Myeloma .pptx presnatation for newcomers

Myeloma.pptx presnatation for newcomers

1. Considerations for Relapsed/Refractory MM After Multiple Lines of Therapy Shaji K. Kumar, MD Thomas G. Martin, MD Supported by educational grants from Amgen, Janssen Biotech, Inc. administered by Janssen Scientific Affairs, LLC, Karyopharm Therapeutics Inc., Pfizer, Inc., Regeneron Pharmaceuticals, Inc., Takeda Pharmaceuticals U.S.A., Inc. Provided by Clinical Care Options, LLC in partnership with the International Myeloma Foundation.

2. About These Slides Please feel free to use, update, and share some or all of these slides in your noncommercial presentations to colleagues or patients When using our slides, please retain the source attribution: These slides may not be published, posted online, or used in commercial presentations without permission. Please contact [email protected] for details Slide credit: clinicaloptions.com

3. Faculty Shaji K. Kumar, MD Mark and Judy Mullins Professor of Hematological Malignancies Chair, Myeloma Amyloidosis Dysproteinemia Group Consultant, Division of Hematology Mayo Clinic Rochester, Minnesota Shaji K. Kumar, MD: consultant/advisor (paid to institution): K36, AbbVie, Amgen, Antengene, ArcellX, AstraZeneca, BeiGene, Bluebird Bio, Bristol-Myers Squibb, Janssen, Loxo Oncology, Oncopeptides, Roche/Genentech, Sanofi; consultant/advisor: Secura Biotherapeutics, Takeda, Trillium; researcher (paid to institution): AbbVie, Allogene, Amgen, AstraZeneca, Bristol-Myers Squibb, Carsgen, GlaxoSmithKline, Janssen, Novartis, Roche/Genentech, Regeneron, Takeda.

4. 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, consultant: GlaxoSmithKline; researcher (paid to institution): Amgen, Janssen, Sanofi.

5. How do you select therapy for an “average” patient who has experienced multiple relapses?

6. Myeloma Treatment Paradigm Induction Induction followed by continuous therapy Consolidation Maintenance SCT Eligible SCT Ineligible Diagnosis and Risk Stratification Tumor Burden Relapse 1 Relapse 2 Relapse 3 Relapse 4 Refractory Disease

7. Development of Resistance in MM Kumar et al, Mayo Clin Proc. Keats et al, Blood. 2012;120(5):1067 6 5 4 3 2 1 Duration of therapy ( mos ) 70 Overall response rate (≥PR) (%) 60 50 40 30 20 10 1 2 3 4 5 6 Regimen number after T0 5.3 3.2 2.8 3.1 1.9 1.3 58% 45% 30% 15% 0% 0% Duration of therapy Response rate 5 unique clones at diagnosis Variable chemotherapy response Minor drug resistant clone lethal

8. What Is Refractoriness to Therapy? Refractory MM is defined as disease that is: Nonresponsive while on primary or salvage therapy OR progresses within 60 days of last therapy Nonresponsive disease is defined as failure to achieve minimal response or progressive disease on therapy Can be primary refractory or relapsed/refractory

9. Lines of Therapy or Drug Class Refractoriness Goel et al, Unpublished Survival Probability 1.0 0.75 0.50 0.25 Number of lines of therapy: 1 2 3 ≥4 Number of drug class refractory: ≥3 1 2 20 40 60 80 Time 20 40 60 80 Time

10. Refractoriness May Be Dose Independent Goel et al, Unpublished PFS Probability 1.0 0.75 0.50 0.25 Refractoriness: Not refractory Refractory at Std Dose Refractory at Low Dose 40 80 120 160 Time 25 50 75 100 Time

11. Outcomes of Triple Class Refractory Patients Median time to development of TCR was 2.9 years from diagnosis of MM Median PFS was 4 months and OS was 1 year from TCR status Zanwar S, et al. Leukemia. 2022;36:873.

