Teclistamab in combination with daratumumab and lenalidomide in multiple myeloma (MajesTEC-2 study)

Introduction: Combination of daratumumab (Dara) and lenalidomide (Len) may enhance the function of teclistamab (Tec), potentially resulting in improved antimyeloma activity in a broader population. We present initial safety and efficacy data of Tec-Dara- Len combination in patients with multiple myeloma (MM) in a phase 1b study (MajesTEC-2;NCT04722146). Method(s): Eligible patients who received 1-3 prior lines of therapy (LOT), including a proteasome inhibitor and immune-modulatory drug, were given weekly doses of Tec (0.72-or- 1.5 mg/kg with step-up dosing) + Dara 1800 mg + Len 25 mg. Responses per International Myeloma Working Group criteria, adverse events (Aes) per CTCAE v5.0, and for cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) per ASTCT guidelines, were assessed. Result(s): 32 patients received Tec-Dara- Len (0.72 mg/kg, n = 13;1.5 mg/kg, n = 19). At data cut-off (11 July 2022), median follow-up (range) was 5.78 months (1.0-10.4) and median treatment duration was 4.98 months (0.10-10.35). Median age was 62 years (38-75);87.5% were male. Median prior LOT was 2 (1-3), 18.8% were refractory to Dara and 28.1% refractory to Len. CRS was most frequent AE (81.3% [n = 26], all grade 1/2), 95% occurred during cycle1. Median time to onset was 2 days (1-8), median duration was 2 days (1-22). No ICANS were reported. Frequent Aes (>=25.0% across both dose levels) were neutropenia (75.0% [n = 24];grade 3/4: 68.8% [n = 22]), fatigue (43.8% [n = 14];grade 3/4: 6.3% [n = 2]), diarrhoea (37.5% [n = 12];all grade 1/2), insomnia (31.3% [n = 10];grade 3/4: 3.1% [n = 1]), cough (28.1% [n = 9];all grade 1/2), hypophosphatemia (25.0% [n = 8];all grade 1/2), and pyrexia (25% [n = 8];grade 3/4: 6.3% [n = 2]). Febrile neutropenia frequency was 12.5% (n = 4). Infections occurred in 24 patients (75.0%;grade 3/4: 28.1% [n = 9]). Most common were upper respiratory infection (21.9% [n = 7]), COVID-19 (21.9% [n = 7]), and pneumonia (21.9% [n = 7]). Three (9.4%) had COVID-19 pneumonia. One (3.1%) discontinued due to COVID-19 infection and this patient subsequently died of this infection. Overall response rate (ORR, median follow-up) was 13/13 (8.61 months) at 0.72 mg/kg and 13/16 evaluable patients (less mature at 4.17 months) at 1.5 mg/kg. 12 patients attained very good/better partial response at 0.72 mg/kg dose, and response was not mature for 1.5 mg/kg group. Median time to first response was 1.0 month (0.7-2.0). Preliminary pharmacokinetic concentrations of Tec-Dara- Len were similar as seen with Tec monotherapy. Tec-Dara- Len- treatment led to proinflammatory cytokine production and T-cell activation. Conclusion(s): The combination of Tec-Dara- Len has no new safety signals beyond those seen with Tec or Dara-Len individually. Promising ORR supports the potential for this combination to have enhanced early disease control through the addition of Tec. These data warrant further investigation.

Anaplastic extramedullary plasmacytoma resistant to novel therapies: A case report

The treatment of choice for extramedullary plasmacytoma (EMP) is radiotherapy (RT). It is under discussion whether the management of an anaplastic form of EMP requires the addition of systemic therapy. We present a case of a 66-year-old male who was diagnosed with anaplastic plasmacytoma of the maxillary sinus. After the exclusion of multiple myeloma, Dara-VMP (daratumumab, bortezomib, melphalan, and prednisolone) regimen was initiated. During the third cycle of Dara-VMP, a progression of the tumor was observed. RT and BRd (bendamustine, dexamethasone, and lenalidomide) regimen were initiated. After 4 cycles of BRd, disease progression was established. KRd (carfilzomib, lenalidomide, and dexamethasone) regimen was initiated. The first cycle of KRd was not completed, as the patient was diagnosed with COVID-19. After the infection, the progression of EMP was observed. In this case, the anaplastic EMP was resistant to RT and chemotherapy regimens with novel agents, including a monoclonal antibody, an immunomodulatory drug, and proteasome inhibitors. Copyright © 2023 the author(s), published by De Gruyter, Berlin/Boston.

