100

100

PFS

35-Mo PFS: 92%

60 40 20 0

OS

80

Patients (%)

Patients (%)

80

35-Mo OS: 96%

60 40 20

Median follow-up: 35.2 (5.4-53.2) 0

10

20

Mos

0 30

40

50

 6 patients progressed (biological PD, n = 5) ‒ 4 patients with PD were at ultrahigh risk Mateos. ASH 2019. Abstr 781.

Median follow-up: 35.2 (5.4-53.2) Median follow-up: 35.2 (5.4-53.2) 0

10

20

30

Mos

40

50

60

 3 patients died; only 1 was considered a treatment-related death

Registration

Aggressive Smoldering Curative Approach Evaluating Novel Therapies (ASCENT)

Induction (4 cycles) Car + Len + Dara + Dex

Consolidation (4 cycles) Car + Len + Dara + Dex

Intensification (4 cycles) Car + Len + Dara + Dex

Maintenance Car + Len + Dara for 1 year

Observation 5 years

NCT03289299.

So What Should We Do Today?

Confirm SMM diagnosis, advanced imaging required

High risk SMM

Clinical trials OR Len Dex

If no Rx very close observation

So What Should We Do Today?

Confirm SMM diagnosis, advanced imaging required

High risk SMM

Clinical trials OR Len Dex

If no Rx

very close observation

So What Should We Do Today?

Confirm SMM diagnosis, advanced imaging required

High risk SMM

Standard risk SMM

Clinical trials OR Len Dex

Follow up every 3 months

Evolving phenotype If no Rx very close observation

So What Should We Do Today?

Confirm SMM diagnosis, advanced imaging required

Multiple HR features

High risk SMM

Standard risk SMM

Treat as myeloma?

Clinical trials OR Len Dex

Follow up every 3 months

Evolving phenotype If no Rx very close observation

kumar.shaji@mayo.edu

THANK YOU

Now, letâ&#x20AC;&#x2122;s return to our patient case

Patient Scenario  A 56-year-old woman was noted to have elevated total protein during routine evaluation and underwent additional testing ‒ Hb: 13.2 g/dL ‒ Serum calcium: 9.2 mg/dL, creatinine: 0.8 mg/dL, LDH: normal, B2M: 3.7 mg/dL ‒ SPEP: 2.3 g/dL M spike (IgG kappa), serum FLC – kappa 40 mg/dL, lambda 1.2 mg/dL, k:l ratio 33

 Bone marrow biopsy showed 40% plasma cells, FISH shows t(4;14)  Whole body low-dose CT negative for lytic lesions  MRI spine shows marrow heterogeneity, no lesions

Assessment 1: Now, what would you recommend next for this patient?

1. Continue observation and repeat testing in 6 months 2. Continue observation and repeat testing in 2 months 3. Start treatment with lenalidomide/dexamethasone 4. Start treatment with bortezomib/lenalidomide/dexamethasone with plans for an ASCT after 4 cycles 5. Enroll in a clinical trial 6. Uncertain

Panel Discussion: Diagnosis and How to Manage Smoldering Myeloma

This activity is provided by the Annenberg Center for Health Sciences at Eisenhower and developed in partnership with Clinical Care Options, LLC and the International Myeloma Foundation.

Individualized Approaches to Frontline Treatment Selection Philippe Moreau, MD

Professor of Clinical Hematology Head, Hematology Department University Hospital HĂ´tel-Dieu Nantes, France

Faculty Philippe Moreau, MD

Professor of Clinical Hematology Head, Hematology Department University Hospital HĂ´tel-Dieu Nantes, France Philippe Moreau, MD, has disclosed that he has received consulting fees from AbbVie, Amgen, Celgene, Janssen, and Sanofi.

Agenda  What patient and disease factors guide therapy decisions?

–

Impact of age, performance status, and comorbidities on therapy selections

–

When to use 3-drug vs 4-drug regimens?

 Current therapeutic options for transplant eligible and ineligible patients –

Triplet therapies

–

Quad therapies

 New therapeutic strategies for transplantation, consolidation, and maintenance

Patient Case Example: 73-Year-Old Male Presents with:  Bone pain  Anemia Hb: 10.2 g/dL  Serum electrophoresis: M-spike: 4.2 g/dL; IF: IgG K  Bone marrow aspirate: 30% plasma cells  Cytogenetics (FISH): t(11;14)  Low-dose whole-body CT: diffuse bone lesions, spine  Creatinine: 0.9 mg/dL; β2-M: 2.5 mg/L, albumin 3.8 g/dL, LDH < normal  symptomatic multiple myeloma, ISS1, R-ISS1

Presurvey 2: In your current clinical practice, what would you recommend for this patient?

1. Rd until progression 2. VRD x 8 followed by Rd until PD 3. VRD lite followed by R until PD 4. VMP-daratumumab x 9 followed by daratumumab until PD 5. Rd + daratumumab, until PD 6. VRD x 4 ď&#x192; ASCT prepared by mel 200 ď&#x192; len maintenance until PD 7. Uncertain

Expert Recommendations Expert Recommendations Brian G.M. Durie, MD Shaji Kumar, MD Thomas G. Martin, MD Philippe Moreau, MD S. Vincent Rajkumar, MD Jesús San-Miguel, MD

Rd + daratumumab, until PD Rd + daratumumab, until PD RVd x 4  ASCT  Len maintenance Rd + daratumumab, until PD VRD x 8  Rd until PD Rd + daratumumab, until PD Dara + VMP with bortez maintenance

Phase III Trials in NDMM Not Eligible for ASCT Trial

Regimen

n

mPFS

mOS

Vista1

VMP

344

24 (TTP)

56.4

1. San Miguel. ASH. 2011. Abstr. 476

Phase III Trials in NDMM Not Eligible for ASCT Trial

Regimen

n

mPFS

mOS

Vista1

VMP

344

24 (TTP)

56.4

FIRST2

Rd cont

535

26

59.1

1. San Miguel. ASH. 2011. Abstr. 476. 2. Facon. Blood. 2018;131:301.

SWOG 0777 Trial

Treatment-naïve MM without intent for immediate ASCT* (N = 525) Stratifications: ISS, intent to transplant at progression

R

VRd┼: Bortezomib Lenalidomide Dexamethasone (n = 264) Eight 21-day cycles Rd: Lenalidomide Dexamethasone (n = 261) Six 28-day cycles

Rd Primary endpoint: PFS

Rd Len: 25 mg PO until progression

*All high-risk 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..

Carfilzomib, lenalidomide, and dexamethasone (KRd) versus bortezomib, lenalidomide, and dexamethasone (VRd) for initial therapy of newly diagnosed multiple myeloma: results of ENDURANCE (E1A11) phase 3 trial Shaji K. Kumar, Susanna J. Jacobus, Adam D. Cohen, Matthias Weiss, Natalie Scott Callander, Avina A. Singh, Terri L. Parker, Alexander Menter, Alex Yang, Benjamin Marshall Parsons, Pankaj Kumar, Prashant Kapoor, Aaron Seth Rosenberg, Jeffrey A. Zonder, Edward Anthony Faber, Sagar Lonial, Paul G. Richardson, Robert Z. Orlowski, Lynne I. Wagner, S. Vincent Rajkumar

https://ecog-acrin.org

EDURANCE: PFS from Induction Randomization  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

Kumar. ASCO 2020 Abstr LBA3.

 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

Phase III Trials in NDMM Not Eligible for ASCT Trial

Regimen

n

mPFS

mOS

Vista1

VMP

344

24 (TTP)

56.4

FIRST2

Rd cont

535

26

59.1

SWOG7773

VRD

242* 91**

43 34

75 65

Endurance4

VRD

542 # 167 ##

34.4 37

3-year:84% NA

*: median age: 64; ** > 65 years; # median age 65; ## > 70 years 1. San Miguel. ASH. 2011. Abstr. 476. 2. Facon. Blood. 2018;131:301. 3. Durie. Lancet. 2017;389:519. 4. Kumar. ASCO 2020 Abstr LBA3.

Phase III ALCYONE Trial: PFS with Dara + VMP vs VMP in NDMM â&#x20AC;˘ Median (range) follow-up: 40.1 (0-52.1) months 42-month PFS

Progression-free survival, %

100

Daratumumab monotherapy phase

80

60

48% D-VMP: median 36.4

40

20

14%

HR, 0.42; 95% CI, 0.34-0.51; P <0.0001

VMP: median 19.3

0 0

3

6

9

12

15

18

21

24

30

33

36

39

42

45

48

51

78 188

67 173

51 160

29 113

15 63

7 26

0 9

0 0

Months

Patients at risk VMP D-VMP

27

356 350

304 322

278 312

263 298

246 292

207 265

171 243

128 220

110 207

93 202

D-VMP continued to demonstrate a significant PFS benefit with extended follow up Mateos. Lancet. 2020;395:132. Mateos. ASH 2019. Abstr 859.

Phase III Trials in NDMM Not Eligible for ASCT Trial

Regimen

n

mPFS

mOS

Vista1

VMP

344

24 (TTP)

56.4

FIRST2

Rd cont

535

26

59.1

SWOG7773

VRD

242* 91**

43 34

75 65

Endurance4

VRD

542 # 167 ##

34.4 37

3-year: 84% NA

Alcyone5

VMP-Dara

356

36.4

42-Mo: 75%

*: median age: 64; ** > 65 years; # median age 65; ## > 70 years 1. San Miguel. ASH. 2011. Abstr. 476. 2. Facon. Blood. 2018;131:301. 3. Durie. Lancet. 2017;389:519. 4. Kumar. ASCO 2020 Abstr LBA3. 5. Mateos. ASH 2019.

Abstr 859.

