IMWG Conference Series 2023: Making Sense of Treatment

ASH 2023 • • •

Total Attendance: 32,000 - 28,000 in-person attendees - 4,000 virtual attendees Total Number of Abstracts: 7,000 Myeloma Abstracts: over 1,000 - Oral Presentations: 136 + LBA & Plenary - Posters: about 850 2

Thank you to our sponsors!

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Phase 3 Randomized Study of Daratumumab + Bortezomib, Lenalidomide, and Dexamethasone (VRd) Versus VRd Alone in Patients With Newly Diagnosed Multiple Myeloma Who Are Eligible for Autologous Stem Cell Transplantation: Primary Results of the PERSEUS Trial* *ClinicalTrials.gov Identifier: NCT03710603; sponsored by EMN in collaboration with Janssen Research & Development, LLC.

Pieter Sonneveld,1 Meletios A. Dimopoulos,2 Mario Boccadoro,3 Hang Quach,4 P. Joy Ho,5 Meral Beksac,6 Cyrille Hulin,7 Elisabetta Antonioli,8 Xavier Leleu,9 Silvia Mangiacavalli,10 Aurore Perrot,11 Michele Cavo,12 Angelo Belotti,13 Annemiek Broijl,1 Francesca Gay,14 Roberto Mina,14 Inger S. Nijhof,15,16 Niels W.C.J. van de Donk,15 Eirini Katodritou,17 Fredrik Schjesvold,18 Anna Sureda Balari,19 Laura Rosiñol,20 Michel Delforge,21 Wilfried Roeloffzen,22 Tobias Silzle,23 Annette Vangsted,24 Hermann Einsele,25 Andrew Spencer,26 Roman Hajek,27 Artur Jurczyszyn,28 Sarah Lonergan,1 Tahamtan Ahmadi,29 Yanfang Liu,30 Jianping Wang,30 Diego Vieyra,30 Emilie M.J. van Brummelen,30 Veronique Vanquickelberghe,30 Anna Sitthi-Amorn,30 Carla J. de Boer,30 Robin Carson,30 Paula Rodriguez-Otero,31 Joan Bladé,32 Philippe Moreau33 1Erasmus MC Cancer Institute, Rotterdam, The Netherlands; 2National and Kapodistrian University of Athens, Athens, Greece; 3Myeloma Unit, Division of Hematology, University of Torino, Azienda Ospedaliero-Universitaria Città della Salute e della

Scienza di Torino, Torino, Italy; 4University of Melbourne, St Vincent’s Hospital, Melbourne, Australia; 5Institute of Haematology, Royal Prince Alfred Hospital and University of Sydney, Camperdown, NSW, Australia; 6Ankara University, Ankara, Turkey; 7Department of Hematology, Hôpital Haut Lévêque, University Hospital, Pessac, France; 8Department of Hematology, Careggi Hospital and University of Florence, Firenze, Italy; 9University of Poitiers, CHU and Inserm 1313, Poitiers, France; 10Hematology Division, IRCCS Fondazione Policlinico San Matteo, Pavia, Italy; 11CHU de Toulouse, IUCT-O, Université de Toulouse, UPS, Service d’Hématologie, Toulouse, France; 12IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia “Seràgnoli”, Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Università di Bologna, Bologna, Italy; 13Department of Hematology, ASST Spedali Civili di Brescia, Brescia, Italy; 14Division of Hematology 1, AOU Città della Salute e della Scienza di Torino, University of Torino and Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy; 15Department of Hematology, Amsterdam University Medical Center, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands; 16Department of Hematology, St. Antonius Hospital, Nieuwegein, The Netherlands; 17Department of Hematology, Theagenion Cancer Hospital, Thessaloniki, Greece; 18Oslo Myeloma Center, Department of Hematology, Oslo University Hospital, Oslo, Norway, and KG Jebsen Center for B-cell Malignancies, University of Oslo, Oslo, Norway; 19Hematology Department, Institut Català d’Oncologia - Hospitalet, IDIBELL, University of Barcelona, Barcelona, Spain; 20Hospital Clínic de Barcelona, IDIBAPS, Barcelona, Spain; 21University of Leuven, Leuven, Belgium; 22University Medical Center Groningen, Groningen, The Netherlands; 23Department of Medical Oncology and Hematology, Cantonal Hospital St. Gallen, St. Gallen, Switzerland; 24Department of Hematology, Rigshospitalet, Copenhagen, Denmark; 25Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany; 26Malignant Haematology and Stem Cell Transplantation Service, Alfred Health-Monash University, Melbourne, Australia; 27University Hospital Ostrava and Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic; 28Plasma Cell Dyscrasias Center, Department of Hematology, Jagiellonian University Medical College, Kraków, Poland; 29Genmab US, Inc., Plainsboro, NJ, USA; 30Janssen Research & Development, LLC; 31Department of Hematology, Cancer Center Clínica Universidad de Navarra, Pamplona, Navarra, Spain; 32Hospital Clínic de Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain; and GEM/PETHEMA; 33Hematology Department, University Hospital Hôtel-Dieu, Nantes, France

Presented by P Sonneveld at American Society of Hematology Annual Meeting; December 9-12, 2023; San Diego, CA, USA.