12. General Principles Treatment choice depends on refractoriness to drugs/classes At least 1 drug from a nonrefractory class preferred Consider PS, age and comorbidities when selecting drug/doses Take into account prior toxicities/residual toxicities Treat to maximum response and maintain on 1 drug until progression or tolerability

13. What Are the Options? Immune approaches BCMA ADC – Belantamab* BCMA CAR T - (Ide-Cel, Cilta-Cel) BCMA bispecific - Teclistamab Targeted agents XPO1 inhibitor - Selinexor CELMODs Venetoclax – Bcl2 inhibitor *Belantamab was recently withdrawn from US market

14. BCMA in Multiple Myeloma 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 Cho. Front Immunol. 2018;10:1821. Antibody–Drug Conjugates Cytotoxic Payload Released Into Cell CAR T-Cells Bispecific T-Cell Engagers BCMA MM Cell Death scFv Viral Vector Signaling Domain CAR T-Cell Cytotoxic Cytokines CD3 T-Cell NK Cells, Monocytes BCMA Bispecific Antibodies CD3 T-Cell

15. Targeting BCMA: Belantamab Humanized, afucosylated IgG1 anti-BCMA antibody conjugated to a microtubule-disrupting agent MMAF via a stable, protease-resistant maleimidocaproyl linker  Median PFS was 2.9 months (95% CI 2.1–3.7) in the 2.5 mg/kg cohort and 4.9 months (2.3–6.2) in the 3.4 mg/kg cohort. Lonial S, et al. Lancet Oncol. 2020;21(2):207-221. MM Cell Death BCMA MM Cell Effector Cell Fc Receptor ADCC/ADCP X Lysosome BCMA BCMA ADC Mechanisms of Action: ADC ADCC Immunogenic cell death BCMA recept or signaling inhibition

16. T-Cell Strategies: Nonspecific to Specific Singh AK, et al. Lancet Oncol. 2020;21(3):e168-e178. Adoptive T cell therapy strategies Limitations Donor lymphocyte infusion: high-dose radiation ± chemotherapy to kill tumor cells in bone marrow, followed by rescue with healthy donor marrow stem cells Marrow aplasia Graft-vs-host disease Poor efficacy Lymphokine-activated killer cells: recipient’s PBMCs stimulated with IL2 in vitro for enrichment of NK and T cells, followed by infusion of cells with IL-2 treatment Production failure Limited efficacy Tumor-infiltrating lymphocytes : recipient’s lymphocytes are isolated from excised tumor and grown in vitro with IL2, followed by infusion of cells with IL-2 treatment after lymphodepleting chemotherapy Production failure Limited efficacy CAR T-cell Therapy Recipient’s T-cell are transduced with an artificial chimeric T cell receptor (CAR) using a viral vector, followed by infusion of CAR T-cells after lymphodepleting chemotherapy

17. BCMA CAR T-Cells Intracellular domain Extracellular domain Ide-cel Raje NS, et al. J Clin Oncol 2018;36:8007. Martin et al, ASH 2021. scFv scFv CD3 ζ 4-1BB Contains BCMA-specific extracellular scFv-targeting domain with 4-1BB co-stim and CD3 ζ signaling domains CD8 α hinge/TM domain T-cell activation domain Costimulatory domain Targeting domain Cilta -cel VHH VHH CD3z 4-1BB Contains 2 BCMA-targeting single-chain antibody designed to confer avidity

