IMWG Conference Series: ASCO & EHA 2022

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Thank you to our sponsors!

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KEY QUESTIONS 2022-2026


We’re back!!!

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Bruno Paiva, PharmD, PhD Brian G.M. Durie Outstanding Achievement Award Recipient


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Hervé Avet-Loiseau, MD, PhD Robert A. Kyle Lifetime Achievement Award Recipient


IMWG Mission “To conduct collaborative basic, clinical, and translational research to improve outcomes for myeloma patients while providing scientifically validated, critically appraised consensus guidelines for the myeloma community globally.”

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IMWG Chairpersons Brian G.M. Durie

Cedars-Sinai Outpatient Cancer Center, Los Angeles, CA

S. Vincent Rajkumar Mayo Clinic, Rochester, MN

Jesús San Miguel

University of Navarra, Pamplona, Spain

Nikhil Munshi

Dana-Farber Cancer Institute, Boston, MA

Philippe Moreau

University Hospital of Nantes, France

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Plenary Sessions Early Disease Minimal Residual Disease (MRD) Frontline Therapy Early Relapse Later Relapse 1


Early Disease Session Chair: Brian G.M Durie, MD International Myeloma Foundation 11


Is screening the way to go? Sigurdur Kristinsson, PhD, University of Iceland

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RCT of MGUS screening, work-up, and follow-up Excluding indolent disease p<0.001 p<0.05

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13

92

133


….and SMM is very common Prevalence of SMM in 40 years and older is 0.5%

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Thorsteinsdottir S et al. Abstract #151 ASH 2021


Should we screen for MGUS? • Active screening identifies significantly higher number of individuals with full-blown malignancy and smoldering disease • Early detection and intervention is achievable • Although our findings are encouraging, until final results of the iStopMM study become available, including data on survival and quality of life, we advise against systematic MGUS screening in healthy individuals

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What’s required to have simple precise testing for HR SMM? Bruno Paiva, PhD, PharmD Clínica Universidad de Navarra

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Identifying SMM patients with no risk of transformation

Including tumor and immune biomarkers

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Termini R & Žihala D, et al. Manuscript under review


CTCs can replace BM PCs in the IMWG risk model for SMM

Similar performance between minimally and partially invasive models 2/20/0.015 Model (>0.015% CTCs)

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2/20/20 Model (>20% BMPC)

Termini R & Žihala D, et al. Manuscript under review


What’s next for decisive treatment of HR SMM? María-Victoria Mateos, MD, PhD University Hospital of Salamanca 19


GEM-CESAR :Outcomes Median follow-up: 54.6 (6.2-71) months

Landmark TT biological Progression at the end of maintenance by MRD status

TTP to symptomatic disease

MRD-ve MRD+ve

HR: 0.32; 95% CI: 0.11-0.84, p=0.02 Number of patients at risk 90

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88

87

85

Number of patients at risk 83

70

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4 pts progressed to symptomatic disease and in 3 pts, the progression was first asymptomatic Mateos MV et al. ASH 2021. poster presentation

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MRD-ve

44

44

44

44

44

37

13

1

MRD+ve

24

24

24

24

24

16

7

0

Biological progression occurred in 7 pts during maintenance and in 19 additional patients after finalising maintenance. Three pts finally progressed to symptomatic disease


Aggressive Smoldering Curative Approach Evaluating Novel Therapies and Transplant (ASCENT)

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E3A06: Phase 3 clinical trial Len vs Observation in patients with asymptomatic Smoldering Multiple Myeloma (n=182)

Treatment Hazard Ratio = 0.28 [95% CI: (0.12-0.63)], p-value 0.0005

Criteria: PCBM ≥ 10% and sFLC ratio >8 or <0.125 Mayo2008: PCBM ≥ 10% + MC ≥ 3g/dl Mayo2018: 2/20/20

Early treatment with R significantly prevented the progression to MM especially in the patients at high risk of progression

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Lonial S et al. JCO 2020


What’s next for decisive treatment in HR SMM patients? • I don’t know..... • More evidence is coming.... Based on new phase 3 clinical trials • Clinical trials with BCMA-bs mABs and BCMA CAR-T cells are coming... • We should maybe to ask to the patients.....

• Sagar Lonial will explain what is decisive for treat HR SMM patients....