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PERSEUS: Study Design

• Transplanteligible NDMM • Age 18-70 years • ECOG PS ≤2

Consolidation

VRd

V: 1.3 mg/m2 SC Days 1, 4, 8, 11 R: 25 mg PO Days 1-21 d: 40 mg PO/IV Days 1-4, 9-12

D-VRd

DARA: 1,800 mg SCb QW Cycles 1-2 Q2W Cycles 3-4

V: 1.3 mg/m2 SC Days 1, 4, 8, 11 R: 25 mg PO Days 1-21 d: 40 mg PO/IV Days 1-4, 9-12

D-VRd

DARA: 1,800 mg SCb Q2W VRd administered as in the VRd group

VRd administered as in the VRd group 4 cycles of 28 days

Maintenance

VRd

TRANSPLANT

Key eligibility criteria:

1:1 Randomization (N = 709)a

Induction

R

R 10 mg PO Days 1-28 until PD

D-R

DARA: 1,800 mg SCb Q4W R: 10 mg PO Days 1-28

2 cycles of 28 days

Primary endpoint: PFSc Key secondary endpoints: Overall CR rate,c overall MRD-negativity rate,d OS

MRD positive

Continue D-R until PD

MRD negative

Discontinue DARA therapy only

28-day cycles

Discontinue DARA therapy only after 24 months of D-R maintenance for patients with CR and 12 months of sustained MRD negativity

Restart DARA therapy upon confirmed loss of CR without PD or recurrence of MRD

ECOG PS, Eastern Cooperative Oncology Group performance status; V, bortezomib; SC, subcutaneous; PO, oral; d, dexamethasone; IV, intravenous; QW, weekly; Q2W, every 2 weeks; PD, progressive disease; Q4W, every 4 weeks; MRD, minimal residual disease; CR, complete response; OS, overall survival; ISS, International Staging System; rHuPH20, recombinant human hyaluronidase PH20; IMWG, International Myeloma Working Group; VGPR, very good partial response. aStratified by ISS stage and cytogenetic risk. bDARA 1,800 mg co-formulated with rHuPH20 (2,000 U/mL; ENHANZE  drug delivery technology, Halozyme, Inc., San Diego, CA, USA). cResponse and disease progression were assessed using a computerized algorithm based on IMWG response criteria. dMRD was assessed using the clonoSEQ assay (v.2.0; Adaptive Biotechnologies, Seattle, WA, USA) in patients with VGPR post consolidation and at the time of suspected CR. Overall MRD-negativity rate was defined as the proportion of patients who achieved both MRD negativity (10 –5 threshold) and CR at any time.

Presented by P Sonneveld at American Society of Hematology Annual Meeting; December 9-12, 2023; San Diego, CA, USA.

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PERSEUS: Progression-free Survival

% surviving without progression

Median follow-up: 47.5 months

48-month PFS

100

84.3%

80

67.7%

60

D-VRd VRd

40 20 0

HR, 0.42; 95% CI, 0.30-0.59; P <0.0001 0

3

6

9

12

15

18

21

24

No. at risk VRd 354 D-VRd 355

335 345

321 335

311 329

304 327

297 322

291 318

283 316

278 313

27 30 Months 270 309

258 305

33

36

39

42

45

48

51

54

247 302

238 299

228 295

219 286

175 226

67 90

13 11

0 0

58% reduction in the risk of progression or death in patients receiving D-VRd HR, hazard ratio; CI, confidence interval.

Presented by P Sonneveld at American Society of Hematology Annual Meeting; December 9-12, 2023; San Diego, CA, USA.

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PERSEUS: Overall CR Rates

100

Response rate, %

90

P <0.0001 Odds ratio, 3.13 (95% CI, 2.114.65)

≥CR 87.9%

80

≥CR 70.1%

70

60 50

69.3

40

44.6 sCR

30

CR

20 10

VRd Subgroup

18.6

25.4

0

D-VRd (n = 355)

D-VRd

Odds ratio (95% CI)

no. of patients with ≥CR/total no. (%)

Sex Male 143/205 (69.8) Female 105/149 (70.5) Age <65 years 186/267 (69.7) ≥65 years 62/87 (71.3) Race White 226/323 (70.0) Other 22/31 (71.0) ISS stage I 129/178 (72.5) II 84/125 (67.2) III 34/50 (68.0) Type of MM lgG 122/185 (65.9) Non-lgG 73/96 (76.0) Cytogenetic risk Standard risk 182/266 (68.4) High risk 59/78 (75.6) Indeterminate 7/10 (70.0) ECOG performance status 0 160/230 (69.6) ≥1 88/124 (71.0)

VRd (n = 354)

185/211 (87.7) 127/144 (88.2)

3.08 (1.86-5.12) 3.13 (1.69-5.80)

235/261 (90.0) 77/94 (81.9)

3.94 (2.43-6.37) 1.83 (0.91-3.68)

289/330 (87.6) 23/25 (92.0)

3.03 (2.02-4.53) 4.70 (0.91-24.25)

167/186 (89.8) 101/114 (88.6) 44/55 (80.0)

3.34 (1.87-5.95) 3.79 (1.91-7.54) 1.88 (0.77-4.58)

178/204 (87.3) 72/78 (92.3)

3.54 (2.12-5.90) 3.78 (1.45-9.83)

234/264 (88.6) 63/76 (82.9) 15/15 (100)

3.60 (2.27-5.70) 1.56 (0.71-3.44) NE (NE-NE)

195/221 (88.2) 117/134 (87.3)

3.28 (2.00-5.39) 2.82 (1.49-5.34) 0.1

1

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Favors VRd Favors D-VRd

• Overall CR rate was significantly higher with D-VRd versus VRd • CR rate was improved with D-VRd versus VRd across subgroups P value (2-sided) was calculated with the use of the stratified Cochran–Mantel–Haenszel chi-squared test.

Presented by P Sonneveld at American Society of Hematology Annual Meeting; December 9-12, 2023; San Diego, CA, USA.