18. KarMMa: Ide-Cel Outcomes Munshi NC, et al. NEJM. 2021;384:705-716. Munshi NC, et al. ASCO 2020. Abstr 8503.

19. CARTITUDE-1: Cilta-Cel Outcomes 19 sCR VGPR PR Best response = ≥VGPR: 94.9% sCR: 82.5% Responses deepened over time from the 1-year follow-up PFS by MRD and Response Status Survival Probability 0.8 0.6 0.4 0.2 1 3 6 9 12 15 18 21 24 27 30 33 36 39 42 Progression-Free Survival (Mo) PFS rate: 78.8% (95% CI: 51.5-91.8) PFS rate: 73.0% (95% CI: 52.1-85.9) PFS rate: 64.2% (95% CI: 51.9-74.1) PFS rate: 54.9% (95% CI: 44.0-64.6) Median PFS not reached (95% CI: 24.5-NE) MRD negative ≥12 mo sCR patients 55% at 27 mo Usmani. ASCO 2022. Abstr 8028. Lin. EHA 2022. Abstr P961. Usmani. SOHO 2022. Abstr MM-181.

20. Summary of Trials With Bispecific Abs Teclistamab 1 Elranatamab 2,3 ABBV-383 4 REGN5458 5 Talquetamab 6 Cevostamab 7 Target BCMA BCMA BCMA BCMA GPCR5D FcHR5 N 165 55 60 167 (all dose levels) 143 (QW dosing) 161 P2D 1500 μ g/kg SC QW 76 mg SC QW 40 mg or 60 mg IV Q3W 200 mg IV QW, then Q2W 405 μ g/kg SC QW 800 μ g/kg SC Q2W -- Median lines of Rx 5 (2-11) 5 (2-14) 5 (3-12) 6 5 (2-13) 6 (2-18) % triple refractory 100% 91% 83% 90% 74% 85% % penta refractory 65% -- -- -- 29% 68% Overall response % 63% 64% 60% 75% (at ≥ 200 mg) 73% 57% (higher doses) Complete response % 39% 38% 29% 38% 29% 8.4% DoR, mo 18.4 mo 17.1 mo NR (median f/u: 8.4 mo) NR 9.3 mo 11.5 mo Infection 76% 52% 43% -- 57% -- CRS % 72% 61% 72% 48% 79% 81% Neurotoxicity % 15% (3% ICANS) 2.2% ICANS -- -- -- 14.3% ICANS 1. Moreau. NEJM. 2022;387:495. 2. Raje. ASH 2022. Abstr 158. 3. Lesokhin. ASCO 2022. Abstr 8006. 4. Voorhees. ASH 2022. Abstr 1919. 5. Bumma. ASH 2022. Abstr 4555. 6. Chari. ASH 2022. Abstr 157. 7. Trudel. ASH 2021. Abstr 157.

21. Comparing T-Cell Approaches CAR T Bispecific Abs Efficacy ORR >80% 55-75% Durability of response mPFS > 12 mo mPFS > 12 mo Availability Limited slots, cell therapy facility Wider availability Off the shelf? No, 4-6 week turn around time Off the shelf Toxicity Higher rates of CRS, ICANS Mostly grade 1-2 Time off therapy? Yes, one time treatment Continuous therapy Hospitalization ~30 days (inpatient or outpatient hospital) Limited to step up dosing phase Prolonged cytopenias More common Less common Infection risk High (shorter duration) High (continued while on Rx)

22. Current Limitations With CAR T-Cell Therapy Lesch S. Seminars in Cancer Biology. 2020;65:80–90. Patient Selection Stable of progressive disease after CT Relapsed or ineligible for ASCT Good medical condition Production Platforms Long-term vs short-term genetic modification Random vs site-specific transgene integration Ex vivo vs In vivo transduction Off-the-shelf CAR T-cells Toxicity Cytokine release syndrome: most prevalent AE; elevated inflammatory cytokines due to immune activation On-target off-tumor recognition : shared target antigen expression on malignant and healthy tissue; severity from manageable to severe AE (death) Neurotoxicity : reversible in most cases; pathophysiology remains unknown Relapse Rate ALL adults: 21% to 45% ALL children: 20% to 67% CLL: 0% to 25% DLBCL: 0% to 11%