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Minimal Residual Disease Session Chair: Jesús San Miguel, MD, PhD Clínica Universidad de Navarra 24


Where are we with standardized accessible treating? Alberto Orfao, MD, PhD University of Salamanca 25


MRD POSITIVITY RATES ACCORDING TO SENSITIVITY OF NGS vs NGF NGF

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NGS

Paiva et al, J Clin Oncol 2020

Perrot et al, Blood 2018


IVDD compliant or FDA authorized MM-MRD assays FDA authorized (2018) clonoSEQ® (NGS) assay :

• Centralized (1 center) multiplexed PCR and NGS high-sensitive assay (>1.9 cells at <10-6). • FDA authorized 09/2018 • Approximate cost: $ 950/test

PNL-10027-03_clonoSEQ-Technical-Information available at www.clonoseq.com/technical-summary

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Current IVDD (2022) NGF Product:

• 1 box with 6 color lyophilized cocktail + 2 liquid drop ins. • FACSLyricTM and FACS CantoTM data acquisition. • Infinicyt AG&I data analysis and reporting. • Sensitivity: 20 cells at <2x10-6 • IVDD compliant CE-IVD and RUO. • Approximate cost: US$ 133/test (US$ 2,665/20 tests).


Simultaneous MM MRD + CAR-T cells + Immune Monitoring Apheresis T cells

B cells 0.15% 2 cells/µl Tumor plasma cells 4.8% 67 cells/µl

BCMA

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CAR-T infusion

Day +7

CAR-T peak

Relapse

Month +7

CAR-T cells 0.04% 0.2 cells/µl

CAR-T cells 0.01% B cells 0.3 cells/µl 0.04% Tumor plasma 0.2 cels/µl cells 2.4% 11 cells/µl

BCMA

Month +6

INCAR

CAR-T cells 34.3% 79 cells/µl

BCMA

B cells 0.25% 10 cells/µl Tumor plasma cells 0.01 % 0.4cells/µl

BCMA

CAR-T cells 0.06% cells/µl 0.3plasma Tumor cells 0.65 % 10cells/µl

BCMA


What is the value of an MRD negative test? Hervé Avet-Loiseau, MD, PhD University Cancer Center of Toulouse 29


Importance of sensitivity B

P a t i e n ts ( % )

10 0

75

50

P < 0.0 01

< 10

25

-6

-6

-5

-5

-4

[1 0 ;10 [ [1 0 ;10 [ =10

0 0

-4

12

24

36

48

39 10 4 2

8 0 0 1

T im e s in c e M R D a s se s sm en t

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N a t risk -6 < 10- 5 -6 [10 -5 ;1 0 - 4 [ [10 ;1 0 -4[ = 10

87 29 23 32

83 23 17 19

73 17 10 7

Perrot A, Blood 2018


Cassiopeia trial

Percent survival

PFS M RD <10-5 post-consolidation 100

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0

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No del17p no t(4;14) del17p t(4;14)

0

20

40

60

Months

80

100


Conclusions

• Requirement to include MRD in all the upcoming trials 10-6 is the required sensitivity level

• MRD should be performed independently of CR achievement • MRD seems to not overcome cytogenetics

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How should MRD positive patients be managed? Jesús San Miguel, MD, PhD Clínica Universidad de Navarra

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How should MRD positive patients be managed MRD positivity…………The driver MRD negativity……. The goal

Why is better to use MRD+ve to drive therapeutic decisions ….treatment adaptation? Pitfalls on MRD negativity  Quality of BM samples: Patchy infiltration & Hemodilution (affects both NGS & NGF)

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 Unsustain MRD


Identification of MRD+ve patients with favorable immune profiles and superior outcome Time-to progression (%) MRD+

MRD+ with high normal MRDPC recovery and favorable immune profile median TTP: NR

median TTP: 16m PCA3

B-precursors Erythroblasts

median TTP: NR

P =.001

PCA1

clonal PCs

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normal PCs

Time from MRD assessment (months)

Multivariate analysis based on the distribution of 15 immune cell populations (including normal and clonal PCs) in the BM at the time of MRD assessment: Recovery of B cells and neutrophils production…..good prognosis Arana P, et al. Blood 2015 126:721


Frontline Therapy Session Chair: S. Vincent Rajkumar, MD Mayo Clinic, MN

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Is a “Quadruplet” the new standard of care? S. Vincent Rajkumar, MD Mayo Clinic, MN

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Key Questions

• Can we improve on VRd and DRd triplets? • Change the triplet? • Add to the triplet (quadruplet)?