TCR Alpha Beta and CD19+ Depleted Haploidentical Peripheral Stem Cell Transplantation Using Reduced Toxicity Conditioning Regimen with Pharmacokinetics Guided Busulfan, Fludarabine, Thiotepa and Thymoglobulin Offers Durable Donor Engraftment in Children with Primary Immune Deficiency Disorders

Background: Allogeneic hematopoietic cell transplantation (HCT) with ex vivo T cell receptor (TCR) alphabeta+ T cell and CD19+ B cell depletion is an effective approach for children with primary immune deficiency disorders (PIDD) as it combines advantages of high CD34+ cell dose facilitating rapid engraftment with low risk of Graft Versus Host Disease (GVHD). The ideal pre-conditioning regimen that facilitates robust donor engraftment without increasing risk of transplant related mortality has not been well defined with this approach. Method(s): We report the outcomes of 4 pediatric subjects: Chronic Granulomatous Disease (CGD) (2), Wiskott Aldrich Syndrome (WAS) (1), and RAC2 deficient Severe Combined Immunodeficiency (1) who underwent haploidentical HCT with TCRalphabeta+ T cell/CD19+ depletion at Johns Hopkins All Children's Hospital/Moffitt Cancer Center from 2020-2022 (NCT04414046). Pre-conditioning regimen consisted of distal thymoglobulin (7.5 mg/kg), fludarabine (175 mg/m2), thiotepa (10 mg/kg) and pharmacokinetic guided busulfan targeting a cumulative area under curve (cAUC) (65-75 mgxhr/L). Rituximab (200 mg/m2) was administered on day +1. Result(s): The median age at HCT was 51 months (range 10-163 months). All patients received mobilized peripheral blood stem cells from HLA- haploidentical donors (paternal=1, maternal=1 sibling=2). Median busulfan cAUC for all patients was 69 mgxhr/L (range 65-76). Median CD34 and TCR alphabeta T cell dose was 9.13x106 cells/kg (range 7.0-18.9x106) and 0.7x105 cells/kg (range 0.09-1.0x105). Median times to neutrophil and platelet engraftment were 11 days (9-12) and 11 days (range 8-15), respectively. All 4 patients are alive with median follow-up of 19.5 months (range 7-24). One patient developed late VOD without organ dysfunction that resolved with defibrotide. At last follow up, peripheral T and myeloid chimerisms exceeded 90% in all 4 patients. Average time to CD4 recovery (> 200x106/L) was 142 days. Pre-existing inflammatory bowel disease in CGD (n=1) and WAS (n=1) patients resolved immediately following transplant. There was no graft failure, and none developed Grade III-IV acute or extensive chronic GVHD. Patient with WAS developed recurrent autoimmune cytopenias requiring corticosteroids, rituximab, sirolimus and daratumumab, and ultimately resolved. Viral reactivations included EBV (n= 1), adeno (n= 1), HHV6 (n= 2), BK (n=1), norovirus (n=1), and late HSV (n=1), all responded to antivirals without disease. All patients acquired SARS-Cov-2 after transplant and recovered without sequelae. Conclusion(s): TCR alphabeta+ and CD19+ depleted haploidentical transplantation using a reduced toxicity conditioning regimen with pharmacokinetic guided busulfan, fludarabine, thiotepa and thymoglobulin is well-tolerated in young children with PIDD that results in rapid, durable engraftment with low likelihood of GVHD and graft rejection.Copyright © 2023 American Society for Transplantation and Cellular Therapy

A comparison of peripheral blood stem cell collection outcomes for multiple myeloma, mobilization matters in the era of IMiD induction

Collection of peripheral blood stem cells (PBSCs) for autologous stem cell transplant (ASCT) requires mobilization from the bone marrow. There is variation in mobilization choice;during the COVID-19 pandemic BSBMT&CT guidelines recommended using granulocyte-colony stimulating factor (G-CSF) alone to minimize the use of chemotherapy. We report on the impact of mobilization regimen on stem cell collection, and whether IMiD-containing induction therapy impacts on mobilization and consequently transplant engraftment times for 83 patients undergoing ASCT at Leeds Teaching Hospitals. Cyclophosphamide plus G-CSF (cyclo-G) mobilization yielded more CD34+ cells (8.94 vs. 4.88 x106/kg, p = < 0.0001) over fewer days (1.6 vs. 2.4 days, p = 0.007), and required fewer doses of salvage Plerixafor than G-CSF only (13.6% vs. 35%, p = 0.0407). IMiD-containing induction impaired all of these factors. CD34+ doses > 8x106/kg were more frequent with Cyclo-G (62% vs. 11%, p = 0.0001), including for those receiving IMiD 1st line induction (50% vs. 13.3%, p = 0.0381). Note that 92.6% of those receiving IMiD-free inductions were mobilized with Cyclo-G. The novel agents used in modern induction regimens (e.g Daratumumab) have been shown to impair yields, increasing the importance of optimizing mobilization regimens in the first instance. Furthermore, as cellular therapies become established in the management of multiple myeloma emerging data highlights the potential benefits of stem cell top up in the management of the haematological toxicities of these therapies. Our findings support re-adoption of Cyclo-G as the gold standard for mobilization to optimize PBSC harvesting and ensure sufficient cells for subsequent ASCTs.Copyright © 2023 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.

