Cracking the Code to Successful Stem Cell Mobilization in Multiple Myeloma

i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.

This slide deck will explore strategies for successful stem cell mobilization in multiple myeloma, focusing on optimizing peripheral blood stem cell collection for autologous hematopoietic stem cell transplantation (ASCT). Hamza Hashmi, MD, Assistant Attending in the Myeloma & Cell Therapy Service at Memorial Sloan Kettering Cancer Center and Assistant Professor of Clinical Medicine at Weill Cornell Medical College  will share insights on improving outcomes through interdisciplinary approaches and addressing mobilization challenges. Start the activity now!

STATEMENT OF NEED

Multiple myeloma is the leading indication of autologous hematopoietic stem cell transplantation (ASCT) in hematologic malignancies, with high-dose therapy followed by ASCT representing a potentially curative treatment modality for eligible patients. Collecting peripheral blood stem cells (PBSCs) is an essential component of ASCT, and the collection of sufficient autologous PBSCs relies on the successful mobilization of hematopoietic stem cells from the bone marrow niche into circulation. Stem cell mobilization strategies differ in terms of stem cell yields, safety considerations, and resource utilization, and mobilization failure remains a concern in spite of the incorporation of novel agents into conventional methods. Therefore, it is crucial that clinicians apply interdisciplinary strategies to mitigate poor mobilization and optimize ASCT outcomes (Wei & Wei, 2023). In this activity, Dr. Hamza Hashmi, Assistant Attending in the Myeloma & Cell Therapy Service at Memorial Sloan Kettering Cancer Center and Assistant Professor of Clinical Medicine at Weill Cornell Medical College, will share insights into cracking the code to successful stem cell mobilization in multiple myeloma.

TARGET AUDIENCE

Hematologists, medical oncologists, advanced practitioners, oncology nurses, and other health care professionals involved in the treatment of patients with multiple myeloma.

LEARNING OBJECTIVES

Upon completion of this activity, participants should be able to

Evaluate current and emerging data on stem cell mobilization regimens in patients with MM
Identify patients eligible for ASCT and at high risk of mobilization failure
Apply interdisciplinary strategies to mitigate poor mobilization and optimize ASCT outcomes

1. Hamza Hashmi, MD Assistant Attending, Myeloma & Cell Therapy Service Memorial Sloan Kettering Cancer Center Assistant Professor of Clinical Medicine Weill Cornell Medical College Cracking the Code to Successful Stem Cell Mobilization in Multiple Myeloma

2. Disclosures A dvisory board/panel: Janssen S peaker's bureau: Janssen, Karyopharm i3 Health has mitigated all relevant financial relationships

3. Learning Objectives MM = multiple myeloma: ASCT = autologous hematopoietic stem cell transplantation. Evaluate current and emerging data on stem cell mobilization regimens in patients with MM Identify patients eligible for ASCT and at high risk of mobilization failure Apply interdisciplinary strategies to mitigate poor mobilization and optimize ASCT outcomes

4. Case Study: Mr. AJ PET = positron emission tomography; CT = computed tomography. 65-year-old African-American male presents with 1-month history of right rib pain, not relieved by over-the-counter analgesics Labs reveal hemoglobin 9.5 g/dL, creatinine 2.1 mg/dL, calcium 12.5 mg/dL, monoclonal M-protein 3.5 g/dL, IgA kappa, serum kappa free light chain 120 mg/L, lambda free light chain 1.1 mg/L, kappa lambda light chain ratio >100 Whole-body PET/CT revealed multiple lytic lesions in the axial and appendicular skeleton with a compression fracture at T8 vertebrae. Bone marrow biopsy revealed 80% kappa-restricted plasma cells

5. Case Study: Mr. AJ (cont.) RXT = radiotherapy; D-RVd = daratumumab/lenalidomide/bortezomib/dexamethasone; BMBx = bone marrow biopsy; BMT = bone marrow transplantation. Patient receives 30 Gy of palliative RXT to L5 spine and pelvis for pain control followed by 8 cycles of D-RVd induction chemotherapy with 25 mg of lenalidomide BMBx reveals residual 20% clonal plasma cells. Whole-body PET/CT is without evidence of active myeloma bone disease Patient is evaluated by BMT service with plan for f ilgrastim ± plerixafor- based steady-state mobilization

