Transplant-eligible Patients Research Articles

Real World Data of Axicabtagene Ciloleucel As Second Line Therapy for Patients with Large B Cell Lymphoma: First Results of a Lysa Study from the French Descar-T Registry

Background and Significance: Axicabtagene ciloleucel (axi-cel) has demonstrated superior efficacy as second-line therapy (2L) over standard of care chemo-immunotherapy in transplant-eligible patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL). In ZUMA-7 trial, 180 patients were randomized to receive axi-cel in 2L, achieving an estimated 4-year overall survival of 54% after a median follow-up of 47 months. In the ALYCANTE phase II study, 62 transplant-ineligible patients with R/R LBCL were treated with axi-cel as 2L, resulting in a 3-month complete metabolic response rate of 71% with a median progression free survival of 11.8 months. Here, we report the first real-world data of axi-cel as 2L for patients with early R/R LBCL treated in French centers. Study Design and Methods: DESCAR-T is a French nationwide registry collecting real-life data of all patients treated with approved CAR T-cell therapies (NCT04328298). All patients were informed before inclusion in the registry. The goal of the present analysis was to describe patients' characteristics, treatment course, and outcomes of all patients consecutively included in DESCART registry since July 2022, and infused with axi-cel according to the early access program supported by French authorities for patients with LBCL in early relapse (< 1 year) or refractory after a first line treatment. Results: Between July 2022 and March 2023, axi-cel was ordered and leukapheresis was performed for 85 patients. The first axi-cel infusion was performed in September 2022 and enrollment increased rapidly with 51 new patients waiting for a leukapheresis at the time of data cut-off in March 2023. No manufacturing failures occurred, at the data cut-off, 78 patients were infused with axi-cel in 22 centers, and 7 patients died before axi-cel infusion (5 because of progression, 2 from other cause). Among the 78 patients infused, 48 (61.5%) were male, median age was 60 years (range: 23-79), 35% were over 65 years old and 5% over 70 years old. Most patients had primary refractory disease (n = 58, 74.3%), a good performance status (n = 62, 79.5% ECOG 0-1), stage III-IV disease (n = 59, 75.6%) and elevated LDH (n = 48, 61.5%). The median time between leukapheresis and axi-cel infusion was 36 days, and 65 patients (83%) received bridging therapy, primarily immuno-chemotherapy (n = 57, 73%). At the time of lymphodepletion, patients had progressive (n = 35, 54%) or stable disease (n = 6, 9%), with only 23 patients (29%) responding to bridging therapy. The median follow-up since CAR-T-cells infusion was 1.1 month (range: 0-6). Safety information was reported for 65 patients: CRS occurred in 95% of patients, however only 3 patients (<5%) had a grade 3 or higher CRS. Neurotoxicity occurred in 43% of the cases, with 6 patients (9%) presenting grade 3 or higher toxicity. Furthermore, 13 patients (21%) were transferred to intensive care unit. Four patients (5%) died, 3 from lymphoma progression (missing data for the remaining patient). Among the 52 patients with at least 1 month of follow-up: the overall response and complete response rates at 1 month were 76.9% and 57.7% respectively (Figure 1). Conclusion: These preliminary results demonstrated that axi-cel in 2L for R/R LBCL is feasible and safe in real-life for transplant and non-transplant eligible patients. Although follow-up of our population remains short, early assessments of response are in line with those described in ZUMA-7 study. Inclusion in DESCART registry is on-going and updated results with at least 3 months of follow-up since infusion will be presented at the meeting.

Evidence-Based Recommendations for Induction Treatment of Newly Diagnosed Transplant-Eligible Multiple Myeloma Patients; A Scoping Review

Introduction Multiple myeloma is a hematological malignancy characterized by the uncontrolled proliferation of plasma cells within the bone marrow, with an increasing incidence and mortality in the last decade. Eligibility for stem cell transplantation plays a crucial role in determining the approach to treatment, with transplant eligible patients undergoing triple induction therapy with an immunomodulatory agent, a proteasome inhibitor, and steroid. We aimed to review the recent data on the available treatment options for newly diagnosed multiple myeloma (NDMM) in transplant eligible patients. Methods A scoping review was conducted according to the PRISMA 2020 guidelines utilizing the PubMed and Embase databases. The inclusion criteria was phase II or III clinical trials pertaining to the use of triple and quadruple therapy in NDMM patients, from the year 2010 onwards. A total of 2377 search results were screened, with 510 undergoing full-text screening against the inclusion criteria. Covidence was used to facilitate the screening process (Figure 1). Results Forty studies were included in the analysis. Eleven trials were based on Daratumumab induction. Additionally, two trials each utilized Isatuximab and Carfilzomib-based induction. One trial employed induction therapy containing Elotuzumab, and another utilized Cyclophosphamide. Addition of Daratumumab to the triplet regimen resulted in significant improvements in response rates and depth of responses. CASSIOPEIA trial demonstrated a notable improvement in minimal residual disease (MRD), with VTd treatment yielding 44% MRD, while Dara-VTd regimens achieved 64% MRD. Similarly, complete response (CR) rates increased from 26% to 39%, respectively. GRIFFIN trial revealed a remarkable 55% reduction in the risk of disease progression for patients with Dara-RVd . Moreover, the estimated 48-month progression-free survival (PFS) rate was 87.2% in the Dara-RVd group, compared to 70% in the RVd group. Notably, the median PFS was not reached in either treatment arm. The Lyra trial, which analyzed Dara-CyBorD followed by Dara maintenance, demonstrated a CR rate of 48.7% for transplant patients and 29.8% for non-transplant patients, respectively. Additionally, the MASTER trial revealed that Dara-KRd/autologous hematopoietic cell transplant (AHCT) led to a high rate of MRD negativity, with 80% of patients achieving MRD negativity. The two-year PFS was 87%. Furthermore, the addition of Isatuximab and Carfilzomib to the treatment regimen demonstrated favorable outcomes in terms of MRD and PFS (Table 1). The addition of Elotuzumab did not lead to a significant improvement in outcomes. Moreover, caution is warranted when using Cyclophosphamide, given its less favorable safety profile and limited additional benefit in survival outcomes (MRD: 27% in +Cyclophosphamide arm vs. 35% without), including a temporary decline in health-related quality of life. Conclusion In conclusion, this scoping review underscores the significance of individualized treatment approaches for multiple myeloma based on clinical trial results. Each induction regimen has shown varying levels of efficacy and safety, offering clinicians flexibility to tailor treatments for different patient populations. The results from these trials will serve as valuable benchmarks and inform future research in the quest for improved therapies for NDMM patients.

Long-Term Safety and Efficacy Results of Belantamab Mafodotin Plus Lenalidomide and Dexamethasone in Transplant Ineligible Patients with Newly Diagnosed Multiple Myeloma: An Updated Part 1 Analysis from the Phase 1/2 Belard Trial

Introduction The preferred upfront treatment of transplant ineligible (TI) patients (pts) with newly diagnosed multiple myeloma (NDMM) consists of the combination of lenalidomide and dexamethasone (Rd) with a third antimyeloma agent of a different mechanism of action (e.g., proteasome inhibitors or anti-CD38 monoclonal antibodies). Belantamab mafodotin (belamaf; GSK2857916), an antibody-drug conjugate targeting BCMA, has shown efficacy in pretreated MM pts, while preclinical data demonstrate synergy between belamaf and lenalidomide, with no overlapping toxicities. Thus, there is a strong rationale for investigating the belamaf-Rd triplet in TI NDMM pts. Methods BelaRd (NCT04808037) is an open-label, phase 1/2 study conducted in Greece, aiming to enroll 66 TI NDMM pts. Eligible are adult pts with ECOG PS 0-2 and adequate organ function. Part 1 evaluates the safety/tolerability of three belamaf doses (2.5/1.9/1.4 mg/kg) plus Rd in 36 pts and establishes the recommended phase 2 dose (RP2D). In this part, belamaf is initially administered q8w and, depending on toxicity, dosing may be adjusted to q12w. Ocular exams include Snellen best corrected visual acuity (BCVA) and slit lamp corneal evaluation. Ocular symptoms are classified by CTCAE v5.0, while the Ocular Surface Disease Index (OSDI) captures dry eye disease and activities of daily living (ADL).Herein, we present updated safety and efficacy results of all Part 1 pts with an extended follow-up time (cut-off date 05/06/2023). Results Of the 36 pts [median age: 72.5 years; male: 19 (53%)] in Part 1, 29 (81%) are still on treatment, while 7 (19%) have discontinued [6 pts due to belamaf-unrelated fatal events: (COVID-19: 1/1/2; Pneumonia: 1/1/0, for cohorts 2.5/1.9/1.4 respectively); 1 pt withdrew consent]. The median belamaf administrations and number of cycles reached were 6/7/7 and 20.0/22.5/20.0, for the respective cohorts. The most common (≥10% of pts) non-ocular ≥ Gr3 treatment-emergent adverse events were fatigue (21 pts, 58%; [7 (58%)/7 (58%)/7 (58%)]), diarrhoea (8 pts, 22%; 2 (17%)/3 (25%)/3 (25%)]), rash (6 pts, 17%; [2 (17%)/2 (17%)/2 (17%)]), COVID-19 (5 pts, 14%; [2 (17%)/1 (8%)/2 (17%)]) and insomnia (4 pts, 11%; 0/4 (33%)/0]) , while no ≥Gr3 thrombocytopenias and infusion-related reactions were reported. Regarding ≥Gr3 infections other than COVID-19, pneumonia was reported for 3 (8%) pts [1/1/1 (8%)] and lower respiratory tract infection for 1 (3%) pt [0/0/1(8%)]. Regarding ocular adverse events (OAEs), among 216/244/201 BCVA assessments in cohorts 2.5/1.9/1.4, a meaningful BCVA decline (BCVA <20/50) with at least 3 lines drop in the better seeing eye, was observed in 21 (10%)/24 (10%)/17 (8%), while BCVA ≤20/200 with at least 3 lines drop in the better seeing eye was noted in only 2 (1%)/3 (1%)/8 (4%), with a median time to resolution of 1 month. Across all cohorts, the most frequently reported ≥Gr 3 ocular symptom was decreased vision (26/665, 4%), while ≥Gr3 keratopathy was noted in <2% of assessments. Regarding OSDI, from 202/234/196 responses received, the number of “all/most” of the time worst responses in the ocular symptoms category were 6 (3%)/6 (3%)/8 (4%), while the respective proportions in the ADL category were 6 (3%)/4 (2%)/3 (2%). The overall response rate was 100% across all cohorts: More specifically CR or better was achieved by 7 (58%)/6 (50%)/6 (50%), VGPR by 3 (25%)/5 (42%)/3 (25%) and PR by 2 (17%)/1 (8%)/3 (25%) pts in cohorts 2.5/1.9/1.4, with a median time to first response of 1 month. Finally, at a median follow-up of 20.3 months, no disease progression was observed, median PFS and median time to progression were not reached ( Figure 1) and responses continue to deepen across all cohorts. Conclusions Over an extended follow-up period, the belamaf-Rd triplet has proven a safe and effective combination for the upfront treatment of TI NDMM pts, with no long-term safety signals. Furthermore, the extended dosing schedule for belamaf had a minimal impact in vision-related functioning, as very low rates of meaningful BCVA decline and “most/all” OSDI responses were noted across all cohorts, with a rapid time to resolution. Meanwhile, a very promising clinical activity is observed, with rapid, deep and durable responses across all dose levels. Consequently, after validation with bigger pt numbers, this novel combination may well be a very attractive frontline option for this vulnerable and difficult-to-treat pt population.