23. CAR T: Toxicity Bonnifant et al. Molecular Therapy — Oncolytics . 2016;3:16011. Insertional oncogenesis Neurological toxicity Cytokine release syndrome On-target, off-tumor toxicity Anaphylaxis/allergy response to mouse-derived and/or recombinant proteins

24. Pathophysiology of CRS June C, et al. Science . 2018;359:1361-1365. Neurotoxicity: delirium, aphasia, seizures, cerebral edema, intracranial hemorrhage Hemodynamic instability: tachycardia, hypotension, capillary leak syndrome Organ dysfunction: AST and ALT elevation, hyperbilirubinemia, respiratory failure Altered blood-brain barrier, increase vascular permeability Inflammatory cytokine release, macrophage mediator release

25. CRS Consensus Grading Grade 1 Grade 2 Grade 3 Grade 4 Fever Temp: ≥38 o C Temp: ≥38 o C Temp: ≥38 o C Temp: ≥38 o C with Hypotension None Not requiring vasopressors Requiring vasopressor ± vasopressin Requiring multiple vasopressors (excluding vasopressin) Hypoxia None Requiring low-flow nasal cannula or blow-by Requiring high-flow nasal cannula, facemask, nonrebreather mask, or Venturi mask Requiring positive pressure (eg, CAPA, BiPAP, intubation and mechanical ventilation) Neelapu et al., Nat Rev Clin Oncol 2018 Lee et al., Biol Blood Marrow Transplant 2019 Riegler et al., Therap and Clin Risk Manag 2019 Clinical Grading and Management CRS Grade 1 Fever, myalgia, malaise, headache Monitor fluid status Empiric treatment for febrile neutropenia Supportive care (eg, antipyretics, analgesics) CRS Grade 2 Hypotension (see table above) Hypoxia (<40% O 2 required) Grade 2 organ toxicity Closely monitor all organ functions, including cardiac Supportive care Supportive care Tocilizumab ± corticosteroids No Yes CRS Grade 3 Hypotension (see table above) Hypoxia (≥40% O 2 required) Grade 3 organ toxicity, grade 4 transaminitis CRS Grade 4 Hypotension (see table above) Hypoxia (see table above) Grade 4 organ toxicity, except transaminitis Is patient older or with considerable comorbidities? CRS Fever Hypotension Hypoxia Organ toxicity Cardiac Respiratory GI Hepatic Renal Dermatologic Coagulopathy Grade CRS Manage according to grade of CRS Step 1 Step 2 Step 3

26. ICANS Can be biphasic Early phase overlaps with CRS Often mild (Grade 1-2) and short lived (2-4 days) May respond to tocilizumab Delayed May be up to 2-4 weeks after CAR T-cell infusion May be more severe and prolonged Steroids preferred therapy Tocilizumab generally not effective

27. Therapy of ICANS Supportive care Anti IL-6 therapy for ≥1 ICANS if CRS present Glucocorticosteroids Airway protection Anticonvulsants (levetiracetam, benzodiazepines) EEG monitoring Imaging Multidisciplinary team approach

28. Conclusions Therapeutic advances have led to prolonged survival in MM, but it remains a chronic disease Newer drugs increase the options available Treatment of myeloma requires a long-term strategy Key is delivering the best “package” of treatment at a given stage Optimal combinations and sequencing are key Risk-stratified approach in clinic Future will be developing more individualized approaches

29. Case variation: What patient and disease factors would change your treatment approach?

30. Natural History of MM Induction Consolidation Maintenance Symptomatic MM Newly Diagnosed MYELOMA M Protein (g/L) 20 50 100 1. RELAPSE 2. RELAPSE REFRACTORY RELAPSE Frontline therapy Plateau remission 2nd-line therapy EARLY RELAPSE 3rd-line therapy SMM Early Relapse (1-3 Prior Lines) Isa/Dara + Pd/Kd Late Relapse (4+) BCMA (CAR, BsAb>>Bela) Frontline QUADS - Dara-RVd Tom Martin What Are the Options for Relapsed and Refractory Multiple Myeloma? Refractory Relapse Seli combos Recycle agents