Phase III Trials in NDMM Not Eligible for ASCT Trial

Regimen

n

mPFS

mOS

Vista1

VMP

344

24 (TTP)

56.4

FIRST2

Rd cont

535

26

59.1

SWOG7773

VRD

242* 91**

43 34

75 65

Endurance4

VRD

542 # 167 ##

34.4 37

3-year: 84% NA

Alcyone5

VMP-Dara

356

36.4

42-Mo: 75%

MAIA6

Rd-Dara

368

30-Mo: 71%

Immature

*: median age: 64; ** > 65 years; # median age 65; ## > 70 years 1. San Miguel. ASH. 2011. Abstr. 476. 2. Facon. Blood. 2018;131:301. 3. Durie. Lancet. 2017;389:519. 4. Kumar. ASCO 2020 Abstr LBA3. 5. Mateos. ASH 2019.

Abstr 859. 6. Facon. NEJM. 2019;380:2104.

ASH2020 – Kumar et al – MAIA Follow-up : 4 years

Median NR (55+ ?) vs 34 mos

Kumar. ASH 2020. Abstr 2276.

Overview of Median PFS in Recent Phase III Trials in Patients Not Eligible for ASCT ?

55 50

NR; Estimate based on HR 0.55

45 40

36.4

35.1

mPFS

35 29.7

30

25.3

25 20

18.3

34

31.9

26

19.1

15 10 5 0

mPFS

VMP (VISTA) 18.3

VMP VMP-D Rd (SWOG Rd (ECOG) Rd (FIRST) Rd (MAIA) (ALCYONE) (ALCYONE) 0777) 19.1

IMiD-free

35

25.3

26

29.7

31.9

RVd Lite (O'Donnell) 35.1

RVd (SWOG 0777) 34

RdD (MAIA) 55

IMiD-foundation

1. San Miguel. ASH. 2011. Abstr. 476. 2. Dimopoulos. ASH 2018. Abstr 156. 3. Rajkumar. Lancet Oncol. 2010;11:29.

4. Facon. Blood.2018;131:301. 5. Durie. Lancet. 2017;389:519. 6. Facon. ASH 2018. Abstr LBA-2. 7. Oâ&#x20AC;&#x2122;Donnell. Br J Haematol.

2018;182:222.

Direct comparison between trials is not intended and should not be inferred. HR, hazard ratio; NR, not reached; NSCT, non-stem cell transplant; PFS, progression-free survival; Rd, lenalidomide, low-dose dexamethasone; RdD, daratumumab, lenalidomide, dexamethasone; RVd, lenalidomide, bortezomib and dexamethasone; VMP; bortezomib, melphalan, prednisone.

Accumulative Lines of Therapy Received by Age at Diagnosis : Best Therapy Should Be Used Upfront in Elderly Patients 100

93

<70 years, n = 165

89

90

70+ years, n = 174

80

Percent

70 59

60 50 40

35

35

30 20 10 0

17

11

6 0

18 7

1

2

3

Accumulative Lines of Therapy

4

4

2 5

Courtesy of A Spencer

PFS and OS by Frailty Level in the FIRST Study Category

Score

Age • ≤ 75 years • 76-80 years • > 80 years

0 1 2

Charlson Comorbidity Index • ≤1 • >1

0 1

ECOG PS • 0 • 1 • ≥2

0 1 2

Sum of scores • Non-frail • Frail

0-1 ≥2

Facon. Leukemia. 2020;34:224.

Modified RVd (RVd-lite) in Transplant-Ineligible MM Induction NDMM Ineligible for ASCT

Consolidation

RVd-lite R: 15 mg days 1–21 V: 1.3 mg/m2 SCa weekly d: 20 mgb 9 x 35-day cycles

Maintenance

RV days 1–21 R: 15 V: 1.3 mg/m2b SC days 1, 15

Rd until PD or unacceptable side-effects

mgc

6 x 28-day cycles

Response rate

a The

SD

90

MR

PR

VGPR

CR

PFS

sCR

Survival (probability)

100

12

80

Patientse (%)

Baseline N = 50 characteristics, % Median age 73 (65–91) (range), years ISS stage at diagnosis I 38 II 34 III 28 ECOG PS score 0 50 1 36 2 14

70 50 40

≥ VGPR: 66%

32

60

ORR: 86%

22

30 20 10 0

• • • •

20 6 N = 50

2

1.0 0.8 0.6

Median follow-up: 30 months

0.4

Median PFS: 35.1 months

0.2 0.0

0

No. of patients at risk 50

6

12

18

24

30

36

42

49

45

39

31

20

4

2

Time (months)

≥ CR was 44% (ITT population, N = 50) ORR was 86%, ≥ VGPR was 66% for patients evaluable for responsea after 4 cycles (n = 46) Median TTR was 1.1 months Grade 3/4 peripheral neuropathy was 2%, neutropenia was 14%

first 10 patients received BORT IV for cycle 1 only followed by SC administration. Subsequent patients received BORT SC. b Days 1, 2, 8, 9, 15, 16, 22, 23 for patients ≤ 75 years; days 1, 8, 15, 22 for patients > 75 years. c Or last tolerated dose as of cycle 9. d Optional. e 6% of patients received < 4 cycles of therapy and were therefore not evaluable. MR, minimal response; TTR, time to response.

O’Donnell. Br J Haematol. 2018;182:222.

Eligibility for ASCT Yes Induction: 3-drug regimens VTD VCD RVD PAD 200 mg/m2 Melphalan followed by ASCT

No First option: VMP, Rd, VRD Second option: VCD, MPT Other options : BP, CTD, MP

Maintenance Lenalidomide

...”< 66 years Or fit patients < 70 years in good clinical condition”…

FRONTLINE THERAPY ESMO guidelines Moreau et al, Ann Oncol 2017

Philippe Moreau, MD

INDUCTION ASCT prepared by melphalan 200 mg/m2 (Consolidation) Maintenance

Philippe Moreau, MD

VRD x 6, 458 patients GEM2012 trial

VGPR or better in the 426 patients Who initiated cycle 6

Response rates in the ITT N = 458

6.4%

Median number of CD34+ cells (3 cycles) : 4.66 106/kg Rosinol. Blood 2019;134:1337.

CASSIOPEIA Study Design Consolidation

D-VTd

D-VTd

D: 16 mg/kg IV QW Cycles 1-2, Q2W Cycles 3-4 V: 1.3 mg/m2 SC Days 1, 4, 8, 11 T: 100 mg/day PO d: 20-40 mg IV/POa

VTd

VTd administered as in the D-VTd arm

D: 16 mg/kg IV Q2W V: 1.3 mg/m2 SC Days 1, 4, 8, 11 T: 100 mg/day PO d: 20 mg IV/POa

T R A N S P L A N T

VTd

VTd administered as in the D-VTd arm

4 Cycles of 28 days

D monotherapy

D 16 mg/kg IV Q8W until PD (2 years maximum, then observation until PD)

Observation

until PD (2 years maximum)

2 Cycles of 28 days

Part 1

Moreau. The Lancet. 2019 Jul 6;394:29.

Maintenance

Philippe Moreau, MD

Part 2

Follow-up

• Transplanteligible NDMM • 18-65 years • ECOG 0-2

Induction

Patients with ≥PR Second randomization (1:1)

Key eligibility criteria:

First randomization (1:1)

• Phase 3 study of D-VTd versus VTd in transplant-eligible NDMM (N = 1,085), 111 sites from 9/2015 to 8/2017

Efficacy: Response Rates Over Time 65% VGPR or better 100 90

7 7

Patients (%)

80

13 9

70 60

VTd

D-VTd

7 2

29

47

40

52 45

30 20 10 0

53

54

50

20 6

10

51

9 5

28 7 Postinduction

34 16 8 PostASCT

9 7

Moreau. The Lancet. 2019 Jul 6;394:29.

10

Postconsolidation

SD/PD/NE

23

PR

10 PostASCT

Postinduction

VGPR

Philippe Moreau, MD

CR

sCR

12 10 Postconsolidation

Efficacy: MRD (Flow Cytometry; 10–5)

MRD-negative rate, %

70

P <0.0001 63%

60 50

43%

40 30 20 10 0

D-VTd (n = 543)

VTd (n = 542)

D-VTd superior across all subgroups including high-risk cytogenetics and ISS stage III

Subgroup

VTd

D-VTd

Odds Ratio (95% CI)

minimal residual disease negative, n (%)

Sex 192 (61) 131 (41) Male 154 (68) 105 (47) Female Age 56 (68) 38 (42) <50 years 290 (63) ≥50 years 198 (44) Site 287 (64) 204 (45) IFM 59 (65) 32 (38) HOVON ISS disease stage 137 (67) 103 (45) I II 155 (61) 96 (41) 54 (64) 37 (46) Ill Cytogenetic profile at trial entryc 49 (60) 38 (44) High risk 296 (64) 197 (43) Standard risk Baseline creatinine clearance 205 (62) 139 (44) >90 ml/min 141 (67) ≤90 ml/min 97 (43) Baseline hepatic function 310 (65) 216 (43) Normal 36 (57) 20 (48) Impaired Type of multiple myelomad lgG 201 (61) 122 (39) 61 (66) 59 (49) Non-lgG ECOG performance status 172 (65) 112 (44) 0 174 (63) 124 (44) ≥1

2.22 (1.62–3.05) 2.37 (1.62–3.48) 2.84 (1.53–5.28) 2.19 (1.68–2.85) 2.16 (1.65–2.81) 3.05 (1.65–5.65) 2.48 (1.68–3.67) 2.21 (1.54–3.18) 2.14 (1.15–4.00) 1.88 (1.02–3.46) 2.35 (1.80–3.07) 2.07 (1.51–2.84) 2.64 (1.79–3.89) 2.40 (1.85–3.10) 1.47 (0.67–3.21) 2.43 (1.77–3.34) 2.00 (1.15–3.50) 2.39 (1.68–3.41) 2.17 (1.55–3.04) 1

5

VTd Better D-VTd Better

Moreau. The Lancet. 2019 Jul 6;394:29.