Tolerability in Transplant-Ineligible Patients with Newly Diagnosed Acute Myeloid Leukemia Treated with Venetoclax Based Combination Therapy: A Systematic Review and Meta-Analysis of Phase III Randomized Controlled Trials

Introduction Therapeutic challenge remains in older patients with acute myeloid leukemia (AML) with significant comorbidities who are not fit for induction chemotherapy and haemopoietic stem cell transplantation. Leukemic cells depend on BCL-2 protein (anti-apoptotic protein) for their survival. Venetoclax is a selective small-molecule BCL-2 inhibitor which binds to BCL-2 resulting in apoptosis of leukemic cells. In recent years, venetoclax has been approved in combination with azacitidine or low dose cytarabine in transplant-ineligible patients with newly diagnosed AML (ND AML). However, there are notable toxicities. The purpose of our meta-analysis is to determine tolerability, rates of treatment emergent serious adverse events (SAE), treatment discontinuation (TD) and treatment interruption (TI), dose reduction and 30-day mortality in transplant-ineligible patients with ND AML treated with venetoclax based combination therapy. Methods We systematically conducted a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts from inception through June 30 th, 2023. Phase III RCTs utilizing venetoclax in transplant-ineligible patients with ND AML that mention tolerability, rate of treatment discontinuation and interruption, dose reduction, treatment emergent serious adverse events, 30-day mortality were incorporated in the analysis. Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran's Q- statistic. Fixed effects model was applied. Results A total of 637 transplant-ineligible patients with ND AML from 2 phase III RCTs (VIALE-A and VIALE-V) were eligible. VIALE-A and VIALE-V compared azacitidine + venetoclax vs azacitidine + placebo, and venetoclax + low dose cytarabine vs placebo + low dose cytarabine respectively. The randomization ratio was 2:1 in both studies.TD due to treatment emergent adverse events (TEAE) was noted in 104 (24.5%) of venetoclax group vs 45 (21.2%) in control group with RR of 1.15 (95% CI: 0.85 -1.57; P = 0.37).TI due to TEAE was higher in the venetoclax group (68.9%) compared to control group (55.6%) with RR of 1.24 (95% CI: 1.08 -1.42; P = 0.002). 21 (4.9%) of patients in venetoclax group and 10 (4.7%) in the control group required dose reduction of treatment due to TEAE, RR 1.03 (95% CI: 0.50 -2.16; P = 0.93).Treatment emergent SAEs were reported in 77.4% in the venetoclax group vs 60% in control group (RR, 1.30; 95% CI: 1.15-1.46; P <0.0001). 30-day mortality was reported in 39 (9.1%) of patients in the venetoclax group and 20 (9.4%) in the control group with RR of 0.96 (95% CI: 0.58 -1.60; P = 0.89). Conclusions Our meta-analysis showed that there was no significant difference in the rate of treatment discontinuation and dose reduction due to adverse events in transplant-ineligible patients with ND AML treated with venetoclax combination regimens, compared to control arm although rates of treatment emergent SAEs and treatment interruption were considerably higher in the venetoclax-treated arm. However, the 30-day mortality rate was similar between the two groups. Longer follow up and timely supportive care are required to improve treatment emergent SAEs and treatment interruption.

The Impact of Epstein-Barr Virus Infection on Second Cancer Development in Newly Diagnosed Myeloma Patients Treated with Lenalidomide in the UK NCRI Myeloma XI Trial

Background Several factors have been linked to second primary malignancy (SPM) development in myeloma patients, including advanced age, immunocompromise and therapy, such as melphalan and lenalidomide (len). The impact of infection, including EBV is yet to be elucidated. Here we address this in the context of the UK NCRI Myeloma XI Trial for newly diagnosed transplant eligible (TE) and transplant non-eligible (TNE) patients. Methods Myeloma XI was a phase III, randomised, multi-centre, parallel group design, open-label trial comparing cyclophosphamide, thalidomide, len, carfilzomib and bortezomib induction combinations and len maintenance treatment in TE and TNE patients. TE patients received high dose melphalan supported by autologous stem cell transplantation (ASCT). Patients in both pathways were randomised to maintenance with len or observation. In total, 4358 patients entered. Planned SPM analysis was conducted in May 2019, with 318 patients developing an SPM prior to that point. Median follow-up from trial entry was 60 months (IQ range 47-76). A nested cohort analysis was performed to determine EBV infection and immunity status in 170 SPM patients for which serum samples were available. Forty-two trial patients who did not develop an SPM were used as a control group. EBV assessment time-points included pre-induction, post induction, 4 months post ASCT (TE only) and 1 year post induction. Peripheral blood serum samples were tested for EBV EBNA IgG Antibody/index (LIAISON®), EBV VCA IgM Antibody/Index (LIAISON®) and EBV positivity was determined using the artus® EBV RG PCR Kit from Qiagen. Active or recent EBV infection was evidenced by a positive EBV IgM antibody and/or EBV PCR. Results Of the 170 patients, 208 SPM were noted with 147 patients developing 1 SPM and 23 patients developing ≥2. One hundred and five patients developed an SPM following maintenance randomisation, with 76 receiving len and 29 being observed. The remaining 65 patients developed an SPM prior to maintenance. Eighty-four SPMs were diagnosed in 68 TE patients and 124 SPMs in 102 TNE patients. Of the 170 SPM patients, 8 had evidence of recent or active infection at the time of testing, evidenced by either IgM EBV antibodies (n=5), positive EBV PCR (n=2) or both (n=1). The median EBV DNA copies/ml was 353 (range 337-428). The median IgM antibody titre was 71.5U/ml (26 - >160). No patients in the control group had evidence of recent EBV infection (p=0.36). Of the 8 patients with evidence of EBV infection, 6 developed >1 SPM, Table 1. Five had been treated in the TE pathway, with all developing post maintenance randomisation, and 4 of the 5 receiving len maintenance. None of the 3 TNE patients received len maintenance, with 2 developing an SPM prior to maintenance randomisation. The median time from EBV testing to SPM diagnosis was 17·9 months (0.5-51.7). Two of the EBV positive patients developed a haematological SPM: myelodysplastic syndrome and Hodgkin lymphoma. Four patients developed a solid malignancy: lung, breast, ovary, and colon. The remaining cases were non-melanoma skin cancers, Table 1. Immune status (EBV IgG) was also determined. In TE patients, the median EBV IgG titre was 65.3U/ml at diagnosis (<3 - 600, n=48), falling to 28.1U/ml following induction (<3 - 326, n=41) and recovering to 44.2U/ml one year post ASCT (<3 - 600, n=22). In TNE patients, the median IgG titre at diagnosis was 39.1U/ml (<3 to 517, n=72), falling to 31.2U/ml 4 months post induction (<3 - 287, n=42) and recovering to 51.3U/ml after 1 year (<3 - 554, n=41). In the SPM patients the IgG EBV titres were noted to be <20U/ml in 5 of the 8 patients. Three of the eight patients had no detectable EBV IgG level (<3U/ml) Conclusions These data suggest that EBV infection is unlikely to be a risk factor for SPM development in myeloma patients. This is supported by the finding that EBV IgG titres were consistent with immunity in most patients (>20U/ml) and even in the patients with possible EBV infection, EBV DNA was only identified in 3 patients, and at a low level. In addition, the SPM developed are not classically associated with EBV infection or reactivation. It is noted that EBV infection status was not always determined at the time of SPM development. Despite this, the data does show that EBV immunity recovers following therapy, even in the post ASCT setting. EBV monitoring is therefore not supported by this work, although in patients who develop ≥2 SPM, further clarification is required.