31. Therapy: Approved and Experimental Products Competitive Landscape for Triple-Class Refractory Novel Drugs Novel Monoclonal Antibodies BCMA/ADCs BCMA Bispecifics Cellular Therapies BCMA CARs Iberdomide, CC-92480 SAR442085 Hexabody-CD38 Mezagitamab (TAK-079) Belantamab mafodotin Teclistamab Elranatamab ABBV-383 Idecabtagene vicleucel Ciltacabtagene autoleucel Selinexor Modakafusp alfa (TAK-573) AMG-424 GBR-1343 CC-99712 CC-93269 REGN5458 Zevo-cel (CT053) ddBCMA Orva-cel (JCARH125) Venetoclax CFT7455 Degraders Immune – Toxin TA K-169 SEA-BCMA SEA-BCMA Non-BCMA Cevostamab Talquetamab ALLO-715 Clinical trial always a consideration!!

32. Clinical/Practical Issues Apheresis candidate Limited prior alkylator/steroid-therapy Cyclophosphamide Bendamustine Melphalan High-dose dex Bridging/No bridging Candidate Can proceed without bridging => ideal Has options for bridging therapy Will have limited disease burden at LD What Are the Important Clinical Factors to Consider for CART Therapy CAR T-cell therapy candidate Not rapidly progressive disease Can be “off” tmt for apheresis Adequate blood counts No significant comorbidities No O2 requirement No significant cardiac history Can survive sepsis Can deal with Logistics + has Care Team Has disease that is responding to therapy Proceeding after 4 th line better than 8 th

33. Comparing Options: Other BCMA/Non-Immune Modalities CAR T-Cell Bispecific mAbs Re-cycle/Seli Treatment logistics Specialized center, time for production Burden, available? Off the shelf, Requires hospital stay Is local therapy possible? Oral and SC/IV, Generally available Toxicity vs efficacy Best Candidates Fit, good PS, No rapid progression Can survive sepsis, Can travel to COE Reasonable PS Possibly limited cycles Toxicities CRS, neurotoxicity, cytopenias CRS, infection, cytopenias Nausea, thrombocytopenia Cost > $400K >$30k/month ~$20-30K/mo

34. Selinexor: the STORM trial Chari. NEJM. 2019;381:727. SINE: selective inhibitor of nuclear export - XPO1 STORM, phase 2b study (N = 122) Median prior lines: 7 (3–18) All patients were penta-exposed and triple-class refractory Median duration of treatment: 9.0 weeks (range: 1-60) TEAEs, % All grade Grade 3 or 4 Thrombocytopenia 73 59 Fatigue 73 25 Nausea 72 10 Anemia 67 44 Hyponatremia 37 22 Neutropenia 40 21 FDA approved in 2020 EMA approved in 2021 ORR 26% TCR=100% SELINEXOR 80 MG, DEX 20 MG – 2X/WK

35. Data From Phase I/IIb STOMP Trial With Selinexor-Based Triplets SVd (N = 40) 1 SKd (N = 32) 2 SPd (N = 60) 3 Dara-Sd (N = 32) 4 Patient Population 50% PI refractory, 3 median prior lines of therapy 9% with prior carfilzomib (3% refractory), 44%/22% bort/ixa refractory, 4 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 sens/ naive: 84 PI refractory: 43 All: 78.1 Triple class refractory: 66.7 Pom-sens/ naive: 54 Pom-refractory: 36 All: 69 Dara-naive: 73 ≥CR, % 11 5 15.7 2.2 VGPR, % 26 19 28.1 50.0 19.6 7.1 34 37 PR, % 47 19 34.4 16.7 32.6 26.8 34 37 Median PFS, mo 17.8 6.1 15.0 23.7 12.3 -- 12.5 -- 1. Bahlis. Blood. 2019;132:2546. 2. Gasparetto. Br J Cancer. 2022;126:718. 3. Chen. ASH 2020. Abstr 726. 4. Gasparetto. ASCO 2020. Abstr 8510 .