6. MM Background BM = bone marrow; OS = overall survival; IMiDs = immunomodulatory drugs; PIs = proteasome inhibitors; CD38 = cluster of differentiation 38; mAbs = monoclonal antibodies. SEER, 2024; Siegel et al, 2024; Raab et al, 2009; Kumar et al, 2008; Palumbo et al, 2011; Pasvolsky et al, 2023. MM is characterized by malignant plasma cells that accumulate in the BM, leading to bone destruction, organ damage, and bone marrow failure Median age for diagnosis of MM is 69 years The American Cancer Society estimates 35,780 new MM cases and 12,540 deaths in the United States in 2024 MM is the second most common hematologic malignancy, historically associated with median OS of 24-30 months The development of high-dose chemotherapy and ASCT, IMiDs, PIs, anti-CD38 mAbs, and other novel therapies has greatly expanded therapeutic options for newly diagnosed MM Currently, median OS exceeds 45-82 months, with ASCT playing a pivotal role in the treatment paradigm for MM

7. Approach to Transplant- Eligible NDMM NDMM = newly diagnosed MM; PS = performance status; Dara = daratumumab; VRD = bortezomib/lenalidomide/dexamethasone; KRd = carfilzomib/lenalidomide/dexamethasone; MSK ABMT SOP = Memorial Sloan Kettering Adult BMT Service Standard Operating Procedure; CR = complete response; HDT = high-dose therapy; KR = carfilzomib/lenalidomide; VD-PACE = bortezomib/dexamethasone/cisplatin/doxorubicin/cyclophosphamide/etoposide; EMD = extramedullary disease; PCL = plasma cell leukemia; auto = autologous; allo = allogeneic. Voorhees et al, 2023; Sonneveld et al, 2023; Gay et al, 2021; Gay et al, 2023; McCarthy et al, 2017; Nooka et al, 2014; Dimopoulos et al, 2018; Usmani et al, 2021; Giralt et al, 2014; Ghandili et al, 2023; Maffini et al, 2019. Consider VD-PACE for bulky EMD or PCL cytoreduction Consider planned auto/allo for ultra–high-risk Stem cell mobilization; adequate stem cell harvest (≥8×10 6 CD34+ cells/kg) as per MSK ABMT SOP HDT-ASCT ASCT-eligible patients Patients with good PS and adequate organ function Dara-VRd x4 cycles Dara- KRd x4 cycles Standard-risk High-risk Consider consolidation with induction regimen for patients who do not achieve CR or better Lenalidomide ± dara maintenance KR maintenance

8. ASCT in MM Background PFS = progression-free survival; CD34 = cluster of differentiation 34; PBSC = peripheral blood stem cell; HSPC = hematopoietic stem and progenitor cells. Parrondo et al, 2020; Wei & Wei, 2023; Giralt et al, 2014; Giralt et al, 2009. HDT-ASCT has been shown to increase the depth of response, PFS, and OS in eligible MM patients Recommendations for stem cell collection dose: Minimum target: 2 x 10 6 CD34+ cells/kg Recommended: 3-5 x 10 6 CD34+ cells/kg (single) or 8-10 x 10 6 CD34+ cells/kg (2; tandem) CD34+ cell dose plays a role in engraftment and outcomes  accelerated hematological reconstitution (shortened platelet and neutrophil engraftment time), improved OS, and reduced length of hospitalization with higher doses The collection of sufficient autologous PBSCs relies on the successful mobilization of HSPCs from the BM niche into circulation