Efficacy and Safety of Daratumumab in Combination with Bortezomib, Thalidomide, and Dexamethasone Regimens in Newly Diagnosed Multiple Myeloma with Renal Insufficiency in Real-World: A Non-Interventional Prospective Multicenter Observational Study

Background: Renal impairment (RI) is one of the common serious complications of MM. The DARE Phase 2 clinical study is daratumumab-based regimen for the treatment of MM patients with renal insufficiency, which is designed to use daratumumab in combination with dexamethasone for the treatment of RRMM with severe renal insufficiency. According to the updated data, after 8.3 months of follow-up, the 6-month PFS rate was 48.6%, ORR was 41.4%, renal response rate (RRR) was 20.7%. CASSIOPEIA phase III clinical study showed that with the extension of treatment time, the sCR rate and minimal residual disease (MRD) negative rate in D-VTd group were significantly improved compared with those in VTd group. According to the evidence from previous large phase III clinical trials of daratumumab in NDMM as well as its DARE phase II study and clinical case reports, daratumumab based treatment has a rapid onset of action in the treatment of MM patients with severe renal insufficiency, effectively response to the disease and improve the renal function of patients. An observational, multi-center, non-interventional study was designed to evaluate the safety and efficacy of daratumumab in combination with VTD in NDMM patients with renal dysfunction in real-world clinical practice. (NCT 05561049) Methods:NDMM patients older than 18 years and with a glomerular filtration rate(eGFR) of less than 40 ml/min were enrolled. Patients received VTD for C1, then go to DaraVTD for C2-4. The dose of Daratumumab was 16 mg/kg I.V. every week for 2cycles(cycles 2-3) , 16 mg/kg I.V. every 2 weeks for one more cycles;“Thalidomide”: 100 mg, P.O., Days 1-28/1-4 cycles;“Bortezomib”: 1.3 mg/m2, SC, Days 1, 4, 8, 11/1-4 cycles; Dexamethasone: 20-40mg, PO/I.V., qw/1-4 cycles. After induction therapy, patients entered consolidation therapy. Transplant eligable patients undergo stem cell collection and autologous stem cell transplantation followed by consolidation with DVTd regimen for 2 more cycles. Four more cycles of consolidation with DVTd were performed in transplant ineligible patients. The primary endpoint of this study is to evaluate VGPR+ rate after consolidation. The secondary endpoint is ORR, renal response rate (RRR), CR rate, MRD negativity after consolidation, and DOR, PFS, OS. NCI CTCAE V5.0 criteria were used to evaluate adverse events. Result: From Jan 1th to June 30 th 2023, 23 patients were enrolled. The median age of these 23 patients was 64 (34-78), 69.6%(16/23) was male.(Table 1) Among the 18 patients who have had response evaluation, the ORR was 94.4%. median onset time of response was 2 months. After induction therapy, the ORR was 100%, 50% patients had gotten CR. After consolidation, All patients were above VGPR and CR and were NGS MRD negative.55.5% patients(10/18) achieved renal remission after one cycle, while 86.7% after 2 cycles, 91.7% after 3 cycles and 100% after 4cycles. Among the 20 patients who have had adverse events evaluation. The main treatment-related adverse events were hematological toxicity, including neutropenia (n=10/20, grade 1-2 for 6 pts and grade 3-4 for 4 pts), lymphopenia (n=5/20, grade 1-2 for 5 pts) and thrombocytopenia (n=8/20, grade 1-2 for 6 pts and grade 3-4 for 2 pts). One patient with acute pancreatitis had to stop treatment. Other toxicities to date included pneumonia (n=5/20, grade 1 for 4 pts and grade 2 for 1 pts), peripheral neuropathy (n=10/20, grade 1 for 7 pts and grade 2 for 3 pts), and rash(n=5). The infusion related reactions were 37.5%(n=6/18, grade 1 for 4 pts and grade 2 for 2 pts). Conclusion: In Chinese NDMM patients with RI, quad-drug induction of DVTD with/without ASCT consolidation showed nice tolerability and high overall response of disease even with a high percentage of high-risk patients. This preliminary study also suggested excellent efficacy with rapid improvement in renal function. The most common adverse events were hematological toxicity. Updated results will be presented at the following phase.

Responses and Outcomes after Second-Line Therapy in Transplant-Eligible Patients with DLBCL Relapse over 1 Year after First-Line Therapy

Introduction Chimeric antigen receptor T-cell therapy (CAR T) is approved as second-line therapy in patients with large B cell lymphoma (LBCL) that is refractory to, or relapsed within 1 year of, initial therapy. In patients with LBCL that relapses more than 1 year after completion of initial therapy, salvage chemoimmunotherapy followed by high-dose chemotherapy and autologous stem cell transplant (ASCT) remains the standard of care for transplant-eligible patients. However, data on the outcomes of salvage chemoimmunotherapy with intent for ASCT for this specific population are lacking. Methods We retrospectively reviewed patients with relapsed LBCL more than 1 year after 1 st line therapy who received salvage treatment. We included patients seen at our institution prior to the start of salvage therapy, who began therapy between 1/2008 and 1/2023, and were treated with stated intent to proceed to ASCT. We excluded patients with CNS involvement at relapse and those not evaluable for response. The primary outcome was progression-free survival (PFS), defined as the time from initiation of salvage therapy to LBCL progression or death. Event-free survival (EFS) was defined as time from salvage initiation to change in lymphoma therapy, disease progression, or death. Additional key outcomes included overall survival (OS), overall response rate (ORR) and complete response rate (CRR) to salvage therapy, and outcomes after subsequent CAR T. Outcomes for important subgroups using baseline characteristics were compared. ORR and CRR were compared using Fisher's exact test. PFS, EFS and OS were estimated using the Kaplan-Meier method, and differences were tested by the log-rank test. Results A total of 78 patients met inclusion criteria, with characteristics summarized in Table 1. Median time from completion of initial therapy to relapse was 31.2 months (range, 12.3 - 177 months). CRR to salvage therapy was 76%, with a 94% ORR. In 60 patients who completed ASCT, CRR was 85%. With a median of 45 months' follow-up from salvage initiation, median PFS was 50 months (95% confidence interval (CI) of 25 - NR), and median EFS was 29.2 months (95% CI, 19.6 - NR)( Figure 1). Median OS was 132 months (95% CI 108 - NR). On subgroup analysis, factors significantly associated with shorter PFS were time from last treatment to relapse < 36 months, Ann Arbor stage 3-4, LDH above normal, and increased international prognostic index at relapse. Other factors such as age, gender, salvage regimen, extranodal disease, cell of origin, transformation from indolent lymphoma, bulky disease, and marrow involvement at relapse, were not significantly associated with PFS. Comparing response to salvage in 60 ASCT recipients, patients in CR (n=52) had longer median PFS than those in PR (n=8) (108 vs 33 mo), but this was not statistically significant (p = 0.4). In 33 patients who received 3 rd line therapy or beyond, 16 (48%) received CAR T therapy; 7 proceeded directly to CAR T after inadequate response to salvage, and 9 had progression after completion of ASCT and received CAR T. Among all patients, CRR after CAR T was 81% and ORR 94%, with median PFS and OS not reached; PFS and OS at 24 months after CAR T were 63% and 81%, respectively. Discussion To our knowledge, this is the first study to specifically evaluate outcomes of ASCT-eligible patients with relapsed LBCL more than 1 year after initial therapy, who did not meet FDA criteria for CAR T-cell therapy. We observed highly favorable outcomes, with longer PFS and OS compared to studies that evaluated late LBCL relapses (Hilton LK., JCO 2023, Harrysson S., BJH 2022), possibly reflecting the exclusive use of modern salvage regimens with intent for ASCT, improvements in subsequent therapies, or bias related to the single-center design. In patients who received CAR T in 3 rd line or later, frequent and durable responses were seen. However, due to the small sample size, whether CAR T should be considered as an alternative to ASCT in patients with late LBCL relapse remains unknown. Our data represent a benchmark for patients with LBCL relapses >12 months after completion of frontline therapy and may help inform patient counseling and future clinical trial designs.

Phase II Trial of Daratumumab, Bortezomib, Lenalidomide and Dexamethasone in High-Risk Smoldering Multiple Myeloma

Background: Daratumumab, bortezomib, lenalidomide and dexamethasone (D-RVD) has shown high rates of minimal residual disease (MRD) negativity in newly-diagnosed multiple myeloma (MM) and is now a standard regimen in transplant-eligible patients. Lenalidomide has shown to delay progression in patients with high-risk smoldering multiple myeloma (HR-SMM) and curative intent trials with carfilzomib-based therapy and stem cell transplantation have been recently reported in HR-SMM leading to deep responses but with concern for treatment-related toxicities. Thus, we proposed to examine the activity and safety of fixed duration D-RVD in patients with HR-SMM, with MRD-adaptive duration of therapy. Methods: This is a phase II, open-label study evaluating D-RVD in HR-SMM. Eligibility criteria includes HR-SMM per Mayo 2018 “20-2-20” model and other previously established criteria including Mayo 2008 criteria, PETHEMA criteria, evolving type of SMM, and high-risk FISH. Treatment with D-RVD is 2 years (24 cycles) with daratumumab subcutaneous (SQ) per standard dose and schedule, bortezomib 1.3mg/m2 SQ on days 1, 8, 15 for cycles 1-6 then biweekly until completion of cycle 24, lenalidomide 25mg on days 1-21 for cycles 1-6 followed by 15mg d1-21 from cycles 7-24 with weekly low dose dexamethasone. All eligible patients undergo stem cell collection after 6 cycles of therapy. The primary objective is rate of MRD-negativity at 2 years. Secondary objectives include PFS, ORR, and safety. In part 2 of the study, patients that are MRD-positive after 2 years of treatment will be randomized to observation vs continued therapy with daratumumab and lenalidomide for an additional 24 months. The primary objective of part 2 is rate of MRD conversion from positive to negative. Results: At the time of data cut off in May 2023, 38 patients have been enrolled to part 1 with a median follow up of 18 months. The median age is 62 years old (range 36-77) with 23 females (61%) and 15 males (39%). The median plasmacytosis of enrolled patients was 20%, with median M-protein of 2.17 g/dL and median FLC ratio of 8.1. Twenty-four patients (62%) had at least one high-risk FISH abnormality (fifteen with 1q gain, four with t(4;14), one with t(14;16) and one with del 17p). Eight patients (21%) had more than one high-risk FISH abnormality. Most common grade 3 toxicities included neutropenia (13%), ALT increased (8%), and diarrhea (8%). Upper respiratory infections occurred in 61% of patients but were mostly low-grade (COVID-19 infection in 11 patients, 1 with grade 3). No patients discontinued therapy due to toxicity. Of the 35 patients that completed at least 2 cycles of therapy, the ORR is 100% with 43% CR, 34% VGPR and 17% PR with responses deepening over time. Seventy-seven percent of patients achieved VGPR or greater. MRD was evaluable in 22 patients at 6 months with MRD negativity rate of 59% and 14% at thresholds of 10 -5 and 10 -6, respectively. At 12 months, 20 patients were MRD-evaluable with 65% and 20% achieving MRD negativity at 10 -5and 10 -6, respectively. Of the 10 MRD-evaluable patients at 24 months, 60% were MRD negative at 10 -5 and 40% at 10 -6. No patients have progressed on treatment. Stem cell collection was successful in all eligible patients with average stem cell yield of 5.53 x 10 6 CD34+ cells/kg. Conclusions: D-RVD in HR-SMM demonstrates significant activity, including a 100% ORR and high rates of MRD-negative disease, preventing progression to overt myeloma.