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PERSEUS: Overall and Sustained MRD-negativity Ratesa MRD Negativity (10–5)

MRD Negativity (10–6)

P <0.0001b Odds ratio, 3.40 (95% CI, 2.47-4.69)

P <0.0001b Odds ratio, 3.97 (95% CI, 2.90-5.43)

60

60

P <0.0001c Odds ratio, 4.42 (95% CI, 3.22-6.08)

80

80

75.2%

MRD-negativity rate, %

80

Sustained MRD Negativity (10–5) 12 months

65.1%

60

64.8%

47.5%

40

40

20

20

20

0

0

0

D-VRd (n = 355)

VRd (n = 354)

32.2%

D-VRd (n = 355)

40

VRd (n = 354)

29.7%

D-VRd (n = 355)

VRd (n = 354)

• Deep and durable MRD negativity was achieved with D-VRd • 64% (207/322) of patients receiving maintenance in the D-VRd group discontinued DARA after achieving sustained MRD negativity per protocold aMRD-negativity rate was defined as the proportion of patients who achieved both MRD negativity and CR. MRD was assessed using bone marrow aspirates and evaluated via next-generation sequencing (clonoSEQ

assay, version 2.0; Adaptive Biotechnologies, Seattle, WA). bP values were calculated with the use of the stratified Cochran–Mantel–Haenszel chi-squared test. cP value was calculated with the use of Fisher’s exact test. dAfter 24 months of maintenance therapy, DARA was discontinued in patients who achieved CR and sustained MRD negativity (10 –5) for 12 months.

Presented by P Sonneveld at American Society of Hematology Annual Meeting; December 9-12, 2023; San Diego, CA, USA.

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PERSEUS Primary Analysis: Conclusions • D-VRd (DARA SC) induction followed by ASCT, D-VRd consolidation, and D-R maintenance significantly improved PFS versus VRd induction followed by ASCT, VRd consolidation, and R maintenance in transplant-eligible patients with NDMM (HR, 0.42; P <0.0001) – 48-month PFS rates: 84.3% versus 67.7%

• D-VRd regimen significantly improved depth of response versus VRd regimen – Overall CR rates: 87.9% versus 70.1%

– Overall MRD-negativity rates: 75.2% versus 47.5%

• Observed safety profile was consistent with the known safety profiles for DARA SC and VRd • These data from the phase 3 PERSEUS study demonstrate the clinically meaningful benefit of quadruplet D-VRd followed by D-R maintenance

These randomized phase 3 results support D-VRd followed by D-R maintenance as a new standard of care for transplant-eligible patients with NDMM

Presented by P Sonneveld at American Society of Hematology Annual Meeting; December 9-12, 2023; San Diego, CA, USA.

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PERSEUS: Overall Survival 100 D-VRd VRd

% surviving

80 60 40 20

VRd (n = 354)

34 (9.6)

44 (12.4)

Events, n (%)

HR, 0.73 0

D-VRd (n = 355)

0

3

6

9

12

15

18

21

24

36

39

42

45

48

51

54

57

No. at risk VRd 354 D-VRd 355

27 30 33 Months

343 347

337 343

334 341

328 338

322 335

322 331

319 329

317 329

315 326

303 321

298 316

296 312

263 284

127 135

27 21

1 1

0 0

310 325

307 323

OS data trend favorably for D-VRd Presented by P Sonneveld at American Society of Hematology Annual Meeting; December 9-12, 2023; San Diego, CA, USA.

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Abstract #4 | Presentation at the 65th ASH Annual Meeting and Exposition | December 9‒12, 2023

Results of the Phase III Randomized IsKia Trial: Isatuximab-Carfilzomib-LenalidomideDexamethasone Vs Carfilzomib-Lenalidomide-Dexamethasone as Pre-Transplant Induction and Post-Transplant Consolidation in Newly Diagnosed Multiple Myeloma Patients Francesca Gay, MD, PhD1,2; Wilfried Roeloffzen, MD, PhD3; Meletios Athanasios Dimopoulos, MD, PhD4; Laura Rosiñol, MD, PhD5; Marjolein van der Klift, MD, PhD6; Roberto Mina, MD1,2; Albert Oriol Rocafiguera, MD7; Eirini Katodritou, MD8; Ka Lung Wu, MD, PhD9; Paula Rodriguez Otero, MD, PhD10; Roman Hájek, MD, PhD11,12; Elisabetta Antonioli, MD13; Mark van Duin, PhD14; Mattia D'Agostino, MD1,2; Joaquín Martínez-López, MD, PhD15; Elena M. van Leeuwen-Segarceanu, MD, PhD16; Paola Tacchetti, MD, PhD17; Niels W.C.J. van de Donk, MD, PhD18; Katja Weisel, MD19; Luděk Pour, MD20; Jakub Radocha, MD, PhD21; Angelo Belotti, MD22; Fredrik Schjesvold, MD, PhD23,24; Joan Bladé, MD, PhD25; Hermann Einsele, MD, PhD26; Pieter Sonneveld, MD, PhD14; Mario Boccadoro, MD27; Annemiek Broijl, MD, PhD28 1. Division of Hematology, Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy; 2. Division of Hematology, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino, University of Torino, Torino, Italy; 3. Department of Hematology, University Medical Center Groningen, Groningen, the Netherlands; 4. Hematology and Medical Oncology, Department of Clinical Therapeutics, National and Kapodistrian University of Athens School of Medicine, Athens, Greece; 5. Amyloidosis and Myeloma Unit, Department of Hematology, Hospital Clínic de Barcelona, IDIBAPS, Barcelona, Spain; 6. Department of Internal Medicine, Amphia Hospital, Breda, the Netherlands; 7. Institut Català d'Oncologia and Institut Josep Carreras, Hospital Germans Trias i Pujol, Barcelona, Spain; 8. Department of Hematology, Theagenion Cancer Hospital, Thessaloniki, Greece; 9. ZNA Stuivenberg, Lange Beeldekenstraat 267, 2060, Antwerp, Belgium; 10. Clínica Universidad de Navarra, Pamplona, Spain; 11. Department of Haematooncology, University Hospital Ostrava, Ostrava, Czech Republic; 12. Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic; 13.