9. Pathways in HSPC Mobilization CXCR4 = C-X-C chemokine receptor type 4; SDF-1 = stromal cell-derived factor 1; G-CSF = granulocyte-colony stimulating factor; PTH = parathyroid hormone; HSPG = heparin sulfate proteoglycans; VLA4 = very late antigen-4; VCAM = vascular adhesion cell molecule; S1-P = sphingosine-1-phosphate; EP4 = E-type prostanoid receptor 4; PGE2 = prostaglandin E2; NSAIDs = nonsteroidal anti-inflammatory drugs. Panch et al, 2017. Adhesion molecules retain HSPCs in the BM CXCR4 receptors on HSPCs interact with chemokine SDF-1 A disruption in this interaction causes mobilization of HSPCs Modulated by: G-CSF: SDF-1 downregulation and release of proteases Plerixafor and motixafortide : block CXCR4 binding to SDF-1 Plerixafor OR motixafortide

10. Factors Associated With Poor Mobilization PB = peripheral blood. Wei & Wei, 2023; Hsu et al, 2023; Giralt et al, 2014; Hulin et al, 2021. Patient- and Disease-Related Older age (>70) Extensive BM involvement Treatment-Related Induction therapy >6 months before stem cell mobilization Prior radiotherapy involving marrow rich sites Multiple lines of chemotherapy (4+) Previous exposure to melphalan, fludarabine, platinum-containing regimens, alkylating agents, lenalidomide, or daratumumab At Time of Mobilization Absolute monocyte count <500/µL Platelet count <150,000/µL Low pre-apheresis PB CD34+ cell count Low Day 1 apheresis yield History of mobilization failure

11. Current HSPC Mobilization Strategies GM-CSF = granulocyte-macrophage colony stimulating factor. Wei et al, 2023; Crees et al, 2023. Cytokine mobilization alone: G-CSF or GM-CSF Filgrastim ± plerixafor Filgrastim + chemotherapy ± plerixafor Pegfilgrastim + plerixafor Filgrastim + m otixafortide

12. Mobilization Schedules With Stem Cell Mobilizers SQ = subcutaneous. Shi et al, 2024; Mozobil ® prescribing information, 2023; Aphexda ® prescribing information, 2023. Medication Mobilization Days Primary Collection Days Primary Collection Days Optional Collection Days 1 (Thurs) 2 (Friday) 3 (Sat) 4 (Sun) 5 (Mon) Apheresis session 5 Apheresis session 6 (Tues) Apheresis session 7 (Wed) Apheresis session 8 (Thurs) Apheresis session G-CSF SQ 10 µg/kg in AM (9:00 AM) ALONE OR PLUS: Plerixafor SQ 0.24 mg/kg in PM (9:00 PM) OR 11 hours (or 15-17 hours) prior to initiation of apheresis Motixafortide SQ 1.25 mg/kg in PM (9:00 PM) 10-14 hours prior to initiation of apheresis

13. Plerixafor SDF-1⍺ = stromal cell-derived factor 1 alpha. Mozobil ® prescribing information, 2023. Plerixafor is an inhibitor of the CXCR4 chemokine receptor and blocks binding of its ligand SDF-1 α , resulting in mobilization of HSPCs from BM into the PB Mechanism of Action In combination with G-CSF to mobilize HSPCs to the PB for collection and subsequent autologous transplantation in patients with MM and non-Hodgkin lymphoma Indication Initiate plerixafor after filgrastim has been administered daily for 4 days  ≤83 kg: 20-mg dose or select dose based on 0.24 mg/kg actual body weight >83 kg: select dose based on 0.24 mg/kg actual body weight, maximum 40 mg/day Administer by SQ injection approximately 11 hours prior to initiation of apheresis (15-17 hours) Renal impairment: if creatinine clearance is ≤50 mL/min, decrease dose by one-third to 0.16 mg/kg, maximum 27 mg/day Dose and Administration