Integrated analysis of randomized controlled trials evaluating bortezomib + lenalidomide + dexamethasone or bortezomib + thalidomide + dexamethasone induction in transplant-eligible newly diagnosed multiple myeloma.

Providing the most efficacious frontline treatment for newly diagnosed multiple myeloma (NDMM) is critical for patient outcomes. No direct comparisons have been made between bortezomib + lenalidomide + dexamethasone (VRD) and bortezomib + thalidomide + dexamethasone (VTD) induction regimens in transplant-eligible NDMM. An integrated analysis was performed using patient data from four trials meeting prespecified eligibility criteria: two using VRD (PETHEMA GEM2012 and IFM 2009) and two using VTD (PETHEMA GEM2005 and IFM 2013-04). The primary endpoint was met, with VRD demonstrating a noninferior rate of at least very good partial response (≥ VGPR) after induction vs VTD. GEM comparison demonstrated improvement in the ≥ VGPR rate after induction for VRD vs VTD (66.3% vs 51.2%; P = .00281) that increased after transplant (74.4% vs 53.5%). Undetectable minimal residual disease rates post induction (46.7% vs 34.9%) and post transplant (62.4% vs 47.3%) support the benefit of VRD vs VTD. Treatment-emergent adverse events leading to study and/or treatment discontinuation were less frequent with VRD (3%, GEM2012; 6%, IFM 2009) vs VTD (11%, IFM 2013-04). These results supported the benefit of VRD over VTD for induction in transplant-eligible patients with NDMM. The trials included are registered with ClinicalTrials.gov (NCT01916252, NCT01191060, NCT00461747, and NCT01971658).

Targeted NGS Panel Guides Risk-Adapted Treatment Intention in Newly Diagnosed Myeloma Patients

Introduction While overall survival has improved, patients with high-risk multiple myeloma (MM) have poor outcomes. Fluorescent in situ hybridisation (FISH) is widely used to identify high-risk genomic features at diagnosis, but a significant minority of patients classified with standard-risk disease progress rapidly and in retrospect may have warranted more intense frontline therapy. Recently, we implemented the Myeloma Genome Project Panel (MGPP) into clinical workflows - a myeloma-specific targeted sequencing panel capturing 228 genes, 6 translocation regions and 56 copy number abnormalities (CNAs) in a single assay [PMID: 35522533]. Given that MGPP captures many prognostic regions beyond the limited number assessed by FISH, there is potential to better identify high-risk patients. However, the utility of MGPP in supporting clinical risk designation and therapy choice when compared with FISH in newly diagnosed MM is unknown. Methods A prospective cohort study was conducted to compare the impact of MGPP vs. FISH on baseline risk stratification and treatment intention, in 55 unselected newly diagnosed MM patients. For MGPP, libraries were generated from 100ng DNA from bone marrow (BM) derived CD138 + MM cells and matched germline peripheral blood (Roche KAPA HyperCap Target Enrichment/Hyperplus kit). Reads were aligned to hg38, and somatic mutations, CNAs and translocations called with a custom pipeline. ISO-accredited FISH analysis was performed in NHS laboratories. In a multicentre multidisciplinary team (MDT) meeting, four blinded haematologists independently reviewed each clinical case presented twice with either FISH or MGPP, in a random order. Clinicians designated risk status and treatment intentions using a structured proforma. Therapeutically actionable variants could be selected as per the MyDRUG trial [ClinicalTrials.gov: NCT03732703]. A consensus MDT outcome for high-risk or more intensive therapy required at least 3 out of 4 concordant decisions. Results Data is presented here for 23 of 55 patients. The mean age was 68.9 years, 57% were transplant eligible, with R-ISS-1 (35%), R-ISS-2 (26%) and R-ISS-3 (39%). Firstly, MGPP had greater technical success than FISH, reporting successfully in 100% vs. 83% cases from the same diagnostic BM samples respectively (n=4 assay failures with FISH). Secondly, MGPP reported more genomic features than FISH, detecting 231 vs. 18 somatic variants at 127 vs. 7 regions, respectively. Thirdly, MGPP captured equivalent loci at greater resolution, detecting subclonal CNAs missed by FISH (Figure 1). In a head-to-head comparison with FISH, these additional genomic insights from MGPP influenced clinical treatment decisions. A clinician-led MDT reclassified 9 (39%) patients designated as standard-risk by FISH to high-risk status when presented with MGPP (Table 1). Reclassified patients were enriched for prognostically significant MYC translocations (17%) and subclonal 17p loss (22%), 1p loss (17%) and 1q gain (13%) CNAs that were missed by FISH. Altered risk designation influenced frontline treatment intention; clinicians opted for intensification of induction therapy in 13% (FISH) vs. 48% (MGPP) high-risk patients, and considered tandem autologous transplant as an option in 0% (FISH) vs. 23% (MGPP) transplant-eligible patients. FISH identified a therapeutically actionable variant in 3 (13%) patients [venetoclax, n=3]. MGPP identified 13 (57%) additional patients with opportunity for targeted therapy [MEK inhibitor, n=11; BRAF V600E inhibitor, n=2], which the MDT considered as a treatment option in all cases if available in trial. The full dataset and analysis will be presented at time of the conference. Conclusions We demonstrate that MGPP impacts clinical risk designation and treatment intention in newly diagnosed MM. MGPP had greater technical assay success than FISH and captured a greater range and depth of somatic variants. Importantly, these additional insights led a clinical MDT to reclassify 39% patients as high-risk, consider intensification regimen in 39% cases and potential for actionable targeted therapy in 57% patients. Our results support MGPP as a robust alternative to FISH in supporting risk-adapted treatment decisions. We will implement MGPP in additional large prospective cohorts over the next year, to better understand its prognostic utility and feasibility in routine clinical workflows.

Replacing Steroids in Transplant-Ineligible Multiple Myeloma: The Phase 2 Isatuximab-Bortezomib-Lenalidomide-Dexamethasone Rest Study

Background: Standard therapies for patients with newly diagnosed multiple myeloma (NDMM) who are ineligible for autologous stem cell transplantation (ASCT) have been lenalidomide-dexamethasone (Rd), bortezomib-lenalidomide-dexamethasone (VRd) or bortezomib-melphalan-prednisone (VMP). The benefit of adding an anti-CD38 monoclonal antibody (mAb) to the standard treatments of VMP and Rd has been demonstrated in two large phase 3 studies, achieving overall response rates (ORR) of 90.9% and 92.9% in the daratumumab-VMP arm and the daratumumab-Rd arm, respectively (Facon, 2019, Mateos, 2018). Isatuximab is an anti-CD38 mAb approved in combination with pomalidomide-dexamethasone and carfilzomib-dexamethasone to treat relapsed/refractory MM. The drug has also shown clinical responses as combination therapy to treat NDMM (Trudel, 2019). Corticosteroids have been the backbone of most myeloma-targeted therapies since the discovery of their effectiveness. Due to the continuous treatment paradigm, the cumulative dose of corticosteroids in patients is substantial. Steroids inflict reduction in both short- and long-term quality of life and increase patients' receptiveness to infections. Infections are one of the main reasons for complications and death during active first line treatment and the rate rises with age (Mothy, 2019). Instead of reducing or removing corticosteroids, isatuximab will replace corticosteroids to evaluate the effectiveness and safety of the novel regime of isatuximab-bortezomib-lenalidomide. Aim: The study will evaluate isatuximab (Isa) in combination with bortezomib (V) and lenalidomide (R) with minimal dexamethasone (d) as first-line treatment in transplant-ineligible patients. The primary endpoint is the number of patients who achieve measurable residual disease negative (Euroflow NGF 10 -5) complete response during and/or after 18 cycles of study treatment. Secondary endpoints include progression free survival, overall survival, overall response rate, safety evaluations and patient-reported outcome. Methods: The REST study is an academic, single arm, open-label, phase 2 study of NDMM patients ineligible for ASCT. 51 patients are included and receive Isa-VRd (Isa: 10 mg/kg IV Days 1, 8, 15, 22 during cycle 1, Q2W cycle 2-18; V: 1, 3 mg/m 2 SC Days 1, 8, 15 during cycle 1-8; R: 25 mg PO Days 1-21 during all cycles; d: 20 mg PO Days 1, 8, 15, 22 only for the first 2 cycles), all 28-day cycles. Results: Recruitment was completed in January 2023. Baseline characteristics, safety summary and preliminary results can be found in Table 1. The median age is 77 years, range 70-88 years. Twenty-nine patients developed 60 grade >3 non-hematological adverse events (AE), including infections (n=26), syncope (n=5), diarrhea (n=4), skeletal pain (n=4), arrhythmias (n=3), acute renal failure (n=3), increased transaminases (n=3), venous thromboembolism (n=2), arthritis (n=2), gastrointestinal hemorrhage (n=2), peripheral sensory neuropathy (n=2), edema (n=1), hyperglycemia (n=1), rash (n=1) and opiate intoxication (n=1). At a median follow up of 12 months, the ORR was 100% (51/51) with very good partial response or better at80.3% (41/51). Forty-four patients are still on study. One patient died from septicemia with staphylococcus aureus, four patients discontinued due to disease progression, one patient due to poor compliance and one patients for safety reasons judged by the investigator. Conclusions: Isa-VRd in the transplant ineligible population with a median age of 77 years has a tolerable safety profile. Isa-VRd is showing encouraging preliminary efficacy in NDMM ineligible for transplant. Follow-up is ongoing. Acknowledgements: Sanofi funded this research.