Hematology Unit, AOU Careggi, Florence, Italy; 14. Department of Hematology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands; 15. Hematology Department, Hospital Universitario 12 de Octubre, Medicine Department Complutense University, CNIO, Madrid, Spain; 16. Department of Hematology, St. Antonius Hospital, Nieuwegein, the Netherlands; 17. IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy; 18. Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Hematology, Cancer Center Amsterdam, Amsterdam, the Netherlands; 19. Department of Oncology, Hematology and BMT, University Medical Center of Hamburg-Eppendorf, Germany; 20. Department of Internal Medicine, Hematology and Oncology, University Hospital Brno, Brno, Czech Republic; 21. 4th Department of Internal Medicine-Hematology, University Hospital Hradec Kralove, Charles University, Faculty of Medicine in Hradec Kralove, Hradec Kralove, Czech Republic; 22. Department of Hematology, ASST Spedali Civili di Brescia, Brescia, Italy; 23. Oslo Myeloma Center, Department of Hematology, Oslo University Hospital, Oslo, Norway; 24. KG Jebsen Center for B cell malignancies, University of Oslo, Oslo, Norway; 25. Hematology Department, Hospital Clinic, IDIBAPS, Barcelona, Spain; 26. Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany; 27. European Myeloma Network, EMN, Italy; 28. Erasmus MC Cancer Institute, Rotterdam, Netherlands

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IsKia EMN24 Study Design 42 active sites; enrollment: Oct 7, 2020 ‒ Nov 15, 2021

Induction

Post-ASCT consolidation Light consolidation

Four 28-day cycles

4×KRd K: 20 mg/m2 IV dd 1 cc 1 only; followed by 56 mg/m2 IV dd 8,15 cc 1 and dd 1,8,15 cc 2-4 R: 25 mg PO daily dd 1-21 d: 40 mg PO dd 1,8,15,22

Key eligibility criteria: TE NDMM patients aged <70 years Stratification: - Centralized FISH (standard risk/missing vs. high risk defined as del(17p) and/or t(4;14) and/or t(14;16); - ISS (I vs. II and III)

R

Four 28-day cycles

Twelve 28-day cycles

MOBILIZATION

4×KRd

12×KRd

K: 56 mg/m2 IV dd 1,8,15

Cy: 2-3 g/m2

cc 5-8 R: 25 mg PO daily dd 1-21 d: 40 mg PO dd 1,8,15,22

K: 56 mg/m2 IV dd 1,15 R: 10 mg PO dd 1-21 d: 20 mg PO dd 1,15

followed by G-CSF for stem-cell collection

4×Isa-KRd

and

Isa: 10 mg/kg IV dd 1,8,15,22 cc 1, followed by 10 mg/kg IV dd 1 and 15 cc 2 to 4.

K: 20 mg/m2 IV dd 1 cc 1 only; followed by 56 mg/m2 IV dd 8,15 cc 1 and dd 1,8,15 cc 2-4 R: 25 mg PO daily dd 1-21 d: 40 mg PO dd 1,8,15,22

MEL200-ASCT MEL: 200 mg/m2

MRD by NGS

followed by ASCT

4×Isa-KRd Isa: 10 mg/kg IV dd 1,15 cc 5-8 K: 56 mg/m2 IV dd 1,8,15 cc 5-8 R: 25 mg PO daily dd 1-21 d: 40 mg PO dd 1,8,15,22

MRD by NGS

12×Isa-KRd Isa: 10 mg/kg IV d 1 K: 56 mg/m2 IV dd 1,15 R: 10 mg PO dd 1-21 d: 20 mg PO dd 1,15

MRD by NGS

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MRD by NGS

TE, transplant-eligible; NDMM, newly diagnosed multiple myeloma; FISH, fluorescence in situ hybridization; del, deletion; t, translocation; ISS, International Staging System stage; R, randomization; Isa, isatuximab; K, carfilzomib; R, lenalidomide; d, dexamethasone; IV, intravenous; dd, days; cc, cycles; PO, orally; Cy, cyclophosphamide; G-CSF, granulocyte colony-stimulating factor; MEL, melphalan; ASCT, autologous stem-cell transplantation; MRD, minimal residual disease; NGS, next-generation sequencing; PFS, progression-free survival.

Primary Endpoint: Post-consolidation MRD negativity (ITT analysis) 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0%

NGS, 10-6

OR 1.67, p=0.049 77% 67% Patients (%)

Patients (%)

NGS, 10-5

Isa-KRd (N=151)

KRd (N=151)

100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0%

OR 2.29, p<0.001 67% 48%

Isa-KRd (N=151)

KRd (N=151)

≥VGPR after consolidation was 94% in both arms; ≥CR 74% vs 72% and sCR 64% vs 67% in the IsaKRd vs KRd arms.

Consistent MRD results were detected by next-generation flow

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In the logistic regression analysis, ORs, 95% CIs, and p-values were adjusted for stratification factor.

MRD, minimal residual disease; ITT, intention to treat; NGS, next-generation sequencing; OR, odds ratio; p, p-value; Isa, isatuximab; K, carfilzomib; R, lenalidomide; d, dexamethasone; CI, confidence interval.