36. Toxicity With Selinexor Therapy: 2x/wk vs QWk Dosing Select TEAEs, % STORM: Selinexor/Dex (n = 123) 1 BOSTON: Selinexor-Vd (n = 195) 2,3 All Grade 3/4 All Grade 3/4 Hematologic 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 Gastrointestinal 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 Constitutional 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. 3. Grosicki. Lancet. 2020;396:1563. Supportive CARE IV fluids Salt tablets Antiemetics (3 prophylaxis) Ondansetron Olanzapine + _______ Growth factors G-CSF Romiplostim Appetite stimulants Energy stimulants

37. Venetoclax in RRMM: BCL-2 Inhibition 1. Kumar. ASH 2016. Abstr 488. 2. Touzeau . Leukemia. 2018;32:1899. 3. Souers. Nat Med. 2013;19:202. 4. Ponder. Cancer Bio Ther. 2016;17:769. 5. Matulis. Leukemia. 2016;30:1086. venetoclax BCL-2 BCL-X L PI Apoptosis Dexamethasone MCL-1 NOXA Survival Patients, % 10 20 30 40 sCR CR 3% 4% 8% 6% 4% 10% 13% 13% 3% 3% VGPR PR 50 All patients (N = 66) t(11;14) (n = 30) Non-t(11;14) (n = 36) Objective Response Rates in All Patients Venetoclax is a selective, orally available small-molecule BCL-2 inhibitor; active in R/R MM 1 Use in patients with t(11;14) Venetoclax (daily dose up to 1,200 mg) has an acceptable safety profile in R/R MM, predominantly in patients with t(11;14) abnormality and favorable BCL-2 family profile Rationale for Combination Therapy with Venetoclax 2-5

38. BELLINI: Promise of Venetoclax + Bortez/Dex in t(11;14)-Positive Myeloma OS PFS Harrison. ASH 2019. Abstr 142. PFS Ven + Bd Pb o+ Bd Median, mo Not reached 9.3 HR (95% CI) 0.09 (0.02-0.44) P value .003 OS Ven + Bd Pbo + Bd Median, mo Not reached Not reached HR (95% CI) 0.68 (0.13-3.48) P value .647 33 3 6 9 12 15 18 21 27 30 24 Mo PFS 1.0 0.8 0.6 0.4 0.2 Ven + Bd Pbo + Bd Censored + Patients at Risk, n 20 15 18 12 16 11 14 9 14 6 12 5 12 2 11 2 8 1 3 1 1 1 + + + + + + + + + + + + + + + + + + 33 3 6 9 12 15 18 21 27 30 24 Mo OS 1.0 0.8 0.6 0.4 0.2 Ven + Bd Pbo + Bd Censored + Patients at Risk, n 20 15 19 15 19 14 19 14 19 14 19 13 19 13 18 11 14 7 6 3 1 1 + + + + + + + + + + + + + + + + + + + + + + + + + Slide credit: clinicaloptions.com

