Adapting Clinical Practice to a Rapidly Changing Therapeutic Landscape in Multiple Myeloma

Provided by Clinical Care Options, LLC In partnership with the International Myeloma Foundation

Adapting Clinical Practice to a Rapidly Changing Therapeutic Landscape in Multiple Myeloma Friday, December 10, 2021 11:30 AM - 2:00 PM Atlanta, Georgia Friday Satellite Symposium on Adapting Clinical Practice to a Rapidly Changing Therapeutic Landscape in Multiple Myeloma, preceding the 63rd ASH Annual Meeting and Exposition.

Supported by educational grants from Bristol-Myers Squibb; Genentech, a member of the Roche Group; GlaxoSmithKline; Janssen Biotech, Inc. administered by Janssen Scientific Affairs, LLC; Karyopharm Therapeutics; Oncopeptides; Pfizer, Inc.; and Sanofi Genzyme.

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 Jesús F. San-Miguel, MD, PhD

Director of Clinical and Translational Medicine Universidad de Navarra Pamplona, Spain Jesús 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, Regeneron, Roche, Sanofi, SecuraBio, and Takeda.

Faculty Philippe Moreau, MD

Professor of Clinical Hematology Head, Hematology Department University Hospital Hôtel-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 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 funds for research support from Amgen, Johnson & Johnson / Janssen, Sanofi, and Seattle Genetics, and has received consulting funds from GlaxoSmithKline and Oncopeptides.

For Your Safety  Your health and safety are important to us!  In accordance with ASH policy, all attendees must be fully vaccinated, and masks are required  Please remember to wear your mask if you are not actively eating or drinking  Extra masks and hand sanitizers are available for your convenience

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: In-Person Learners  Using the keypad to vote ‒ When prompted, press the number corresponding to your answer OR use the track ball to select your response

 Using the keypad to text in a question ‒ Type in your question using the keypad ‒ To submit, press the green square

 Using the microphone to ask a question during Q&A ‒ Press and HOLD button with microphone icon

Polling and Questions: Online Learners  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. Nurse 5. Pharmacist 6. 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 healthcare professional, 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  Evidence for Treating High-Risk Smoldering MM Jesús F. San-Miguel, MD, PhD  Therapeutic Strategies for Newly Diagnosed MM That Are Eligible for ASCT Philippe Moreau, MD  Therapeutic Strategies for Newly Diagnosed MM That Are Ineligible for ASCT Philippe Moreau, MD  Tailoring Management for Patients With MM in First Relapse S. Vincent Rajkumar, MD  Managing Triple Class Refractory MM (Excluding BCMA Targeted Therapies) Brian G.M. Durie, MD  Evolving Role for BCMA-Targeted Therapies for MM Thomas G. Martin, MD  Proposed 2022 Treatment Algorithms for MM

Case Discussion 1: Evidence for Treating High-Risk Smoldering MM

Faculty Jesús F. San-Miguel, MD, PhD

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

Patient Case  A 51-year-old asymptomatic woman was found to have an IgAk paraprotein during a routine exam ‒ Her M-protein component was 1.2 g/dL ‒ Free light chain ratio, renal function, hemoglobin, and calcium levels were normal

 A diagnosis of MGUS was established and follow-up every 6 months was recommended  She remained stable for 3 years, at which time she consulted with a myeloma expert ‒ Her current M-protein: 2.3 g/dL; FLC ratio: 35; BJ proteinuria: 500 mg/24h ‒ Bone marrow biopsy: 32% plasma cells (97% clonal), with t(4;14) ‒ CT was negative, but MRI showed 1 focal lesion

 A diagnosis of SMM was established

Presurvey 1: In your current clinical practice, what would you recommend for this 51-year-old patient?

1. Continue observation and 6-mo follow-up until diagnosis of active myeloma 2. Begin treatment with a lenalidomide-based regimen 3. Begin treatment with triplet induction followed by ASCT 4. Uncertain

Expert Recommendations Expert Recommendations Brian G.M. Durie, MD

Begin treatment with triplet induction followed by ASCT

Thomas G. Martin, MD

Continue observation and 6-mo follow-up until diagnosis of active myeloma

Philippe Moreau, MD

Unsure*

S. Vincent Rajkumar, MD Jesús San-Miguel, MD

Begin treatment with a lenalidomide-based regimen Begin treatment with triplet induction followed by ASCT *Active myeloma vs SLIM ?

Evidence for Treating High-Risk Smoldering MM How to Identify Risk of Progression and Early Treatment Intervention

Jesús F. San Miguel Universidad de Navarra, Spain

Risk of Progression: Smoldering MM to Active MM Mayo Classification

Spanish Classification

PCs BM Infiltration ≥ 10% and MC ≥ 3g/dL

BM PCs ≥ 10% or MC ≥ 3g/dL AND

> 95% aPC/BMPC + paresis 1.0

TTP: 2 yrs

P = .003

Median: 23 m

TTP: 8 yrs

Group 2: PC ≥ 10%, MC < 3 g/dL

TTP: 19 yrs

Group 3:PC < 10%, MC ≥ 3 g/dL

Time to progression (%)

Group 1:PC ≥ 10%, MC ≥ 3 g/dL

Group 1:

0.8

> 95% aPC/BMPC AND paresis

0.6

Median: 73 m

0.4

Group 2:

> 95% aPC/BMPC OR paresis

0.2

Median: NR 0

Group 3: No adverse factors 0

Kyle R, et al. N Engl J Med. 2007;356:2582-2590.

24

48

72

Months

96

120

Pérez-Persona E, et al. Blood. 2007;110:2586-2592

IMWG: Progression by Risk Group (n=1151 pts)

100

Probability of progression (%)

90

Characteristics included in the model

High-risk group

80 70

Intermediate-risk group

60

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

50

Low-risk group

40 30 20 10 0 0

2

Risk Stratification Groups

4

6

Number of Risk Factors

8

10

12

Time to progressions (years)

14

16

18

Hazard Ratio (95% CI) vs 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

Mateos et al BCJ Oct 2020

IMWG: Risk Score to Predict Progression Risk at 2 Years A more precise and individualized scoring tool to classify individuals by risk of progression using the entire spectrum of values for each patient 100

% with progression

High-risk group (> 12) 80

Intermediate-risk group (9-12)

60

Low-intermediate-risk Group (5-8)

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

MyeRisk Calculator

Risk Factor Coefficient P-value Score FLC Ratio 0-10 (reference) 0 > 10-25 0.69 0.014 2 > 25-40 0.96 0.004 3 > 40 1.56 <0.0001 5 M protein (g/dL) 0-1.5 (reference) 0 > 1.5-3 0.95 0.0002 3 >3 1.30 <0.0001 4 BMPC% 0-15 (reference) 0 > 15-20 0.57 0.04 2 > 20-30 1.01 0.0002 3 > 30-40 1.57 <0.0001 5 > 40 2.00 <0.0001 6 FiSH abnormality 0.83 <0.0001 2 Total Risk Score 2-Year Progression, n (%)

0-4 5-8 9-12 > 12

3.7% 25.4% 48.9% 72.6%

San Miguel. ASCO 2019. Abstract 8000. Mateos et al BCJ 2020

High Risk SMM: Factors Identifying 50% Risk of Progression at 2 Years  Evolving SMM: For the MC: Increase by > 25% in 2 consecutive measurements within 6 mo For Hb: decrease of ≥ 0.5 g/dL Hb within 12m of diagnosis.. For Risk scoring *  BJ proteinuria ( if > 500 mg/24h the TTP is 13m)  Circulating PC >0,02%  High-risk Cytogenetics: t(4;14), del(17p), 1q, MYC structural variants and MYC-IG translocations  Genomic Profiling (score > 0.26). DNA Repair, MYC, MAP Kinase mutations**  MRI: New focal lesion or increase of an existing FL or progressive diffuse infiltration  PET/CT: Positive PET without lysis * Vsram et al (BCJ 2021) patients evolving to a high-risk score may benefit from early intervention therapeutic approaches. * * Annand et al (ASH 2021 Abst 723) Genomic subtypes in SMM

Circulating tumor cells predict risk of progression in SMM patients > 78% of SMM patients had CTC > Untreated SMM patients with high CTC levels (≥0.02%) showed ultrahigh risk of transformation (11 months) vs those with <0.02% CTCs and undetectable CTCs > CTCs were selected as an independent prognostic factor for TTP, together with the M-protein and sFLC ratio (the % of BM tumor cells was not significant)

> Additional Messages: Evaluation of CTCs in PB outperformed quantification of BM tumor burden in SMM and the 2/20/20 model can be replaced by the 2/20/0.02% model. Allows frequent monitoring ( evolving pattern) > Thus, CTC assessment should be part of the diagnostic workup of SMM

JJ Garcés ASH 2021 Abstr 76 TTP, time-to-progression; sFLC, serum free-light chain ratio

Rationale for Early Intervention in High-Risk SMM  To treat the disease early: to achieve cure



Early detection and intervention is a pre-requisite for cure in most malignancies



Why is the standard of care in MM no treatment until CRAB? Risk of harm: clonal selection, toxicities.

Numerous clinical trials in SMM (~ 75 in clinicaltrials.gov )

TO CURE THE DISEASE

TO DELAY THE DISEASE PROGRESSION

Len-Dex vs Observation (n = 119) Median f/u: 12,8y OS TTP Len-dex,: 9.5 yrs

Len-dex, NR

Observation, 8.5 yrs Observation,:

Len vs Observation (n = 182)

2.1 yrs

Treatment Hazard Ratio: 0.28 [95% CI: 0.12-0.63], P = 0.0005

HR: 0.57, (95%CI: 0.34-0.96), p<0.032 HR: 0.25, 95%CI: 0.16-0.40, p<0.0001

43% reduction in the risk of death HR 0.15 in Mayo High Risk 2/20/20 vs 0.50 in Intermediate Risk Mateos MV, et al. NEJM. 2013. Mateos MV, et al. Lancet Oncology 2016; Mateos EHA2020 Abstr EP950

Lonial S et al. J Clin Oncol. 2020 Apr 10;38(11):1126-

Len-dex vs no treatment: OS from progression to active disease (n = 119) Median follow-up: 10.8 years

Len-dex, median OS: 6.4 yrs

Observation, median OS: 4.7 yrs

In the observation arm patients received optimized treatments: 43% PI based, 45% Pi+IMiDs; 28% ASCT (vs 60%; 23% & 18% in the experimental arm)

P=0.55

Early treatment does not induce more resistant relapses Mateos MV, EHA 2020

Phase 2 Clinical trials for intermediate to high risk SMM patients Phase

n

ORR/CR/MRD-ve

PFS/OS

Elo-Rd

2

50

84%/6%/NE

100%/1 death

Ixa-Rd

2

48

94%/31%/18%

100%/-

KRdx8+Len maint

2

54

100%/72%/53% sustain 5y

90% @8y

Efficacy of Rd plus something else seems to be superior in SMM than MM Small series of patients Randomized trials are ongoing/planned

Isatuximab monotherapy

2

24

63%/-/5% (CR pts)

At 14m: 90%

Dara monotherapy intense/interm/short

2

41/41/41

CR: 4.9%/9.8%/0%

At 24m: 90%/82%/75% Ghobrial I, et al. ASH 2018: abstract 154 Bustoros M et al. ASH 2019: abstract 580 Mateos MV, et al. ASH 2019: Abstract 781 Landgren O et al. JAMA 2017

Landgren O et al. Leukemia 2020 Manansanch E ASH 2019

Curative Strategy for High-Risk Smoldering

(CESAR trial) (n = 90)

KRDx6 + ASCT+ KRDx2 + LenDex x 2y

Response category

 CR

Progressive disease MRD –ve, 10-5

Induction (n=90)

HDT-ASCT (n=90)

Consolidation (n=90)

Maintenance (n=90)

41%

65%

72%

63%

1 (1.5%)*

-

-

7 (7%)**

40%

63%

68%

52%

After median follow-up of 55 months (range: 6.2-71), 3 patients progressed to symptomatic disease (all 3 had at baseline ≥1 of the biomarkers defining myeloma-defining events) At 5 years, 94% of patients remain alive and progression-free and 95% of patients remain alive

*Progressions were biochemical **Progressions were biochemical progressions in the 6 patients and symptomatic in 1 pt during maintenance Mateos et al ASH 2021 Abs 1829

ASCENT: KRd-D Study design

Primary endpoint: Rate of confirmed sCR • Secondary objectives: Safety, PFS, OS, MRD negativity •

Toxicity profile

Results to date: • 54 patients accrued • Median patient age 63 years • 6% have completed maintenance, 56% consolidation, 80% induction and 17% in induction phase • ≥1 patient needed a dose modification • ≥ grade 3 AE seen in 43% of patients

Quadruplet regimen KRd-D is well tolerated in high-risk SMM AE, adverse event; CR, complete response; KRd-D, carfilzomib, lenalidomide, dexamethasone, daratumumab; MRD, minimal residual disease; OS, overall survival; PFS, progression-free survival; sCR, stringent complete response.