14. G-CSF + Plerixafor Pivotal Trial: AMD3100-3102 Study 1 According to International Myeloma Working Group (IMWG) Response Criteria. ECOG = Eastern Cooperative Oncology Group; PR = partial response; ITT = intention-to-treat. DiPersio et al, 2009. Trial design (n=302): Prospective, phase 3, double-blind, placebo-controlled Eligibility criteria: 18-78 years of age Confirmed diagnosis of MM ECOG PS 0–1 Adequate organ function undergoing first ASCT in first or second CR or PR 1 n=148 G-CSF (10 µg/kg) SQ Days 1-5 (and 6-8 if needed) Plerixafor (0.24 mg/kg) SQ beginning Day 4 for up to 4 days n=154 G-CSF (10 µg/kg) SQ Days 1-5 (and 6-8 if needed) Placebo 1:1 Primary end point: Proportion of patients collecting ≥6 x 10 6 CD34+ cells/kg within 2 apheresis sessions Secondary end points: Proportion of patients collecting ≥2 x 10 6 CD34+, ≥6 x 10 6 CD34+ cells/kg, within 4 or less apheresis sessions; number of apheresis days required to reach ≥6 x 10 6 CD34+ cells/kg ITT

15. DiPersio et al, 2009. Mobilization Schedule Medication Mobilization Days Primary Collection Days Optional Collection Days 1 2 3 4 5 Apheresis session 6 Apheresis session 7 Apheresis session 8 Apheresis session G-CSF SQ 10 µg/kg in AM PLUS: Plerixafor SQ 0.24 mg/kg in PM 11 hours prior to apheresis G-CSF + Plerixafor Pivotal Trial: AMD3100-3102 Study (cont.)

16. DiPersio et al, 2009; Micallef et al, 2018. Proportion With ≥6 x 10 6 CD34+ Cells/kg in ≤2 Apheresis Days Proportion With ≥6 x 10 6 CD34+ Cells/kg in ≤4 Apheresis Days Proportion With ≥2 x 10 6 CD34+ Cells/kg in ≤4 Apheresis Days Median Number of Apheresis Days Median Number of CD34+ Cells/kg G-CSF + plerixafor (n=148) 71.6% 75.7% 95.3% 1.0 10.96 G-CSF + placebo (n=154) 34.4% 51.3% 88.3% 4.0 6.18 P <0.001 P <0.001 P =0.031 P <0.001 P <0.001 The most common adverse events related to plerixafor were gastrointestinal disorders (diarrhea, nausea, vomiting) and injection site reactions (erythema) Long-term follow up with plerixafor showed no difference in OS or PFS with addition of plerixafor at 5 years G-CSF + Plerixafor Pivotal Trial: AMD3100-3102 Study (cont.)

17. AEs = adverse events. DiPersio et al, 2009. Safety Most Common AEs Related to Study Treatment (≥5% Patients) Plerixafor (n=147) Placebo (n=151) Any related AEs, n(%) 95 (64.6%) 67 (44.4%) Gastrointestinal disorders Diarrhea 27 (18.4%) 8 (5.3%) Nausea 24 (16.3%) 11 (7.3%) Vomiting 8 (5.4%) 4 (2.7%) General disorders and administration site conditions Fatigue 12 (8.2%) 5 (3.3%) Injection site erythema 30 (20.4%) 5 (3.3%) Musculoskeletal and connective tissue disorders Bone pain 14 (9.5%) 12 (7.9%) Nervous system disorders Headache 8 (5.4%) 13 (8.6%) Paresthesia 11 (7.5%) 11 (7.3%) G-CSF + Plerixafor Pivotal Trial: AMD3100-3102 Study (cont.)

18. Case Study: Mr. AJ (continued) Mr. AJ is slated to collect 5 x 10 6 cells/kg for 2 potential transplants He receives filgrastim 10 µg/kg for 4 consecutive days as well as plerixafor 0.24 mg/kg the night before the first apheresis session Peripheral blood CD34+ count on Days 5, 6, and 7 of apheresis cycle remains low at 5/µL, 8/µL, and 6/µL, with decreasing platelet count on each day. Patient denies any other mobilization-related adverse events Patient collects 1.4 x 10 6 cells/kg after 3 days of apheresis