Post-consolidation MRD negativity by NGS Subgroup analysis 10-5 cut-off

10-6 cut-off OR (95% CI)

Overall

Interaction p

1.67 (1.00–2.80)

OR (95% CI) Overall

2.29 (1.43–3.67)

Cytogenetic risk

Cytogenetic risk

as per IMWGa

as per IMWGa

Standard risk High risk N of HRCA:

1.70 (0.92–3.12) 2.30 (0.68–7.76)

0.6638

0 HRCA 1 HRCA 2+ HRCA

1.60 (0.75–3.41) 1.86 (0.76–4.57) 2.76 (0.52–14.56)

0.839

R-ISS I II‒III

1.48 (0.58–3.75) 1.79 (0.94–3.43)

R2-ISS I II III–IV

1.14 (0.36–3.60) 3.08 (1.13–8.38) 1.49 (0.67–3.27)

Favors KRd

Standard risk High risk N of HRCA:

2.10 (1.22–3.61) 0.203 4.95 (1.48–16.61)

0, 1, 2+ HRCAb

0, 1, 2+ HRCAb

0.15

Interaction p

1

14.56 Favors Isa-KRd

0 HRCA 1 HRCA 2+ HRCA

2.21 (1.14–4.27) 0.2982 2.04 (0.88–4.70) 9.05 (1.57–52.14)

0.7401

R-ISS I II‒III

2.03 (0.89–4.63) 2.35 (1.30–4.26)

0.7766

0.3844

R2-ISS I II III‒IV

1.76 (0.66–4.69) 3.71 (1.54–8.93) 1.92 (0.92–4.02)

0.4363

0.20 Favors KRd

1

52.14 Favors Isa-KRd

15

aHigh-risk cytogenetics per IMWG criteria were defined as the presence of t(4;14), t(14;16), or del(17p); Chng WJ, et al. Leukemia. 2014 Feb;28(2):269-77. doi: 10.1038/leu.2013.247. b1 HRCA was defined as the presence of one of the following high-risk cytogenetic abnormalities:

del(17p13.1), t(4;14) (p16.3;q32.3), t(14;16) (q32.3;q23), gain(1q21), or amp(1q21); 2+ HRCA was defined as the presence of at least two high-risk cytogenetic abnormalities. cR2-ISS definition: A value was assigned to each risk feature according to their OS impact (ISS III 1.5, ISS II 1, del(17p) 1, high LDH 1, t(4;14) 1, and 1q+ 0.5 points). Patients were stratified into four risk groups according to the total additive score: low (R2-ISS-I, 0 points), low-intermediate (R2-ISS II, 0.5-1 points), intermediate-high (III, 1.5-2.5 points), high (IV, 3-5 points). See D'Agostino M et al. J Clin Oncol. 2022 Oct 10;40(29):3406-3418. doi: 10.1200/JCO.21.02614. Erratum in: J Clin Oncol. 2022 Dec 1;40(34):4032. dPalumbo A, et al. J Clin Oncol. 2015 Sep 10;33(26):2863-9. doi: 10.1200/JCO.2015.61.2267. Abbreviations: MRD, minimal residual disease; OR, odds ratio; CI, confidence interval; p, p-value; R-ISS, Revised International Staging System stage; R2-ISS, Second Revision of the International Staging System stage; K, carfilzomib; R, lenalidomide; d, dexamethasone; Isa, isatuximab; del, deletion; t, translocation; amp, amplification.

Post-consolidation MRD negativity by NGS Subgroup analysis by cytogenetic risk NGS, 10-5

Very high risk

100%

Patients (%)

90% 80%

NGS, 10-6

Very high risk

100% 90%

79% 72%

78%

77% 65%

70% 60%

70% 53%

50%

40%

40%

30%

30%

20%

20%

10%

10%

0%

0%

1 HRCA Isa-KRd

69%

65%

60%

50%

0 HRCA

77%

80%

2+ HRCA KRd

1 HRCA was defined as the presence of one of the following high-risk cytogenetic abnormalities: del(17p13.1), t(4;14) (p16.3;q32.3), t(14;16) (q32.3;q23), gain(1q21), or amp(1q21); 2+ HRCA was defined as the presence of at least two high-risk cytogenetic abnormalities.

48%

53%

27%

0 HRCA

1 HRCA Isa-KRd

2+ HRCA KRd 16

MRD, minimal residual disease; NGS, next-generation sequencing; HRCA, high-risk cytogenetic abnormalities; Isa, isatuximab; K, carfilzomib; R, lenalidomide; d, dexamethasone; del, deletion; t, translocation; amp, amplification.

Conclusions •

Isa-KRd significantly increased post-consolidation 10-5 and 10-6 MRD negativity, as compared with KRd

•

Isa-KRd significantly increased 10-5 and 10-6 MRD negativity after each treatment phase (Induction, Transplantation, Consolidation) .

•

Isa-KRd consistently increased MRD negativity at 10-5 and 10-6 in all subgroups of patients, including high-risk and very high-risk disease.

•

Isa-KRd treatment was tolerable, with a toxicity profile similar to that in previous reports.

•

10-6 MRD negativity cut-off is more informative.

•

1-year sustained MRD negativity will be available in 2024

•

With a longer follow-up, this trial can offer the opportunity to explore the correlation 17 between depth of MRD negativity and PFS/OS. Isa, isatuximab; K, carfilzomib; R, lenalidomide; d, dexamethasone; MRD, minimal residual disease; PFS, progression-free survival; OS, overall survival.

18

Minimally Invasive Assessment of Measurable Residual Disease (MRD) in Multiple Myeloma (MM) M Lasa, L Notarfranchi, C Agullo, N Buenache, C Gonzalez, A Zherniakova, S Castro, J J Perez, V González de la Calle, M T Cedena, S Barrio, A Martin-Muñoz, L Burgos, D Alignani, M J Calasanz, P Rodriguez-Otero, L Rosiñol, F De Arriba, E M. Ocio, A Oriol, L Palomera, Y Gonzalez, A Sureda, M T Hernandez, M E Clavero Sanchez, A Ibañez, C Gomez, A Orfao, M V Mateos, J J Lahuerta, J Blade, J San Miguel, J Martinez-Lopez, N Puig and B Paiva, on behalf of the PETHEMA/GEM cooperative group Abstract #339, Saturday 9th, 4:30pm