Kumar et al., ASH 2020: Abstract 2285 (poster presentation)

To treat or not to treat Should the doctor decide for the patient or should the patients decide by themselves after appropriate information??

Now, let’s go back to our case

Patient Case, Recap  A 51-year-old asymptomatic woman was found to have an IgAk paraprotein during a routine exam ‒ Her M-protein component was 1.2 g/dL ‒ Free light chain ratio, renal function, hemoglobin, and calcium levels were normal

 A diagnosis of MGUS was established and follow-up every 6 months was recommended  She remained stable for 3 years, at which time she consulted with a myeloma expert ‒ Her current M-protein: 2.3 g/dL; FLC ratio: 35; BJ proteinuria: 500 mg/24h ‒ Bone marrow biopsy: 32% plasma cells (97% clonal), with t(4;14) ‒ CT was negative, but MRI showed 1 focal lesion

 A diagnosis of SMM was established

Assessment 1: Now, what would you recommend for this 51-yearold patient?

1. Continue observation and 6-mo follow-up until diagnosis of active myeloma 2. Begin treatment with a lenalidomide-based regimen 3. Begin treatment with triplet induction followed by ASCT 4. Uncertain

Poll 5: Which of the following patients is higher risk?

Case A: A 51-year-old asymptomatic woman with an M-protein of 2.3 g/dL; FLC ratio of 25; BJ proteinuria of 500 mg/24h; and normal renal function, hemoglobin levels and calcium levels.

BM biopsy: 28% plasma cells (97% clonal), with t(4;14). CT was negative, but MRI showed 1 focal lesion.

Case B: A 51-year-old asymptomatic woman with an M-protein of 2 g/dL; FLC ratio of 25; and normal renal function, hemoglobin levels and calcium levels. BM biopsy: deletion 13q. Imaging shows lytic lesions in the skull and 1 in the clavicle.

1. Case A 2. Case B 3. Both have similar risk 4. Unsure

Expert Recommendations Expert Recommendations Brian G.M. Durie, MD

Both have similar risk

Thomas G. Martin, MD

Case B

Philippe Moreau, MD

Unsure

S. Vincent Rajkumar, MD

Unsure

Jesús San-Miguel, MD

Both have similar risk

Acknowledgments

Investigators including cases in trials of the Spanish Myeloma Group, and most of all, the patients!

Panel Discussion: Treating High-Risk Smoldering MM

Case Discussion 2: Current Therapeutic Strategies for Newly Diagnosed MM That Are Eligible for ASCT

Patient Case Example  60-year-old male presents with bone pain  Exam shows: ‒ Anemia with 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: 80 μM/L ; beta2microglobulin: 2.5 mg/L, albumin 3.8 g/dL, LDH < normal value   Symptomatic multiple myeloma, ISS1, R-ISS1

Presurvey 2: In your current clinical practice, which of the following strategies would you recommend for this patient?

1. VRD x 4 + ASCT + len maintenance 2. VTD-daratumumab x 4 + ASCT + len maintenance 3. VRD-daratumumab x 4 + ASCT + len maintenance 4. VRD x 8 + len maintenance 5. KRD-daratumumab x 8 + len maintenance 6. VCD x 4 + ASCT + len maintenance 7. Uncertain

Expert Recommendations Expert Recommendations Brian G.M. Durie, MD

VRD x 4 + ASCT + len maintenance

Thomas G. Martin, MD

VRD x 4 + ASCT + len maintenance

Philippe Moreau, MD

VTD-daratumumab x 4 + ASCT + len maintenance VRD-daratumumab x 4 + ASCT + len maintenance

S. Vincent Rajkumar, MD Jesús San-Miguel, MD

VRD x 4 + ASCT + len maintenance VTD-daratumumab x 4 + ASCT + len maintenance VRD-daratumumab x 4 + ASCT + len maintenance* *Not yet approved in Spain.

Important issues: 1 – Triplet or quadruplet induction 2 – Frontline or delayed ASCT 3 – High-risk disease: more aggressive strategies?

4 – Maintenance: len single-agent or 2 drugs?

Front-line treatment of symptomatic multiple myeloma outside clinical trials (EHA-ESMO guidelines 2021) Eligibility for autologous stem cell transplant (ASCT)

YES Induction First option: VRd [II, B] DaraVTD [I,A] If first option is not available VTD [I,A] / VCD [II,B] 200 mg/m2 melphalan followed by ASCT [I,A] Lenalidomide maintenance [I,A] DaraVTD, daratumumab/bortezomib/thalidomide/dexamethasone; Rd, lenalidomide/dexamethasone; VCD, bortezomib/cyclophosphamide/ dexamethasone; VMP, bortezomib/melphalan/prednisone; VRd, bortezomib/lenalidomide/dexamethasone; VTD, bortezomib/thalidomide/dexamethasone.

Dimopoulos MA, et al. Ann Oncol. 2021; 32(3):309-322.

47

Triplet or quadruplet induction?

Philippe Moreau, MD

IFM DFCI 2009 Trial 700 patients < 66y, Newly diagnosed symptomatic MM 3 RVD

5 RVD

MEL200 + ASCT 2 RVD

12 months Lenalidomide maintenance

Attal et al, New Engl J Med 2017

Updated PFS (primary endpoint) Median follow up

89.8 months

Median PFS 47.3 months (Transplantation, arm B)

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

0.70 [0.59;0.83]

30% reduction in the risk of progression or death in patients receiving transplant Perrot et al; ASH 2020, oral presentation

MRD profiling of patients with std- vs high-risk CAs in the PETHEMA/GEM2012MENOS65 trial

49%

Goicoechea. Blood 2021.

37%

MRD profiling of patients with std- vs high-risk CAs in the PETHEMA/GEM2012MENOS65 trial

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

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

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

VTd

VTd

VTd administered as in the D-VTd arm

VTd administered as in the D-VTd arm

4 Cycles of 28 days

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

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)

•

Observation until PD (2 years maximum)

2 Cycles of 28 days

Part 1

Moreau et al. Lancet 2019; 394: 29–38

Part 2

5

Efficacy: MRD (Flow Cytometry; 10–5)1 VTd Subgroup

P < .0001

D-VTD (n = 543)

VTD (n = 542)

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

Sex Male Female Age <50 years ≥50 years Site IFM

D-VTd

Odds Ratio (95% CI)

minimal residual disease negative, n (%) 131 (41) 105 (47)

192 (61) 154 (68)

2.22 (1.62–3.05) 2.37 (1.62–3.48)

38 (42) 198 (44)

56 (68) 290 (63)

2.84 (1.53–5.28) 2.19 (1.68–2.85)

204 (45)

287 (64)

2.16 (1.65–2.81)

HOVON 32 (38) ISS disease stage I 103 (45) II 96 (41) Ill 37 (46) Cytogenetic profile at trial entryc High risk 38 (44) Standard risk 197 (43) Baseline creatinine clearance >90 ml/min 139 (44) ≤90 ml/min 97 (43) Baseline hepatic function Normal 216 (43) Impaired 20 (48) Type of multiple myelomad lgG 122 (39) Non-lgG 59 (49) ECOG performance status 0 112 (44) ≥1 124 (44)

59 (65)

3.05 (1.65–5.65)

137 (67) 155 (61) 54 (64)

2.48 (1.68–3.67) 2.21 (1.54–3.18) 2.14 (1.15–4.00)

49 (60) 296 (64)

1.88 (1.02–3.46) 2.35 (1.80–3.07)

205 (62) 141 (67)

2.07 (1.51–2.84) 2.64 (1.79–3.89)

310 (65) 36 (57)

2.40 (1.85–3.10) 1.47 (0.67–3.21)

201 (61) 61 (66)

2.43 (1.77–3.34) 2.00 (1.15–3.50)

172 (65) 174 (63)

2.39 (1.68–3.41) 2.17 (1.55–3.04) 1

1. Moreau P, et al. Lancet. 2019;394:29-38.

VTd Better

5 D-VTd Better

10

55

Updated Analyses From First Randomization Confirm Benefits of D-VTd vs VTd Induction/Consolidation Median follow-up: 44.5 months

PFS

Median OS: not reached

100

Median PFS: not reached 80

80 Patients alive (%)

Patients progression free and alive (%)

100

OS

60

Median PFS: 51.5 months

40

20

0

Median OS: not reached

60

40

20

HR 0.58 (95% CI 0.47–0.72) P<0.0001

0

36 42 12 18 24 30 Progression-free survival (months)

48

54

60

499

472

434

391

345

312

191

90

26

0

507

495

478

452

426

395

237

119

29

0

0

6

Patients at risk VTd

542

D-VTd

543

HR 0.54 (95% CI 0.37–0.79) D-VTd: 41 deaths VTd: 73 deaths

D-VTd

VTd

D-VTd

VTd 48

54

60

305

151

42

0

327

162

37

0

36 42 24 30 Overall survival (months)

0

6

12

18

Patients at risk VTd

542

531

521

505

494

481

468

D-VTd

543

536

526

520

517

510

498

CI, confidence interval; D-VTd, daratumumab, bortezomib, thalidomide, and dexamethasone; HR, hazard ratio; OS, overall survival; PFS, progression-free survival; VTd, bortezomib, thalidomide, and dexamethasone.

Philippe Moreau et al., Lancet Oncol 2021, https://doi.org/10.1016/ S1470-2045(21)00428-9

Avet-Loiseau et al. ASH2021, abs 82

VRD or VTD-dara?

5

Moreau et al., Immunotherapy.

2021 Feb;13(2):143-154.

MAIC for OS VTD-dara vs VRD, HR 0.31 VTD-dara vs VCD, HR 0.35 VTD-dara vs VD, HR 0.38

5

VRD or VRD-dara?

5

GRIFFIN

•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

D-RVd

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

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 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

21-day cycles

Maintenance: Cycles 7-32d D-R D: 16 mg/kg IV Day 1 Q4W or Q8We R: 10 mg PO Days 1-21 Cycles 7-9; 15 mg PO Days 1-21 Cycle 10+

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

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: 28-day cycles

MRD (NGS 10–5), CR, ORR, ≥VGPR

Stem cell mobilization with G-CSF ± plerixaforb

oorhees et al. Blood. 2020 Aug 20;136(8):936-945.