19. Lenalidomide and Daratumumab DiPersio et al, 2009; Chhabra et al, 2023. MM plerixafor pivotal trial was conducted prior to the daratumumab/anti-CD38 mAbs and quadruplet induction therapy era A recent post-hoc analysis was done to examine the effect of daratumumab- and lenalidomide-containing quadruplet induction therapy on stem cell mobilization and yields and to evaluate engraftment kinetics to explore potential effects on stem cell recovery in NDMM Data from the MASTER and GRIFFIN trials were analyzed MASTER trial: 4 28-day cycles in the single arm D-KRd: daratumumab plus carfilzomib, lenalidomide, dexamethasone GRIFFIN trial: 4 21-day cycles randomized to: RVd: lenalidomide, bortezomib, dexamethasone D-RVd: daratumumab with RVd Impact of Inclusion in Quadruplet Induction Therapy in NDMM

20. Chhabra et al, 2023. Impact of Inclusion in Quadruplet Induction Therapy in NDMM Lenalidomide and Daratumumab (cont.)

21. Lenalidomide and Daratumumab (cont.) DiPersio et al, 2009; Chhabra et al, 2023. Among patients who underwent mobilization: MASTER, D-KRd: 98% (114 of 116)  ASCT, median CD34+ cell dose of 3.2 x 10 6 CD34+ cells/kg GRIFFIN, D-RVd: 99% (94 of 95)  ASCT, median CD34+ cell dose of 4.2 x 10 6 CD34+ cells/kg GRIFFIN, RVd: 98% (78 of 80)  ASCT, median CD34+ cell dose of 4.8 x 10 6 CD34+ cells/kg Patients who collected with G-CSF alone in the first mobilization cycle: 100% (4 of 4) in D-KRd, 89 % (17 of 19) in D-RVd, and 96% (27 of 28) in RVd Impact of Inclusion in Quadruplet Induction Therapy in NDMM

22. Lenalidomide and Daratumumab (cont.) DiPersio et al, 2009; Chhabra et al, 2023. Patients who did not meet the center-specific minimally required CD34+ cell yield in the first mobilization attempt: MASTER, D- KRd : 7% (8 of 116) 5 patients in upfront plerixafor and 3 patients in rescue plerixafor GRIFFIN: D- RVd 2% (2 of 95) GRIFFIN: RVd 6% (5 of 80) 4 cycles of daratumumab- and lenalidomide-based quadruplet induction therapy had a minimal impact on stem cell mobilization and allowed predictable stem cell harvesting and engraftment in all patients who underwent ASCT Impact of Inclusion in Quadruplet Induction Therapy in NDMM

23. Plerixafor Impact at Different Peripheral CD34+ Thresholds Shah et al, 2020. Single-center, retrospective analysis included patients with MM and other plasma cell dyscrasias who underwent mobilization with G-CSF followed by autologous stem cell collection between January 2012 and December 2016 Primary end points Evaluation of changes in mean plerixafor utilization and apheresis days and assessment of the impact on overall mobilization costs Secondary end points Description of the impact of lenalidomide use on mobilization and evaluation of the rate of mobilization failure

24. NS = not specified. Shah et al, 2020. The combined cost of plerixafor and apheresis procedures at a threshold of 40 cells/µL is close to that at a threshold of 15 cells/µL, while saving 26 apheresis days per 100 patients Peripheral Blood CD34+ Threshold to Initiate Plerixafor Mean Plerixafor Doses Per Mobilization Mean Apheresis Days Per Mobilization Calculated Cost Per Mobilization (Apheresis and Plerixafor) < 15 cells/µL n=66 1.32 2.15 $37,506 <20 cells/µL n=130 1.65 2.17 $40,164 <40 cells/µL n=148 1.74 1.89 $37,182 P =0.026 P =0.011 P =NS Peripheral CD34+ Threshold for Plerixafor Administration