Evolution of Clinical Trials in Oncohematology in a Reference Center: Does It Worth a Dedicated Structure?

Introduction: As part of the reorganization of our outpatient activity in onco-hematology (OH), questions were raised about the relevance of dedicating a specific structure to clinical research in this field. These questions arise all the more so as the proportion of OH clinical trials (CT) in our center has increased from 10% to 45% of all CT between 2000 and 2020. The aim of this study is to assess the evolution of this activity and thus to consider the interest of such a structure. Material(s) and Method(s): A retrospective data review of new CT related to OH in our center from 2016 to 2021 was performed. The evolution of 3 key indicators was assessed: distribution of OH CT among all CT, main OH indications and preferred routes of administration. Results and discussion: Over the period 2016-2021, OH CT represented an average of 32% of newly activated CT corresponding to 34% in 2016 and 48% in 2021 (approximately 90 CT start each year for a total of 420 CT in our center). A short decrease was observed in 2019 and 2020, 25% and 24% respectively, probably related to Covid-19. In terms of sterile preparations, OH represented steadily more than 60% of our activity over the period. The main indications were lymphomas (30%), acute myeloid leukemias (AML - 19%), myelodysplastic syndromes (12%) and CT related to transplant center (12%) in steady distribution overtime. Only new CT in myeloma increased from 7% to 18% in relation with increased subcutaneous (SC) use of daratumumab. Regarding preferred routes of administration, an increased trend in oral and SC routes is observed (respectively 53% and 7% in 2016 vs. 69%and 28% in 2021). The increasing use of SC intensified in 2017 as part of the arrival of AML treatments combining azacitidine (SC) with venetoclax (oral). New CT using the intravenous route decreased from 70% in 2016 to 51% in 2021 even if bispecific antibodies araised in 2021. Focusing in 2021, 1359 visits (772 in day hospital for protocol chemotherapy and 597 for oral treatment) were observed, i.e. 6 patients per day. Conclusion(s): This review showed OH's activity growth in our center. The increasingly frequent use of SC and oral routes requires that patients be fully informed and trained about their own management. In this context, a pharmacist has its place and could best inform patients about the adverse effects of new complex therapies (antibodies, targeted therapy). A unique place, organized and dedicated to clinical research in OH, would allow patients benefiting from a structured and exhaustive support as well as meeting all the healthcare professionals involved and finally ensuring the conditions for optimal care.

Benefits of switching from intravenous to subcutaneous daratumumab: Perspectives from UK healthcare providers.

Daratumumab is a CD38-directed monoclonal antibody indicated to treat multiple myeloma (MM). Daratumumab was initially administered intravenously (IV), subsequently a subcutaneous (SC) formulation was developed to increase convenience of administration. The UK was an early adopter of SC daratumumab and, as such, this report provides consensus recommendations from a group of UK MM experts, with the aim of facilitating the transition from IV to SC daratumumab for other European healthcare providers. The switch from IV to SC daratumumab has been beneficial to patients and healthcare providers, as it simplifies treatment, reduces pressure on hospitals and can improve patients' quality of life.

Leukoencephalopathy During Daratumumab-Based Therapy: A Case Series of Two Patients with Multiple Myeloma.

Leukoencephalopathy in the setting of multiple myeloma (MM) is a rare demyelinating condition, with few reported cases in literature. Daratumumab is a CD38 targeted monoclonal antibody that has been widely used for the management of MM. In the absence of central nervous system (CNS) disease, many medication-induced leukoencephalopathy cases reported with MM, including daratumumab-induced, are associated with progressive multifocal leukoencephalopathy (PML) and John Cunningham (JC) virus. Currently, there are no reported cases of daratumumab-induced leukoencephalopathy among patients without CNS involvement or PML. We discuss 2 patients who developed leukoencephalopathy while receiving daratumumab-based therapy without evidence of PML or CNS disease. Both patients had baseline MRIs without significant white matter changes before daratumumab-based therapy. Patients began experiencing neurological deficits about 6 to 8 months after daratumumab-based therapy initiation. One patient passed away before being assessed for improvement of symptoms with daratumumab cessation. The second patient had some stabilization of symptoms after cessation; however, the leukoencephalopathy remained irreversible. As the class of anti-CD38 monoclonal antibodies expands in MM therapy, we highlight a potential treatment complication and the importance of detecting leukoencephalopathy early among patients receiving anti-CD38 therapy. We recommend vigilant monitoring of any new or worsening neurological symptoms to avoid serious complications of irreversible leukoencephalopathy.