6

Daratumumab (DARA) Plus Lenalidomide, Bortezomib, and Dexamethasone (RVd) in Patients (Pts) with Transplant-Eligible Newly Diagnosed Multiple Myeloma (NDMM): Updated Analysis of Griffin after 24 Months of Maintenance PFS after 24 months of maintenance Updated response rates

Updated MRD-negativity rates

Laubach et al. ASH2021, Abstract 79

6

Role of consolidation

Philippe Moreau, MD 6

Stadtmauer et al. J Clin Oncol 2019; jan 17

6

Progression-free survival

Stadtmauer et al. J Clin Oncol 2019; jan 17

6

EMN02/HO95 MM study design

VCD induction x 3-4 cycles + PBSC collection

R1

VMP x 4 cycles Bortezomib 1.3 mg/m2 d 1,4,8,11,22,25,29,32/42 Melphalan 9 mg/m2 d 1-4/42 Prednisone 60 mg/m2 d 1-4/42 (497 pts)

Melphalan (HDM) 200 mg/m2 single or double ASCT (695 pts)

VRD consolidatio n x 2 cycles Maintenance lenalidomide

R2

until PD No consolidation

Stratification factor: ISS I vs II vs III *Randomization to VMP or HDM was 1:1 in centers with a fixed single ASCT policy Randomization to VMP or HDM-1 or HDM-2 was 1:1:1 in centers with a double ASCT policy

Results of R1 were reported in Cavo M, et al. Lancet Haemat 2020.

Sonneveld et al; ASH 2020, oral presentation

EMN02/HO95 CONSOLIDATION: PFS

HR=0.81 (0.68-0.96), p=0.016

Sonneveld et al; J Clin Oncol 2021

EMN02/HO95 MM

66

Role of tandem ASCT

5-year PFS 53.5% vs 44.9%

5-year OS 83.3% vs 72.6%

Cavo et al. Lancet Haematol 2020; https://doi.org/10.1016/S2352-3026(20)30099-5

Maintenance single agent

Maintenance with lenalidomide

McCarthy et al. J Clin Oncol 2017

Dimopoulos et al. The Lancet 2019; 393:253-264

Ixazomib Plus Lenalidomide/Dexamethasone (IRd) Versus Lenalidomide /Dexamethasone (Rd) Maintenance after Autologous Stem Cell Transplant in Patients with Newly Diagnosed Multiple Myeloma: Results of the Spanish GEM2014MAIN Trial

Rosinol et al. ASH2021, abs 466

Gay et al – Lancet Oncol 2021

Gay et al – Lancet Oncol 2021

AURIGA Phase 3 study: Design • Objective: to evaluate the conversion rate to MRD negativity after maintenance treatment with DARA SC plus len vs len alone in patients with NDMM who are MRD positive after ASCT

NDMM, newly diagnosed multiple myeloma; VGPR, very good partial response; MRD, minimal residual disease; ASCT, autologous stem cell transplant; len, lenalidomide; PO, oral; DARA SC, daratumumab subcutaneous; QW, weekly; Q2W, every 2 weeks; Q4W, every 4 weeks; NGS, next-generation sequencing; PD, progressive disease; PFS, progression-free survival; CR, complete response; sCR, stringent complete response; OS, overall survival; HRQoL, health-related quality of life; FPI, first patient in.

Shah et al., ASH 2019; abstract 1829

KRD-dara without ASCT

MIDAS study : MInimal res Disease Adapted Strategy Induction and PBSC harvest

Risk-adapted consolidation and maintenance MRD 10-6 : 55 vs 70%

standard-risk group (MRD NGS <10-5)

Arm A

IsaKRD x 6

lenalidomide (3 years)

Arm B

ASCT + IsaKRD x 2

lenalidomide (3 years)

R 1:1 825 patients)

660 patients)

IsaKRD x 6

MRD

(28-day cycle)

MRD 10-6 : 20 vs 40%

PBSC Harvest after cycle 3 (G-CSF+- plerixafor)

High-risk group (MRD NGS >10-5)

Arm C

ASCT + IsaKRD x 2

Isa-iberdomide (3 years)

Arm D

Tandem ASCT

Isa-iberdomide (3 years)

R 1:1

Now, let’s return to our case

Patient Case Example  60-year-old male presents with bone pain  Exam shows: ‒ Anemia with 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: 80 μM/L ; beta2microglobulin: 2.5 mg/L, albumin 3.8 g/dL, LDH < normal value   Symptomatic multiple myeloma, ISS1, R-ISS1

Assessment 2: Now, which of the following strategies would you recommend for this patient?

1. VRD x 4 + ASCT + len maintenance 2. VTD-daratumumab x 4 + ASCT + len maintenance 3. VRD-daratumumab x 4 + ASCT + len maintenance 4. VRD x 8 + len maintenance 5. KRD-daratumumab x 8 + len maintenance 6. VCD x 4 + ASCT + len maintenance 7. Uncertain

Case Discussion 3: Current Therapeutic Strategies for Newly Diagnosed MM That Are Ineligible for ASCT

Patient Case Example  74-year-old female presents with diffuse bone pain  Exam shows: ‒ Anemia with Hb: 9.0 g/dL ‒ Serum electrophoresis: M-spike: 5.2 g/dL, IF: IgG K ‒ Bone marrow aspirate: 32% plasma cells ‒ Cytogenetics (FISH): no 17p, no t(4;14), no t(14;16) ‒ Low-dose whole body CT: diffuse bone lesions, spine ‒ Creatinine: 100 μM/L; creatinine clearance: 45 mL/min; beta2-microglobulin: 5.7 mg/L, albumin 35 g/dL, serum LDH > upper limit of normal   Symptomatic multiple myeloma, ISS3, R-ISS3

Presurvey 3: In your current clinical practice, which of the following strategies would you recommend for this patient?

1. VRD x 8 followed by Rd until progression 2. VMP-dara + dara maintenance until progression 3. Rd until progression 4. Rd-daratumumab until progression 5. VMP x 9 6. VCD x 6 followed by len until progression 7. Uncertain

Expert Recommendations Expert Recommendations Brian G.M. Durie, MD

Rd-daratumumab until progression

Thomas G. Martin, MD

Unsure

Philippe Moreau, MD

Rd-daratumumab until progression

S. Vincent Rajkumar, MD Jesús San-Miguel, MD

VRD x 8 followed by Rd until progression VRD x 8 followed by Rd until progression* VMP-dara + dara maintenance until progression *Not available in all centres

Important issues : 1 – Combinations with CD38 antibodies upfront ?

2 – Use of frailty score 3 – Management of AEs 4 – Fixed duration of treatment until progression

Frontline treatment of symptomatic multiple myeloma outside clinical trials (EHA-ESMO guidelines 2021) Eligibility for autologous stem cell transplant (ASCT)

NO First option DaraRd [I,A] DaraVMP [I,A] VRd [I,A] If first option is not available VMP [I,A] Rd [I,A]

DaraRd, daratumumab/lenalidomide/dexamethasone; DaraVMP, daratumumab/bortezomib/melphalan/prednisone; DaraVTD, daratumumab/bortezomib/thalidomide/dexamethasone; Rd, lenalidomide/dexamethasone; VMP, bortezomib/melphalan/prednisone; VRd, bortezomib/lenalidomide/dexamethasone

Dimopoulos MA, et al. Ann Oncol 2021; 32(3):309-322.

87

Updated analysis SWOG777 – Durie et al Blood Cancer J 2020

Median PFS (months)

65 (54, 82)

OS at 5 years Median follow-up 84 months

Updated analysis SWOG777 – Durie et al Blood Cancer J 2020

ALCYONE phase 3 study of daratumumab + VMP in NDMM Key eligibility criteria: •Transplantineligible NDMM •ECOG 0-2 •Creatinine clearance ≥40 mL/min •No peripheral neuropathy grade ≥2

1:1 Randomization (N = 706)

VMP × 9 cycles (n = 356)

D-VMP × 9 cycles (n = 350) Daratumumab: 16 mg/kg IV Cycle 1: once weekly Cycles 2-9: every 3 weeks

+ Same VMP schedule

Stratification factors •ISS (I vs II vs III) •Region (EU vs other) •Age (<75 vs ≥75 years)

Primary endpoint:

Bortezomib: 1.3 mg/m2 SC Cycle 1: twice weekly Cycles 2-9: once weekly Melphalan: 9 mg/m2 PO on Days 1-4 Prednisone: 60 mg/m2 PO on Days 1-4

•PFS

D Cycles 10+ 16 mg/kg IV Every 4 weeks: until PD

• Cycles 1-9: 6-week cycles • Cycles 10+: 4-week cycles

Mateos, M-V, et al. N Engl J Med. 2018;378:518:28

Follow -up for PD and surviv al

Secondary endpoints: •ORR •≥VGPR rate •≥CR rate •MRD (NGS; 10–5) •OS •Safety

Statistical analyses •360 PFS events: 85% power for 8-month PFS improvement •Interim analysis: ~216 PFS events

42-month OS

75% : D-VMP 62% : VMP

OS

HR: 0.60 (95% CI 0.46-0.80) P=0.0003

HR: 0.42 (95% CI 0.34-0.51) P<0.0001

PFS D-VMP: median 36.4 VMP: median 19.3

Median follow-up: 40.1 months

Mateos et al Lancet 2020; 395: 132–41

Mateos, M-V, et al. N Engl J Med. 2018;378:518:28

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

Key eligibility criteria: •Transplantineligible NDMM •ECOG 0-2 •Creatinine clearance ≥30 mL/min

1:1 Randomization

D-Rd (n = 368) Daratumumab (16 mg/kg IV) 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 mg PO or IV weekly until PD

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

Stratification factors •ISS (I vs II vs III) •Region (NA vs other) •Age (<75 vs ≥75 years)

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

Cycle: 28 days

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

Facon et al. Lancet Oncol 2021 60-month PFS rate 52.5% D-Rd: median, NR 28.7%

PFS

Rd: median, 34.4 months HR: 0.53 (95% CI 0.43-0.66); P<0.0001

60-month OS rate 66.3% D-Rd: median, NR Rd: median, NR

Median Survival : 10 years ?

53.1%

OS HR: 0.68 (95% CI 0.53-0.86); P=0.0013

Thierry Facon et al., Lancet Oncol 2021, https://doi.org/10.1016/ S1470-2045(21)00466-6

Frailty subgroup analysis of MAIA ORR and ≥CR rate

% surviving without progression

PFS in the total non-frail and frail subgroups

n (%) Patients with a TEAE with outcome of death Patients with a serious TEAE Treatment discontinuations due to TEAEs Deaths

Total Non-frail (n=395) D-Rd Rd (n=196) (n=199)

Frail (n=334) D-Rd (n=168)

Rd (n=166)

7 (4)

7 (4)

20 (12)

20 (12)

123 (63)

126 (63)

125 (74)

121 (73)

13 (7)

31 (16)

17 (10)

32 (19)

26 (13)

46 (23)

57 (34)

57 (34)

Clinical benefit of D-Rd, regardless of frailty status Sonja Zweegman et al., Abstract B05, EMN 2021 Facon T et al. N Engl J Med. 2019;380:2104-15.