Philippe Moreau, MD

10

Efficacy: PFS From First Randomization

â&#x20AC;˘ Median (range) follow-up: 18.8 (0.0-32.2) months

18-month PFS 93%

% surviving without progression

100

D-VTd

80

60

Events, n (%)

40

20

D-VTd (n = 543)

VTd (n = 542)

45 (8)

91 (17)

HR (95% CI)

0.47 (0.330.67)

P value

<0.0001

85% VTd

Primary and final PFS analysis of Part 1

0 0

3

6

9

12

No. at risk D-VTd VTd

15

18

21

24

27

30

33

185 163

122 104

61 50

14 14

0 0

Months 543 542

520 519

501 497

492 475

442 413

346 319

261 233

53% reduction in the risk of progression or death in the D-VTd arm Moreau. The Lancet. 2019 Jul 6;394:29.

Post-consolidation PFS by MRD Status (MFC; 10–5) % surviving without progression

100

D-VTd MRD–

80 D-VTd MRD+ 60

MRD–

vs MRD+

40

HR (95% CI)

20

0.48 (0.30-0.78)

<0.0001

0.0028

P value

VTd MRD+

D-VTd vs VTd

0.31 (0.20-0.50)

VTd MRD–

0 0 No. at risk D-VTd MRD– VTd MRD– D-VTd MRD+ VTd MRD+

6

12

18

24

44 27 17 23

0 0 0 0

Months 344 232 148 243

241 167 105 152

132 88 53 75

PFS benefit for D-VTd versus VTd in patients achieving MRD negativity Avet-Loiseau et al. EHA 2019

78

Randomized Phase 2 GRIFFIN Study: RVd + Daratumumab in ASCT-Eligible Patients1

Key eligibility criteria: •Transplanteligible NDMM •18-70 years of age •ECOG PS score 0-2 •CrCl ≥30 ml/min

1:1 Randomization

Induction: Cycles 1-4 D-RVd 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

T R A N S P L A N T

Consolidation: Cycles 5-6

Maintenance: Cycles 7-32

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

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 Cycle 10+

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

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

21-day cycles

28-day cycles

Stem cell mobilization with G-CSF ± plerixafor Voorhees. Blood. 2020;136:936.

• 35 sites in US with enrollment from 12/2016 and 4/2018

Endpoints & 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 (measured by clonoSEQ; NGS 10–5), CR, ORR, ≥VGPR

GRIFFIN: Responses Deepened Over Time D-RVd 100 90 80

≥CR: 19.2%

12.1 7.1

6.1

Patients (%)

70 60 50

21.2

52.5

0

42.4

≥CR: 51.5%

62.6

59.6

30

10

7.2 6.2

9.1

40

20

≥CR: 27.3%

sCR Odds Ratio: 1.98 (95% CI, 1.12-3.49; P = 0.0177) ≥CR Odds Ratio: 2.53 (95% CI, 1.33-4.81; P = 0.0045)

39.4 26.3

End of induction

17.2 16.2

12.1

8.1

End of ASCT

End of consolidation

≥CR: 79.8%

≥CR: 13.4%

RVd 14.4 5.2

43.3 46.4

sCR CR VGPR PR SD/PD/NE

≥CR: 19.6%

32.0

≥CR: 42.3%

10.3

30.9 35.1

15.5 18.6

25.8

18.6

13.4

3.0

8.2

8.2

8.2

7.2

Clinical cutoff

End of induction

End of ASCT

End of consolidation

Clinical cutoff

Response rates and depths were greater for D-RVd at all time points Voorhees. Blood. 2020;136:936.

45.4

≥CR: 60.8%

Post-Consolidation MRD Negativity D-RVd

RVd

Odds Ratio (95% CI)

MRD negative regardless of response

46/104 (44.2)

15/103 (14.6)

4.70 (2.38-9.28)

<0.0001

MRD negative with CR or better

30/104 (28.8)

10/103 (9.7)

3.73 (1.71-8.16)

0.0007

In patients achieving CR or better

30/51 (58.8)

10/41 (24.4)

4.65 (1.76-12.28)

0.0014

In patients who received ASCT

45/94 (47.9)

14/78 (17.9)

4.31 (2.10-8.85)

<0.0001

MRD-Negative Status (10–5),a n (%)

P valueb

In ITT population

D-RVd improved MRD-negativity (10–5) rates at the end of consolidation aThe threshold of MRD negativity was defined as 1 tumor cell per 105 white cells. MRD status is based on assessment of bone marrow aspirates by next-generation sequencing in accordance with International Myeloma Working Group criteria. MRD assessments occurred in patients who had both baseline (with clone identified/calibrated) and post-baseline MRD (with negative, positive, or indeterminate result) samples taken (D-RVd, n = 71; RVd, n = 55). Patients with 81 a missing or inconclusive assessment were considered MRD positive. bP values were calculated from the Fisher’s exact test.

D-RVd: Estimated PFS and OS (>95%) at 2 Years…

12-month PFS rate 96.9% 95.3% 80 60 40

0

9

12 15 18 21 24 27 30 Months

103 104

93 98

77 93

71 89

69 89

No. at risk RVd D-RVd

•

67 88

64 86

46 59

20 27

6 5

0 0

97.9%

… but impressive results also achieved in the RVd arm !!

0

3

6

9

12 15 18 21 24 27 30 Months

99 99

96 99

88 97

No. at risk RVd D-RVd

103 101 104 100

Median follow-up = 22.1 months

Voorhees. Blood. 2020;136:936. Voorhees ASH 2019. Abstr 691.

D-RVd RVd

93.4%

40

0

6

95.8%

60

20

3

24-month OS rate

80

20

0

12-month OS rate 99.0%

100

% surviving

% surviving without progression

100

24-month PFS rate 95.8% D-RVd 89.8% RVd

84 96

78 93

55 70

29 36

7 9

0 0

Role of tandem ASCT

5-year PFS 53.5% vs 44.9% Cavo et al. EMN02 study

5-year OS 83.3% vs 72.6%

Maintenance with lenalidomide

McCarthy. JCO. 2017;35:3279.

Dimopoulos et al. The Lancet 2019;393:253.

GEM14

Arm A Lena/dexa

R Arm B Lena/dexa + Ixazomib d 1,8,15

MRD assessment

GEM12menos65

Maintenance trial after ASCT MRD neg

MRD pos

MRD annual

Stop

Lena/dexa X 3 years

CASSIOPEIA – 1080 patients – ASCO 2019

Eligibility for ASCT Yes Induction: 3-drug regimens VTD + CD38 RVD + CD38

No First option: VMP, Rd, VRD Second option: VCD, MPT

200 mg/m2 Melphalan followed by ASCT Tandem for high-risk disease ?

Consolidation: Triplet + CD38 ?

Other options : BP, CTD, MP

Maintenance Lenalidomide + Ixa / CD38

FRONTLINE THERAPY ESMO guidelines, 2020 ?

Now, letâ&#x20AC;&#x2122;s return to our patient case

Patient Case Example: 73-Year-Old Male Presents with:  Bone pain  Anemia Hb: 10.2 g/dL  Serum electrophoresis: M-spike: 4.2 g/dL; IF: IgG K  Bone marrow aspirate: 30% plasma cells  Cytogenetics (FISH): t(11;14)  Low-dose whole-body CT: diffuse bone lesions, spine  Creatinine: 0.9 mg/dL; β2-M: 2.5 mg/L, albumin 3.8 g/dL, LDH < normal  symptomatic multiple myeloma, ISS1, R-ISS1

Assessment 2: Now, what would you recommend for this patient?

1. Rd until progression 2. VRD x 8 followed by Rd until PD 3. VRD lite followed by R until PD 4. VMP-daratumumab x 9 followed by daratumumab until PD 5. Rd + daratumumab, until PD 6. VRD x 4 ď&#x192; ASCT prepared by mel 200 ď&#x192; len maintenance until PD 7. Uncertain

Panel Discussion: Individualized Approaches to Frontline Treatment Selection

This activity is provided by the Annenberg Center for Health Sciences at Eisenhower and developed in partnership with Clinical Care Options, LLC and the International Myeloma Foundation.

How to Treat Relapsed/Refractory Multiple Myeloma in 2020 JesĂşs F. San-Miguel MD, PhD

Director of Clinical and Translational Medicine Universidad de Navarra Pamplona, Spain

Disclosures JesĂşs F. San-Miguel, MD, PhD, has disclosed that he has received consulting fees from AbbVie, Amgen, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Karyopharm, Merck Sharpe & Dohme, Novartis, Roche, Sanofi, and Takeda.

Case Discussion 3: Managing a patient with relapsed disease after â&#x2030;Ľ 1 line of therapy

Patient Case Example  A 66-year-old man was diagnosed with IgA lambda R-ISS Stage-III myeloma ‒ BM showed 60% PC with t (4;14) plus 1q gain ‒ MC: 25 g/L; Hb: 10 g/dL, creatinine: 1.2 mg/dL; calcium: 9.2 mg/dL ‒ Extensive bony disease

 He received Dara-VTD + ASCT achieving sCR but MRD+, planned maintenance with lenalidomide for 2 years  After 23 months, he relapsed (18 months from ASCT)

Presurvey 3: In your current clinical practice, how would you treat this patient?