19

Kinetics and Biology of Circulating Tumor Cells (CTCs) and Measurable Residual Disease (MRD): Two Dynamic High-Risk Clones in Multiple Myeloma (MM) C Guerrero, R Termini, JJ Garcés, MJ Calasanz, R Ríos-Tamayo, ME Cabezudo, L Rosiñol, J Bargay, A Pérez, A Oriol, V Cabañas, MJ Nájera, ME González García, E Ocio, A Sureda, F de Arriba, MT Hernández, A García Griñón, J Martínez López, MJ Blanchard, MS González, R Iglesias, A Orfao, MV Mateos, JJ Lahuerta, J Bladé, JF San Miguel, MT Cedena, N Puig, Bruno Paiva, on behalf of the PETHEMA (Programa para el Estudio de la Terapéutica en Hemopatías Malignas) / GEM (Grupo Español de Mieloma) cooperative study group

Abstract #871, Monday 11th, 2:45 PM

20

MRD kinetics risk stratification in active MM GEM2012MENOS65 – GEM2014MAIN trials: 1,759 MRD assessments Median follow-up 6-yrs

Stable MRD levels Evolving MRD levels

94% 95%

90% 75%

P = 0.014

Overall survival (%)

Sustained MRDnegativity

Progression-free survival (%)

Median follow-up 6-yrs

66%

5% Time after consolidation

Time after consolidation

Time after consolidation

Time after consolidation

21

MRD kinetics outperform a single assessment Independent prognostic value along with the R2-ISS

R2-ISS

C-index (se)

0.820

0.611 0.566

0.617

0.567 MRD kinetics

ISS

RISS

R2ISS MRD pre- MRD maint. kinetics

22

The unmet need of minimally invasive MRD assessment The requirement of invasive BM aspirates hinders routine implementation

MRD

Clinical trials

Routine practice 23 Authors’ opinion

Investigate the complementarity and prognostic value of new multimodal minimally invasive MRD assessment in MM

PB

n= 242/242 BloodFlow

CTCs

n = 27/242 Plasma cfDNA

N= 242 or Maintenance observation PETHEMA/GEM Clinical trials

Serum

CloneSight

n= 168/242 QIP-MS

Mutations

M-component

24

Prognostic value of MRD assessment using BloodFlow

Progression-free survival (%)

MRD+ associated with 12-fold increment in the risk of progression and/or death

MRD

No.

Median PFS

PFS @1y

Negative

220

NR

94%

Positive

22

3 mo

46%

Hazard ratio 11.7 (P < .001)

Time since MRD assessment (months)

25

MRD assessment in PB using BloodFlow and in BM using NGF

Progression-free survival (%)

Analysis restricted to 136 patients with paired samples

MRD PB / BM

No.

Median PFS

PFS @1y

-/-

99

NR

97%

-

- / + & +/-

26

NR

88%

3.4 (P = .14)

+/+

11

3 mo

45%

19.7 (P < .001)

Hazard ratio

Time since MRD assessment (months)

26

BloodFlow and QIP-MS showed more balanced NPV and PPV CloneSight showed the highest PPV but low NPV

BloodFlow

QIP-MS

78% NPV 96% PPV

82% NPV 70.5% PPV

Are these methods complementary for improved prediction of PFS?

27

Complementarity between BloodFlow and QIP-MS

Progression-free survival (%)

MRD detection by either method resulted in increased risk of progression

MRD BF & QIP-MS

No.

Median PFS

PFS @1y

Hazard ratio

-/-

129

NR

98%

-

-/+

26

NR

80%

9.8 (P = .002)

+/-

2

2 mo

0%

97.7 (P < .001)

+/+

11

8 mo

46%

29.5 (P < .001)

Time since MRD assessment (months)

28

Complementarity between BloodFlow and QIP-MS

Progression-free survival (%)

3/129 (2%) double negative MRD patients progressed thus far

MRD BF & QIP-MS

No.

Median PFS

PFS @1y

Hazard ratio

-/-

129

NR

98%

-

-/+

26

NR

80%

9.8 (P = .002)

+/-

2

2 mo

0%

97.7 (P < .001)

+/+

11

8 mo

46%

29.5 (P < .001)

Double-negative MRD detection in PB and serum using BloodFlow and QIP-MS achieved a NPV of 84% (ie, MRD negativity in BM using NGF) Time since MRD assessment (months)

29

Conclusions •

BloodFlow and QIP-MS are empowered to detect MRD with high sensitivity in PB and serum

•

The presence of CTCs was systematically associated with dismal PFS

•

BloodFlow showed very high PPV and QIP-MS achieved the highest NPV

•

The complementarity between these methods enabled the identification of multimodal MRD negative patients with very low risk of relapse

•

This study paves the way towards minimally invasive MRD assessment in MM patients on maintenance or observation 30

We thank the patients and caregivers

31

32

Abstract #340, Session 652, Saturday, December 9, 4:00 PM – 5:30 PM

Mass Spectrometry-Based Assessment of M-Protein in Peripheral Blood during Maintenance Therapy in Multiple Myeloma (MM) in the Phase III ATLAS Trial Tadeusz Kubicki, Dominik Dytfeld, David Barnidge, DJ Sakrikar, Gabriella Lakos, Anna Przybyłowicz-Chalecka, Krzysztof Jamroziak, Paweł Robak, Jarosław Czyż, Agata Tyczyńska, Agnieszka Druzd-Sitek, Krzysztof Giannopoulos, Tomasz Wróbel, Adam Nowicki, Tomasz Szczepaniak, Anna Łojko-Dankowska, Magdalena Matuszak, Lidia Gil, Bartosz Puła, Łukasz Szukalski, Agnieszka Końska, Jan M Zaucha, Jan Walewski, Damian Mikulski, Olga Czabak, Tadeusz Robak, Ken Jiang, Jennifer H Cooperrider, Andrzej J Jakubowiak, Benjamin A Derman