GEM2017FIT Trial: Induction Therapy with Bortezomib-Melphalan and Prednisone (VMP) Followed By Lenalidomide and Dexamethasone (Rd) Versus Carfilzomib, Lenalidomide and Dexamethasone (KRd) Plus/Minus Daratumumab (D), 18 Cycles, Followed By Consolidation and Maintenance Therapy with Lenalidomide and Daratumumab: Phase III, Multicenter, Randomized Trial for Elderly Fit Newly Diagnosed Multiple Myeloma (NDMM) Patients Aged between 65 and 80 Years

Background: In transplant-ineligible patients (pts) with NDMM, VMP and Rd have been standards of care. The Spanish Myeloma Group examined induction with VMP followed by Rd, and results were particularly striking for “fit” pts aged 65-80 with a CR rate of 47% and an MRD negative rate (MRD(-)) of 20%. The median PFS was 34 months (m) and 4-years (yrs) OS rate was 70%. Pts and study design: Based on this background, we consider VMP9-Rd9 as control arm and compared with KRd or D-KRd. Induction included 18 cycles, followed by 4 D-Rd consolidation cycles for the two first arms (to evaluate if anti CD38 consolidation might compensate its absence as induction). Subsequently, pts were stratified by MRD (positive and negative) to maintenance therapy with D-R vs observation. Frailty was evaluated with Geriatric Assessment in Hematology (GAH scale) considering as fit those younger than 80 years and with a punctuation between 0 and 42. VMP and Rd were given at conventional doses and in the K-based regimens, K was given at dose of 36mg/m 2 twice weekly during C1-2 and at 56 mg/m 2 weekly since C3. R was given at standard dose and D was planned as IV but switched to SC, both at the conventional dose and schedule. The primary endpoint was to evaluate the MRD(-) rate (NGF 10 -5) at the end of induction to compare both experimental arms, KRd and D-KRd to the control-one, VMP-Rd. A step-down testing procedure was applied, whereby inference for a test in the pre-defined hierarchy was dependent upon statistical significance having been achieved for the previous tests in the hierarchy. No formal adjustment for multiplicity of contrasts is required. Secondary endpoints referred to the induction phase included the serological responses, PFS and OS probabilities at 18 cycles and safety profile. Results: 540 pts were screened and 78 were screening failures. 462 pts were randomized to VMP-Rd (154 pts), KRd (154 pts) and D-KRd (153 pts but one patient was not evaluable). Baseline characteristics of the pts were comparable in the three arms with a median age of 72 and around one third older than 75 years. Nearly one third of pts in the three arms had ISS 3 and 15% had extramedullary disease. A total of 369 out of 461 pts have completed the 18 induction cycles (128 in VMP-Rd, 122 in KRd and 119 in D-KRd) and were evaluable for the primary endpoint. The MRD(-) rate at 10 -5 was 32% for VMP-Rd, 69% for KRd (p<0.0001) and 79% for D-KRd (p<0.0001). At 10 -6, the MRD(-) rate was also significantly superior for KRd (59%) and D-KRd (75%) in comparison with VMP-Rd (24%) (p values <0.0001). The ORR at the end of induction was comparable in the three arms (87%, 89% and 89%, respectively) but the sCR/CR rate was significantly higher for KRd (59%) and D-KRd (61%) in comparison with VMP-Rd (40%) (p-values <0.0001). At 18 m, the proportion of pts alive and progression-free was 79% for VMP-Rd and 87% for KRd and D-KRd, respectively. Only two pts who achieved MRD negativity have progressed thus far. The OS at 18 m in the VMP-Rd, KRd and D-KRd arms was 91%, 95% and 90%, respectively. There were 48, 44 and 40 pts who early discontinued therapy in VMP-Rd, KRd and D-KRd, respectively, due to progressive disease (VMP-Rd: 23; KRd: 9;D-KRd: 6) or toxicity (VMP/Rd:8; KRd: 14; D-KRd: 6). Death occurred in 12 pts treated with D-KRd being infections the cause in 10 pts (Covid-19 in 3); 5 pts in the KRd arm (4 infections (Covid-19 in 1)) and 6 pts in VMP-Rd arm (infections in 4 pts). Concerning hematological toxicity during induction, G3/4 neutropenia was higher in VMP-Rd (50%) than KRd (24%) (p<0.0001) and similar to D-KRd (47%). G3/4 thrombocytopenia was also higher in VMP-Rd (34%) than the other two arms (16% and 17%, p<0.0001)). G3/4 infections rate was comparable in the three arms (12% in VMP-Rd and 15%-16% in KRd and D-KRd). Cardiovascular G3/4 events were higher in KRd (11%) and D-KRd (14%) than in VMP-Rd (5%) (p<0.0001) being hypertension and cardiac failure the most frequent-ones. Conclusions: The trial met its primary end point and the MRD(-) rates of 69% for KRd and 79% for D-KRd were significantly higher than VMP9-Rd9 (32%). Overall, the VMP-Rd arm had higher rates of neutropenia, while the D-KRd arm had higher rates of infections leading to death. The trial is ongoing to evaluate long term outcomes.

Safety and Efficacy of Bortezomib-Pomalidomide-Dexamethasone (VPD) As Novel Induction Therapy in Newly-Diagnosed Multiple Myeloma: Updated Data from an Ongoing Single Arm Phase-II Investigator- Initiated Clinical Trial (PRIME Study)

Introduction: Pomalidomide is a third-generation immunomodulatory drug approved for relapsed and/or refractory Multiple Myeloma (RRMM). In a phase 3 OPTIMISMM trial, Pomalidomide, Bortezomib, and Dexamethasone demonstrated superior efficacy in patients with RRMM. PRIME study (CTRI/2019/10/021618) is testing Bortezomib, Pomalidomide and Dexamethasone combination in Newly Diagnosed Multiple Myeloma (NDMM). Initial data of 26 patients was presented as abstract in 63rd ASH Annual Meeting and Exposition. Current abstract is reporting the results of 46 patients with a longer follow up of this ongoing study. Objectives: Primary objective is to determine the efficacy of VPD regimen by measuring Minimal Residual Disease (MRD) assessment by flow-cytometry after 9 cycles of VPD. Secondary objectives are to determine response rates, PFS and safety of the regimen Methods: A prospective, single arm, phase II study from a tertiary care center. Both transplant eligible and ineligible patients with NDMM aged between 18-70 years as defined by the International Myeloma Working Group (IMWG) are being recruited in the study. The regimen consists of weekly Bortezomib 1.3mg/sq m, Pomalidomide 2 - 4mg once daily for 21days and Dexamethasone 20mg twice weekly, in a 28 days cycle for 9-12 cycles. Transplant patients planned for 9 cycles and non-transplant patients for 12 cycles of VPD. Eligible patients underwent High dose chemotherapy followed by Autologous HCT after 4-6 cycles of VPD. After Auto HCT 3-5 cycles of VPD given as consolidation therapy. After 9-12 cycles of VPD maintenance treatment given as per institutional practice. A 2-tube 8-colour antibody panel was used for MRD analysis using Flowcytometry (BD FACS CANTO-II) and analysed on Kaluza version. 1.3 software. A valve of < 0.001% was considered as MRD negative. Results: In this ongoing study, out of the proposed 50 patients, 46 patients were enrolled between April 2020 to June 2023. Median follow up is 24.5 months. The median age was 55 years (38-70), and gender ratio 1:1. At disease presentation, bone lesions was the commonest (91.3%, n 42) finding. The most common myeloma subtype was IgG Kappa in 43.5% (n 20). High risk cytogenetics were seen in 43.5% (n 20) and 43.5% (n 20) of patients were in RISS stage III (Table 1). Out of 46 patients 41 (89.1%) have completed 4 cycles and 30 (65.2%) patients have completed 9 cycles of VPD till last follow up (June, 2023). One patient had withdrawn consent, two patients were out of study due to increasing peripheral neuropathy (Grade 3). Five deaths occurred, 2 post cycle 8 and 3 after cycle 9. Four deaths were due to infections (COVID 19 and bacterial) and one due to progressive disease. Five patients underwent auto HCT (between Cycle 4 to 6). No patient failed stem cell mobilization, 2 patients required plerixafor in addition to G-CSF for mobilization. Table-1 shows drug-induced toxicity and response rates. Hematological toxicities were the commonest followed by fever, infections and skin rash. Majority of nonhematological adverse events were grade 1 to 2 and protocol was well tolerated. Protocol adherence was 97.8% (45/46 patients). After 4 cycles (n 43), 13 (30.2%) patients were in stringent complete response (sCR), 2(4.7%) in CR, 24 (55.8%) in very good partial response (VGPR) and 2 (4.7%) in partial response. After 9 cycles (n 35), 16 (45.7%) patients were in sCR, 2(5.7%) in CR and 11 (31.4%) in VGPR. Two (5.7%) patients had progressive disease (PD) and 3 patients were out of study due to consent withdrawn and toxicity. After 4 cycles of VPD 21 (48.8%) patients were MRD negative and MRD negative rate improved after 9 cycles to 74.3% (26 patients). Two years Progression Free survival (PFS) was 77.2% +/- 7.7% (Figure 1), disease free survival was 90.3% +/- 5.3% and overall survival (OS) was 83.1% +/- 7%. Conclusion: Safety data from the PRIME study demonstrates that VPD regimen has a favorable tolerance profile in patients with NDMM and no clinically significant impact on stem cell mobilization or engraftment. Early efficacy signals are encouraging, and recruitment continued. VPD has shown improved depth of response (MRD negativity) and overall response rate. Early follow up results shows promising PFS and OS results. VPD may be a promising induction regimen instead of Dara VRD in resource constrain setting where Daratumumab is not readily accessible. Phase 3 randomized trials are the way forward to its clinical use in frontline setting.