1. PI / lenalidomide / dexamethasone 2. PI / pomalidomide / dexamethasone 3. Anti-CD38 mAb / lenalidomide / dexamethasone 4. Anti-CD38 mAb / pomalidomide / dexamethasone 5. Anti-CD38 mAb / PI / dexamethasone 6. Rescue treatment followed by second ASCT 7. Uncertain

Expert Recommendations Expert Recommendations Brian G.M. Durie, MD Shaji Kumar, MD Thomas G. Martin, MD Philippe Moreau, MD S. Vincent Rajkumar, MD JesĂşs San-Miguel, MD

Anti-CD38 mAb / pomalidomide / dexamethasone Anti-CD38 mAb / PI / dexamethasone Anti-CD38 mAb / PI / dexamethasone Anti-CD38 mAb / PI / dexamethasone Anti-CD38 mAb / PI / dexamethasone Anti-CD38 mAb / pomalidomide / dexamethasone

Patient Case Example, Continued  He was treated with Dara-Vd x 8 cycles and achieved VGPR  He progressed 3 months later

Presurvey 4: In your current clinical practice, what approach would you recommend for this patient now?

1. PI / pomalidomide / dexamethasone 2. Anti-CD38 mAb or elotuzumab / pomalidomide / dexamethasone 3. Anti-CD38 mAb / carfilzomib / dexamethasone 4. Selinexor or selinexor combinations 5. Belantamab or belantamab combinations 6. Venetoclax or venetoclax combinations 7. Melflufen or melflufen combinations 8. Bispecific antibodies or CAR T-cell therapy

Expert Recommendations Expert Recommendations Brian G.M. Durie, MD Shaji Kumar, MD Thomas G. Martin, MD Philippe Moreau, MD S. Vincent Rajkumar, MD JesĂşs San-Miguel, MD

Bispecific antibodies or CAR T-cell therapy Bispecific antibodies or CAR T-cell therapy Bispecific antibodies or CAR T-cell therapy Bispecific antibodies or CAR T-cell therapy PI / pomalidomide / dexamethasone Bispecific antibodies or CAR T-cell therapy

Strategies at Relapse: How to Make the RIGHT CHOICE? Disease-related Factors Type of relapse, cytogenetic risk, extramedullary disease

Efficacy and Toxicity of previous treatments

Patient-related factors

Age (Trx eligibility), comorbidities, frailty

Further options

Response to Therapy is the Key Element to Evaluate Treatment Efficacy and Critical For Survival The definition of CR is suboptimal: ……The term CR is confusing for the patient

Who wouldn't want to know with precision the quality of patients’ response to therapy?

Newly diagnosed 1 x 1012 S.S. Patient

Disease burden CR

1 x 108

Stringent CR

1 x 104

Molecular/flow CR ?Cure?

0.0

Is MRD relevant in the relapse setting ?

Positive vs Negative MRD: Two Different Myelomas Results from an expanded meta-analysis (8,114 patients) NDMM (transplant-eligible)

NDMM (transplant-ineligible)

Progressive improvement in MRD technologies Munshi. ASH 2019. Abstr 4742.

RR MM

MRD Assessment in Pollux and Castor: Impact of Achieving MRD-Negativity (10-5) Pollux (Rd +/- Dara)

Bahlis. Leukemia. 2020;34:1875.

Castor (Vd +/- Dara)

Mateos. Clin Lymphoma Myeloma Leuk. 2020;20:509.

Should We Treat Biochemical Relapses?

PFS and OS According to Biochemical vs Clinical Relapses Endeavor study (n = 211 relapsing after ASCT) Biochemical Relapse PFS

Kd56 (n = 61) Vd (n = 57) 14 (23.0) 20 (35.1) NE 13.7 0.462 (0.232-0.922)

Progression/Death, n (%) Median PFS, mos HR (Kd56/Vd) (95% CI)

Clinical Relapse Progression/Death, n (%) Median PFS, mos HR (Kd56/Vd) (95% CI)

Kd: NR

OS

Kd: NR

Kd56 (n = 403) Vd (n = 408) 157 (39.0) 223 (54.7) 17.7 8.8 0.539 (0.439-0.662)

Kd: 17.7 m

Death, n (%) Median OS, mos HR (Kd56/Vd) (95% CI)

Kd56 (n = 404) Vd (n = 57) 177 (43.8) 196 (48.0) 44.0 36.8 0.801 (0.653-0.982)

Kd: 44 m Death, n (%) Median OS, mos HR (Kd56/Vd) (95% CI)

Kd56 (n = 60) Vd (n = 57) 12 (20.0) 13 (22.8) NE NE 0.768 (0.350-1.683)

Moreau. ASH 2018. Abstr 3243.

Should We Perform a Second ASCT at Relapse ?

66-Year-Old Man Relapsing after VTD + ASCT + Len x 2y:

Decisions based on the duration of the previous response

Late relapse (> 3-4 years post ASCT)

• Aggressive relapse: Reinduction (VRD/KRD +/- Dara) + 2nd ASCT • Biochemical Relapse: Repeat the initial approach or same as above

Early relapse (< 1 year post ASCT)

“Overcome drug resistance” Combination of non cross-resistant agents VRD (KRD)-PACE + Dara  RIC-Allo/CAR-T

Intermediate relapse (2-3 years post ASCT)

“Prolong survival until curative treatments are developed” Sequential novel agent combinations: Dara + PomDex…..KRD…

1st Relapse After Bortezomib-Based Induction (Len Naive or Exposed but Not Refractory) Lenalidomide-Based Regimens: Efficacy (Rd vs triplets with Rd backbone) First relapse after bortezomib-based induction Triplets (with Rd as backbone) DaraRd, KRd, IRd, or ERd

RD

Efficacy PFS HR (▲m)

POLLUX[1] (N = 569) DaraRd vs Rd

ASPIRE[2] (N = 792) KRd vs Rd

ELOQUENT-2[3] (N = 646) ERd vs Rd

TOURMALINE-MM1[4] (N = 722) IRd vs Rd

0.44 (▲ 27 mos)

0.66 (▲ 9.5 mos)

0.72 (▲ 4.5 mos)

0.74 (▲ 5.9 mos)

44.5 mos vs 17.5 mos

26.1 mos vs 16.6 mos

19.4 mos vs 14.9 mos

20.6 mos vs. 14.7 mos

Economical constrains: RD + Cyclophosphamide , VTD ( if TFI > 12 mos) This table is provided for ease of viewing information from multiple trials with different patient populations. Direct comparison across trials is not intended and should not be inferred.

1. Bahlis. Leukemia. 2020;34:1875. 2. Seigel. JCO. 2018;36:728. 3. Dimopoulos. Blood Cancer J. 2020;10:91. 4. Moreau. NEJM. 2016;374:1621.

1st Relapse Following Continuous Lenalidomide/Dex, Len Maintenance, VRD-Rd ... will be considered Len-Refrac

Proteasome Inhibitors-Based Regimens: Efficacy First relapse after IMiD-based induction

Doublets Kd or Vd

Efficacy

PFS HR (▲mos) Len Refract, experimental arm, % (mPFS)

Triplets based on PI DaraVD, PomVD Or Dara-KD

ENDEAVOR (N = 929) Kd vs Vd1,2

KCyDex (N = 198) KCd vs Kd3

CASTOR (N = 498) DaraVd vs Vd4

CANDOR (N = 466) DKd vs Kd5

IKEMA (N = 302) IKd vs Kd6

0.53 (▲ 9) 18.7 vs 9.4 mos

1 (▲ 5) 20.7 vs 15.2 mos

0.31 (▲ 9) 16.7 vs 7.1 mos

0.63 (▲ NE)

NE vs 15.8 mos

0.53 (▲NE)

NE vs 19.2 mos

24% (8.6 mos)

36% (26 mos)

18% (9.3 mos)

31.7% (NA)

32% (NA)

**PANORAMA-1 PanoVD vs VD (n=768)7: mPFS 12 mos vs 8 mos (HR: 0.63 (▲ 4 m) ; 27.6% CR rate; Only 19% Lena Refractory

Economical Constrains. VMP/VCD (16 m; 83% at 1 Yr)8

1. Dimopoulos. Lancet Oncol. 2016;17:P27. 2. Moreau. Leukemia. 2017;31:115. 3. Mateos. ASH 2020. Abstr 415.

4. Spencer. Haematologica. 2018;103:2079. 5. Dimopoulos. Lancet. 2020;396:186. 6. Moreau. EHA 2020. Abstr LB2603.. 7. San-Miguel. Lancet Oncol. 2014;15:1195. 8. Reece. JCO. 2008;26:4777.

Relapse/Refractory to Lenalidomide: Pomalidomide-based Regimens

Efficacy

OPTIMISM (N = 559) ICARIA (N = 307) ELOQUENT (N = 117) APOLLO (N= 304) PVd vs Vd1 EloPd vs Pd3 IsaPd vs Pd2 DPd vs Pd4

PFS HR (▲mos)

0.61 (▲ 4.1) 11.2* vs 7.1m

0.59 (▲ 5.0) 11.5 vs 6.5m

0.54 (▲ 5.6) 10.3 vs 4.7m

0.63 (▲ 5.5) 12.4 vs 6.9m

ORR, %

82 vs 50

60 vs 35

53 vs 26

51 vs 19.6 ≥ VGPR

*17.8 m in Len-Ref 1st - PomCyDex (n = 100): mPFS 7.6 m (10.4 m in PR)5 - KPomDex (EMN-011; n= 60): mPFS 18 m6 • Dara-Kd (CANDOR) in Lena Ref HR 0.457 • Isa-Kd (IKEMA) in Lena Ref HR 0.598 1. Richardson. Lancet Oncol. 2019;20:781. 2. Attal. Lancet. 2019;394:2096. 3. Dimopoulos NEJM. 2018;379:1811. 4. Dimopoulos. ASH 2020. Abstr 412.