33

Methods

ATLAS trial

Interim results (PFS) Key eligibility criteria: ≤100 days after HSCT ≤ 12 months after diagnosis ≤ 2 induction regimens ≥SD after HSCT

KRd pts with standard risk (SR) cytogenetics having reached IMWG MRD negativity after C6 converted to R alone after C8

MALDI-TOF MS

EXENT® Solution Screening

MRD assessment

Cycle 6

Cycle 12

Cycle 18

Cycle 24

Cycle 36

By flow cytometry and/or NGS, 10-5

34

Dytfeld, Lancet Oncology 2023

MS (-) status post cycle 18 was associated with superior progression-free survival (PFS) + NGS(+) + NGS(−)

Group

Group

+ MS(+) + MS(−)

1.00

+ + + ++

+

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

+

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

0.75

+

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

++ ++ +

++

+ ++

+

+ +

+

+

NGS

+

0.50

Threshold: 10-5 0.25

++++ 0.50

++ ++

0.75

p=0.003 HR=0.15 (0.03-0.63)

0.00 0

12

24

36

Months from C18 Group

+ +++

1.00

0.25

+

++++++++

+

p=0.025 HR=0.39 (0.17-0.91)

0.00

0

12

24

36

48

Months from C18

Number at risk:

68

58

29

9

0

28

20

8

2

0

Progression−free survival

Progression−free survival

Progression−free survival

+ ++ + ++ ++

++ ++ ++ + + +

1.00

+

0.75

+ MFC(+) + MFC(−)

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

+ + +

0.50

++ 0.25

MFC Threshold: 10-5

p=0.0002 HR=0.13 (0.04-0.35)

0.00 0

12

24

Months from C18

36

48

35

Double (MS and MRD) negativity is associated with favorable outcomes + + ++ +

1.00

+ MS(−)/MFC(+) or MS(+)/MFC(−) + MS(−)/MFC(−) ++++ +++

Progression−free survival

1.00

+++ ++

+ + + +

0.75

Group

+

++

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

0.50

+ +

+ +

0.25

+ MS(−)/NGS(+) or MS(+)/NGS(−) + MS(−)/NGS(−)

+ +

Progression−free survival

Group

+

+++++ ++

++++++

+

+

+

+ +

+ + + ++

+

+ +

+

++

+

0.75

+

0.50

0.25

p=0.018 HR=0.30 (0.11-0.87)

p=0.038 HR=0.13 (0.01-1.16) 0.00

0.00 0

12

24

36

48

0

12

24

Months from C18

Months from C18

MFC and MS

NGS and MS

36

36

MS results may add prognostic value to MRD negative status + + ++ +

1.00

+ MS(+)/MFC(−) + MS(−)/MFC(−)

++++ +++

Progression−free survival

+

++ + +

+

0.50

+ 0.25

p=0.11 HR=0.40 (0.13-1.27) 0

12

36

48

+ MS(+)/NGS(−) + MS(−)/NGS(−) +

+++++ ++

+

+

++++++

+

+ + + ++

+

++

+ +

+

+

0.75

0.50

0.25

0.00 24

+ +

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

++

0.00

++

1.00

+++ ++

+ 0.75

Group

Progression−free survival

Group

p=0.06 HR=0.14 (0.01-1.58) 0

12

24

Months from C18

Months from C18

MFC and MS

NGS and MS

36

37

Conclusions • MS-based disease assessment in the post-ASCT setting may be feasible.

• Prognostic significance of MS negativity increases with time.

• MS is complementing BM-based MRD assessments.

• Further prospective studies are needed to confirm these conclusions.

38

39

The early benefits and psychological effect of screening for monoclonal gammopathy of undetermined significance Results of the iStopMM study Sæmundur Rögnvaldsson1,2, Sigrun Thorsteinsdottir1,3, Jon Thorir Oskarsson1, Elias Eythorsson1,2, Guðrún Ásta Sigurðadóttir1, Brynjar Viðarsson2, Páll Torfi Önundarson1,2, Bjarni Agnar Agnarsson1,2, Margret Sigurdardottir2, Isleifur Olafsson1,2, Ingunn Thorsteinsdottir2, Andri Steinthor Bjornsson4, Inga Wesman4, Gauti Kjartan Gislason1, Jon Sigurdsson1, Andri Olafsson1, Ingigerdur Solveig Sverssidottir5, Thorir Einarsson Long1,6, Robert Palmason1,6, Signý Vala Sveinsdóttir2,Fridbjorn Sigurdsson7, Asdis Rosa Thordardottir1, Asbjorn Jonsson7, Runolfur Palsson1,2, Olafur Skuli Indriðason2, Elin Ruth Reed1, Gudlaug Katrin Hakonardottir1, Hlif Steingrimsdottir1, Malin Hultcrantz8, Brian GM Durie9, Stephen Harding10, Thor Aspelund1, Ola Landgren11, Thorvardur Jon Love1,2, Sigurður Yngvi Kristinsson1,2 1: Faculty of Medicine, University of Iceland, Reykjavík, Iceland; 2: Landspítali – The National University Hospital of Iceland, Reykjavík, Iceland; 3: Rigshospitalet, Copenhagen, Denmark; 4: Faculty of Psychology, University of Iceland, Reykjavik, Iceland; 5: Sahlgrenska University Hospital, Gothenburg, Sweden; 6: Skåne University Hospital, Lund, Sweden; 7: Akureyri Hospital, Akureyri, Iceland; 8: Myeloma Service, Dept. of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA ; 9: Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Outpatient Cancer Center, Los Angeles, CA, USA; 10: Binding Site Group Ltd., Birmingham, United Kingdom; 11: Myeloma Program, Department of Medicine, University of Miami, Sylvester Comprehensive Cancer Center, Miami.