Impact of Daratumumab on Hematopoietic Stem Cell Mobilization with G-CSF and on-Demand Plerixafor in Newly-Diagnosed Multiple Myeloma Patients

Introduction Autologous stem cell transplantation (ASCT) is a standard of care for transplant eligible (TE) patients with newly diagnosed (ND) multiple myeloma (MM); therefore, an adequate hematopoietic stem cell (HSC) collection is crucial to allow patients to proceed to ASCT and ensure optimal hematologic recovery. A more frequent use of plerixafor (PLX) and lower HSC yields have been reported in patients treated with daratumumab, a backbone of induction therapy for NDMM patients. Chemotherapy-free mobilization with G-CSF and on-demand PLX is an effective mobilization strategy lacking chemotherapy-related toxicities. Here we present the results of a multicenter, retroprospective and prospective, observational study, aiming to compare the impact of daratumumab on HSC mobilization with G-CSF + on-demand PLX in patients with NDMM treated with bortezomib-thalidomide-dexamethasone (VTd) or VTd plus daratumumab (D-VTd). Methods NDMM patients undergoing a first HSC mobilization attempt with G-CSF (10 mcg/kg/day) were enrolled and observed up to 30 days after ASCT. According to its label, on-demand PLX was administered in patients with <20 CD34 + cells/µL after ≥ 4 days of G-CSF or in case <1×10 6 CD34 + cells/kg were collected on the first day of apheresis. The primary endpoint of the study was the rate of poor mobilizing patients (≤2x10 6 CD34 + cells/Kg collected or need for PLX to reach an adequate HSC harvest). Key secondary endpoints included: the rate of suboptimal (2 to 4 CD34 + cells/kg) and optimal (≥4 CD34 + cells/Kg) collection; the median number of apheresis required to obtain ≥2x10 6 CD34 + cells/Kg; the impact of daratumumab on HSC engraftment. Results A total of 190 NDMM patients (median age, 62 years) were enrolled in 2 Italian centres (IRCSS Istituto Clinico Humanitas and Città della Salute e della Scienza di Torino) and analyzed; of these, 70% (133/190) were treated with VTd and 30% (57/190) with D-VTd. The median number of induction cycles was 4 in both groups. Best response after the induction phase was at least very good partial response (VGPR) in 87/133 (65%) and 41/57 (72%) of patients treated with VTd or D-VTd, respectively (p=0.4). The median time from the end of induction to G-SCF administration was 24 days in the VTd group and 29 days in the D-VTd group (p=0.5). The rate of poor mobilizing patients was 31% (41/133) in the VTd group and 54% (31/57) in the D-VTd group (p=0.002), mainly due to a higher rate of PLX use in the D-VTd as compared to the VTd group (53% vs. 28%; p=0.001), while the rate of patients who failed HSC mobilization (≤2x10 6 CD34 + cells/kg collected) was similar in the two groups (2% vs. 3%; p=1). Despite a numerically higher median number of CD34 + cells collected in the VTd group (7.9) as compared to the D-VTd group (7.1; p=0.009), no difference in the rate of patients who collected 2-4 (5% vs. 5%; p=1) and ≥4 CD34 + cells/Kg (95% vs. 95%; p=1) was observed in the VTd and D-VTd groups, respectively. A higher median number of CD34 +/µL on the first day of count was observed in the VTd as compared to the D-VTd group (24.5 vs. 19, p=<0.001). Among patients who had <20 CD34 +/µL [32% (43/133) vs. 51% (29/57)] on the first day of count, a similar increase in the CD34 +/µL (48.5 vs. 55) was observed in the two groups after PLX administration. The median number of apheresis session needed to complete the harvestwas 1 fo the VTd group and 2 in the D-VTd group (p=0.1). Neutrophil and platelet recovery were achieved in 100% of patients with a median time to neutrophil recovery of 15 and 13 days in the VTd and D-VTd groups, respectively (p=<0.001) and a median time to platelet recovery of 16 and 14 days in the VTd and D-VTd groups, respectively (p=0.001). Conclusion G-CSF plus on-demand PLX for HSC mobilization demonstrated to be an effective strategy in NDMM patients treated with VTd with or without daratumumab, resulting in very low rates of mobilization failures irrespective of the use of daratumumab during induction. Despite a higher rate of patients requiring PLX for HSC collection and lower CD34 + yields, the incorporation of daratumumab as part of the induction treatment did not negatively impact the possibility to achieve an optimal HSC collection. Our results, along with the lack of chemotherapy-associated toxicity, support the use of a chemotherapy-free HSC mobilization with G-CSF and on-demand plerixafor also in patients receiving daratumumab upfront.

French Monocentric Experience of Outpatient Step-up Dosing of Teclistamab in Relapsed Refractory Multiple Myeloma

Background Teclistamab is the first approved BCMAxCD3 bispecific antibody for relapsed/refractory multiple myeloma and is available in France since October 2022 through a procedure facilitating patient access to innovation addressing high unmet medical needs (Acces Precoce, AP). Given specific toxicities, associated with novel bispecific therapies, including cytokine release syndrome (CRS), inpatient step-up dosing is usually considered. However, the favorable toxicity profile of teclistamab may be conducive to outpatient administration. Our center is already experienced in outpatient stem cell transplantation for newly diagnosed transplant eligible myeloma patients. Here, we report the characteristics and outcomes of patients treated with teclistamab exclusively in an outpatient setting, including the step-up dosing phase. Methods Among the 32 patients who completed the step-up dosing schedule of teclistamab in our center between January 2021 and July 2023, 15 were treated outside of clinical trials and 8 patients received teclistamab exclusively in an outpatient unit. Eligibility for outpatient step-up dose administration was based on (1) clinical and (2) logistical criteria: 1) general condition maintained, no active infection, no high tumor burden or very rapidly progressing disease; 2) patient agreeing to stay within 30 minutes of transportation to the site for 48 hours after each step-up dose and after the first full dose. The 8 eligible patients underwent specific monitoring at home: consisting of measurement of temperature, blood pressure and oxygen saturation by a homecare nurse twice a day for 15 days. Patients and careers were trained in self-monitoring of the CRS and were provided with a blood pressure monitor and an oxymeter. In addition to the regulatory documents of the French AP, patients were given a practical drug information sheet. Oral dexamethasone was available at home in case of emergency with hospital 24-hour contacts in the event of grade ≥ 2 CRS or any other complication. Results In addition to one patient treated in the MajesTEC3 trial, 7 of the 15 patients treated outside clinical trials since January 2023 (47%) were dosed exclusively in outpatient setting. Median age was 69 years (43-81). Isotype of myeloma was FLC in 5/8 patients. Teclistamab was given after a median of 4 previous lines of therapy (3-7). Dose escalation was carried out in accordance with FDA and EMA recommendations after premedication with dexamethasone. CRS was reported in 3 patients (2 grade 1, 1 grade 2 treated with dexamethasone and tocilizumab). No ICANS or infections G ≥ 2 were reported. ORR was VGPR or better in the majority of the patients (6/8). To date, only one patient required an unplanned admission, of 10 days to manage both grade 2 CRS and CMV reactivation occurred simultaneously. There were no toxicity-related deaths. According to local procedures, all the patients received prophylaxis with antibiotics and antivirals as well as polyvalent immunoglobulins. Cost analysis is ongoing and all the data will be updated at the time of the presentation. Conclusion Outpatient teclistamab step-up dose is feasible with careful patient selection and close at home monitoring, and seems associated with similar safety profiles and efficacy outcomes as inpatient treatment. Outpatient management is cost-effective and may help optimize healthcare resource utilization.

High Rates of Thrombotic Events in Newly Diagnosed Multiple Myeloma Patients Enrolled on the Maia Trial