Early Therapy Intensification for High-Risk Waldenström Macroglobulinemia

Introduction: Waldenström macroglobulinemia is an incurable disease, despite advances in the use of targeted therapy. Aim: To assess the effectiveness of intensive induction immunochemotherapy and its combination with targeted drugs and subsequent autologous stem cell transplantation (auto-SCT). Materials and Methods: Twenty-one patients were selected. Four and 17 patients were in the medium- and high-risk groups, respectively. Twelve patients (57%) had hyperviscosity syndrome, 21 (100%) had anemia, 4 (19%) had platelets <100, 4 had hemolysis, 4 (19%) had cryoglobulinemia, 13 (62%) had lymphadenopathy and splenomegaly, 12 had B-symptoms, 11 had LDH >250 U/L, 6 had albumin <30 g/L, and 11 had β-2-microglobulin >4 mg/L. The mean PIgM was 45.3 g/L and Hb was 82 g/L. Sixteen patients (76%) had an L265P mutation in MYD 88 and 2 patients had del -17p. Results: The mean age of the patients was 51.4 years (33–66 years), with 8 women. Four patients underwent 4 courses - R-EPOCH\R - BAC, 17 patients had the R -EPOCH\R - BAC + ibrutinib, and 15 patients had auto-SCT. BEAM was received by 6 patients. BEAM + daratumumab was received by 9 patients. The overall response was 100%, partial response was 100%, very good partial response was 71%, and CR was 32%. At a median follow-up of 44 months, 5-year overall survival was 93% and 5-year progression-free survival was 87%. After 28 months of observation, progression was observed in 1 patient. One patient died in CR from Covid-19 pneumonia. In the group of patients who received immunochemotherapy with ibrutinib and subsequent high-dose consolidation under the Dara - BEAM program, there was a trend towards an increase in the frequency of CR compared with the rest of the patients: 59% and 18%, respectively. Conclusions: R-EPOCH\ R-BAC + ibrutinib + high-dose consolidation + auto-SCT led to deep responses in 71% of patients. Primary intensification makes it possible to implement the concept of “stop” therapy, which makes it cost-effective. The use of high-dose consolidation according to the Dara-BEAM program increases the effectiveness of treatment. We are continuing the study, which will increase the reliability of the results.

DARATUMUMAB CARFILZOMIB LENALIDOMIDE AND DEXAMETHASONE AS INDUCTION THERAPY IN HIGH-RISK TRANSPLANT ELIGIBLE NEWLY DIAGNOSED MYELOMA PATIENTS: RESULTS OF THE PHASE 2 STUDY IFM 2018-04

Background: High-risk (HR) cytogenetic is associated with poor outcome in transplant eligible (TE) newly diagnosed myeloma multiple myeloma (NDMM). The triplet combination carfilzomib lenalidomide and dexamethasone (KRD) plus transplantation demonstrated high efficacy with faorable safety profile in TE-NDMM patients (FORTE). The addition of daratumumab (Dara) to frontline therapy also improed response rate and progression free-surial in TE-NDMM patients (CASSIOPEIA, GRIFFIN). Double transplant also improed outcome of HR TE NDMM patients (EMN02, STAMINA). Aims: The phase 2 trial 2018-04 from the Intergroupe Francophone du Myelome (IFM) is ealuating an intensie strategy with Dara-KRD induction and consolidation plus double transplant in HR TE NDMM (NCT03606577). Methods: HR MM was defined by the presence of del17p, t(4;14) and/or t(14;16). Stategy includes Dara-KRD induction (6 cycles), autologous stem cell transplantation (ASCT), Dara-KRD consolidation (4 cycles), second ASCT, Dara-lenalidomide maintenance. The primary endpoint was the feasibility of this intensie strategy. Here, we report efficacy and safety analysis of Dara-KRD induction. Results: Fifty patients with preiously untreated NDMM were included from july 2019 to march 2021 in 11 IFM centers Median age was 57 (range 38 -65). ISS stage 3 was present in 12 (24%) patients. Based on inclusion criteria, all patients had HR cytogenetic, including 17p deletion (n=20, 40%), t(4;14) (n=26, 52%) or t(14;16) (n=10,20%). Forty-six patients completed Dara-KRD induction. Two patients discontinued treatment due to seere aderse eent (COVID-19 infection, n=1 ;drug-induced hepatitis, n=1) and 2 patients discontinued treatment due to disease progression. Grade 3-4 treatment related aderse eent (>5% of patients) were neutropenia (38%), anemia (14%), thrombocytopenia (8%), infection (6%), renal insufficiency (6%) and deep-ein thrombosis (6%). Two patients (6%) experienced stem-cell collection failure. Oerall response rate was 96%, including 92 % > ery good partial response. Among 37/46 ealuable patients post induction, Minimal Residual Disease negatiity rate (NGS, 10-5) was 62%. Summary/Conclusion: Dara-KRD as induction prior ASCT is safe and allows deep responses in TE NDMM patients with high-risk cytogenetic profile. IFM 2018-04 study is ongoing and longer follow-up is needed to ealuate safety and efficacy of the oerall strategy with Dara-KRD induction and consolidation plus double transplant in this subset of HR patients.