5. Otero. EHA 2020. Abstract EP982. 6. Sonneveld. ASH 2018. Abstract 801. 7. Dimopoulos. Lancet. 2020;396:186. 8. Moreau. EHA 2020. Abstr LBA2603.

Next-generation IMiDs, CELMoDs™ (Cereblon E3 Ligase Modulation Drugs) in Multiple Myeloma CC-220 (iberdomide)…ORR:32%1 CC-92480……ORR: 54%2

Iber combinations:3

+ Dara (65% Dara Ref)….35% ORR + Btz (100% Btz Ref)….50% ORR

1. Lonial. ASH 2019. Abstr 3119.

2. Richardson. ASCO 2020. Abstr 8500.

3. Van de Donk. ASH 2020. Abstr 724.

Nowakowski. Blood. 2015;126:698.

Management of Patients > 3 line - Novel Drugs Under Development

Novel Alkylators: Melflufen



Melflufen is a highly lipophilic alkylating peptide, belonging to the novel class of Peptidase Enhanced Compounds



Intracellular amino-peptidases that are overexpressed in most malignant cells, will rapidly cleave melflufen releasing the hydrophilic, active alkylating metabolite



In vitro, treatment of tumor cells with melflufen results in 50-fold higher intracellular concentration of alkylating metabolite than those treated with equimolar melphalan alone.

In vivo, human xenograft mouse models treated with melflufen showed prolonged survival.

Melflufen 40 mg iv every 28 days + Dex 40 mg weekly

Phase II O-12-M1 trial

Phase II Horizon trial

RR MM pts ≥ 2 lines and refr. to last line.

N = 45 in combination cohort.

Median 4 (2-14) lines; 64% double refr.; 53% Alkylator refr.

• 125 RRMM pts. Median 5 (2-12) prior lines; 38% patients had high-risk cytogenetics; 88% double refr ; 71% triple refractory (PI + IMiD + anti-CD38)

ORR 31% .......... 5 VGPR & 9 PR patients PFS: 5.7m ….......DOR 8.4m; OS: 20.7m G3/4 AEs: Thromboc. (62%), Neutrop. (58%), Anemia: 42% Richardson. Lancet Haematology. 2020;7:E395.

ORR 29% .

PFS: 4.2 mos. OS: 11.6 mos G3/4AEs: Neutropenia (66%), Thromboc. (69%), Anemia: (37%) Mateos. ASH 2019. Abstr 1883. Richardson. EHA 2020. Abstr S1605.

Anchor Trial…ORR for (Melf-Dex) + Dara: 70%; PFS: 11.5 mos…….+ Btz: 60%

Ocio. ASH 2020. Abstr 417.

Selinexor Combination in Relapsed/Refractory MM •

Exportin 1 (XPO1) is the major nuclear export protein for Tumor suppressor proteins (TSPs, e.g., p53, IkB and FOXO). XPO1 is overexpressed in MM

•

Selinexor is an oral selective XPO1 inhibitor

Phase IIb STORM Trial: Selinexor + Dex (N = 122)1

 7 median prior lines of therapy (range: 3-18)  96% refractory to Btz, Len, carf, pom, dara

PFS

Phase III BOSTON Trial: Selinexor + Vd (N = 402)2  1-3 prior lines of therapy (median: 2; 19% had 3 lines)  76% exposed to prior PI, 38% prior len

Median PFS, Mos SVd 13.93 Vd 9.46 HR: 0.70 (P = .0075)

ORR: 26% ≥ MR 39%; ≥ SD 79% mDOR: 4.4 months mOS: 8.6 months mDOR: 20.3 v 12.9 mos

Median PFS: 3.7 mos

AEs: thrombocytopenia (73%, 58% G3-4), anemia (67%, 44% G3-4), fatigue (73%; 25% G3-4); GI: nausea (72%, 10% G3/4), anorexia (56%; 5% G3/4), weight loss (50%; 1% G3/4)

mOS: NR vs 25 mos

ORR: 76% vs 62% (28% VGPR (17% sCR/CR)) PN G ≥ 2: 21% vs 34%, p=0.001 Seli-Pd (STOMP): 52 Pts: 58% ORR; 12m PFS. Chen. ASH 2020. Abs 726.

1. Chari. NEJM. 2019;381:727. 2. Grosicki. Lancet. 2020;396:1563.

VENETOCLAX+ BortDex vs BortDex ( 291 patients, 2:1 random) BELLINI Study Venetoclax is a small molecule BCL-2 inhibitor1, induces cell death in MM cell, particularly t(11;14) & high BCL2â&#x20AC;¦.0RR: 21%...60%,

PFS in all patients

PFS in patients with t(11;14)

PFS by t(11;14) and BCL2 status PFS

23.2 m (VenBd) 11.4 m (PboBd) HR: 0.60; P = .001 NR vs 9.3; HR: 0.09; P = .003

Venetoclax: 800mg QD; BtzDex: C1-8 /21d....C9/35d ....until progression

NR vs 9.9; HR: 0.30; P < .001

Harrison. ASH 2019. Abstr 142.

Belantamab Mafodotin (DREAMM-2 Study) in Refractory MM •

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

N = 196 after ≥ 3 prior lines of therapy; refractory or intolerant to IMiDs, PIs, and CD38 antibodies Median 7 (3-21) prior lines in 2.5 mg/kg cohort and 6 (3-21) in 3.4 mg/kg cohort OS

ORR: 32-35% (by dose) 18% VGPR, 5% CR or sCR at 3.4 mg/kg ≥ MR 40%; ≥ SD 57% at 3.4 mg/kg Median DOR: 6.2 months

Probability of OS

100 80

Treatment 2.5 mg/kg 3.4 mg/kg

60 40 50% probability 20 0

0 1

2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

Median, Mos (95% CI)

Mos From Randomization Bela maf 2.5 mg/kg (n = 97)

Bela maf 3.4 mg/kg (n = 99)

Main AEs: Corneal events: 72% to 77%; Thrombocytopenia: 36% to

OS

14.9 (9.9-NR)

14.0 (10.0-NR)

57%; Infusion-related reaction: 16% to 21%

PFS

2.8 (1.6-3.6)

3.9 (2.0-5.8) Lonial. ASCO 2020. Abstr 8536.

DREAMM-6: Bela Maf + Vd (ORR: 78%) DREAMM-5: Bela Maf Combinations DREAMM-8: Bela Maf + Pd

Nooka. ASCO 2020. Abstr 8502.

NCT04126200

DREAMM-7: Bela Maf + Vd vs DaraVd DREAMM-9: Bela Maf + SoC in ND MM

NCT04484623 29 Pts ( penta Ref)….86% ORR (Trudel. ASH 2020. Abs 725)

NCT04246047 NCT04091126

MULTIPLE MYELOMA A model for scientific and clinical progress from biology to therapeutics

Progress in MM Cell Biology Prognostic factors and

Discovery of New Drugs Singular mechanism of action

Myeloma subtypes*

Individualised and tailored treatment *MM should not be considered a single entity.

Now, letâ&#x20AC;&#x2122;s return to our patient case

Patient Case Example  A 66-year-old man was diagnosed with IgA lambda R-ISS Stage-III myeloma ‒ BM showed 60% PC with t (4;14) plus 1q gain ‒ MC: 25 g/L; Hb: 10 g/dL, creatinine: 1.2 mg/dL; calcium: 9.2 mg/dL ‒ Extensive bony disease

 He received Dara-VTD + ASCT achieving sCR but MRD+, planned maintenance with lenalidomide for 2 years  After 23 months, he relapsed (18 months from ASCT)

Assessment 3: Now, how would you treat this patient?

1. PI / lenalidomide / dexamethasone 2. PI / pomalidomide / dexamethasone 3. Anti-CD38 mAb / lenalidomide / dexamethasone 4. Anti-CD38 mAb / pomalidomide / dexamethasone 5. Anti-CD38 mAb / PI / dexamethasone 6. Rescue treatment followed by second ASCT 7. Uncertain

Patient Case Example, Continued  He was treated with Dara-Vd x 8 cycles and achieved VGPR  He progressed 3 months later

Assessment 4: What approach would you recommend for this patient now?

1. PI / pomalidomide / dexamethasone 2. Anti-CD38 mAb or elotuzumab / pomalidomide / dexamethasone 3. Anti-CD38 mAb / carfilzomib / dexamethasone 4. Selinexor or selinexor combinations 5. Belantamab or belantamab combinations 6. Venetoclax or venetoclax combinations 7. Melflufen or melflufen combinations 8. Bispecific antibodies or CAR T-cell therapy

Panel Discussion: Managing patients with relapsed disease after â&#x2030;Ľ 1 line of therapy

This activity is provided by the Annenberg Center for Health Sciences at Eisenhower and developed in partnership with Clinical Care Options, LLC and the International Myeloma Foundation.

Triple-Class Refractory: Selecting BCMA-Directed Therapy?

Thomas G. Martin, MD

Clinical Professor of Medicine Co-Director, Myeloma Program University of California, San Francisco Medical Center San Francisco, California

Faculty Thomas G. Martin, MD

Clinical Professor of Medicine Co-Director, Myeloma Program University of California, San Francisco Medical Center San Francisco, California Thomas G. Martin, MD, has disclosed that he has received consulting fees from GSK and funds for research support from Amgen, Johnson & Johnson â&#x20AC;&#x201C; Janssen, Sanofi, and Seattle Genetics.