Background. Patients with newly diagnosed multiple myeloma (NDMM) have a nine-fold increased risk of developing venous thromboembolism (VTE). Despite the availability of the IMWG and NCCN VTE prophylaxis guidelines and updated risk stratification models such as SAVED and IMPEDE, the optimal thromboprophylaxis strategy is unknown, especially in the age of modern daratumumab-containing regimens. To continue highlighting the importance of appropriate thromboprophylaxis for patients with NDMM, we performed a post-hoc analysis of the randomized phase 3 MAIA trial to identify rates of venous and arterial thromboembolism. Methods. This retrospective study, carried out under YODA Project #2021-4663, used data from the randomized phase 3 MAIA trial that investigated lenalidomide and dexamethasone (Rd) with or without daratumumab (DRd) in 733 transplant ineligible (TIE) patients obtained from the Yale University Open Data Access (YODA) Project, which has an agreement with JANSSEN RESEARCH & DEVELOPMENT, L.L.C.. Thrombotic events (TE), including both venous and arterial events (V/ATE) were examined with VTE events including deep vein thrombosis (DVT), pulmonary embolism (PE), and superficial thrombophlebitis (SVT). Arterial events (ATE) included cerebrovascular accidents (CVA) defined as hemorrhagic, ischemic, or verebrobasilar strokes. The incidence and time to event of V/ATE were calculated and graded using the CTCAE v4, with Grade 1 representing nonactionable venous thrombosis, Grades 2-4 representing TEs requiring increasing higher levels of medical intervention, and Grade 5 indicating death was a result of the TE. Rates and time to events were compared between the DRd and Rd arms. Results. Of the included patients, median age was 72 years (range 64-72) and 48% were female. There was no signficant difference between baseline characteristics of sex, race, myeloma subtype, presence of high-risk cytogenetics, or ISS staging between patients that experienced a V/ATE event and those that did not. All grade V/ATE events were 18% (66/363) and 19% (70/365) in the DRd and Rd arms, respectively. Of these, most were VTE events in both arms (16%), with G2-4 actionable VTE event rate of 14.9% vs 14.8% for the DRd and Rd arms, respectively. G5 VTE events were 0.2% in both arms (no G5 ATEs). ATE were 2.2% and 2.7% in the DRd and Rd group, respectively, overall constituting a minority of events. The overall PE rate was higher in the DRd than Rd arm, 6.3% vs 4.7%, DVT was more frequent in the Rd arm, 9.6% vs 7.7%, and rates of SVT rates were similar between both arms at 1.9% and 2.2% for the DRd vs Rd arms, respectively (Table 1). Median time to onset of cumulative TEs was longer in DRd vs Rd arm, 7.15 (0.27 - 63.0) vs 4.65 (0.03 - 58.0) months, respectively. Among these, median time to onset of VTE was similar among the groups [6.57 (0.27 - 63.0) vs 4.48 (0.03 - 52.9) months, respectively] while the median time to onset of ATEs was longer in DRd vs Rd arm, 19.8 (1.70 - 26.6) vs 8.3 (0.67 - 58.5) months. The incidence of VTE events persisted past 24 months and incidence of ATE events increased over time (Figure 1). Analysis regarding prophylactic anticoagulation use and rates of TE based on prophylactic regimen are ongoing. Conclusion. This retrospective study reveals the highest reported rates of VTE in any modern therapy dataset. In patients with transplant ineligible NDMM, we show that the TE risk persists past 24 months of treatment in patients on DRd or Rd therapy. Similar to observations in the GRIFFIN trial, the addition of daratumumab did not increase the risk of TE. Our report highlights the critical need for further investigation of optimal prophylactic strategies and their duration for patients with NDMM.

Low Levels of Circulating Tumor Cells Correlate with Favorable Clinical Outcome and Unique Biological Features in Newly Diagnosed Multiple Myeloma Patients

Introduction Circulating tumor cells (CTCs) have been proposed as a prognostic biomarker in newly-diagnosed MM (NDMM) but their low frequency questions their use in clinical practice. Lower CTC levels (cut-off <0.01-0.07%) correlate with a favorable prognostic outcomes in transplant-eligible (TE) patients (pts); however, several issues remain to be addressed. On clinical grounds, it remains unclear whether there is a similar prognostic cut-off value for transplant-ineligible (TI) pts. Furthermore, it is not clear whether the CTCs mimic the characteristics of a single (main)-site bone marrow (ΒΜ) myeloma cells or if they represent the total disease burden, i.e. in cases with extramedullary or macrofocal disease. Moreover, there is limited information of the biological factors that may lead myeloma cells to egress their primary BM site. Methods BM and matched peripheral blood (PB) samples from 550 NDMM pts (210 TE, 340 TI) were evaluated with NGF (median LOD 2.1x10 -6) for the presence of myeloma cells. Various multivariable regression models including CTCs, R-ISS, cytogenetic status and LDH were assessed to define the optimal clinical CTC cut-off. The BM niche profiling was examined with mass cytometry (CyTOF, n=15 pts, 8 with no CTCs, 7 with CTCs higher than the cut-off) and various multicolor flow cytometry panels (n=199 pts including 56 pts with no CTCs) that allowed the detection of 32 distinct immune populations. Results The median value of CTCs was 0.01% of total PB cells (range: 0.0002%-63%) and in 57/550 (10.4%) pts CTCs could not be detected. Increased levels of CTCs correlated with ISS III stage (median: 0.037%, 0.007% and 0.002% for pts with ISS-3, ISS-2 and ISS-1, respectively; p<0.0001), high risk cytogenetics (median: 0.038% vs. 0.006% in standard risk, p<0.0001), and higher levels of b2-microglobulin and BM infiltration. Median follow-up was 41 months (range: 5-66 months). PFS and OS were gradually worsened towards a CTCs log increment, independently of ISS, cytogenetic status and LDH. Hence, pts with undetectable CTCs had the most favorable prognosis with a 5-year PFS and OS of 83% and 97% respectively. The optimal clinical CTCs cut-off that stratified pts into two distinct prognostic groups was defined at the level of 0.02%, which was common for both TE (median PFS: NR in both high and low CTC subsets; p<0.01) and TI subgroups (median PFS: 47 for low vs. 23 months for high CTCs subset, p<0.0001). Importantly, this cut-off, together with the phenotypic classification of pts (MGUS-like, MM-like etc.) could be incorporated in the established R-ISS system, providing an improved ptnts' stratification. The 2-year achievement of MRD negativity was 45%, 67% and 73% for pts with high, low and undetectable CTCs and median time for MRD negativity was 34, 17 and 12 months, respectively (p<0.001). Of note, pts with high CTCs who achieved MRD negativity, modulated their unfavorable risk status and showed similar PFS with those who had low CTCs. In 73/493 (14.8%) pts with detectable CTCs, there was an obvious phenotypic inconsistency between BM myeloma cells and CTCs, either in regard to the relative ratio of the detected (sub)clones, or the appearance of ≥1 phenotypically distinct clonal populations, which were present only in BM or PB. Pts with phenotypic inconsistencies had higher CTC levels and more often diffuse MRI patterns than those with a phenotypic agreement (frequency: 40% vs. 10%; p<0.01). To better understand the heterogeneous dissemination of myeloma cells to PB, we compared the BM niche profiles of pts with high CTC levels (>10 -3) and those with no CTCs. The analyses highlighted clear differences in the BM composition of the two groups with the BM of pts with no CTCs showing significantly lower levels of T cells, NK cells, TAMs and an increased naïve/memory B cell ratio. Of note, no differences were observed in the prevalence of immunosuppressive cell subsets (Tregs, MDSCs) between the two groups. Discussion The presence of CTCs at levels >0.02% confers an adverse prognostic factor for NDMM pts, irrespective of their transplant status. On the contrary, pts with no CTCs have the more favorable outcome and share unique microenvironmental features, which may eliminate CTCs dissemination. Since the liquid biopsy seems to be a better representative of the entire tumor load than a single tissue biopsy, the CTC analysis serves as the new hallmark for the real-time evaluation of a patient's disease and immune status.

Results of the Phase III Randomized Iskia Trial: Isatuximab-Carfilzomib-Lenalidomide-Dexamethasone Vs Carfilzomib-Lenalidomide-Dexamethasone As Pre-Transplant Induction and Post-Transplant Consolidation in Newly Diagnosed Multiple Myeloma Patients

Background. The current standard treatment for transplant-eligible (TE) patients (pts) with newly diagnosed multiple myeloma (NDMM) consists of quadruplet induction with proteasome inhibitors, immunomodulatory agents, dexamethasone and anti-CD38 monoclonal antibody followed by high-dose melphalan and autologous stem-cell transplant (MEL200-ASCT), with subsequent consolidation. The phase III IsKia trial assessed efficacy and safety of isatuximab-carfilzomib-lenalidomide-dexamethasone (IsaKRd) as pre-ASCT induction and post-ASCT consolidation vs KRd. Methods. TE NDMM pts aged <70 years were enrolled and randomized. IsaKRd pts received 4 28-day cycles of Isa: 10 mg/kg IV days 1, 8, 15, 22 cycle 1, followed by 10 mg/kg days 1, 15 cycles 2-4; K: 20 mg/m 2 IV day 1 cycle 1, followed by 56 mg/m 2 IV days 8, 15 cycle 1 and days 1, 8, 15 cycles 2-4; R: 25 mg PO daily days 1-21; d: 40 mg PO days 1, 8, 15, 22; MEL200-ASCT and 4 consolidation cycles with IsaKRd at the same schedule. KRd pts received 4 KRd induction cycles; MEL200-ASCT and 4 KRd consolidation cycles (K, R and d at the same schedule as in the IsaKRd arm). The primary endpoint was the rate of minimal residual disease (MRD) negativity by next-generation sequencing (NGS; 10 -5) after consolidation in the intention-to-treat (ITT) population. MRD was tested in all pts who achieved at least a very good partial response (≥VGPR). Key secondary endpoints were the rate of NGS MRD negativity (10 -5) after induction and PFS. MRD rates were evaluated in an ITT analysis (pts with missing MRD data or who achieved ≤PR were considered as MRD positive). The data cut-off for the analysis was May 22, 2023. Results. 302 pts were enrolled and randomized (151 in both the IsaKRd and KRd arms). Pt characteristics were well balanced between the two arms: median age was 61 vs 60 years, respectively; 18% vs 19% of pts had high-risk (HiR) cytogenetic abnormalities (CA) [del(17p) and/or t(4;14) and/or t(14;16)]; 9% vs 8% had ≥2 HiR CA [double hit; including del(17p), t(4;14), t(14;16) and gain/amp(1q)]. In ITT analysis, the rates of MRD negativity at the 10 -5 cut-off after consolidation (primary endpoint) were 77% vs 67% (OR 1.67; p=0.049) with IsaKRd vs KRd; the respective rates of MRD negativity at the 10 -6 cut-off were 67% vs 48% (OR 2.29; p<0.001); consistent MRD results were detected by next-generation flow. ≥VGPR after consolidation was 94% in both arms; ≥CR 74% vs 72% and sCR 64% vs 67% in the IsaKRd vs KRd arms. The MRD negativity advantage, both at 10 -5 and 10 -6, was retained in all subgroups analyzed ( Figure), with similar benefit in pts with standard-risk (SR) and HiR features. In particular, the 10 -5 MRD negativity rates with IsaKRd were 76% in HiR and 77% in double-hit pts, comparable to the one in SR pts (79%). In the KRd arm, the 10 -5 MRD negativity rates were 58% in HiR and 53% in double-hit pts, inferior to the one in SR pts (70%). The 10 -6 MRD negativity rates with IsaKRd were 72% in HiR, 77% in double-hit pts and 67% in SR pts. The MRD negativity rate after induction (first key secondary endpoint) was also significantly higher with IsaKRd vs KRd (10 -5: 45% vs 26%, OR 2.34, p<0.001; 10 -6: 27% vs 14%, OR 2.36, p=0.004), with a consistent benefit in all subgroups. After induction, the MRD negativity rates in HiR and double-hit pts treated with IsaKRd were: 10 -5, HiR 60%, double-hit 54%; 10 -6, HiR 40%, double-hit 31%. The MRD negativity rates after ASCT were also significantly better with IsaKRd vs KRd (10 -5: 64% vs 49%, OR 1.93, p=0.006; 10 -6: 52% vs 27%, OR 3.01, p<0.001), with a consistent advantage in all subgroups. At the current follow-up (median, 20 months, IQR 18-23), there was no difference in PFS (95% at 1 year in both arms). 55% of pts had ≥1 hematologic adverse events (AEs) with IsaKRd vs 43% with KRd; main grade 3-4 hematologic AEs in IsaKRd vs KRd were neutropenia (37% vs 22%) and thrombocytopenia (15% vs 17%). 41% of pts had ≥1 non-hematologic AEs with IsaKRd vs 37% with KRd, including infections (16% vs 12%), gastrointestinal (7% vs 5%), vascular (2% vs 7%) and cardiac events (1% vs 4%). Discontinuation for toxicity was 6% in IsaKRd vs 5% in KRd arms; treatment-related deaths were 4 with IsaKRd (2 COVID, 1 pneumonia, 1 pulmonary embolism) and 1 with KRd (septic shock). Conclusion. In TE NDMM pts, the addition of isatuximab to KRd induction and consolidation significantly increased MRD negativity rates in every treatment phase as compared to KRd, with no new safety concerns. This benefit was retained in HiR pts.