UPDATE AND FOLLOW-UP OF NEWLY DIAGNOSED MULTIPLE MYELOMA (NDMM) WITH HIGH-RISK CYTOGENETIC (HRC)

Background: Despite therapeutic strategies improvement, there is still a subgroup of NDMM patients (pts) that pose a clinical challenge, whose represents a <20%, we refer to HRC. HRC Pts are associated with a poor prognosis and aggressive course, although, recent studies propose different clinical evolution according to the cytogenetic alteration (CA). IMWG identified a 4-year progression free survival (PFS) of 12% and OS of 35%. Aims: Describe our clinical experience and therapeutic management, also the clinical-biochemical alterations at diagnosis in a heterogeneous NDMM HRC's cohort. Evaluate survival curves according to HRC. Methods: Descriptive and retrospective analysis, using clinical and analytical NDMM HRC patient's data from 2009 to 2022 at Guadalajara University Hospital. 61/201 pts were selected in the MM treatment (tto) protocols. FISH results were not found in <30% NDMM, due to lack of metaphases or no request. Pts with t(4;14), t(14;16), gain 1q, t(14;20), plasmablastic leukemia and/or del(17p13) were classified as HRC. Survival data and Pearson (P) correlation were used. P value <0.05 was considered significant. Results: Total HRC NDMM 61 pts were analyzed. 21 of 61 pts (35%) were diagnosed with stage monoclonal gammopathy of undetermined significance (MGUS) prior to HRC NDMM, with a mean 4 years (y) (IR 2-10 y), greater % representation of MGUS were del17p (38), gain 1q (48), t (14;16) (4,5) and del17p + gain1q (9,5). Clinical characteristics data at diagnosis according to HRC are shown in Table 1. Pts receiving 1st line were 100% (61), 90,2% of the pts received bortezomib (V) - based induction, of them 29% (n=16) were treated with alkylating agents, 49,1% (n=27) received IMIDs and 18,2% (n=10) V with dexamethasone (d), plus two of these pts received regimens composed of 3xVCd + 3xVPd and the other dara-VRd. 25 pts (40,98%) were transplant eligible (TPH). 2nd line, 32 pts (52,5%), (n=3) VTD-PACE, (n=6) daratumumab (n=1 alone, 3 R, 1 V, 1 K), (n=1) Kdexa, (n=1) Pocydex and (n=9) V plus 3 IMIDs, 2 alkylating, 2 P or 2 alone and (n=12) IMIDs and alkylatings in combination. 5 pts (8,2) were TPH (1 alogenic). 3rd line, 16 pts (26,2), just 3 pts were TPH. 4th line, 7 pts (11,4), 1 pts were TPH. 5th line, 4 pts (6,5). 6th line, 2pts (3,3). In the last lines, the use of triplets with pomalidomide, karfilzomib or intensive chemotherapy prevail. After a median follow-up of 3 y (IR 1,6-6,2) from diagnosis, pts had relapsed at least one time (60,6%) and more than 3 times (11,5%), and 25 had died (40,9%), 16 of them due to infections (14 bacteremia, 2 COVID), 5 cardiorespiratory arrest and 3 due to progression. (Image 1) represents PFS y OS for only 5 CA, as data were no representative in other CA. Correlation between ISS and ISS-R data were only able to execute in HRC gain1q, due to lack of sample in other CA. We found a P coefficient of 0.568399 or 56.83% (p- <0.00578, CI 95%). Summary/Conclusion: Our case series continues with a longer survival curve compared to those commented in other studies. As cytogenetic abnormalities (t(4;14), t(14;16), t(14;20) and gain1q), similar % of representation are described as Kumar. Nat Rev Clin Oncol. 2018, except for del(17p), 23% vs 10%. From the second line, the probability of receiving a new line, the duration of tto and the interval without tto decreased with each line of tto. As treatment lines progress, therapeutic combinations are more heterogeneous and less concordant. A further longer follow-up and higher HRC NDMM pts's recruitment will be necessary to clarify the response to tto regimens based on individual cytogenetic groups.