25. Impact Of Lenalidomide Use on Mobilization 1 P values from Kruskal-Wallis test. 2 P value = 0.058: none and ≤6 cycles; <0.001: none and >6 cycles; 0.001: ≤6 and >6 cycles. 3 P value = 0.274: none and ≤6 cycles ; 0.011: none and >6 cycles; 0.04: ≤6 and >6 cycles. 4 P value = 0.013: none and ≤6 cycles; 0.004: none and >6 cycles; 0.197: ≤6 and >6 cycles. Shah et al, 2020. Patients who received more than 6 cycles of lenalidomide demonstrated impaired mobilization and required more apheresis sessions ( P <0.011) and greater plerixafor use ( P <0.001) to achieve target stem cell yields Characteristics Lenalidomide Use None <6 cycles >6 cycles P value 1 Number of patients 74 115 41 Plerixafor doses, mean 1.18 1.46 2.10 <0.001 2 Apheresis days, mean 1.80 1.94 2.34 0.014 3 Day 4 PB CD34+ (median, /µL) 17.40 10.74 9.38 0.003 4 Day 5 PB CD34+ (median, /µL) 58.70 55.13 55.08 0.201 Collection yield (mean, x 10 6 /kg) 8.43 8.74 7.97 0.0136

26. Impact Of Lenalidomide Use on Mobilization (cont.) Cowan et al, 2021. Single-center, retrospective analysis of patients with MM who attempted stem cell mobilization and collection between January 2012 and July 2015 Prior lenalidomide exposure did not have a statistically significant impact on the absolute number of CD34+ cells collected or on the duration of collection based on a multivariate linear regression analysis for association between receipt of >6 cycles of lenalidomide Linear multivariate analysis showed trend toward decreasing collection yield with increasing cycles of lenalidomide ( P =0.205) Recommendation: refer to autologous mobilization prior to 6 cycles of lenalidomide-based therapy

27. Stem Cell Mobilization Algorithm Slide courtesy of Hamza Hashmi, MD.   Pegfilgrastim can be given at 6- or 12-mg dose on Day 3 Plerixafor dosing may vary based on weight (<83 kg) and renal function (creatinine clearance <50 mL/min). Review with PharmD Preemptive Steady State Mobilization Pegfilgrastim 6 mg SQ Day 3 (9:00 AM) If using G-CSF instead, use 10 µg/kg starting on Day 4 (not Day 3) Plerixafor 24 mg SQ Day 1 (9:00 PM) PB CD34+ reaches peaks 10-18 (average ~14) hours after plerixafor Tips for Poor Mobilizers If given 6 mg pegfilgrastim , consider daily G-CSF 10 ug/kg at 7 am starting Day 2 Review plerixafor dose with PharmD Revisit collection goal with MD if goal not met For failed collection, remobilize 2-4 weeks later, consider chemomobilization , discuss with group 1 ASCT goal = 2.5 x 10 6 /kg 2 ASCT goal = 5.0 x 10 6 /kg PB CD34+ cell count on Day 1 (7:00 AM) PB CD34+ cell count <5 PB CD34+ cell count 5-10 (for 1 ASCT) or 10-20 (for 2 ASCT) or prior day collection yield <1 x 10 6 /kg PB CD34+ cell count >10 (for 1 ASCT) or >20 (for 2 ASCT) or prior day collection yield ≥1 x 10 6 /kg (1 ASCT) or ≥2 x 10 6 /kg (2 ASCT) Hold apheresis, notify MD, give plerixafor + G-CSF Proceed with apheresis, notify MD, give plerixafor plus G-CSF Proceed with apheresis, give plerixafor Repeat on all days of collection

28. Motixafortide CXCL12 = C-X-C motif chemokine ligand 12. Aphexda ® prescribing information, 2023. Stem cell mobilizing agent that selectively inhibits CXCR4 binding to SDF-1α/CXCL12, resulting in mobilization of HSPCs from the BM into the PB Mechanism of Action Combination with G-CSF to mobilize HSPCs to the PB for collection and subsequent autologous transplantation in patients with MM Indication Initiate motixafortide after filgrastim has been administered daily for 4 days  Recommended dosage is 1.25 mg/kg by SQ injection 10-14 hours prior to initiation of apheresis A second dose of motixafortide can be administered 10-14 hours before a third apheresis, if necessary Dose and Administration