Progression-Free Survival (%)

Issues to consider

• Cost • Toxicity • Metrics of success • MRD • PFS • OS

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KRd vs VRd

100

80

60

40

20

0 0

6

12

18

24

30

36

42

48

54

60

Time from Randomization (Months) 545 542

KRd VRd

• Level of Evidence • Can treatment be individualized: Risk and Response directed • Patient Population

401 377

252 243

187 183

Numbers at Risk 127 83 59 114 73 43

Rajkumar SV © 2022

38 31

25 26

13 14

3 0


DETERMINATION: study design and patient disposition DETERMINATION: Delayed vs Early Transplant with Revlimid Maintenance and Antimyeloma Triple Therapy RVd cycle 1 (N=729) Randomization (N=722) Stratified by: ISS disease stage Cytogenetic risk

Arm A: RVd-alone (N=357)

RVd cycles 2-3

Stem cell collection

Arm B: RVd+ASCT (N=365)

RVd cycles 2-3

Stem cell collection

Each RVd cycle (21 days):

R 25 mg/day PO, days 1-14 V 1.3 mg/m2 IV/SC, days 1, 4, 8, 11 Dex 20/10 mg PO, days 1, 2, 4, 5, 8, 9, 11, 12

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R maintenance (N=291)

RVd cycles 4-8

Melphalan 200 mg/m2 + ASCT (N=310)

RVd cycles 4-5

Induction ± ASCT + consolidation treatment duration = ~6 months

R maintenance (N=289)

Lenalidomide maintenance Months 1-3: 10 mg/day Month 4 onwards: 15 mg/day

Primary endpoint: PFS

Secondary endpoints: response rates; DOR; TTP; OS; QoL; safety

d/Dex, dexamethasone; DOR, duration of response; ISS, International Staging System; IV, intravenous; PO, orally; R, lenalidomide; SC, subcutaneous; TTP, time to progression; V, bortezomib


DETERMINATION: Key findings – efficacy Highly significant increase in progressionfree survival (PFS) with use of ASCT •Risk for patients of their disease progressing was 53% higher for those not receiving ASCT

Patients alive and free from disease progression after 5 years

%

0

10

% RVd+ASCT RVd alone

Similar response rates between arms

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0

Patients alive after 5 years

20

40

50

40

60

55.6 60

80

80.7 79.2 RVd+ASCT RVd-alone 82.7 79.6

80 60

40

41.5

100 Response rate, %

•But patients remain in response for longer with RVd+ASCT vs RVd-alone: 56.4 months vs 38.9 months •In patients who were tested to date, the proportion with no remaining traces of disease (‘MRD-negative’) was higher: 54.4% vs 39.8% •But those patients achieving MRD do just as well in terms of PFS, regardless of treatment

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RVd+ASCT

No difference in overall survival (OS) •Patients have been followed for a median of 76 months •Only 28% of patients received delayed ASCT to date, with others all treated with next generation novel agents and monoclonal antibodies

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46.9

97.5

95

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20 0

Complete response or better

Very good partial response or better

Partial response or better


GRIFFIN TRIAL: Dara-VRd vs VRd Quadruplets as Initial Therapy

Sustained MRD- (12 months): 44% vs 13% 55% vs 32% in HR MM; HR: 2.52 (1.01-6.32)

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Laubach J, et al. ASH 2021


Panel Discussant Thierry Facon, MD Chu Lille France

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Quadruplet Regimens in TE Patients • No study is perfect but… • VRD > VTD (consensus), D-VTD > VTD (cassiopeia), D-VRD > VRD (griffin) • Even before the read out of the phase 3 D-VRD vs.VRD Perseus study, we may assume that CD38- ImiDs- PI- D is standard for induction/consolidation in TE patients • This will allow us 1. to avoid additional (useless) studies 2. to focus on new challenges – use of CART in front-line, use of Bispecific Abs, optimized maintenance, duration of therapy, treatment of HR patients…

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Quadruplet Regimens in TNE Patients ? (1)

DRd is the major SOC – Do we need more ? What is next ?

• The 2020 Mayo Clinic recommendation has still some VRD. Unexpectedly Dara is added for HR in TE but no Dara for TNE, only VRD, in the absence of data for VRD in HR elderly. • Equate and Benefit studies support the view that DRd is the SOC. • Isa and Dara VRD studies (Imroz and Cepheus) will read out soon but these studies have excluded frail patients (Cepheus) or patients over 80 years (Imroz) – the conclusion might be that 4 drugs are better than 3 for elderly fit.

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Quadruplet Regimens in TNE Patients ? (2)

DRd is the major SOC – Do we need more ? What is next ?