RISK AND PATTERN OF INFECTIONS IN NEWLY DIAGNOSED PATIENTS OF MULTIPLE MYELOMA VACCINATED UPFRONT AGAINST PNEUMOCOCCUS & INFLUENZA

Background: Infections contribute to an early mortality risk of 15 percent in newly diagnosed multiple myeloma(NDMM) cases. There is a limited literature on the type of infections in fully vaccinated NDMM patients. Aims: To study epidemiology, clinical profile and predictors of infection in NDMM who are immunised against pneumococci and influenza. Methods: NDMM patients were prospectively studied for 6 months for the pattern of infections . All patients were vaccinated with pneumococcal and Influenza vaccine at diagnosis. PJP prophylaxis and fluconazole prophylaxis was given for patients receiving high dose steroids while acyclovir was given to all. Infections were classified as microbiologically defined, clinically defined and fever of unknown focus according to definitions published by the International Immunocompromised Host Society. Severity of infections were graded according to the NCI CTCAE Ver5. Results: Forty-eight NDMM patients with a median age 55 years comprising of 26 males and 22 females were enrolled. Renal involvement was noted in 42% of enrolled patients and two third of them required renal replacement therapy. ISSIII and R-ISS III were 70.8 % and 62.5 % respectively. 85% had poor performance status(ECOG ≥2) at baseline. RVD was the most common regimen (37%)used. 6 patients received daratumumab based regimen. Treatment response of atleast VGPR was seen in 97 % of NDMM patients. A total of 19 episodes of infections were observed during 6 months. All episodes of infections were reported in the first 45 of myeloma diagnosis(Median 6 days;Range 0-45). Ten of these episodes of infection were diagnosed during the initial evaluation for myeloma defining events. Microbiological diagnosis was possible in 63 %. Commonest infectious agent was COVID 19(n=8) followed by Gram negative bacteria (n=5) viz E.coli and Klebsiella pneumoniae . None of the eight patients who developed COVID 19 infection had received COVID vaccine as they antedated the operationalisation of national guidelines for immunisation. Respiratory and the urinary tract were the most common focus of infection. All critically ill COVID patients succumbed to progressive respiratory failure and all patients with mild and moderate COVID illness recovered uneventfully. Early mortality in our cohort of forty eight patients was twenty percent(n=10). Three fourths of infections in our cohort were Grade≥3 severity. A total of seven deaths were attributable to infectious diseases in this cohort of NDMM patients. Imune paresis was seen in eighty four percent of patients at diagnosis. On follow up at 6 months;immune paresis had persisted in only thirty seven percent. Regression analysis of variables with odds of infection is shown in Table 1 Baseline BMI<18.5 kg/m2;albumin<3g/dl and ISS or R-ISS stage ≥ 2 was found to be have statistically significant odds of predicting infection risk in the cohort of patients. The choice of myeloma regimen, presence of high risk cytogenetics and response to therapy did not correlate with increased odds of infection in our cohort. Summary/Conclusion: Conclusion In this prospective study of NDMM patients vaccinated against pneumococci and influenza at baseline;infection attributable early mortality was 14.5 %. Advanced stage of presentation, hypoalbuminemia and baseline BMI < 18.5 kg/m2 correlated with increased odds of infection. COVID vaccination and COVID appropriate behavioural practices may mitigate COVID related outcomes including deaths in myeloma patients.

Switching to daratumumab SC from IV is safe and preferred by patients with multiple myeloma.