Patient Scenario  67-year-old male presented with standard risk IgG kappa MM ‒ B2M 3.4, Alb 3.6, LDH 150, Cr 1.1, Ca 8.7, FISH: hyperdiploid (+5, +9, +15)  He has received 3 prior lines of therapy ‒ RVd for 6 cycles followed by ASCT and continuous R maintenance for 36 months (progresses on maintenance –refractory to R 10 mg QD) ‒ DaraKd for 19 months achieves VGPR then progresses (Triple class refractory) ‒ EloPd for 6 cycles achieves PR then PD (3 prior lines: refractory to R/P/K/Dara)  Options for triple-class drug refractory (IMiD, PI, CD38) are limited

Presurvey 5: In your current practice, what would you recommend next for this patient?

1. Triplet or quadruplet combination with previously used agents 2. Cyclophosphamide-based combination chemotherapy 3. Selinexor + dexamethasone 4. Belantamab mafodotin 5. BCMA-targeted CAR T-cell 6. BCMA-targeted bispecific T-cell engager 7. Salvage ASCT 8. Salvage AlloSCT 9. Uncertain

Expert Recommendations Expert Recommendations Brian G.M. Durie, MD Shaji Kumar, MD Thomas G. Martin, MD Philippe Moreau, MD S. Vincent Rajkumar, MD JesĂşs San-Miguel, MD

BCMA-targeted CAR T-cell BCMA-targeted CAR T-cell BCMA-targeted CAR T-cell BCMA-targeted CAR T-cell Cyclophosphamide-based combination chemotherapy BCMA-targeted CAR T-cell

Poll 5: What would be your expectation for survival in patients with R/R MM? 1. Triple-class refractory: expected OS > 2 years 2. Triple-class refractory: expected OS 1-2 years 3. Triple-class refractory: expected OS < 10 months 4. Penta-refractory: expected OS > 6 months 5. Survival not measurable with novel BCMA-targeted therapies 6. Uncertain

Expert Recommendations Expert Recommendations Brian G.M. Durie, MD Shaji Kumar, MD Thomas G. Martin, MD Philippe Moreau, MD S. Vincent Rajkumar, MD JesĂşs San-Miguel, MD

Triple-class refractory: expected OS > 2 years Triple-class refractory: expected OS 1-2 years Triple-class refractory: expected OS < 10 months Triple-class refractory: expected OS 1-2 years Triple-class refractory: expected OS > 2 years Triple-class refractory: expected OS 1-2 years

Patients with Triple-Class Refractory MM - The unmet need with poor prognosis • MAMMOTH Study • Retrospective review of R/R MM • 275 patients • PI, IMiD, and CD38 exposed • Median OS was < 9 months in MAMMOTH in patients with disease refractory to anti-CD38 mAbs

Median OS in MAMMOTH study from T0 mOS (95% CI), months All: 8.6 (7.2–9.9) Not triple-refractory: 11.2 (5.4–17.1) Triple- and quad-refractory: 9.2 (7.1–11.2) Penta-refractory: 5.6 (3.5–7.8)

• Median OS was < 6 months if penta-refractory • Current treatment options include conventional chemotherapy, salvage ASCT, recycling previous regimens, selinexor + dexamethasone, belantamab mafodotin and clinical trials

Gandhi. Leukemia. 2019;33:2266.

Triple-Class Refractory: When All Else Fails Chemotherapy

HDAC / ADC XPO inhibitors

Monoclonal Antibodies

IMiDs / CELMoDs/ Novel Drugs

BCMA Abs Bispecifics/ ADCs

Cellular therapies BCMA CARs

Doxorubicin, Liposomal doxorubicin

Panobinostat/ Vorinostat

Next Gen 38 SAR442085

CC-220 (Iberdomide), CC-92480

Teclistamab AMG-701, CC-93269

Cilta-cel (JNJ-4528) Ide-cel (bb2121), Orva-cel (JCARH125)

Cyclophosphamide, Bendamustine, Melphalan

Belantamab Mafodotin

TAK-079, TAK-573, TAK-169

Venetoclax Melflufen

TNB-3838, REGN5458 PF-06863135

LCAR-B38M, bb21217, P-BCMA-101

Selinexor

MOR202, Others

BFCR4350A Talquetamab

MEDI2228, CC-99712 FOR46

Lummicar-2 (CT053) ALLO-715 ALLO-605 (TurboCAR)

PACE, HyperCAD

*Blue = approved

Green = ongoing clinical trials

9

Immunotherapy for MM - Targets and Therapeutics • BCMA Therapeutics

• Current MM Targets • BCMA • • • • • • • • •

GPRC5D FcRH5 CD138 CD38 CD19 SLAMF7 ASCT2 CD229 Kappa light chain

• CARs

• Idecaptagene Vicleucel

• Ciltacabtagene autoleucel BCMA

• ADCs

• Belantamab mafodotin • MEDI2228

• Bispecific antibodies T-cell

• Teclistamab • ~6 others at ASH2020 Cho. Front Immunol 2018; 9:1821

Belantamab Mafodotin (GSK2857916): A BCMA-Targeted Antibody Drug Conjugate ADC

• Belantamab mafodotin • afucosylated anti-BCMA • Toxin – MMAF • Phase I study – Part 2: 3.4 mg/kg Q3W – Potent activity (ORR ~60%) – Ocular toxicity (~63%) – Thrombocytopenia (34%)

BCMA

Lysosome

BCMA

ADCC Effector Cell

BCMA

GSK2857916

x

• humanized, IgG1

BCMA

Fc Receptor

Malignant Plasma Cell

Fc region of –Target specific the antibody –Enhanced ADCC Linker

–Stable in circulation

Drug

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

Cell death

Mechanisms of Action: 1. ADC mechanism 2. ADCC mechanism 3. Immunogenic cell death

Tai. Blood. 2014;123:3128.

Trudel. Lancet Oncol. 2018;19:1641.

DREAMM-2 Study Design A phase II, open-label, randomized 2-dose study in RR MM after an anti-CD38 therapy.

Primary analysis of DREAMM-2 completed at median follow-up of 6.3 and 6.9 months for the 2.5 mg/kg and 3.4 mg/kg cohorts, respectively. Additional analysis was completed at 13 months of follow-up. *Patients stratified based on number of previous lines of therapy (≤4 vs >4) and presence or absence of high-risk cytogenetic features; **According to International Myeloma Working Group 2016 criteria.

Treatment until disease progression or unacceptable toxicity

• Measurable disease • ECOG PS 0-2 • 3 or more prior lines of antimyeloma therapy • Refractory to a PI and an IMiD and progression on an anti-CD38 antibody • Prior anti-BCMA therapy excluded • Prior auto-SCT allowed; allo-SCT excluded

RANDOMIZE 1:1*

POPULATION

Primary Outcome

Belantamab mafodotin 2.5 mg/kg IV, every 3 weeks (n=97) Belantamab mafodotin 3.4 mg/kg IV, every 3 weeks (n=99)

ORR: % of patients with ≥PR**

Characteristic

Key baseline characteristics=>

Key Secondary Outcomes

 DOR (time from ≥PR until PD or death due to PD  Other efficacy: CBR, PFS, OS, TTBR, TTR  Safety, including keratopathy (MECs)

2.5 mg/kg

3.4 mg/kg

Median prior Lines

7 (3-21)

6 (3-21)

Triple class exposed

~100%

~100%

BCMA, B-cell maturation antigen; CBR, clinical benefit rate; DOR. duration of response; ECOG PS, Eastern Cooperative Oncology Group performance status; IMiD, immunomodulatory imide drug; IV, intravenous; MEC, microcyst-like epithelial change; ORR, overall response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; RRMM, relapsed/refractory multiple myeloma; SCT, stem-cell transplantation; TTBR, time to best response; TTR, time to response.

1. Lonial. Lancet Oncol. 2020;21:207‐221. 2. Lonial. Poster presented at: ASCO 2020. Abstr 436.

DREAMM-2 Results Key efficacy data Response

2.5 mg/kg N = 97

Follow-up ORR, n (%) sCR CR VGPR PR

Key safety data 3.4 mg/kg N = 99

13 months 31 (32%) 2 (2%) 5 (5%) 11 (11%) 13 (13%)

35 (35%) 2 (2%) 3 (3%) 18 (18%) 12 (12%)

Median PFS (95% CI), mo

2.8 (1.6-3.6)

3.9 (2.0-5.8)

Median DoR estimate, mo

11

6.2

Median OS estimate, mo

13.7

13.8

• ORRs were comparable in both HR and SR patients

Lonial. Lancet Oncol. 2020;21:207-221.

Lonial. 2020 ASCO Annual Meeting. Abstr 436.

2.5 mg/kg N = 95

3.4 mg/kg N = 99

Grade 3-4 AE (≥20%) Keratopathy Thrombocytopenia Anemia

44 (46%) 21 (22%) 20 (21%)

42 (42%) 32 (32%) 27 (27%)

Serious AE SAE leading to death

40 (42%) 3 (3%)

47 (47%) 9 (9%)

AE, n (%)

• Overall safety at 2.5 mg/kg

• Keratopathy (Gr 1-4) • Thrombocytopenia (Gr 1-4)

72% 38%

• 2 deaths were considered potentially treatment related:

• 2.5 mg/kg: sepsis (n = 1) • 3.4 mg/kg: hemophagocytic lymphohistiocytosis (n = 1)

• Overall rates of anemia and thrombocytopenia were higher in HR than SR

ADC Summary in RRMM • What more do we need?