Few questions; Does DRd need to be improved for SR, frail patients, achieving rapid VGPR/CR ? Other 3-drug R (CD38-Bisp.,Len-Bisp.,new CellMods-Bisp…) ? Other 4- drug R (CD38-Len-Bispe) ? TNE but CARTE ? Role for CART strategies in older patients ? Cost and affordability remain major issues

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Is early integration of CAR T-cell therapy the next step? Tom Martin, MD University of California San Francisco 46


CARTITUDE-5 and 6: - Randomized, ph 3 - NDMM - 5 TI - 6 TE CARTITUDE-6

Early MRD will lead to late PFS benefit - And hopefully early FDA approval

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Quad Induction

(4-6 cycles) Q/Triplet Induction (4-6 cycles)

CAR T-cell (1x 4wk)

Tumor Burden

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(+/- after CAR)

CAR T-cell (1x 4wk)

12,000/yr

Quad Induction followed by continuous therapy (8-12 cycles or more?) QUADS

VGPR

CAR

NDMM #’s 32,000/yr

Maintenance Relapse

SCT ineligible

SCT eligible

ND Myeloma treatment paradigm in 5+ years

TCE

CR MRD

Goal 80-90% Sustained MRD (-)

6,000/yr 14,000/yr

Next Gen CAR

PD


Which other therapies warrant consideration in frontline setting? Paul G. Richardson, MD Dana-Farber Cancer Institute

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BCMA-targeted agents: a 4th treatment pillar for NDMM? IMiDs

PIs

mAbs

Lenalidomide

Bortezomib

Daratumumab

Pomalidomide

Carfilzomib

Isatuximab

Ixazomib

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BCMAtargeted therapies

Belantamab mafodotin

CAR Ts (ide-cel, cilta-cel)

Bispecifics/ BiTEs


Conclusions: Integration and Impact of Novel Agent Combinations in NDMM, Including Immune Therapies • Innovations (PIs, IMiDs, mAbs) to date have produced significant improvements in PFS and OS in NDMM

• Recent approvals will augment this, with Quads emerging as a new standard

• Next wave of immune therapies: crucially, are they agnostic to mutational thrust? • Baseline immune function is a key barrier to success and may be targetable • CAR T therapies are moving into the NDMM setting • Next-generation mAbs, including ADCs and Bispecifics, represent true new novel mechanisms • BCMA-targeted approaches may become a fourth pillar of NDMM treatment

• New insights to mechanisms of drug action are further expanding treatment/immuno-therapeutic opportunities with combinations

• Next-generation small molecules and targeted therapy show promise – e.g., selinexor, CELMoDS

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under investigation in NDMM, together with other novel agents in development in the relapsed setting (e.g. non-BCMA-targeting Bispecifics, venetoclax, melflufen, and more)


Early Relapse Session Chair: Philippe Moreau, MD, PhD University Hospital Nantes

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How do we sequence after quad induction? Philippe Moreau, MD, PhD University Hospital Nantes

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Transplant ineligible Quad induction, progression on R + CD38 - PI-based : VD + Pom, VD + Cyclo, K?D + pom, KD + Cyclo Ixa-cyclo-dex - Pom-based : Pom VD, PomCycloD, PomD-Elo - Clinical trials : Iber-ixa-dex (IFM)

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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]

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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.


Will an IMiD backbone likely be replaced? Meletios Dimopoulos, MD National and Kapodistrian University of Athens 56


ESMO/ΕΗΑ 2021 recommendations for first relapse

plus DaraPomDe x

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Dimopoulos MA, et al. Ann Oncol 2021;32(3):309-322/Hemasphere 2021;5(2):e528.


Conclusions • The combinations of anti-CD38 Mabs with carfilzomib offer the best results for patients with early RRMM who were previously treated with lenalidomide-based regimens, especially in those who are refractory to lenalidomide. • Although combinations of pomalidomide offer inferior results in this setting, pomalidomide continues to be a valuable drug for those who cannot tolerate carfilzomib. • Challenge: the use of both daratumumab and lenalidomide at first line. • Anti-BCMA based therapies (i.e. belantamab mafodotin) with pomalidomide may be a suitable option for patients who were treated with both lenalidomide and daratumumab at frontline. Need for phase 3 data • CAR-T cells might also be a viable option in this setting, but we need the data to support this. Encouraging results from late RRMM.