DRd vs Rd: adverse events D-Rd (n = 364) Any grade

Rd (n = 365)

Grade 3 or 4

Any grade

Grade 3 or 4

 Rate of IRRs for D-Rd

Hematologic, n (%) Neutropenia

207 (57)

182 (50)

154 (42)

129 (35)

Anemia

126 (35)

43 (12)

138 (38)

72 (20)

Thrombocytopenia

68 (19)

27 (7)

69 (19)

32 (9)

Lymphopenia

66 (18)

55 (15)

45 (12)

39 (11)

Nonhematologic, n (%) Diarrhea

207 (57)

24 (7)

168 (46)

15 (4)

Constipation

149 (41)

6 (2)

130 (36)

1 (<1)

Fatigue

147 (40)

29 (8)

104 (28)

14 (4)

Peripheral edema

140 (38)

7 (2)

107 (29)

2 (<1)

Back pain

123 (34)

11 (3)

96 (26)

11 (3)

Asthenia

117 (32)

16 (4)

90 (25)

13 (4)

Nausea

115 (32)

5 (1)

84 (23)

2 (<1)

Pneumonia

82 (23)

50 (14)

46 (13)

29 (8)

Deep vein thrombosis, pulmonary embolism, or both

43 (12)

23 (6)

49 (13)

23 (6)

was 41% (grade 3/4: 3%)

 Incidence of invasive

SPMs was 3% for D-Rd and 4% for Rd – Hematologic SPM 0.5% in each arm

 TEAEs with outcome

of death were 7% for D-Rd and 6% for Rd

Facon et al., ASH 2018; abstract LB-2

was

Now, let’s return to our case

Patient Case Example  74-year-old female presents with diffuse bone pain  Exam shows: ‒ Anemia with Hb: 9.0 g/dL ‒ Serum electrophoresis: M-spike: 5.2 g/dL, IF: IgG K ‒ Bone marrow aspirate: 32% plasma cells ‒ Cytogenetics (FISH): no 17p, no t(4;14), no t(14;16) ‒ Low-dose whole body CT: diffuse bone lesions, spine ‒ Creatinine: 100 μM/L; creatinine clearance: 45 mL/min; beta2-microglobulin: 5.7 mg/L, albumin 35 g/dL, serum LDH > upper limit of normal   Symptomatic multiple myeloma, ISS3, R-ISS3

Assessment 3: Now, which of the following strategies would you recommend for this patient?

1. VRD x 8 followed by Rd until progression 2. VMP-dara + dara maintenance until progression 3. Rd until progression 4. Rd-daratumumab until progression 5. VMP x 9 6. VCD x 6 followed by len until progression 7. Uncertain

Panel Discussion: Current Therapeutic Strategies for Newly Diagnosed MM

Case Discussion 4: Tailoring Management for Patients With MM in First Relapse

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.

Patient Case Example  52-year-old male with relapsed MM presents for evaluation of right leg pain over the last month ‒ MRI reveals a lytic lesion in the right femur ‒ PET CT reveals increased FDG uptake in lesion, and additional enhancing lesions in the lumbar spine, both humeri, and multiple ribs  He was first diagnosed with standard risk myeloma 4 years ago, and underwent 4 cycles of bortezomib, lenalidomide, dexamethasone (VRd) initial therapy followed

by ASCT ‒ He had achieved CR and had since been on lenalidomide 10 mg per day for maintenance

Patient Case Example  Currently, labs show ‒ Hgb: 11.5 g/dL ‒ Calcium: 10.5 mg/dL ‒ Creatinine: 1.1 mg/dL

 M spike: 1.5 gm/dL IgG kappa  Serum free kappa: 110 mg/L; Serum free lambda: 10 mg/L; Serum FLC ratio: 11  Bone marrow biopsy: 40% plasma cells  FISH: del 17p present

Presurvey 4: In your current clinical practice, which of the following regimens would you recommend for treatment of his relapsed MM? 1. Belantamab mafodotin 2. Carfilzomib, lenalidomide, dexamethasone 3. CD38 mAb, lenalidomide, dexamethasone 4. CD38 mAb, carfilzomib, dexamethasone 5. Selinexor, bortezomib, dexamethasone 6. Referral for CAR T-cell therapy 7. Uncertain

Expert Recommendations Expert Recommendations Brian G.M. Durie, MD

CD38 mAb, carfilzomib, dexamethasone

Thomas G. Martin, MD

Referral for CAR T-cell therapy CD38 mAb, carfilzomib, dexamethasone

Philippe Moreau, MD

CD38 mAb, carfilzomib, dexamethasone

S. Vincent Rajkumar, MD

CD38 mAb, carfilzomib, dexamethasone

Jesús San-Miguel, MD

CD38 mAb, carfilzomib, dexamethasone

Selection of Regimen

• Timing of the relapse • Response to prior therapy • Aggressiveness of the relapse • Performance status

Rajkumar SV, Kyle RA. N Engl J Med 2016;375:1390-1392.

CANDOR Trial: DKd versus Kd

The Lancet 2020 396186-197DOI: (10.1016/S0140-6736(20)30734-0) Copyright © 2020 Elsevier Ltd Terms and Conditions

IKEMA Trial: Isatuximab-Kd versus Kd

The Lancet 2021 3972361-2371DOI: (10.1016/S0140-6736(21)00592-4) Copyright © 2021 Elsevier Ltd Terms and Conditions

APOLLO Trial: DPd versus Pd

The Lancet Oncology 2021 22801-812DOI: (10.1016/S1470-2045(21)00128-5) Copyright © 2021 Elsevier Ltd Terms and Conditions

ICARIA Trial: Isatuximab-Pd versus Pd PFS

Attal M, et al. The Lancet 2019 DOI: (10.1016/S0140-6736(19)32556-5)

OS

113

OPTIMISMM Trial: PVd versus Vd

The Lancet Oncology 2019 20781-794DOI: (10.1016/S1470-2045(19)30152-4) Copyright © 2019 Elsevier Ltd Terms and Conditions

First Relapse¶

Not Refractory to Lenalidomide*

DRd

Dara refractory: KRd Frail: IRd, ERd

Refractory to Lenalidomide

DKd (or Isa Kd) or DPd (or Isa Pd)

Dara refractory: KPd Alternatives: PVd, VCd

*Relapse occurring while off all therapy, or while on small doses of single-agent lenalidomide, or on bortezomib maintenance ¶

Consider salvage auto transplant in all eligible patients

Principles

• Prefer triplets • At least two new drugs • Consider transplant in eligible patients • Clinical trials

Now, let’s go back to our case

Patient Case Example  52-year-old male with relapsed MM presents for evaluation of right leg pain over the last month ‒ MRI reveals a lytic lesion in the right femur ‒ PET CT reveals increased FDG uptake in lesion, and additional enhancing lesions in the lumbar spine, both humeri, and multiple ribs  He was first diagnosed with standard risk myeloma 4 years ago, and underwent 4 cycles of bortezomib, lenalidomide, dexamethasone (VRd) initial therapy followed

by ASCT ‒ He had achieved CR and had since been on lenalidomide 10 mg per day for maintenance

Patient Case Example  Currently, labs show ‒ Hgb: 11.5 g/dL ‒ Calcium: 10.5 mg/dL ‒ Creatinine: 1.1 mg/dL

 M spike: 1.5 gm/dL IgG kappa  Serum free kappa: 110 mg/L; Serum free lambda: 10 mg/L; Serum FLC ratio: 11  Bone marrow biopsy: 40% plasma cells  FISH: del 17p present

Assessment 4: Now, which of the following regimens would you recommend for treatment of his relapsed MM? 1. Belantamab mafodotin 2. Carfilzomib, lenalidomide, dexamethasone 3. CD38 mAb, lenalidomide, dexamethasone 4. CD38 mAb, carfilzomib, dexamethasone 5. Selinexor, bortezomib, dexamethasone 6. Referral for CAR T-cell therapy 7. Uncertain

Panel Discussion: Patients With MM in First Relapse

Case Discussion 5: Expert Guidance for Managing Triple Class Refractory MM (Excluding BCMA-Targeted Therapies)

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.

Patient Case Example  67-year-old female originally presented with standard risk IgG kappa MM ‒ B2M 3.4, Alb 3.9, LDH nl, Cr 1.3, Ca 9.7, FISH: +5, +9, +17, del13q, m-prot 3.4, KLC 130 mg/L, LLC 6 mg/L

 She has received 4 prior lines of therapy ‒ LINE1: Rd for 1 yr  response VGPR then R maintenance for 24 mths (PFS: 36m; PD on R) ‒ LINE2: VCd for 18 months  achieves VGPR then progresses (refract to PI/IMiD) ‒ LINE3: Dara-Pd for 9 months  achieves PR then progresses (refract to PI/IMiD/CD38) ‒ LINE4: Carfilzomib + dex for 6 cycles achieves PR then PD (3 prior lines: refractory to R/P/K/Dara)

 The disease has now progressed and she does not look or feel well ‒ WBC 3, ANC 1.5, Hgb 8, plat 65, m-protein 0.5 gm/dL, KLC 2500 mg/L, Cr 1.8, LDH >ULN ‒ PET scan shows multiple osseous lesions and 1 new 4x4 cm hepatic lesion in R lobe

Presurvey 5: In your current clinical practice, considering the limitations of BCMA-based therapy, what would be your next choice?

1. Selinexor and dexamethasone 2. Selinexor and a PI (bortezomib or carfilzomib) + dexamethasone 3. Cyclophosphamide-based intensive chemotherapy 4. VD-PACE 5. Venetoclax-based therapy (off-label) 6. Refer to a center that has access to BCMA-directed therapies 7. Hospice 8. Uncertain

Expert Recommendations Expert Recommendations Brian G.M. Durie, MD

Cyclophosphamide-based intensive chemotherapy

Thomas G. Martin, MD

Cyclophosphamide-based intensive chemotherapy

Philippe Moreau, MD

Refer to a center that has access to BCMA-directed therapies

S. Vincent Rajkumar, MD

Refer to a center that has access to BCMA-directed therapies

Jesús San-Miguel, MD

Refer to a center that has access to BCMA-directed therapies

Triple-Class Refractory: The Un-met Need in RRMM HDAC / ADC Chemotherapy XPO inhibitors

Approved BCMA

Doxorubicin, Liposomal doxorubicin

Panobinostat/ Vorinostat

Belantamab Mafodotin

Cyclophosphamide Bendamustine, Melphalan

Venetoclax*

Ide-cel (bb2121)

PACE, HyperCAD

Selinexor + Dexamethasone

Blue = FDA approved, non-BCMA (*approved for leukemia)

Cellular therapies BCMA CARs

BCMA Abs Bispecific

Teclistamab Cilta-cel (JNJ-4528) AMG-701, LCAR-B38M TNB-383B REGN5458 Elranatamab CC-93269

Zevorcabtagene autoleucel bb21217

MEDI2228, CC-99712

ALLO-715 ALLO-605 (TurboCAR)

Green: BCMA approved

Purple = not approved

Selinexor: An XPO1 Inhibitor  Exportin 1 (XPO1): nuclear exporter for majority of tumor suppressor proteins, glucocorticoid receptor, and eIF4E-bound oncoprotein mRNAs  Selinexor: an XPO1 inhibitor that induces nuclear retention and activation of TSPs and the GRPs in the presence of steroids and suppresses oncoprotein expression

Selinexor PI. Gravina. J Hematol Oncol. 2014;7:85. Culjkovic-Kraljacic. Cell Rep. 2012;2:207.

 FDA approved in combination with Vd after ≥1 previous therapy or with dex after ≥4 previous therapies and refractory to ≥2 PIs, ≥2 IMiDs, and an anti-CD38 mAb

Slide credit: clinicaloptions.com

STORM: Phase II Study of Selinexor + Dexamethasone in Triple-Class Refractory Myeloma Treatment-experienced patients with triple-class refractory MM* and adequate organ function† (N = 122)

Selinexor 80 mg PO + Dexamethasone 20 mg QW2 on Days 1, 3 of 28-day cycle

Until PD

*Previously treated with bortezomib, carfilzomib, lenalidomide, pomalidomide, daratumumab, an alkylating agent, and glucocorticoid, with disease documented to be refractory to ≥1 PI, ≥1 IMiD, daratumumab, a glucocorticoid, and last therapy. †Creatinine clearance ≥20 mL/min; ANC ≥1000/mm3; platelets ≥75,000/mm3 or ≥50,000/mm3 if BM plasma cells ≥50%; Hb ≥8.5 g/dL.

 Refractory ‒ PI, IMiD, Dara: 100% ‒ Car/Pom/Dara: 96% ‒ Bort/Car/Len/Pom/Dara: 68%

 ORR: 26.2% (penta refractory: 25.3%)  Median OS: 8.6 mo Chari. NEJM. 2019;381:727.