1. Improved response rates and durability with combinations Trudel et al. ASH 2020, Abstr 725: Belantamab + Pom Popat et al. ASH 2020 , Abstr 1419: Belantamab + Vd

2. Improved safety

Split/intermittent dosing of Belantamab Novel toxin: Kumar et al. ASH 2020 , Abstr 179 – MEDI2228 [pyrrolobenzodiazepine dimer] Shah et al. ASH 2020, Abstr 3030 – STRO-001 [maytansinoid]

3. Additional targets

CD74/CD46/SLAMF7

4. Mechanism of resistance Antigen loss P-glycoprotein

BCMA CAR T-Cell Studies: Efficacy Ide-cel (bb2121) PhII Cell Dose

150

Median follow-up, mos

300

450

13.3

bb21217

Cilta-cel (JNJ-4528)

Orva-cel (JCAR-H125)

150

300

450

0.75 x 106 / kg

300

450

600

17.6

4.0

3.3

11.5 (3.0 â&#x20AC;&#x201C; 17.0)

9.5

8.8

2.3

Response Rate ORR

50%

69%

82%

83%

43%

57%

100%

95%

89%

92%

CR

25%

29%

39%

33%

0%

14%

86%

37%

42%

29%

4

70

54

7

6

4

21

11

11

3

50%

31%

48%

100%

83.3%

100%

85.7%

Median DoR, mos

NR

9.9

11.3

11.1

NR

NR

NR

NR

NR

NR

Median PFS

2.8

5.8

12.1

NR

NR

NR

NR

9.3

NR

NR

MRD Evaluable for MRD, # MRD- (%)

72.7% 90.9%

100%

[updates at ASH2020: Cilta-cel PhII, bb2121 PhI, bb2121-7, Poseida BCMA-CAR, CD19-BCMA dual targeted CAR, Allo715-BCMA] Munshi. ASCO 2020. Abstr 8503. Berdeja. ASH 2019. Abstr 927. Berdeja. ASCO 2020. Abstr 8505; Mailankody. ASCO 2020. Abstr 8504.

BCMA CAR T-Cell Studies: Safety Ide-cel (bb2121) PhII

bb21217

Cilta-cel (JNJ-4528)

Orva-cel (JCAR-H125)

84%

66%

93%

89%

4% / <1% / <1%

5% / 0% / 3%

7%

3%

Median Onset, Days

1 (1 – 12)

3 (1 – 20)

7 (2 – 12)

2 (1 – 4)

Median Duration

5 (1 – 63)

4 (1 – 28)

4 (2 – 64)

4 (1 – 10)

18%

24%

10%

13%

3% / 0% / 0%

5% / 3% / 0%

3%

3%

Median Onset, Days

2 (1 – 10)

7 (3 – 24)

NR

4 (1 – 6)

Median Duration

3 (1 – 26)

NR

NR

4 (1 – 10)

Cytokine Release Syndrome All Grades Grade 3 / 4 / 5

Neurotoxicity All grades Grade 3 / 4 / 5

[updates at ASH2020: Cilta-cel PhII, bb2121 PhI, bb2121-7, Poseida BCMA-CAR, CD19-BCMA dual targeted CAR, Allo715-BCMA] Munshi. ASCO 2020. Abstr 8503. Berdeja. ASH 2019. Abstr 927. Berdeja. ASCO 2020. Abstr 8505; Mailankody. ASCO 2020. Abstr 8504.

CAR T-Cell Summary in RRMM

• What more do we need?

CARTITUDE 1 – JNJ-4528

1. Improved CARs

Faster Manufacturing or Off-the-shelf Better T-cells – Tscm/cm Persistence: a good “second wave”

2. Improved patient selection Early relapse (1-3 PLT) Frontline: replace ASCT? Lower burden of disease

3. Additional targets and combinations GPRC5D +/- BCMA CD19 + BCMA CAR + BISPECIFIC, CAR + CelMOD

4. Mechanism for resistance Antigen loss Myeloma “stem cell”

Madduri. ASH 2019. Abstr 577. Raje. ASCO 2018. Abst 8007.

Teclistamab â&#x20AC;&#x201C; ASCO 2020 Dosing - Weekly step-up

STUDY ENROLLMENT AND RESULTS - 78 patients enrolled - 6 PLT, 31% HR cytogenetics - 80% triple class refractory - Toxicity: - CRS: overall 56% - Neurotox: 8% Gr 1-4 (3% Gr 3-4) Usmani. ASCO 2020. Abstr 100.

Teclistamab - Results CR

VGPR

PR

Usmani. ASCO 2020. Abstr 100.

BCMA Bispecific mAb Studies: Efficacy AMG420

CC-93269

Teclistamab

400 ug/day

610 mg and 6 mg

270 ug / kg

N

10

9

12

Median follow-up, mos

NR

NR

NR

ORR

70%

88.9%

67%

CR

50%

44.4%

25%

10

NR

5

50%

NR

80%

9.0 (range 5.8 – ≥13.6)

11 of 13 ongoing

16 of 21 ongoing

Dose

Response Rate

MRD Evaluable for MRD, # MRD- (%) Median DoR, mos

[Many bispecific antibody updates and new presentations at ASH 2020] Topp. JCO. 2020;38:775. Abstr 8503. Costa. ASH 2019. Abstr 143. Usmani. ASCO 2020. Abstr 100

Bispecific Summary in RRMM â&#x20AC;˘ What more do we need?

1. Phase II study results

Optimized step-up dosing Responses in RRMM including EMD and HR Convenient schedule for long-term dosing

2. Improved safety

Outpatient administration Prophylactic use of tocilizumab/other CRS mitigation strategies

3. Additional targets

CD38/SLAMF7/GPRC5D/FcRH5

4. Improved response rates and durability with combinations Bispecific mAb + IMiDs, PIs, CD38 Abs Bispecific + CelMODs

Disadvantages

Advantages

BCMA Therapeutics – Advantages/Disadvantages Antibody–drug conjugate

CAR T-cells

Bispecific antibody

Off-the-shelf

Personalized

Off the shelf

Targeted cytotoxicity Not dependent on T-cell health

Targeted immuno-cytotoxicity

Targeted immuno-cytotoxicity

No lymphodepletion No steroids

Single infusion (“one and done”)

No lymphodepletion Minimal steroids

Available to any infusion center Outpatient administration

Potentially persistent Fact accredited center required (hospitalization likely required)

Initial hospitalization required

Currently requires REMS/Ophtho

CRS and Neurotoxicity; requires ICU and Neurology services

CRS and Neurotoxicity possible

Single agent activity low in CD38 refractory patients

Dependent on T-cell health (manufacturing failures)

Dependent on T-cell health (T-cell exhaustion)

Requires continuous administration

Requires significant support social – caregiver required

Requires continuous administration

$$

$$$$

$$$

Sequencing of BCMA Targeted Therapeutics • As of Now  Belantamab Mafodotin [only FDA approved modality] • Triple Refractory => many centers chose clinical trial

Sequencing of BCMA Targeted Therapeutics • As of Now  Belantamab Mafodotin [only FDA approved modality] • Triple Refractory => many centers chose clinical trial

• In 1st /2nd Quarter 2021  there will be a choice [Guideline from IMS]

• BCMA Targeted CAR T-cell (Ide-cel)  Fit, well-resourced, triple refract • Belantamab Mafodotin  less fit, limited social support, rapidly progressive • 3rd/4th Quarter potentially a second CAR – Cilta-cel may be approved

Sequencing of BCMA Targeted Therapeutics • As of Now  Belantamab Mafodotin [only FDA approved modality] • Triple Refractory => many centers chose clinical trial

• In 1st /2nd Quarter 2021  there will be a choice [Guideline from IMS]

• BCMA Targeted CAR T-cell (Ide-cel)  Fit, well-resourced, triple refract • Belantamab Mafodotin  less fit, limited social support, rapidly progressive • 3rd/4th Quarter potentially a second CAR – Cilta-cel may be approved

• In 2022 and beyond  other CARs, ADCs and bispecific mAbs • • •

CD38 + triplet (induction)  BCMA CAR consolidation  BCMA – ADC early relapse CD38 + doublet/triplet for induction  bispecific maintenance  BCMA-ADC relapse BCMA-ADC + doublet induction  GPRC5D CAR at relapse  FcRH5 bispecific RRMM

Future Strategies in Multiple Myeloma Where and in what combination will immunotherapy have the most Impact?

Newly Diagnosed MYELOMA Symptomatic

M Protein (g/L)

100

MM

50

SMM

Plateau remission

EARLY RELAPSE

Front-line therapy

2.

RELAPSE

Induction

REFRACTORY RELAPSE

1.

RELAPSE

--- QUAD (mAb) Consolidation

20

2nd-line therapy

Maintenance

Frontline QUAD: No transplant

3rd-line therapy

Early Relapse (1-3 Prior Lines) Novel CAR (Different target) Novel Ab: ADC vs. Trivalent Ab

MRD (+): Consolidation: CAR vs. Bispecific MRD (-): Maintenance: Len (CELMoD)/mAb vs. Bispecific

Late Relapse (off-the shelf) Third party cellular therapy (NK + T) Crispr strategies

Conclusions: Next Generation Therapeutics • Triple Class Refractory is an UNMET Need

• Belantamab mafodotin: BCMA-ADC  approved in this population • BCMA directed CAR T-cell therapeutics  will be available soon • Initial bispecific antibody results promising • Off-the-shelf products, toxicity is manageable • Bind BCMA, GPRC5D, FCRH5

• Need better understanding mechanisms of resistance • Loss of antigen • T cell burnout/exhaustion

• Combinations of novel-novel drugs on-going • Sequencing of these therapeutics will be important and future sequencing studies will be important

Now, letâ&#x20AC;&#x2122;s return to our patient case

Patient Case Example: R/R MM  67-year-old male presented with standard risk IgG kappa MM ‒ B2M 3.4, Alb 3.6, LDH 150, Cr 1.1, Ca 8.7, FISH: hyperdiploid (+5, +9, +15)

 He has received 3 prior lines of therapy ‒ RVd for 6 cycles followed by ASCT and continuous R maintenance for 36 months (progresses on maintenance –refractory to R 10 mg QD) ‒ DaraKd for 19 months achieves VGPR then progresses (Triple class refractory) ‒ EloPd for 6 cycles achieves PR then PD (3 prior lines: refractory to R/P/K/Dara)

 Options for triple-class drug refractory (IMiD, PI, CD38) are limited  Approved agents are available ‒ Belantamab mafodotin ‒ Selinexor + Dex ‒ Alkylator therapy [cyclophosphamide-based, bendamustine, 2nd autologous SCT]

Assessment 5: Now, what would you recommend next for this patient?