INTRODUCTION: Two phase 3 studies demonstrated superior efficacy of intravenous daratumumab (DARA IV) plus bortezomib/melphalan/prednisone (ALCYONE) or lenalidomide/dexamethasone (Rd; MAIA) versus standard-of-care regimens for transplant-ineligible newly diagnosed multiple myeloma. In these studies, patients could switch from DARA IV to subcutaneous daratumumab (DARA SC) while receiving daratumumab monotherapy in ALCYONE (as of Cycle 11) or daratumumab plus Rd in MAIA. The phase 3 COLUMBA study demonstrated noninferiority of DARA SC to DARA IV. DARA SC reduced administration time, allowing patients to spend less time in healthcare settings, a relevant practical consideration for patient care in the COVID-19 pandemic/settings of limited healthcare resources. METHODS: DARA SC 1800 mg was administered every 4 weeks, per approved dosing schedules. We evaluated safety and patient-reported experience (ALCYONE only) among patients who switched from DARA IV to DARA SC. RESULTS: Fifty-seven patients in ALCYONE and 135 in MAIA switched to DARA SC. Three (2.2%; MAIA) patients reported injection-site reactions, all of which were mild. No infusion-related reactions occurred with DARA SC. In ALCYONE, >80% of patients preferred DARA SC over DARA IV. Grade 3/4 treatment-emergent adverse events (TEAEs) occurred in 5.3% of patients in ALCYONE and 25.9% in MAIA; one (0.7%; MAIA) patient experienced a TEAE with an outcome of death. CONCLUSION: For transplant-ineligible newly diagnosed multiple myeloma, DARA SC (monotherapy/with Rd) was safe and preferred over DARA IV. ClinicalTrials.gov, NCT02195479/NCT02252172.

Retrospective review of outcomes of patients with multiple myeloma with COVID-19 infection (two-center study)

Background: Coronavirus-2 has profound effects on patients (pts) with Multiple myeloma (MM). At the beginning of the pandemic, COVID-19 infection resulted an overall mortality around 54% (cook et al. BMJ 2020). Here, we report an updated morbidity and fatality for MM. Methods: After obtaining IRB approvals from each participating institute, retrospectively, between January 1, 2021 and August 30, 2021, we identified pts with MM and COVID-19 in two myeloma centers (Levine Cancer Institute (LCI) & the University of Kansas medical center (KUMC). Results: We identified 162 MM pts who had COVID- 19 (LCI n=132, UKMC n=30), including 57% males, with median age of 64 years. Current or former smoking reported in 40% of pts. Most pts have associated comorbid conditions: hypertension (45%), hypogammaglobulinemia (32%), CKD (30%), DM (22%), obesity (16.6%), CHF (14%), and CAD (13.5%). Within 3 months prior to infection, treatment included immunomodulatory combinations in 35%, proteasome inhibitors in 28 %, and Daratumumab in 26.5%. Symptoms are summarized in table. 69% had Mild symptoms (no need for hospitalization), 20 % had moderate symptoms (requiring hospitalization), and 9.8% had severe symptoms (ICU level of care). The 18% of pts required oxygen: 6 pts required invasive oxygenation and 3 pts needed vasopressors. The 32% of pts had RRMM, 29.5% on maintenance, and 12% was getting induction. Regarding MM response: >VGPR in 45% and PD in 18%. The 78 pts had ASCT prior to COVID-19 infection: only 3 pts < 1 year and 3 pts < 6 months. MM response or ASCT did not affect hospitalization or mortality.The case fatality rate (CFR) was 6%. In the univariate analysis, CKD, DM, HTN and hepatic dysfunction were associated with an increased risk of hospitalization. However, in multivariate analysis, only CKD, hepatic dysfunction, and Hypogammaglobulinemia significantly increased the risk of admission with only age and lymphopenia were associated with increased COVID-19 related fatatlity. Conclusions: With implementation of center-specific disease control measures and universal screening, pts might have lower case severity and fatality rate than was initially reported.

Major risk factors associated with severe COVID-19 outcomes in patients with multiple myeloma: Report from the National COVID-19 Cohort Collaborative (N3C)