100 + +++ +++++ ++ 75 PFS (%)

 Median prior regimens: 7 (range: 3-18)

PFS +++++++

50

++

++

25 0

0

1

2

3

4

Median PFS: 3.7 mo ++

++ + 5 6 Mo

7

+ 8

+ 9

10 11

Slide credit: clinicaloptions.com

Data From Phase I/IIb STOMP Trial With Selinexor-Based Triplets SVd (N = 40)1

SKd (N = 24)2

SPd (N = 60)3

Dara-Sd (N = 32)4

Patient Population

50% PI refractory, 3 median prior lines of therapy

Carfilzomib naive, 50% bortezomib refractory, 3 median prior regimens

87% Len refractory, 70% Pom naive, 3 median prior regimens

94% Dara naive, 85%/76% PI/IMiD refractory, 3 median prior regimens

ORR, %

PI sensitive/ naive: 84

PI refractory: 43

70.8

Pomsensitive/ naive: 54

Pomrefractory: 36

All: 69

Dara-naive: 73

 ≥CR, %  VGPR, %

11

5

16.7

2.2

0

0

0

26

19

33.3

19.6

7.1

34

37

 PR, % Median PFS, mo

47

19

20.8

32.6

26.8

34

37

17.8

6.1

Not reported

12.3

--

12.5

--

1. Bahlis. Blood. 2019;132:2546. 2. Gasparetto. ASCO 2020. Abstr 8530. 3. Chen. ASH 2020. Abstr 726. 4. Gasparetto. ASCO 2020. Abstr 8510.

Slide credit: clinicaloptions.com

Phase III BOSTON Trial: Selinexor + Vd vs Vd in R/R MM  Open-label, controlled, randomized phase III trial Selinexor† 100 mg QW + Bortezomib 1.3 mg/m2 + Dexamethasone 20 mg (n = 194) Bortezomib 1.3 mg/m2 + Dexamethasone 20 mg (n = 97)

PD r ve so ‡ os ed Cr llow a

Patients with progressive measurable MM per IMWG criteria, 1-3 prior therapies, CrCl ≥20 mL/min, ECOG PS 0-2 with adequate hepatic and hematopoietic function* (N = 402)

PD

Vd Cycles 1-8: 21-day cycles with bortezomib on Days 1, 4, 8, 11 and dexamethasone on Days 1, 2, 4, 5, 8, 9, 11, 12; Vd Cycles 9+: 35-day cycles, bortezomib on Days 1, 8, 15, 22 and dexamethasone on Days 1, 2, 8, 9, 15, 16, 22, 23, 29, 30

 Primary endpoint: PFS (per IRC)  Key secondary endpoints: ORR, ≥VGPR, grade ≥2 PN *Defined as ANC > 1000/μL and platelets > 75,000/μL. † Prophylactic 5HT-3 recommended in SVd arm. ‡Crossover to SVd or Sd permitted if IRC confirmed PD. Dimopoulos. ASCO 2020. Abstr 8501.

Planned 40% lower bortezomib and 25% lower dexamethasone dose at 24 wk (8 cycles) in SVd arm vs Vd arm Slide credit: clinicaloptions.com

Phase III BOSTON Trial: PFS (Primary Endpoint) With Selinexor + Vd vs Vd in R/R MM  Baseline characteristics: 49% with 1 prior line of therapy, 48% with high-risk cytogenetics  ORR: 76.4% with selinexor + Vd vs 62.3% with Vd (≥VGPR: 44.6% vs 32.4%) 100

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

PFS (%)

75 50 25 0

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26

Mo Patients at Risk, n SVd 195 187 175 152 135 117 106 89 79 76 69 64 57 51 45 41 35 27 26 22 19 14 Vd 207 187 175 152 138 127 111 100 90 81 66 59 56 53 49 42 35 26 20 16 10 8 Dimopoulos. ASCO 2020. Abstr 8501.

9 5

7 4

6 3

4 3

2 2

Slide credit: clinicaloptions.com

Toxicity With Selinexor-Based Therapy: Twice Weekly vs Weekly Dosing Select TEAEs, %

Hematologic

Gastrointestinal

Constitutional

STORM: Selinexor/Dex (n = 123)1

BOSTON: Selinexor-Vd (n = 195)2

All

Grade 3/4

All

Grade 3/4

Thrombocytopenia

73

59

60.0

39.5

Anemia

67

44

36.4

15.9

Neutropenia Febrile neutropenia

40 --

21 2

14.9 --

8.7 0.5

Leukopenia

33

14

NR

NR

Lymphopenia

16

11

NR

NR

Nausea

72

10

50.3

7.7

Anorexia/decreased appetite

56

5

35.4

3.6

Diarrhea

46

7

32.3

6.2

Vomiting

38

3

20.5

4.1

Fatigue

73

25

42.1

13.3

Weight loss

50

1

26.2

2.1

1. Chari. NEJM. 2019;381:727. 2. Dimopoulos. ASCO 2020. Abstr 8501.

Slide credit: clinicaloptions.com

Venetoclax in t(11;14)+ R/R MM Venetoclax Monotherapy1 Study phase

Venetoclax-Dex in t(11;14)+2

I

I

II

Sample size, n

66

20

31

Median prior lines of therapy, n

5

3

5

60

48

t(11;14)+

t(11;14)-

40

6

CR, %

14

3

5

7

VGPR, %

13

3

25

29

PR, %

13

0

30

13

Median DoR, mo

9.7

NE

12.4

61% at 1 yr

Median TTP, mo

6.6

1.9

12.4

10.8

ORR, %

1. Kumar. Blood. 2017;130:2401. 2. Kaufman. Am J Hematol. 2021; 96:418.

Slide credit: clinicaloptions.com

Phase I/II Study of Daratumumab/Venetoclax/Dex ± Bortezomib in Relapsed, t(11;14)+ Myeloma PFS for VenD

Bahlis. J Clin Oncol. 2021;39:3602

PFS for Dara-VenD

Slide credit: clinicaloptions.com

Phase III BELLINI in R/R MM After 1-3 Prior Lines: A Cautionary Tale +++ ++ ++ +

Investigator-Assessed PFS

60

+

+ + +

40 20 0

Ven + Vd Pbo + Vd + Censored

+++ + ++

++ + +++++

0

3

6

9

Median PFS, mo HR

+++

OS (Second Interim Analysis) ++ + + +

60 40

Ven + Vd

Placebo + Vd

23.2

11.4

0.60 (95% CI: 0.43-0.82; P = .0013)

Kumar. Lancet Oncol. 2020;21:1630. Kumar. ASCO 2020. Abstr 8509.

0 0

++

+ ++ + ++ ++++++ +++++++++++++++++++ +++++++++++ +++ +++ ++++++ + +++++++++++ +++++++++++++++++++ ++++ ++++++++++ + ++ +++ + +

Ven + Vd Pbo + Vd + Censored

20

0 12 15 18 21 24 27 30 33 36 0 3 6 Mo Patients at Risk, n 6 1

+

80

+++ ++ ++ ++ + +++++++++++++++ +++ + ++ +++ +++ +++ + + ++ + + +++++ +++ ++ + ++

Patients at Risk, n Ven + Vd 194 163 140 118 101 89 84 79 64 44 21 Pbo + Vd 97 83 69 57 39 30 22 20 18 12 6 Endpoint

100

OS (%)

PFS (%)

10 0 80

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

194 186 174 165 159 150 144 140 125 95 47 10 97 95 91 88 87 85 80 79 70 53 25 7 Endpoint Median OS, mo HR

Ven + Vd

Placebo + Vd

33.5

NR

0 1

1.460 (95% CI: 0.912-2.337; P = .112) Slide credit: clinicaloptions.com

0

BELLINI: Promise in t(11;14)-Positive Myeloma 1.0 +

PFS

++ + +

+

+

0.6 0.4 0.2 0

+++++

+ 0

Pts at risk, n 20 15

Ven + Bd Pbo + Bd Censored

+

++ +

6

9

12 15 18 21 24 27 30 33 Mos

18 12

16 11

14 9

14 6

PFS Median, months HR (95% CI) P value Harrison. ASH 2019. Abstr 142.

12 2

11 2

0.6 0.4 0.2

+

3

12 5

+ +++++ + ++++ ++++ + + + ++ + ++ +

0.8 OS

PFS

0.8

OS

1.0

8 1

3 1

1 1

Ven + Bd

Pb o+ Bd

Not reached

9.3

0.09 (0.02-0.44) .003

0 0

0

+

Ven + Bd Pbo + Bd Censored

0

3

6

9

Pts at risk, n 20 15

12 15 18 21 24 27 30 33 Mos

19 15

19 14

19 14

19 14

OS Median, mos HR (95% CI) P value

19 13

19 13

18 11

14 7

6 3

1 1

Ven + Bd

Pbo + Bd

Not reached

Not reached

0 0

0.68 (0.13-3.48) .647 Slide credit: clinicaloptions.com

BELLINI: Promise in t(11;14)-Positive Myeloma 1.0 +

PFS

++ + +

+

0.6

+++++

+ +++++ + ++++ ++++ + + + ++ + ++ +

0.8

++ +

0.6

Final OS Results of BELLINI Trial being presented – ASH 2021 Abstract 84

0.4 0.2 0

+

OS

PFS

0.8

OS

1.0

+ 0

Pts at risk, n 20 15

Ven + Bd Pbo + Bd Censored

+

6

9

12 15 18 21 24 27 30 33 Mos

18 12

16 11

14 9

14 6

PFS Median, months HR (95% CI) P value Harrison. ASH 2019. Abstr 142.

12 2

Ven + Bd

Saturday, December 11,0.2 2021: Pbo 10:30 + Bd AM +

3

12 5

0.4

11 2

8 1

3 1

1 1

Ven + Bd

Pb o+ Bd

Not reached

9.3

0.09 (0.02-0.44) .003

0 0

0

+ Censored

0

3

6

9

Pts at risk, n 20 15

12 15 18 21 24 27 30 33 Mos

19 15

19 14

19 14

19 14

OS Median, mos HR (95% CI) P value

19 13

19 13

18 11

14 7

6 3

1 1

Ven + Bd

Pbo + Bd

Not reached

Not reached

0 0

0.68 (0.13-3.48) .647 Slide credit: clinicaloptions.com

Patient Selection  Selinexor-based therapy ‒ FDA-approved dosing and schedule of selinexor/dex should only be used in fit patients with robust counts who can return frequently for follow-up and aggressive supportive care ‒ Triplet combinations using weekly selinexor dosing strategies are active and better tolerated  Venetoclax-based therapy ‒ All t(11;14)+ patients ‒ Venetoclax-based triplets with dex + dara or a PI are highly promising  Note: melphalan flufenamide indication was withdrawn for R/R MM, based on data from the phase III OCEAN trial – abstracts will be presented at ASH 2021 (Abs 2741 and 2732 on Sunday from 6-8 PM)

 More to come on BCMA targeted agents!

Conclusions  Treatment options are available for patients with heavily pretreated, triple-refractory disease  Of the available on label options, considerations including quality of life, prior toxicity and convenience must be discussed with all patients  For the small molecule inhibitors selinexor and venetoclax, the best path forward is with combination strategies ‒ Off-label venetoclax-based therapy should be restricted to t(11;14)+ disease

 Optimal sequencing of these therapies and issues of sequencing of these with BCMA therapies warrants additional investigation  Results of clinical trials evaluating these promising agents in earlier lines of therapy are eagerly anticipated

Now, let’s go back to our case

Patient Case, Recap  67-year-old female originally presented with standard risk IgG kappa MM ‒ B2M 3.4, Alb 3.9, LDH nl, Cr 1.3, Ca 9.7, FISH: +5, +9, +17, del13q, m-prot 3.4, KLC 130 mg/L, LLC 6 mg/L

 She has received 4 prior lines of therapy ‒ LINE1: Rd for 1 yr  response VGPR then R maintenance for 24 mths (PFS: 36m; PD on R) ‒ LINE2: VCd for 18 months  achieves VGPR then progresses (refract to PI/IMiD) ‒ LINE3: Dara-Pd for 9 months  achieves PR then progresses (refract to PI/IMiD/CD38) ‒ LINE4: Carfilzomib + dex for 6 cycles achieves PR then PD (3 prior lines: refractory to R/P/K/Dara)

 The disease has now progressed and she does not look or feel well ‒ WBC 3, ANC 1.5, Hgb 8, plat 65, m-protein 0.5 gm/dL, KLC 2500 mg/L, Cr 1.8, LDH >ULN ‒ PET scan shows multiple osseous lesions and 1 new 4x4 cm hepatic lesion in R lobe

Assessment 5: Now, considering the limitations of BCMA-based therapy, what would be your next choice?