1. Triplet or quadruplet combination with previously used agents 2. Cyclophosphamide-based combination chemotherapy 3. Selinexor + dexamethasone 4. Belantamab mafodotin 5. BCMA-targeted CAR T-cell 6. BCMA-targeted bispecific T-cell engager 7. Salvage ASCT 8. Salvage AlloSCT 9. Uncertain

Panel Discussion: BCMA-Directed Therapy

This activity is provided by the Annenberg Center for Health Sciences at Eisenhower and developed in partnership with Clinical Care Options, LLC and the International Myeloma Foundation.

Myeloma: Future Directions S. Vincent Rajkumar, MD

Edward W. and Betty Knight Scripps Professor of Medicine Mayo Clinic Rochester, Minnesota

Myeloma: Future Directions S. Vincent Rajkumar Professor of Medicine, Mayo Clinic @VincentRK

Scottsdale, Arizona Mayo Clinic College of Medicine Mayo Clinic Comprehensive Cancer Center

Rochester, Minnesota

Jacksonville, Florida

Speaker Name No conflicts to disclose

New Anti-CD38 antibodies

• TAK-079 • MOR 202 • SAR 442085 • Problem: Resistance • Abstract 721: Biallelic loss of BCMA (del 16p) Samur. ASH 2020. Abstr 721

Newer IMiDs/Cel Mods

• Iberdomide (CC-220) (Cereblon ligase modulator)

− ASH 2020 Abstract 724: First Results of Iberdomide + Dara/Dex or Iberdomide + Vd in RR MM

• CC-92480

Image: Matyskiela. J Med Chem 2018;61:535

Bispecific Antibodies

AMG 701: Abstr 181, Saturday 12-1:30 PM Teclistamab: Abstr 180, Saturday 12-1:30 PM CC 93269 Kumar, Rajkumar. JCO 2020. 38;18:2077.

Novel Bispecifics BFCR4350A: Bispecific targeting FcRH5 and CD3

• Cohen et al, Abstract 292: Saturday Dec 5, 2-3:30 PM

Talquetamab: Bispecific targeting GPRC5D and CD3

• Chari et al, Abstract 290: Saturday Dec 5, 2-3:30 PM

Novel CAR-T Approaches

Yi Lin 2020

Novel CAR-T ALLO-647: allogenic, off-the-shelf CAR-T • Mailankody, et al. Abstract 129: Saturday, Dec 5 9:30-11 AM Other approaches • Combined CD19-BCMA • Multiantigen targeting • Individualized targeting • CAR-NK

Myeloma: Future State Multiple Relapse

Refractory to IMiD, PI, Anti-CD38

Rajkumar SV © 2020

Refractory to IMiD, PI, Anti CD38, Alkylators, and Anti BCMA

Myeloma: Future State Multiple Relapse

Refractory to IMiD, PI, Anti-CD38

Anti BCMA strategy

Combinations with Cyclophosphamide that do not have IMiD, PI, Anti CD38

BCMA ADC (eg., Belantamab) Bispecific Anti BCMA BCMA CAR-Ts

Rajkumar SV © 2020

Refractory to IMiD, PI, Anti CD38, Alkylators, and Anti BCMA

Myeloma: Future State Multiple Relapse

Refractory to IMiD, PI, Anti-CD38

Refractory to IMiD, PI, Anti CD38, Alkylators, and Anti BCMA

Anti BCMA strategy Existing drugs: Combinations with Cyclophosphamide that do not have IMiD, PI, Anti CD38

BCMA ADC

Elotuzumab

(eg., Belantamab)

Selinexor

New Monoclonals

Venetoclax

Iberdomide, CC-94480

Bispecific

Panobinostat

New ADCs

Anti BCMA

Bendamustine

New bi-specifics

VDT PACE

New CAR-Ts

BCMA CAR-Ts Rajkumar SV © 2020

New Drugs:

Panel Discussion: Future Directions for Myeloma

Proposed 2021 Treatment Algorithms Panel Discussion

When Should Treatment Be Initiated?

Potential New Myeloma or Smoldering Myeloma

Any Myeloma Defining Events?

•CRAB •≥60% PC •FLC ≥100 •MRI >1 focal lesion

Treat as Myeloma Rajkumar SV © 2020

When Should Treatment Be Initiated?

Potential New Myeloma or Smoldering Myeloma

Any Myeloma Defining Events?

•CRAB •≥60% PC •FLC ≥100 •MRI >1 focal lesion

No Myeloma Defining Events (SMM) High-Risk SMM (Median TTP ≈2 years)

Intermediate or Low-Risk SMM

Treat as Myeloma Rajkumar SV © 2020

When Should Treatment Be Initiated?

Potential New Myeloma or Smoldering Myeloma

Any Myeloma Defining Events?

•CRAB •≥60% PC •FLC ≥100 •MRI >1 focal lesion

Treat as Myeloma

No Myeloma Defining Events (SMM) High-Risk SMM (Median TTP ≈2 years)

Intermediate or Low-Risk SMM

Observation Rajkumar SV © 2020

When Should Treatment Be Initiated?

Potential New Myeloma or Smoldering Myeloma

Any Myeloma Defining Events?

•CRAB •≥60% PC •FLC ≥100 •MRI >1 focal lesion

Treat as Myeloma

No Myeloma Defining Events (SMM) High-Risk SMM (Median TTP ≈2 years)

Early Therapy With Len or Rd

Clinical Trials

Intermediate or Low-Risk SMM

Observation Rajkumar SV © 2020

Myeloma: Frontline Treatment Newly Diagnosed MM* Not Transplant Candidate

VRd x 9 months followed by Len maintenance or DRd

*Based on CALGB 100104, S0777, IFM-2009, CTN 0702, HOVON, MAIA, CASSIOPEIA ¶ VTd/VCd if VRd not available

Rajkumar SV © 2020

Myeloma: Frontline Treatment Newly Diagnosed MM* Not Transplant Candidate

Transplant Candidate VRd¶ or Dara-based quadruplet induction

VRd x 9 months followed by Len maintenance or DRd

Auto-SCT followed by Maintenance (Len for std risk; Len plus Bortezomib for high risk)

*Based on CALGB 100104, S0777, IFM-2009, CTN 0702, HOVON, MAIA, CASSIOPEIA ¶ VTd/VCd if VRd not available

Selected patients with standard risk MM: VRd x4 cycles Len Maintenance Delayed Transplant

Rajkumar SV © 2020

Myeloma: Frontline Treatment Newly Diagnosed MM Not Transplant Candidate

1 - D-Rd

Transplant Candidate 1 - VRD or Dara-based quad induction 2 â&#x20AC;&#x201C; VTD / VCD

2 - VRD followed by Len (VMP-Dara; Rd)

Auto-SCT Maintenance [Len for std risk; (Len)+PI-based for high risk] Tandem for high-risk

No Delayed Transplant Outside clinical trials

P. Moreau

Myeloma: First Relapse First Relapse* Not Refractory to Lenalidomide¶

DRd

Alternatives including if Dara Refractory: KRd or Ixa-Rd

*Consider salvage auto transplant in eligible patients ¶Relapse occurring while off all therapy, or while on small doses of single-agent lenalidomide, or on bortezomib maintenance Rajkumar SV © 2020

Myeloma: First Relapse First Relapse* Not Refractory to Lenalidomide¶

DRd

Alternatives including if Dara Refractory: KRd or Ixa-Rd

Refractory to Lenalidomide

DVd, DPd Isa-Pd

Alternatives including if Dara Refractory: KPd or Dara-KPd, EPd, DKd Frail: Ixa-Pd

*Consider salvage auto transplant in eligible patients ¶Relapse occurring while off all therapy, or while on small doses of single-agent lenalidomide, or on bortezomib maintenance Rajkumar SV © 2020

Myeloma: First Relapse First Relapse Not Refractory to Lenalidomide

1 - DRd

Alternatives including: KRd, IRd, ERd; Kd-Dara / Kd-Isa

Refractory to Lenalidomide

Kd-dara, Kd-Isa Pom-Vd, (PomD-Dara, PD-Isa)

Alternatives: KPD, PDElo Frail: Pd, IxaPd, PCD

! Challenge : patients progressing on frontline dara P. Moreau

Myeloma: Second or Higher Relapse First Relapse Options

â&#x20AC;˘ Any first relapse options that have not been tried (2 new drugs; triplet preferred)

Rajkumar SV Š 2020

Myeloma: Second or Higher Relapse First Relapse Options

• Any first relapse options that have not been tried (2 new drugs; triplet preferred)

Additional Options

• Belantamab mafodotin • VDT-PACE like anthracycline containing regimens • Selinexor • Venetoclax (t11;14 only) • Melphalan • Bendamustine-based regimens • Adding panobinostat • Quadruplet regimens Rajkumar SV © 2020

Myeloma: Second or Higher Relapse First Relapse Options

• Any first relapse options that have not been tried (2 new drugs; triplet preferred) Isa-Pd, or DPd, or DKd, or KPd

Additional Options

• Belamaf • VDT-PACE like anthracycline containing regimens • Cyclo / benda / melphalan • Panobinostat + PI • Venetoclax [only t(11;14)] • Selinexor • Melflufen • CAR-T • Bispecific P. Moreau

Panel Discussion

Thank you!

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