29. GENESIS Trial Crees et al, 2023. Trial design (n=122): Prospective, phase 3, double-blind, placebo-controlled, multicenter study Eligibility criteria: 18-78 years of age Confirmed diagnosis of MM ECOG PS 0–1 Adequate organ function undergoing first ASCT in first or second CR or PR n=80 G-CSF (10 µg/kg) SQ Days 1-5 (and 6-8 if needed) Motixafortide (1.25 mg/kg) SQ on Day 4 (and 6 if needed) n=42 G-CSF (10 µg/kg) SQ Days 1-5 (and 6-8 if needed) Placebo 2:1 ITT Objective: assessing the superiority of motixafortide + G-CSF over placebo + G-CSF to mobilize HSPCs for ASCT in MM

30. GENESIS Trial (cont.) Crees et al, 2023; Aphexda ® prescribing information, 2023. Mobilization Days Medication Mobilization Days Primary Collection Days Optional Collection Days 1 2 3 4 5 Apheresis session 6 Apheresis session 7 Apheresis session 8 Apheresis session G-CSF SQ 10 µg/kg in AM PLUS: Motixafortide SQ 1.25 mg/kg in PM 10-14 hours prior to initiation of apheresis

31. GENESIS Trial (cont.) CI = confidence interval. Crees et al, 2023. The median number of CD34+ HSPCs mobilized in 1 apheresis day with motixafortide + G-CSF was 10.8 x 10 6 vs 2.25 x 10 6 cells kg –1 with placebo + G-CSF Results: Local Laboratory Assessment Motixafortide + G-CSF (n=80) Placebo + G-CSF (n=42) Odds Ratio (95% CI) P Value Percentage of subjects collecting > 6 x 10 6 CD34+ cells/kg in ≤2 apheresis sessions 92.5% 26.2% 53.3 (14.1, 201.3) <0.0001 Percentage of subjects collecting > 6 x 10 6 CD34+ cells/kg in 1 apheresis session 88.8% 9.5% 118 (25.4, 549.4) <0.0001 Percentage of subjects collecting > 2 x 10 6 CD34+ cells/kg in 1 apheresis sessions 96.3% 64.3% 18.90 (4.5, 80.0) <0.0001

32. GENESIS Trial (cont.) OR = odds ratio. Crees et al, 2023. Results: Local Laboratory Assessment No patients in the treatment arm had a 4 th day of apheresis

33. GENESIS Trial (cont.) Aphexda ® prescribing information, 2023. Results: Central Laboratory Assessment Motixafortide + G-CSF (n=80) Placebo + G-CSF (n=42) P value Percentage of subjects collecting > 6 x 10 6 CD34+ cells/kg in ≤2 apheresis sessions 67.5% 9.5% <0.0001 Percentage of subjects collecting > 6 x 10 6 CD34+ cells/kg in 1 apheresis session 63.8% 2.4% <0.0001 Percentage of subjects collecting > 2 x 10 6 CD34+ cells/kg in 1 apheresis sessions 87.5% 38.1% <0.0001

34. GENESIS Trial (cont.) Crees et al, 2023. Time to neutrophil and platelet engraftment, graft durability following transplantation, OS, and PFS were comparable across treatment groups Following administration of either motixafortide or placebo but before apheresis, the median number of PB CD34+ HSPCs in the motixafortide + G-CSF cohort was 116 vs 19 cells μl –1 in the placebo + G‑CSF cohort ( P <0.001) Results