1. Selinexor and dexamethasone 2. Selinexor and a PI (bortezomib or carfilzomib) + dexamethasone 3. Cyclophosphamide-based intensive chemotherapy 4. VD-PACE 5. Venetoclax-based therapy (off-label) 6. Refer to a center that has access to BCMA-directed therapies 7. Hospice 8. Uncertain

Panel Discussion: Managing Triple Class Refractory MM (Excluding BCMA-Targeted Therapies)

Case Discussion 6: Evolving Role for BCMA-Targeted Therapies for MM

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 Oncopeptides and funds for research support from Amgen, Janssen, Sanofi, and Seattle Genetics.

Patient Case Example  77-year-old male presented with standard risk IgG kappa MM ‒ B2M 3.2, Alb 3.8, LDH 150, Cr 1.0, Ca 8.7, FISH: +5, +9, +15, 1q gain

 He has received 4 prior lines of therapy ‒ LINE1: RVd for 8 cycles  response VGPR ‒ LINE1: R maintenance for 36 months (PFS: 43m; then progresses on maintenance – refractory to R 10 mg QD) ‒ LINE2: DaraPd for 18 months  achieves VGPR then progresses (refractory to D/P) ‒ LINE3: Carfilzomib + dex for 6 cycles achieves PR then PD (3 prior lines: refractory to R/P/K/Dara) ‒ LINE4: Oral cyclophosphamide + Pd has stable disease for 4 months then PD

Patient Case Example  He now presents with fatigue and low back pain ‒ M-protein 2.5 g/dL, KLC 150 mg/L, LLC 3 mg/L, LDH normal, Hgb 9, plat 120, Ca 10.1, alb 3.2

 You are considering therapy, but options for triple-class drug refractory (IMiD, PI, CD38) are limited…..

Presurvey 6: In your current practice, what would you recommend next for this patient?

1. “Re-cycling” of agents: triplet combination with previously used agents 2. PI + Selinexor + dexamethasone 3. Belantamab mafodotin 4. BCMA-targeted CAR T-cell (age is not a factor with CAR T-cells) 5. BCMA-targeted bispecific antibody (on-trial) 6. Cyclophosphamide-based combination chemotherapy 7. Other novel clinical trial if available 8. Uncertain

Expert Recommendations Expert Recommendations Brian G.M. Durie, MD

BCMA-targeted CAR T-cell (age is not a factor with CAR T-cells)

Thomas G. Martin, MD

BCMA-targeted bispecific antibody (on-trial) BCMA-targeted CAR T-cell (age is not a factor with CAR T-cells)

Philippe Moreau, MD

BCMA-targeted CAR T-cell (age is not a factor with CAR T-cells)

S. Vincent Rajkumar, MD

BCMA-targeted CAR T-cell (age is not a factor with CAR T-cells)

Jesús San-Miguel, MD

BCMA-targeted CAR T-cell (age is not a factor with CAR T-cells)

Poll 6: What would be your expectation for duration of response to salvage in triple-class-refractory patients?

1. Belantamab mafodotin: expected DOR <6 months 2. Selinexor + dex: expected DOR >6 months 3. CAR T-cell therapy: Ide-cel expected DOR ~11 months; Cilta-cel expected DOR ~22 months 4. Bispecific antibodies (in general): expected DOR >12 months 5. DoR not measurable with novel BCMA-targeted therapies 6. Uncertain

Poll 6: What would be your expectation for duration of response to salvage in triple class–refractory patients?

Correct Answer CAR T-cell therapy: Ide-cel expected DOR ~11 months; Cilta-cel expected DOR ~22 months

Poll 7: What would be your preference for sequential therapy using BCMA-targeted agents?

1. Belantamab mafodotin first, then CAR T-cell–targeting BCMA 2. Belantamab mafodotin first, then bispecific Ab–targeting BCMA 3. CAR T-cell or bispecific Ab therapy first, then belantamab mafodotin 4. Sequential immunotherapies that target different cell surface antigens (eg, BCMA  GPRC5D) 5. I would not give sequential BCMA-targeted therapies, regardless 6. Uncertain

Expert Recommendations Expert Recommendations Brian G.M. Durie, MD

Sequential immunotherapies that target different cell surface antigens (eg, BCMA  GPRC5D)

Thomas G. Martin, MD

Sequential immunotherapies that target different cell surface antigens (eg, BCMA  GPRC5D) Unsure

Philippe Moreau, MD

Sequential immunotherapies that target different cell surface antigens (eg, BCMA  GPRC5D)

S. Vincent Rajkumar, MD

Sequential immunotherapies that target different cell surface antigens (eg, BCMA  GPRC5D)

Jesús San-Miguel, MD

Sequential immunotherapies that target different cell surface antigens (eg, BCMA  GPRC5D)

Triple Class–Refractory RRMM A Focus on BCMA ASH 2021 Thomas Martin

BCMA in Multiple Myeloma

• • • •

GPRC5D FcHR5 SLAMF7 CD38/138

Cho. Front Immunol. 2018;10:1821.

Viral vector

CAR T-Cell Cytoto xic cy tokine s

• Expressed on late memory B-cells committed to PC differentiation and PCs • BCMA plays a role in survival of long-lived PCs • γ-secretase cleaves BCMA from the cell surface, yielding soluble BCMA • Other targets under investigation

Bispecific T-Cell Engagers

CAR T-Cells

e T-C

ll

Signaling domain

CD3

scFv BCMA

Bispecific Antibodies

MM cell death Cytotoxic payload released into cell

CD3

BCMA

Antibody–Drug Conjugates

T-Cell

, cells s NK te y c o mon

Slide credit: clinicaloptions.com

Triple-Class Refractory: When All Else Fails HDAC / ADC Chemotherapy XPO inhibitors Doxorubicin, Liposomal doxorubicin

Panobinostat/ Vorinostat

Cyclophospha mide Bendamustin e, Melphalan

Venetoclax

PACE, HyperCAD

Selinexor + Dexamethasone

Approved BCMA

BCMA Abs TCEs/ADCs

BCMA CARs

Teclistamab* Cilta-cel (JNJ-4528)* Belantamab* Pavurutamab* Mafodotin LCAR-B38M TNB-383B* Ide-cel* (bb2121)

REGN5458* Elranatamab* CC-93269

bb21217

Non-BCMA [Talquetam ab]* [Cevostam ab]*

Zevo-cel (CT053) ALLO-715 ALLO-605 (TurboCAR)

Blue = approved Orange = BCMA approved Green = ongoing clinical trials

Drug Development in MM-TCR: How we arrived here Agent

Setting

Single agent response

With Dexa

PFS

Thalidomide1

Relapsed MM Post-SCTx

30%

52%

EFS 20% at 2 yr

Bortezomib2

RRMM (6 PLT): steroids 99.5%, thal 83%

27%

Lenalidomide3

Prior thal 80%, bort 40%

25%

Carfilzomib5

RRMM (5 PLT): ~100% bort/IMiD

24%

Pomalidomide4

RRMM (5 PLT): 100% bort/len

18%

Isa/Dara6,7

RRMM (5 PLT): 100% bort/IMiD

24-29%

3.7 months

Phase 1 : no Dara (5 PLT:100%-PI/IMiD)

60%

12 months

Phase 2: Dara-required (7 PLT: 100% Dara/PI/IMiD)

32%

2.9 months

Belantamab

8,9

TTP 6.6 months 61%

4.6 months 3.7 months

33%

2.7 months

Weber D. Cancer Control. Sep-Oct 2003;10(y5):375-83. 2Richardson P et al. NEJM. 348 (2003); 2609-2617 3Richardson P. Semin Hematol. 2005 Oct;42(4Suppl4)S915. 4Richardson P et al. Blood. 2014 Mar 20;123(12):1826-32. 5Seigel D et al. Blood. 2012;120(14):2817-25. 6Lonial S, et al. Lancet. 2016 Apr 9;387(10027): 15511560. 7Martin T, et al. Blood Cancer J. 2019 Apr;9(4):41. 8Trudel S et al. Blood Cancer J. 2019 Apr;9(4):37. 9Lonial S et al. Lancet Oncol. 2020 Feb;21(2):207-221 1

Belantamab Mafodotin: Overview • Belantamab mafodotin: a BCMA-directed antibody and microtubule inhibitor conjugate, comprising 3 components 1

Belantamab mafodotin binds to BCMA expressed on normal and malignant PCs

ADC

Belantamab mafodotin is internalized and MMAF is released after proteolytic cleavage from the mAb

BCMA lysosome

Humanized antiBCMA IgG1 mAb that binds to BCMAexpressing MM cells

ADCC/ADCP BCMA

X BCMA

Fc receptor

Effector cell

MM cell

Protease-resistant maleimidocaproyl linker that joins MMAF to mAb and releases payload only in target cell

2

3

MMAF: microtubuledisrupting cytotoxic agent that leads to apoptosis of BCMAexpressing MM cells

Tai. Blood. 2014;123:3128. Farooq. Ophthalmol Ther. 2020;9:889.

MMAF disrupts the microtubule network intracellularly, resulting in cell cycle arrest and apoptosis MM Cell Death

Belantamab mafodotin also induces tumor cell lysis via ADCC and ADCP

Slide credit: clinicaloptions.com

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.

POPULATION •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

Treatment until disease progression or unacceptable toxicity

Primary Outcome

Key Secondary Outcomes

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

Characteristic

Key baseline characteristics=>

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.

(95% CI)

40

Patients (%)

30

32% (21.7-43.6) n=2 n=5

20

n = 11

sCR CR VGPR PR

10 n = 13

0

Belamaf 2.5 mg/kg (N = 97)

Lonial. Cancer 2021;127:4198.

Proportion Alive and Progression Free

Phase II DREAMM-2: Response and DoR at 13 Mo of Follow-up, Belantamab Mafodotin 2.5 mg/kg ORR: % of Patients 1.0

Median DoR (13 mo): 11 mo (95% CI: 4.2-NR)

0.8 0.6 0.4

50% probability

0.2 0

0

1

2

3

4

5

6

7

8

9 10 11 12 13 14 15 16

Duration of Response (Mo)

Patients at Risk, n (number of events) 31 31 27 24 21 18 18 15 15 15 12 10 8 7 3 1 0 (0) (0) (3) (5) (6) (9) (9) (11) (11) (11) (11) (12) (13) (14) (15) (15) (15) Slide credit: clinicaloptions.com

Keratopathy Can Occur With or Without Symptoms No new safety signals observed at 13-mo follow-up 1 patient developed grade 4 corneal ulcer 82% of patients without clinically significant visual acuity change

*Better-seeing eye; represents threshold at which ADL (eg, driving) are affected.

Lonial. ASH 2020. Abstr 3224.