Post-Transplant Cyclophosphamide Equalizes Clinical Outcomes of Allogeneic Hematopoietic Cell Transplantation across Racial and Ethnic Populations

Background Despite being the only curative option for many hematologic malignancies, allogeneic hematopoietic cell transplant (HCT) has been plagued by health disparities due to differences in access, donor availability, and outcomes across racial and ethnic minority populations (REM) (Gragert, NEJM, 2014). Even when a matched donor is available, HCT outcomes for REM patients are historically worse compared to non-Hispanic white (NHW) patients. (Landry, Stem Cell Investigation, 2021). The development of post-transplant cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis has led to increased use of HLA haploidentical (haplo) or mismatched unrelated donors (MMUD) with comparable outcomes to HLA matched HCT (McCurdy, Advances in Hematology, 2015). While PTCy allows for almost every transplant-eligible REM patient to have a suitable donor, there is limited data evaluating whether this transplant platform results in similar outcomes for REM patients compared to NHW patients. The aim of this study was to investigate if disparities in transplant outcomes still exist between REM patients and NHW patients who received an HLA mismatched transplant with PTCy. Methods We retrospectively analyzed 302 consecutive adult patients who underwent haplo or MMUD HCT with PTCy at Moffitt Cancer Center between 2014 and 2022. All endpoints were compared between four groups: NHW, Hispanic-White, Black, and Other (Asian, biracial, or multiracial.) Results In this cohort, 59% (n=178) of patients identified as NHW, 14% (n=41) as Hispanic-White, 16% (n=48) as Black, 7% (n=21) as biracial or multiracial, and 4% (n=11) identified as Asian. Most patients were male (57%). The median age of all patents was 58. The most common indication for transplant was acute myeloid leukemia (48%), myeloablative conditioning (MAC) was utilized in 42%, and 89% received peripheral blood stem cells grafts. REM patients were more likely to be <65 years of age (60% vs 66-90%, p<0.001), female (36% vs 50-54%, p=0.04), and receive MAC conditioning (33% vs 40-71%, p<0.001). Median follow-up was 21 months. In all clinical outcomes, no significant differences were observed between NHW and REM patients. At day 100, the cumulative incidence of Grade II-IV aGVHD was 37% [95% CI 30-44%] for NHW patients, 32% [95% CI, 18-46%] for Hispanic-White patients, 27% [95% CI, 15-40%] for Black patients, and 26% [95% CI, 13-41%] for patients of Other races (p= 0.38). The cumulative incidence of moderate to severe cGVHD at 2 years was 21% [95% CI 15-28%] for NHW patients, 25% [95% CI, 13-39%] for Hispanic-White, 17% [95% CI, 7.8-29%] for Black, and 27% [95% CI, 13-42%] for patients of Other races (p = 0.80). At 2 years, the probability of relapse was 25% [95% CI 19-32%] for NHW patients, 24% [95% CI, 12-39%] for Hispanic-White patients, 27% [95% CI, 15-40%] for Black patients, and 18% [95% CI, 7.1-33%] for patients of Other races (p = 0.97). During the same time interval, non-relapse mortality (NRM) for NHW patients, Hispanic-White patients, Black patients, and patients of Other races were 19% [95% CI, 13-25%], 15% [95% CI, 5.9-27%], 19% [95% CI, 9.4-32%], and 24% [95% CI, 11-40%] (p = 0.73), respectively. At 2 years, relapse free survival (RFS) was 56% [95% CI 49-64%] for NHW patients, 61% [95% CI, 47-79%] for Hispanic-White patients, 54% [95% CI, 41-71%] for Black patients, and 58% [95% CI, 43-78%] for patients of Other races (p = 0.77). Comparably, OS at 2 years for NHW, Hispanic-White patients, Black patients, and patients of Other races was 64% [95% CI, 57-72%], 72% [95% CI, 60-88%], 53% [95% CI, 40-71%], and 63% [95% CI, 49-83%] respectively after two years (p = 0.92). In multivariate analysis, race/ethnicity had no significant impact on incidence of Grade II-IV aGVHD (p= 0.40), moderate/severe cGVHD (p = 0.80), rates of relapse (p = 0.86), NRM (p= 0.77), RFS (p = 0.69), or OS (p = 0.64) (Table). Conclusions These results show that the use of HLA mismatched donor HCT with PTCy achieves comparable clinical outcomes between REM and NHW patients. Our study suggests that PTCy effectively contributes to equitable healthcare in the setting of allogeneic HCT for REM patients.

Use of Combination Premedication Prior to Motixafortide Administration Reduced Severity and Frequency of AEs in the Phase 3 Genesis Trial - a Single Center Analysis

Background: Motixafortide is a novel, high affinity CXCR4 antagonist with extended receptor occupancy that facilitates the migration of hematopoietic stem and progenitor cells from the bone marrow into the peripheral blood in preparation for autologous stem cell transplantation (ASCT). In prior pre-clinical and clinical studies, motixafortide was associated with transient hypersensitivity and injection site reactions. Strategies to mitigate such adverse events (AEs) commonly include agents with antihistamine activity. The Phase 3 GENESIS trial demonstrated that 88.8% of Multiple Myeloma patients mobilized ≥6x10 6 CD34+ cells/kg (local labs) in 1 leukapheresis procedure (LP) following the administration of 1 dose of motixafortide in combination with GCSF. Per initial protocol, premedication with an antihistamine H1 blocker prior to motixafortide administration was provided to all patients. However, during the course of the GENESIS study a protocol amendment was implemented to include premedication with an antihistamine H1 blocker, an H2 blocker, a leukotriene inhibitor and acetaminophen prior to motixafortide administration. Here we report the safety findings in a cohort of patients at who received single drug premedication with an H1 antihistamine prior to the protocol amendment and those who received the updated combination pre-medication regimen following protocol amendment. Methods:The GENESIS trial was a multicenter, randomized, double-blind, placebo-controlled study in 122 transplant-eligible multiple myeloma patients, as previously described (PMID: 37069359). Included in this analysis are 46 patients enrolled at the Washington University in St. Louis; 32 patients were randomized to the motixafortide treatment arm and 14 patients were randomized to the placebo arm. Among motixafortide-treated patients, 22 received a single-agent H1 blocker pre-medication and 10 received a combination pre-medication regimen comprising of an H1 blocker, an H2 blocker, a leukotriene inhibitor and acetaminophen. All pre-medications were administered within 1 hour prior to motixafortide administration. Hypersensitivity AEs included all events coded to the MedDRA terms of urticaria, pruritus, flushing, erythema, rash, hypersensitivity or anaphylaxis. Injection site reactions included all events coded to the MedDRA High Level Term of Injection Site Reaction. All AEs were graded using CTCAE criteria and were recorded up to 30 days from the last dose of motixafortide. Results: Overall, motixafortide was safe and well tolerated with no episodes of anaphylaxis, no Grade 4 AEs and no deaths. The most commonly observed AEs included transient hypersensitivity and injection site reactions. The frequency of motixafortide-associated hypersensitivity AEs of any grade was reduced from 90.9% with single-agent H1 blocker pre-medication to 20% with the combination pre-medication regimen, similar to the 20-25% rate of hypersensitivity AEs reported in the placebo + GCSF cohort (Table 1). In addition, all hypersensitivity AEs that occurred following combination pre-medication were graded mild in severity (Figure 1). Meanwhile the frequency of injection site AEs of any grade was reduced from 95.5% with single-agent H1 blocker pre-medication to 80.0% with the combination pre-medication regimen (Table 1). Furthermore, a notable improvement in severity of injection site AEs was observed, with moderate-severe injection site AEs reduced from 27% with single-agent H1 blocker pre-medication to 0% with the combination pre-medication regimen (Figure 1). Conclusions:Motixafortide was safe and well tolerated with no episodes of anaphylaxis, no Grade 4 AEs and no deaths. Following implementation of a protocol amendment using combination pre-medication with an antihistamine H1 blocker, an H2 blocker, a leukotriene inhibitor and acetaminophen, the frequency and severity of hypersensitivity and injection site AEs associated with motixafortide were markedly improved.