35. GENESIS Trial (cont.) TEAEs = treatment-emergent adverse events. Crees et al, 2023. TEAEs (Frequency >10%) Motixafortide + G-CSF Placebo + G-CSF Any grade Grade 3 Any grade Grade 3 Total, % (n) 93.8% (75 of 80) 27.5% (22 of 80) 83.3% (35 of 42) 4.8% (2 of 42) Local injection site reactions, % (n) Pain 50% (40 of 80) 6.3% (5 of 80) 4.8% (2 of 42) Erythema 27.5% (22 of 80) Pruritis 21.3% (17 of 80) Systemic injection reactions, % (n) Flushing 32.5% (26 of 80) 7.5% (6 of 80) Pruritis 33.8% (27 of 80) 11.3% (9 of 80) Urticaria 12.5% (10 of 80) 1.3% ( 1 of 80) Erythema 12.5% (10 of 80) Bone pain 17.5% (14 of 80) 31.0% (13 of 42) Back pain 17.5% (14 of 80) 14.3% (6 of 42) Nausea 13.8% (11 of 80) 11.9% (5 of 42) Hypokalemia 13.8% (11 of 80) 11.9% (5 of 42) Catheter site pain 11.3% (9 of 80) 14.3% (6 of 42) Safety and Toxicity

36. Comparison Slide courtesy of Hamza Hashmi , MD. Plerixafor Motixafortide Pre-medications required No Yes Post-injection monitoring No Yes, 1 hour Resource utilization Self-administration Site administration Adverse events Gastrointestinal disorders (diarrhea, nausea, vomiting) and injection site reactions (erythema) Injection site reactions and systemic injection reactions Renal dose adjustment Yes No Brand vs generic Brand and generic Brand only Cost $ (Generic) $$$ Number of injections Up to 4 injections (Days 4-7) Up to 2 injections (Days 4 and 6) Insurance/payor coverage Coverage ? Coverage

37. Case Study: Mr. AJ (cont.) IV = intravenous; VGPR = very good partial response. With a failed mobilization attempt, Mr. AJ was advised chemomobilization 3 weeks later Patient receives cyclophosphamide 2 g/m 2 on Day -10, followed by daily filgrastim for 10 days Course was complicated by febrile neutropenia requiring hospitalization and need for IV antibiotics PB CD34+ on Day 1 of apheresis was 25/µL, and patient collected 3.5 x 10 cells/kg on Day 1 and 2.5 x 10 6 on Day 2 of apheresis Patient underwent high-dose chemotherapy followed by stem cell infusion 2 weeks later, achieving VGPR on Day +100 post-BMT

38. Chemomobilization WBC = white blood cell. Wei & Wei, 2023; Johnsrud et al, 2021; Lazzarino et al, 2001; Barlogie et al, 2007; Whitmill , 2016. Option for PBSC mobilization, especially in patients with active disease as it offers both mobilizing effect and possible antitumor activity Takes a longer time (11-13 days) and requires greater resource utilization Hematologic toxicity is the most common complication reported with chemomobilization, and infection has been observed as the most common non-hematologic toxicity Chemomobilization was associated with more complications (30.0% vs 7.4%; P <0.01), including neutropenic fever, emergency department visits, hospitalizations, and increased cost compared with G-CSF–only mobilization (± plerixafor)

39. Chemomobilization (cont.) Awan et al, 2012. No standard PB CD34+ count prior to apheresis Measure PB CD34+ cell count daily when the patient’s WBC count recovers to ≥4,000/ μL or from Day +12 (after chemotherapy) onwards (whichever occurs first) 1 2 3-7 10 11 12 13 14 15 Apheresis Apheresis Apheresis Apheresis Chemotherapy G-CSF 10 µg/kg >24 hrs after chemo G-CSF G-CSF G-CSF G-CSF + plerixafor G-CSF + plerixafor G-CSF + plerixafor G-CSF + plerixafor

40. Current HSPCs Mobilization Strategies Giralt et al, 2014; Giralt et al, 2009; Crees et al, 2023. Cytokine mobilization alone G-CSF ± plerixafor G-CSF + chemotherapy ± p lerixafor G-CSF + motixafortide Place in therapy? First-line mobilization strategies Remobilization options

41. Key Takeaways Plan for collection after 4-6 cycles of quadruplet-based induction chemotherapy Choice of preemptive vs just-in-time use of plerixafor remains institutional workflow–dependent and should aim for optimal resource utilization For patients with mobilization failure or high risk of failure (risk factors) or need for disease control, chemomobilization should be considered The place of motixafortide for mobilization remains unclear at this time; may be considered for patients with prior failure to mobilize

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