Belantamab 2.5 mg/kg (n = 95) Keratopathy (MECs) 68/95 (72%)

In patients with keratopathy (MECs) events grade ≥2 per KVA, 48% (29/60) had >1 event

Symptoms (eg, blurred vision, dry eye) and/or a ≥2-line BCVA decline (better-seeing eye): 53/95 (56%)

BCVA change to 20/50 or worse*: 17/95 (18%)

Of these patients, 76% (13/17) had 1 event and 24% (4/17) had 2 events (no patients had >2 events)

Discontinuation due to corneal AE: 3/95 (3%)

1 patient discontinued due to keratopathy (MECs), 1 due to blurred vision, and 1 due to reduced BCVA

Slide credit: clinicaloptions.com

Future for ADCs in RRMM • Belantamab Mafodotin

1. Improved response rates and durability with combinations

Trudel et al. ASH 2021, Abstr 1653: Belantamab + Pom => 60 pts. (ORR 88.9%) Callander et al. ASH 2021, Abstr 897: Belantamab + alCOS (co-stim T-cell agonist)

2. Improved safety

Split/intermittent/lower dosing of Belantamab - Trudel: expansion cohort with Q8Wk BM - Other ISTs on-going Patient reported ocular symptoms to guide dosing [Popat et al. Abstr 2746]

3. Earlier lines of therapy

• Additional ADCs

1. Multiple targets

CD46/SLAMF7/CD38/CD138

2. Toxicity 3. Mechanism of resistance

T-cell Health, Microenvironment, Antigen loss

Phase I Trial: Updated Analysis of BCMA x CD3 Bispecific Antibody Teclistamab in Patients With R/R MM • First-in-human, open-label, dose-escalation/dose-expansion phase I trial • Dosing switched from IV Q2W to IV or SC weekly with or without step-up dosing Patients with R/R MM or intolerant to established treatments; Hb ≥8 g/dL; PLT ≥75 x 109/L*; ANC ≥1.0 x 109/L; no prior BCMA-targeted agents (N = 149)

RP2D Dosing Schedule Teclistamab 2 step-up doses of 60 μg/kg and 300 μg/kg†

Teclistamab 1500 μg/kg SC QW for cycle 1 onwards†

*In patients with ≥50% BM plasma cells, PLT ≥50 x 109/L. † Patients premedicated with glucocorticoid, antihistamine, and antipyretic with step-up doses and first full dose.

RP2D

Step-Up Dosing: SC (n = 65)

Step-Up Dosing: IV (n = 84)

3000 µg/kg (n = 4)

IV dose escalation cohorts

1500 µg/kg (n = 40) 720 µg/kg (n = 15) 240 µg/kg (n = 7)

Phase I Total Cohort (n = 157)

80 µg/kg (n = 6)

 Key endpoints: Part 1, determine RP2D; Part 2, safety/tolerability at RP2D; antitumor activity, PK/PD Usmani. Lancet. 2021;398:665. Krishnan. ASCO 2021. Abstr 8007.

Slide credit: clinicaloptions.com

SAFETY and EFFICACY:

Phase I Trial of Teclistamab: -CRS: Response at RP2D (1500 µg/kg SC QW)

Gr1+2=> 56.7%

-Neurotox:

DoR at RP2D of Teclistamab

80

TR TR TR TR TR TR

-Neutropenia:

PR

Gr 3-4 =>40%

VGPR

CR

End of Treatment Status Progressive disease by new bone lesion; approved to continue treatment Discontinued (progressive disease) Discontinued (other) On treatment as of March 29, 2021

TR TR TR TR TR

1 sCR

2

3

4

CR

Usmani. Lancet. 2021;398:665.

5

VGPR

6 PR

7

8

9

10

11 12

Minimal response

SD

13 14 PD

Patients (%)

60 40 20 0

18%

sCR

ORR: 70%

ORR: 65%

TR TR TR TR TR TR TR TR TR

0

Gr1-3 => 4.5%

≥CR: 41%

≥CR: 37%

9% 28%

23% 18% 8% RP2D: 1500 µg/kg SC QW (n = 40)

30% 2% Other QW IV and SC Dosing Cohorts (n = 46) Slide credit: clinicaloptions.com

Summary of Bispecific Antibodies in R/R MM Target

Median prior lines, n

Dosing

ORR, %

CRS, %

Neurotoxicity, %

Notes

Teclistamab1 (n = 40 RP2D)

BCMA

5 (2-11)

SC QW for RP2D

65 @ RP2D (70 @ other IV/SC doses)

70 @ RP2D (no grade 3)

2.5 @ RP2D (0 in other SC doses)

SC dosing!

TNB-383B2 (n = 58, 15)

BCMA

6 (3-15)

Q3W

80 @ higher doses (n = 15)

45 (no grade 3)

0

Q3W, allowed for CrCl 30

REGN-54583 (n = 49, 8)

BCMA

5

Q2W

63 @ highest doses (n = 8)

39 (no grade 3)

12

Pavurutamab/ AMG-7014 (n = 85, 6)

BCMA

6 (2-25)

QW

83 @ most recent doses (n = 6)

64 (9% grade 3)

3.8

Elranatamab5 (n = 30)

BCMA

8 (3-15)

SC weekly

70 @ ≥215 μg/kg

73

20

SC dosing!

GPRC5D

6 (2-17)

SC weekly RP2D: 450 μg/kg

53.3 all SC doses (70.0 @ RP2D)

67 all SC (73 @ RP2D) (3% grade 3 @ RP2D)

4.9 all SC (7 @ RP2D)

SC dosing! 16% of pts @RP2D had prior BCMA tx Some grade 3 skin rash, oral toxicity, back pain

FcRH5

6 (2-15)

Q3W

53, higher doses 61, highest dose (n = 18) 63 in prior BCMA (n = 8)

76 (2% grade 3)

28

21% with prior BCMA tx

Drug

Talquetamab6 (n = 82 all SC, 30 RP2D)

Cevostamab7 (n = 53, 34)

1. Usmani. Lancet. 2021;398:665. 2. Rodriguez. ASH 2020. Abstr 293. 3. Madduri. ASH 2020. Abstr 291.

4. Harrison. ASH 2020. Abstr 181. 5. Bahlis. ASCO 2021. Abstr 8006. 6. Berdeja. ASCO 2021. Abstr 8008. 7. Cohen. ASH 2020. Abstr 292.

Future for Bispecific Antibodies in RRMM • Goals for bispecifics in RRMM • •

Outpatient dosing – (low-CRS, neurotoxicity) Convenient administration • SQ dosing • Infrequent (Q4/Q6/Q8/Q12wk)

• Updates at ASH 2021 •

BCMA Directed: ASH 2021

•

Non-BCMA Directed

• • • • •

Teclistamab Phase I/II: Abstract 896:169 RRMM patients treated @ RP2D (77% TCR): ORR 65% A Phase I of Tnb-383B: Abstract 900 => 44 pts @ active dose (66% TCR): ORR 64% Elranatamab: Magnetismm-1: ASH 2021: Abstract 895 => 6 pts @RP2D=> ORR 83% REGN5458 – Phase I/II: ASH 2021: Abstract 160 => 15 pts @ higher doses=> ORR 73.3% Teclistamab + Daratumumab: ASH 2021: Abstract 1647 : 33 RRMM pts=> ORR 74%

• Cevostamab: Abstract 157 : 44pts RP2D=> ORR 54.5% • Talquetamab: Abstract 158 => ORR 70%; 161 (Talq + Dara)

Phase II KarMMa Update: ORR 73% PFS 8.8m PFS by Best Response

1.

0 0.

8 0.

6 0.

4 0.

2 0

0

Patients at Risk, n 150 x 106 4 300 x 106 70 450 x 106 54 Total 128

2

4

6

8

2 56 44 102

1 42 40 83

1 33 36 70

1 29 34 64

CAR T-Cells

No. of Events

Median, Mo (95% Cl)

1.0

150 x 106 300 x 106 450 x 106 Total

3 58 31 92

2.8 (1.0-NE) 5.8 (4.2-8.9) 12.1 (8.8-12.3) 8.8 (5.6-11.6)

0.

8

10 12 Mo 1 24 31 56

1 17 17 35

14

16

18

20

22

1 14 4 19

1 11 1 13

1 7 0 8

1 3 0 4

0 0

Probability for PFS

Probability of PFS

PFS by Target Dose

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

0.

6 0.

4 0.

2 0

CR/sCR VGPR PR 0 Nonresponders

0

2

4

6

8

42 25 27 34

42 25 27 8

42 22 16 3

40 20 10 0

39 16 9 0

10 12 Mo 37 14 5 0

26 8 1 0

14 16 3 0 0

16

18

20

22

11 2 0 0

8 0 0 0

4 0 0 0

0

• PFS increased with higher target dose

• PFS increased by depth of response

• Median PFS: 12 mo with 450 × 106 CAR T-cells

• Median PFS: 20 mo in patients with CR/sCR

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

Slide credit: clinicaloptions.com

Phase II KarMMa Update: Pharmacokinetics PFS by sBCMA Clearance at 2 Mos 300

105 10

4

10

3

10

100 30 sBCMA level

10

2

LLOQ

1 1 0 0 Antidrug AB Positive, % 4 0

Transgene level 2

3 21

4

5

6

Mo

44

7

8

9 58

10

11

12 65

• CAR transgenes detectable in 50% of patients at month 6 and approx. 36% of patients at 1 year • sBCMA decreased with treatment, increased with PD

3

sBCMA Clearance at Mo 2 Yes No P <.0001

1.00

Fraction Progression Free

106

Median sBCMA Level (ng/ml)

Median Transgene Level (copies/μg)

Transgene and sBCMA Levels Over Time

0.75 0.50 0.25 0

0

Patients at Risk, n Yes 80 No 36

5 72 4

1

1 5

2 0

53 2

14 0

4 0

Mo0

• Clearance of sBCMA at month 2 is associated with prolonged PFS

• Anti-CAR antibody (ADA) appeared at Mo 3 Anderson. ASCO 2021. Abstr 8016. Munshi. NEJM. 2021;384:705.

Slide credit: clinicaloptions.com

CARTITUDE-1 Trial With Ciltacabtagene Autoleucel: Response ORR: 97.9%

Patients (%)

10 0 80 60

sCR: 80.4%

≥ VGPR: 94.8%

80.4%

40 20 0

Best response =

14.4% 3.1% sCR

VGPR

PR

 MRD status: almost all (91.8%) evaluable patients were MRD negative

Event

All Patients (N = 97)

Median time to first response, mo (range)

1 (0.9-10.7)

Median time to best response, mo (range)

2.6 (0.9-15.2)

Median time to ≥ CR, mo (range)

2.6 (0.9-15.2)

Median DoR, mo (95% CI)

21.8 (2.18-NE)

 Response rates comparable (range: 95%-100%) across different subgroups* (eg, number of prior lines of therapy, refractoriness, extramedullary plasmacytomas, and cytogenetic risk)

*Subgroups included number of prior lines of therapy (≤4, >4), refractoriness (triple-class, penta-drug), cytogenetic risk (high risk, standard risk), baseline bone marrow plasma cells (≤30%, >30 to <60%, ≥60%), baseline tumor BCMA expression (≥median, <median), and baseline plasmacytomas (including extramedullary and bone based).

Slide credit: clinicaloptions.com Usmani. ASCO 2021. Abstr 8005.

CARTITUDE-1 Trial With Ciltacabtagene Autoleucel: PFS sCR

All patients

18-Mo PFS All Patients: 66.0% (95% CI: 54.9-75.0) sCR: 75.9% (95% CI: 63.6-84.5)

PFS (%)

Median: not reached Median: 22.8 mo (95% CI: 22.8-NE)

18-Mo OS All patients: 80.9% (95% CI: 71.4-87.6)

Median duration of follow-up: 18 mo (range: 1.5-30.5)

Patients at Risk, n All patients Responders with sCR

Usmani. ASCO 2021. Abstr 8005.