40

<10% of myeloma cases are diagnosed at an asymptomatic stage

41 Sigurdardottir, EE et al. (2015) JAMA Oncol; Go, RS (2015) Clin Lymphoma Myeloma Leuk.

Iceland Screens, Treats, or Prevents Multiple Myeloma iStopMM 42

n=80,759 (54%)

Inclusion criteria: -Born ≤1975 -Icelandic resident Exclusion criteria: -Previous lymphoproliferative disease

n=29

n=75,422 (93%)

n=3,543

Only arm 2 and 3: -Previously known MGUS (excluded for this analysis) Psychiatric health: Assessed at registration, after MGUS notification, and annually Intervention arm

Control arm

MM or hrSMM: KRd for2 years irSMM: Rd for 2 years

Rögnvaldsson S et al. (2021) Blood Cancer Journal; 11, 94

43

Results – MGUS progression Progression to SMM or SWM or more advanced

MM WM Other LPs

Intervention arm 26 (1.1%) 17 (0.7%) 27 (1.2%)

SMM SWM

216 (9.1%) 56 (2.4%)

Progression to MM or related clinical disorder

Control arm p 16 (1.4%) 0.84 10 (0.8%) 1.0 14 (1.2%) 1.0 4 (0.3%) 0 (0%)

<0.001 <0.001

44

Results - Progression Progression to MM or related clinical disorder

Before landmark

After landmark

time to progression Screening leads to early-,Mean not over-diagnosis of MM and related clinical disorders 2.0 years vs 3.0 years; p=0.02

45

Results – MM clinical presentation

OR: 0.11 95%CI: 0.002-0.96; p=0.03 OR: 0.24 95%CI: 0.05-0.98; p=0.047

Screening changes the clinical presentation of MM

46

Results – Psychological outcomes Anxiety

Depression

Satisfaction Intervention arm

Control arm

p

0-6 month Moderate to severe anxiety Moderate to severe depression Dissatisfaction with life

3.8% 1.9% 6.3%

1.5% 0.7% 6.0

0.25 0.53 0.99

6-12 months Moderate to severe anxiety Moderate to severe depression Dissatisfaction with life

2.0% 0.9% 8.4%

5.6% 3.1% 9.9%

0.02 0.08 0.64

12-36 months Moderate to severe anxiety Moderate to severe depression Dissatisfaction with life

3.3% 0.5% 12.8%

3.6% 3.4% 15.3%

0.87 <0.001 0.16

Screening does not increase depression, anxiety, or life dissatisfaction

47

Discussion • Screening leads to early-, not over-detection of MM and related disorders • Screening changes the clinical presentation of MM

• Screening does not lead to an increase in depression, anxiety, or dissatisfation with life • Caveats: • How does this affect survival and other long-term outcomes?

• Is it worth it?

• Systematic approach and clear and detailed information and follow up

• Screening fundamentally changes the face of multiple myeloma 48

Progression to CRAB positive MM

49

50

CAR-T Cell Expansion and Cytokine Profiles Correlate with Outcomes in Multiple Myeloma Patients Receiving Ciltacabtagene Autoleucel (Cilta-cel) Junia Vieira dos Santos, MBBS, PhD Laganá Lab, Parekh Lab

Icahn School of Medicine at Mount Sinai American Society of Hematology 2023, 12/09/2023 51

Understanding the determinants of early relapse can help elucidate CAR-T therapy resistance mechanisms.

Dose: 0.75x106 CAR-T cells/kg

Sustained response

Early relapse

52

Peripheral blood CyTOF revealed the dynamics of PB cellular landscape after CAR-T infusion.

T cells Myeloid cells B cells NK cells CAR-T cells

53

Activated CAR-T cell populations were significantly more frequent in the PFS > 18 months group.

CAR-T cell expansion

54

Normalized Protein Expression (NPX)

Distinct cytokine / soluble protein profiles at weeks 1 & 2 post-infusion correlate with length of response. **

***

***

***

**

**

CD27

CD28

IL-12

CD70

IL-10

IL12RB1

Activated / Stimulatory

Regulatory / Immunosuppressive

55

Two endogenous populations (CD8 T naïve and MAIT) were significantly higher in PFS > 18 months group.

BONE MARROW T CELL COMPARTMENT

CD8 Naive

MAIT

7.5

5

*

ns

ns

2.5

10

7.5

*

ns

ns

Baseline

Month 1

Month 2

5

2.5

0

0

UMAP 1 Sugimoto et al, 2022. Biomedicines.

% of MAIT in T-Cell compartment

% of CD8 Naive in T-Cell compartment

UMAP 2

10

Baseline

Month 1

Month 2

https://doi.org/10.3390/biomedicines10123160

56

MDSC cells were significantly increased in patients with a shorter PFS at month 1 after infusion.

BONE MARROW MYELOID COMPARTMENT

MDSC % of MDSC in myeloid compartment

UMAP 2

10

7.5

ns

*

ns

Baseline

Month 1

Month 2

5

2.5

0

UMAP 1 R. J. Tesi, 2019. Trends in Pharmacological Sciences. https://doi.org/10.1016/j.tips.2018.10.008

57

In summary • Expansion of activated CAR-T cells and a higher serum level of cytokines associated with T cell proliferation (IL-12) and activation (CD27 and CD28) correlated with a longer PFS in our cohort.

• Higher counts of central memory CD4 and CD8 CAR-T cells were observed in patients with a longer PFS while higher counts of effector memory CD4 cells were observed in their counterparts.

• In the BM microenvironment, a higher frequency of T cells involved in cellmediated cytotoxic response (CD8 naïve and MAIT) was observed in patients with a longer PFS while a higher frequency of immunosuppressive MDSC cells combined with higher serum levels of IL-10 and CD70 were observed in patients with a shorter PFS.

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58 58

Key ASH Takeaways

59

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