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Is this the best positioning for CAR T-cell / Bi-Specifics? Saad Usmani, MD, MBA, FACP Memorial Sloan Kettering Canter Center 59


Key Goals for 1st Relapse Disease By 2030 •

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Distinguish Relapse Approach by Drug Class Refractoriness • Len Refractory • Functional high risk defined by relapse within two years of 1st Line Therapy: – PI/IMiD Refractory – Daratumumab/IMiD Refractory Distinguish Relapse Approach for High-Risk Disease from Standard Risk – Translocation (11;14) : BCL2 Inhibitor Based Combinations – EMD/PCL: ?? – TP53 Deletion: ?? – MAF/MAFB Overexpression: ?? – Amp 1q21: ?? Find Solutions for Areas of Unmet Need – Dose/Schedules for Creatinine Clearance less than 30 ml/min: ?? – Dose/Schedules elderly frail : ?? Design trials towards defined duration of therapy – Sustained MRD-ve at 10-6 12 months apart: ??

Presented by: Saad Z. Usmani, MD MBA FACP, @szusmani


The Case for Fixed Duration Treatment with Bispecific Antibodies 75 yo RRMM s/p 16 lines, diagnosed in 2001 Line 1: VAD induction, Mel-ASCT, PR Line 2: Thal-Dex, PR Line 3: Bor-Dex, PR Line 4: Len-Dex, PR Line 5: Bor-Dex, PR Line 6: Cyclo-Dex, SD Line 7: CyBorD, SD Line 8: RVd, PR Line 9: RVd-Cy, PR Line 10: Bendamustine-Bor-Dex, SD

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Line 11: Rd, MR Line 12: Pom-Cy-Dex, SD Line 13: Dara, MR Line 14: Dara-Pom-Dex, PR Line 15: Dara-Pom-Cy-Dex. PR Line 16: BCMA directed BsAb in summer 2019. - Off s/p 8 cycles - Still off therapy, MRD-ve by NGS and flow at 10-5


Later Relapse Session Chair: Nikhil Munshi, MD Dana-Farber Cancer Institute

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What are the most promising pipeline agents? Kenneth Anderson, MD Dana-Farber Cancer Institute

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Future Directions Combination PI, IMiD, Dex, CD38MoAb will achieve high rates MRD negativity in NDMM, including high risk MM CARs, BiTEs, Immune therapies will then be compared with ASCT to induce long term MRDwith memory anti-MM immune response Prediction: Long term disease-free survival and potential cure of MM will be achieved with combination targeted and immune therapies to both achieve MRD negativity and restore host memory anti-MM immunity. These patients will then be free of disease and off all therapy..

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Are more inclusive / realistic entry criteria required? Sonja Zweegman, MD, PhD Vrije Universiteit Amsterdam Medical Center 65


NOVEL TRIALS

ALWAYS + CORRELATIVE STUDIES INVESTIGATING BIOLOGY NOT ONLY OF THE DISEASE BUT ALSO OF THE PATIENT ALL-IN STUDIES All races, older + co-morbidities + frail Powered for predefined subgroup analyses

STUDIES DESIGNED SPECIFICALLY FOR SPECIFIC SUBGROUPS Using uniform definitions for subgroups, by example for frailty the IMWG-FI

THEN WE LEARN  WHAT THE VALUE OF THERAPY WILL BE IN REAL LIFE  WHICH PATIENTS BENEFIT WHICH SUPPORTS FUTURE TAILOR-MADE/TARGETED THERAPY

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IMWG| June 2022


What will be the role of the Immune Therapy Registry & Virtual Tissue Bank? Tom Martin, MD University of California San Francisco 67


Conclusions: Immunodatabse in MM • Will enable prospective Real-world evaluations of novel therapies • Will provide Data on sequencing and preferences • Further explorations through VTB will enhance database

• SOON to come

• On-line proposals • Investigators • Pharma • Future VTB studies

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Tom Martin

Bring down costs!


Working Committee Reporting Session Chairs: Brian G.M. Durie, MD International Myeloma Foundation & S. Vincent Rajkumar, MD Mayo Clinic, MN 69


Smoldering Multiple Myeloma Committee Report María-Victoria Mateos, MD, PhD University Hospital of Salamanca & Shaji Kumar, MD Mayo Clinic, MN 70


Bone Disease Committee Report

Evangelos Terpos, MD National and Kapodistrian University of Athens & Jens Hillengass, MD Roswell Park Comprehensive Cancer Center & Suzanne Lentzsch, Columbia University Medical Center 71

Note: Virtual imaging database proposed


Immune Therapy Committee Report Tom Martin, MD University of California San Francisco & Yi Lin, MD, PhD Mayo Clinic, MN 72


Mass Spectrometry Committee Report Brian G.M. Durie, MD International Myeloma Foundation & David Murray, MD, PhD Mayo Clinic, MN Note: Proposed to evaluate low spikes on Mass Spec 73


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Thank you to our sponsors!

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