97

95

85

77

73

78

78

76

71

68

Mo 55

26

9

1

1

0

51

26

9

1

1

0

Slide credit: clinicaloptions.com

BCMA CARTs: Summary - ASH 2020 and ASCO 2021 Patients Median prior regimens Triple refractory, % CAR-T dose ORR CR/sCR PFS CRS, all grades CRS, grade 3/4 Neurotoxicity, all grades Neurotoxicity, grade 3/4

CARTITUDE-11 Cilta-cel Phase 1/2 97

CRB-4012 Ide-cel Phase 1 62

KarMMa3 Ide-cel Phase 2 128

LUMMICAR-24 Zivo-Cel Phase 1b 20

PRIME5 P-BCMA-101 Phase 1/2 55

GC012F6 Dual CAR-T BCMA+CD19 19

6

6

6

5

8

5

87.6%

69.4%

84.0%

85%

60%

95%

0.71×106 50, 150, 450 and (range 0.5-0.95×106) 800 x 106

150, 300, 450 x106

1.5-1.8/2.5-3.0 x108 0.75-15 x106

1.0-3.0 x105

97.9% 80.4% 66%@ 18m 94.8% 4%

75.8% 38.7% 8.8m 75.8% 6.5%

50%/69%/82.0% 25%/29%/39% 12m @450ml 50%/76%/96% 0/7%/6%

94.0% 28%

67%b NR

94.7% 84.2%

77%/83%a 0%

17% 0%

95% 11%

20.6%

35.5%

0/17%/20%

15%/17%a

3.8%

0%

10.3%

1.6%

0/1%/6%

8%/0a

3.8%

0%

1.5-1.8/2.5-3.0 x108 dose, b0.75x106 dose BCMA, B-cell maturation antigen; CAR-T, chimeric antigen receptor T-cell therapy; CRS, cytokine release syndrome; NR, not reported a

1. Usmani et al., ASCO 2021: Abstract 8005; 2. Lin et al., ASH 2020: Abstract 131; 3. Anderson et al., ASCO 2021: Abstract 130; 4. Kumar et al., ASH 2020: Abstract 133; 5. Costello et al., ASH 2020: Abstract 134; 6. Jiang et al., ASCO 2021: Abstract 8014

1.0

Adult B-ALL (19-28z, MSKCC)

0.8 0.6 Low disease burden

0.4

P = .01

0.2 0

High disease burden 0

10

20

30

40

50

60

Mo Since T-Cell Infusion

Probability of Continued Remission

Probability of Event-Free Survival

CAR T-Cell Therapies in Heavily Pretreated MM Patients: Relapse is Commonplace Pediatric B-ALL (19-41BBz, Tisagenlecleucel) 1.

0 0.8 0.6 0.4 No. of patients: 61 No. of events: 17 Median duration of remission: not reached

0.2 0

0

2

4

6

1.

0 0.

8 0.

6 0.

4 0.

2 0

1.0 0

Multiple Myeloma (BCMA-41BBz, Ide-Cel)

<150 x 106 CAR+ T cells

≥150 x 106 CAR+ T cells

mPFS: 2.6 mo

0 3 Raje. NEJM. 2019;380:1726.

6 9 12 Mo Since bb2121 Infusion

mPFS: 11.8 mo

15

18

21

Probability of PFS

Probability of PFS

Park. NEJM. 2018;378:449.

8

10

12

Maude. NEJM. 2018;378:439.

14

16

Mo Since Onset of Remission

18

20

22

CARTITUDE-1

0.75

0.50

Logrank P <.0001

0.25

0

CARTITUDE-1

Martin.

0 ASCO 2021. Abstr 8045.

5

RW cohort observed 10

Mo

15

RW cohort IPTW adjusted 20

25

Future for BCMA-CAR T-cells in RRMM • Cure needs to be the goal (or a “very long” treatment free interval) • “Wish list” remains long • • • •

Faster manufacturing (or off-the shelf) Better expansion and persistence (optimized T-cells) Dual targeting CARs / less immunogenic CARs Outpatient administration (less CRS and low severity)

• Updates at ASH 2021 • • • • • • •

Fully Human BCMA Directed CAR + GSI •

Seattle (Cowan): ASH 2021: Abstract 551 => ORR 89% [Sunday 4:30-6:00PM]

•

University of Calgary (Maity): ASH 2021: Abstract 327 [Saturday 4:30 PM]

•

18.3% prior BCMA CAR and 76.1% HR-cytogenetics => ORR 94.4%

•

MCARH109 Phase 1 => GPRC5D ASH 2021: Abstract 827 => 12pts ORR 66% (some prior BCMA)

Allo-715 (Mailankody): ASH Abstract 651 n=> ORR 61.5% [Monday 11:00AM] Armoured BCMA Targeting CAR T-cell to overcome exhaustion/enhance persist Phase I/II - Novel Fully Human BCMA CAR T (CT103A) in RRMM: Abstract 547 Lummicar (CT053): Abstract 2821: 14pts in China => ORR 100% Cartitude-2: Abstract 3866 + 2910; Cartitude-5: Abstract 1835 Non-BCMA Directed

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 with rapid and deep responses

Targeted immuno-cytotoxicity

No lymphodepletion No steroids

Single infusion (“one and done”)

No lymphodepletion Minimal steroids

Potentially persistent

Likely available for local administration

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

Currently Requires dose adjustments and holds

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

Disadvantages

Available to any infusion center Outpatient administration

$$

$$$$ - Cure possible?

$$$ - functional cure?

Sequencing of BCMA Targeted Therapeutics • As of now  Belantamab mafodotin is the only easily accessible, FDA approved BCMA targeted therapy • Off-the shelf but REQUIRES collaboration with OPHTHALMOLOGY • Use it if you can…. It’s hard to wait for CARs or bispecifics in a patient with active PD

Sequencing of BCMA Targeted Therapeutics • As of now  Belantamab mafodotin is the only easily accessible, FDA approved BCMA targeted therapy • Off-the shelf but REQUIRES collaboration with OPHTHALMOLOGY • Use it if you can, It’s hard to wait for CARs or bispecifics in a patient with active PD

• Ide-cel is the only BCMA CAR T-cell product FDA approved • Manufacturing limitations have prevented widespread use • If you get a slot  use it, if you have a choice go CAR before ADC • In 1st /2nd Quarter 2022  there should be more availability for CARs • Cilta-cel => Updated PDUFA date 2/28/22

Sequencing of BCMA Targeted Therapeutics • As of now  Belantamab mafodotin is the only easily accessible, FDA approved BCMA targeted therapy • Off-the shelf but REQUIRES collaboration with OPHTHALMOLOGY

• Use it if you can, It’s hard to wait for CARs or bispecifics in a patient with active PD

• Ide-cel is the only BCMA CAR T-cell product FDA approved

• Manufacturing limitations have prevented widespread use • If you get a slot  use it, if you have a choice go CAR before ADC • In 1st /2nd Quarter 2022  there should be more availability for CARs • Cilta-cel => Updated PDUFA date 2/28/22

• Bispecifics will eventually command the largest fraction of the market • Expect approval in 3rd/4th Quarter 2022 (Teclistamab likely first approved)

Sequencing of BCMA Targeted Therapeutics • In 2022 and beyond  CARs and bispecific mAbs may be available • What is best sequence?

• • For FIT: BCMA CAR first then  BCMA – ADC or bispecific on relapse • For FIT: BCMA CAR first then  Other target immunotherapy at relapse (bispecific or ADC) • Less fit  BCMA bispecific or ADC then  Other target (if available) immunotherapy at relapse

Global IMF Immunotherapy Database Project to help decipher sequencing questions!!

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  approved, soon to be universally available • Bispecific antibody results  best off-the-shelf single agent therapy to date • Toxicity is manageable • Can target multiple cell surface proteins  BCMA, GPRC5D, FCRH5,……

• Need better understanding mechanisms of resistance • T cell exhaustion, microenvironment characteristics (regulatory T cells) • Loss of antigen/16p deletion

• Trials of combinations of novel-novel drugs on-going • Sequencing of these therapeutics will be important and future sequencing studies will be important [IMF Immunotherapy Database Project]

Now, let’s go back to our case

Patient Case Example  77-year-old male presented with standard risk IgG kappa MM ‒ B2M 3.2, Alb 3.8, LDH 150, Cr 1.0, Ca 8.7, FISH: +5, +9, +15, 1q gain

 He has received 4 prior lines of therapy ‒ LINE1: RVd for 8 cycles  response VGPR ‒ LINE1: R maintenance for 36 months (PFS: 43m; then progresses on maintenance – refractory to R 10 mg QD) ‒ LINE2: DaraPd for 18 months  achieves VGPR then progresses (refractory to D/P) ‒ LINE3: Carfilzomib + dex for 6 cycles achieves PR then PD (3 prior lines: refractory to R/P/K/Dara) ‒ LINE4: Oral cyclophosphamide + Pd has stable disease for 4 months then PD

Patient Case Example  He now presents with fatigue and low back pain ‒ M-protein 2.5 g/dL, KLC 150 mg/L, LLC 3 mg/L, LDH normal, Hgb 9, plat 120, Ca 10.1, alb 3.2

 You are considering therapy but options for triple-class drug refractory (IMiD, PI, CD38) are limited…..

Assessment 6: Now, what would you recommend next for this patient?

1. “Re-cycling” of agents: triplet combination with previously used agents 2. PI + Selinexor + dexamethasone 3. Belantamab mafodotin 4. BCMA-targeted CAR T-cell (age is not a factor with CAR T-cells) 5. BCMA-targeted bispecific antibody (on-trial) 6. Cyclophosphamide-based combination chemotherapy 7. Other novel clinical trial if available 8. Uncertain

Panel Discussion: Incorporating BCMA-Targeted Therapy

Panel Discussion 7: Introduction to the 2022 MM Care Algorithm

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 © 2021

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 © 2021

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 © 2021

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 © 2021

Myeloma: Frontline Treatment Newly Diagnosed MM* Not Transplant Candidate

VRd x 6 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 © 2021

Myeloma: Frontline Treatment Newly Diagnosed MM* Not Transplant Candidate

Transplant Candidate VRd¶ or Dara-based quadruplet induction

VRd x 6 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 © 2021

Myeloma: Frontline Treatment Newly Diagnosed MM Not Transplant Candidate

1 - D-Rd

Transplant Candidate 1 - VRD or Dara-based quad induction 2 – 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

If Dara Refractory: KRd

*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 © 2021

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

Refractory to Lenalidomide

DKd or Isa-Kd DRd

If Dara Refractory: KRd or Ixa-Rd

Or

If Dara Refractory: KPd

DPd or Isa-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 © 2021

Myeloma: First Relapse First Relapse Not Refractory to Lenalidomide

1 - DRd

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

Refractory to Lenalidomide DKd or Isa-Kd Or DPd or Isa-Pd

Dara refractory: Pd-Elo, KPd, PVd Frail: IxaPd, PCD

Pom-Vd

P. Moreau

Myeloma: Second or Higher Relapse First Relapse Options

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

*Consider ixazomib instead of carfilzomib or bortezomib if an all-oral regimen is needed

Rajkumar SV © 2021

Myeloma: Second or Higher Relapse Additional Options

First Relapse Options

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

• • • • • • • • • • •

CAR-T KCd, VCd, Ixa-Cd Elotuzumab containing regimens Belantamab mafodotin VDT-PACE like anthracycline containing regimens Selinexor Venetoclax (t11;14 only) IV Melphalan Bendamustine-based regimens Adding panobinostat Quadruplet regimens

*Consider ixazomib instead of carfilzomib or bortezomib if an all-oral regimen is needed

Rajkumar SV © 2021

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 Dara-Pd, Kd-Dara, or Kd-Isa (KPd)

Additional Options

• • • • • • • • •

CAR T-cell Belantamab mafodotin Selinexor - dex VDT-PACE like anthracycline containing regimens Bendamustine-based regimens Elo-based regimens Panobinostat + PI Venetoclax [only t(11;14)] Cyclophosphamide-dex P. Moreau

Panel Discussion

Thank you!