39. AEs in ≥25% of Patients in Either Treatment Arm Diarrhea Constipation Fatigue Nausea Insomnia Peripheral neuropathy Upper respiratory tract infection Peripheral sensory neuropathy Thrombocytopenia Neutropenia Anemia Lymphopenia Ven + Vd, grade 1/2 Ven + Vd, grade 3/4 Pbo + Vd, grade 1/2 Pbo + Vd, grade 3/4 Ven + Vd, grade 1/2 Ven + Vd, grade 3/4 Pbo + Vd, grade 1/2 Pbo + Vd, grade 3/4 Most Common Hematologic AEs BELLINI: Safety With Venetoclax + Bortez/Dex Kumar. ASH 2021. Abstr 84. Tx-Emergent Deaths, % Ven + Vd (n = 193) Pbo + Vd (n = 96) Any 7 2 Any AE 6 4 Infection 5 Progressive disease 1 1 Infections Any Grade 3/4 Serious Ven + Vd (n = 193) Pbo + Vd (n =96) 20 40 60 80 60% 50% 20 40 60 80 20 40 60 80 100 35% 31% 33% 32% 38% 23% 29% 30% 31% 27% 30% 27% 19% 25% 27% 36% 28% 10% 27% 25% 10% 0% 82% 78% 41% 29% 35% 29% Infection prophylaxis: PJP, antibacterial, antiviral Tumor lysis prophylaxis: Consider allopurinol Monitor infections: fatal infections higher in venetoclax arm Monitor outpatient for blood counts and TLS

40. Summary of Bispecific Antibodies in RR MM Drug Target Median prior lines, n Dosing ORR, % CRS, % Neurotox, % Notes Teclistamab 1 (n = 165 RP2D) BCMA 5 (2-11) SC QW for RP2D 63% @RP2D 72% @RP2D (no Gr3) 15% (3% ICANS) SC dosing! ABBV-383B 2 (n = 60) BCMA 5 (3-12) IV Q3W 83% @RP2D 72% -- Q3W, allowed for CrCl 30 REGN-5458 3 (n = 167) BCMA 6 IV, QW then Q2W 75% @highest doses 48% -- Elranatamab 4,5 (n = 55) BCMA 5 (2-14) SC QW 64% @RP2D 61% 2.2% ICANS Talquetamab 6 (n = 143 QW dosing) GPRC5D 5 (2-13) SC QW or Q2W 73 % @QW dosing 79% @QW (72% @Q2W) -- SC dosing! 27% @RP2D with prior BCMA tx in previous analyses Some Gr3 infections, skin rash, oral toxicity, back pain Cevostamab 7 (n = 161) FcRH5 6 (2-18) Q3W 57 % @higher doses 81% 14.3% ICANS 21% with prior BCMA tx ; ORR 63% in prior BCMA (n = 8) in previous analyses 1. Moreau. NEJM. 2022;387:495. 2. Voorhees. ASH 2022. Abstr 1919. 3. Bumma . ASH 2022. Abstr 4555. 4. Raje. ASH 2022. Abstr 158. 5. Lesokhin . ASCO 2022. Abstr 8006 . 6. Chari. ASH 2022. Abstr 157. 7. Trudel . ASH 2021. Abstr 157.

41. Recycling Therapy for Relapsed MM: Triplets Preferred With Second Generation IMiDs, PIs, MoAbs Consider all available and/or agents with prior response Active In Len and Bort refractory MM Carfilzomib(K) Pom(P) Dex(d), K cyclophosphamide( Cyt ) d CD38 + Pd, CD38 + Kd Elo Pd, Pcytd Active in Len, Bort, Dara refractory MM KPd , EloPd , Kcytd , Pcytd Active in Len, Pom, Carfil , Bort, Dara Refractory Seli -d, Seli -Pd, Seli-Kd BCMA (ADC, CAR, Bispecific)

42. Conclusions Novel therapies  providing deep and durable responses in RRMM But no cures yet! NEED a PLATEAU and additional therapy needed Rational strategies for sequencing needed Current practice is to volley between targets and agents/classes There will always be room for new CELMoDs, alkylating agents, selinexor, etc Bringing novel therapies to earlier lines will drive FDA approval by MRD response Need to consider: cost, quality of life, accessibility, referral patterns

43. Go Online for More CCO Coverage of Myeloma! CME-certified on-demand webcast of the live symposium (coming soon!) Downloadable slides from the live symposium CCO Conference Coverage on multiple myeloma and other hematologic malignancies clinicaloptions.com/oncology myeloma.org/videos/conversation-myeloma-experts-making-sense-evolving-treatment-landscape