Background: Patients with multiple myeloma (MM), an age-dependent neoplasm of antibody-producing plasma cells, have compromised immune systems due to multiple factors that may increase the risk of severe COVID-19. The NCATS' National COVID Cohort Collaborative (N3C) is a centralized data resource representing the largest multi-center cohort of ∼12M COVID-19 cases and controls nationwide. In this study, we aim to analyze risk factors associated with COVID-19 severity and death in MM patients using the N3C database. Methods: Our cohort included MM patients within the N3C registry diagnosed with COVID-19 based on positive PCR or antigen tests or ICD-10-CM. The outcomes of interest include all-cause mortality (including discharge to hospice) during the index encounter, and clinical indicators of severity (hospitalization/ED visit, use of mechanical ventilation, or extracorporeal membrane oxygenation/ECMO). Results: As of 09/10/2021, the N3C registry included 690371 cancer patients, out of which 17791 were MM patients (4707 were COVID-19+). The mean age at diagnosis was 65.9yrs, 57.6% were >65yo, 46.4% were females, and 21.8% were Blacks. 25.6% had a Charlson Comorbidity Index (CCI) score of ≥2. 55.6% required an inpatient or ED visit, and 3.65% required invasive ventilation. 11.4% developed acute kidney injury during hospitalization. Multivariate logistic regression analysis showed histories of pulmonary disease (OR 2.2;95%CI: 1.7-2.8), renal disease (OR 1.8;95%CI: 1.4-2.4), and black race (p<0.001) were associated with higher risk of severity. Interestingly, smoking status was significantly associated with a lower risk of severity (OR 0.7;95%CI: 0.5-0.9). Further, protective association was also observed between COVID-19 severity and blood or marrow transplant (BMT) (OR 0.52;95%CI: 0.4-0.7), daratumumab therapy (OR 0.64;95%CI: 0.42- 0.99) and COVID-19 vaccination (OR 0.28;95%CI: 0.18-0.44). IMiDs were associated increase in the risk of COVID-19 severity (OR 2.1;95%CI: 1.6-2.7). 2.3% of N3C-myeloma COVID-19+ patients died within the first 10 days, while 4.95% died within 30 days of COVID-19 hospitalization. Overall, the survival probability was 90.5% across the course of the study. Multivariate cox proportional hazard model showed that CCI score ≥2 (HR 4.4;95%CI: 2.2-8.8), hypertension (HR 1.6;95%CI: 1.02- 2.4), IMiD (HR 2.6;95%CI: 1.8-3.8) and proteasome inhibitor (HR 1.6;95%CI: 1.1-2.5) therapy were associated with worse survival. COVID-19 vaccination (HR 0.195;95%CI: 0.09-0.45) and BMT (HR 0.65;95%CI: 0.4-0.995) were associated with lower risk of death. Conclusions: We have identified previously unpublished potential risk factors for COVID-19 severity and death in MM as well as validated some published ones. To the best of our knowledge, this is the largest nationwide study on multiple myeloma patients with COVID-19.

Daratumumab carfilzomib lenalidomide and dexamethasone as induction therapy in high-risk, transplant-eligible patients with newly diagnosed myeloma: Results of the phase 2 study IFM 2018-04

Background: High-risk (HR) cytogenetic is associated with poor outcome in transplant eligible (TE) newly diagnosed myeloma multiple myeloma (NDMM). The triplet combination carfilzomib lenalidomide and dexamethasone (KRD) plus transplantation demonstrated high efficacy with favorable safety profile in TE-NDMM patients (FORTE). The addition of daratumumab (Dara) to frontline therapy also improved response rate and progression free-survival in TE-NDMM patients (CASSIOPEIA, GRIFFIN). Double transplant also improved outcome of HR TE NDMM patients (EMN02, STAMINA). The phase 2 trial 2018-04 from the Intergroupe Francophone du Myelome (IFM) is evaluating an intensive strategy with Dara-KRD induction and consolidation plus double transplant in HR TE NDMM (NCT03606577). Methods: HR MM was defined by the presence of del17p, t(4;14) and/or t(14;16). Stategy includes Dara-KRD induction (6 cycles), autologous stem cell transplantation (ASCT), Dara- KRD consolidation (4 cycles), second ASCT, Dara-lenalidomide maintenance. The primary endpoint was the feasibility of this intensive strategy. Here, we report efficacy and safety analysis of Dara-KRD induction. Results: Fifty patients with previously untreated NDMM were included from july 2019 to march 2021 in 11 IFM centers Median age was 57 (range 38 -65). ISS stage 3 was present in 12 (24%) patients. Based on inclusion criteria, all patients had HR cytogenetic, including 17p deletion (n = 20, 40%), t(4;14) (n = 26, 52%) or t(14;16) (n = 10,20%). Forty-six patients completed Dara-KRD induction. Two patients discontinued treatment due to severe adverse event (COVID-19 infection, n = 1 ;drug-induced hepatitis, n = 1) and 2 patients discontinued treatment due to disease progression. Grade 3-4 treatment related adverse event (> 5% of patients) were neutropenia (38%), anemia (14%), thrombocytopenia (8%), infection (6%), renal insufficiency (6%) and deep-vein thrombosis (6%). Two patients (6%) experienced stem-cell collection failure. Overall response rate was 96%, including 92 % > very good partial response. Among 37 (/46) evaluable patients post induction, Minimal Residual Disease negativity rate (NGS, 10-5) was 62%. Conclusions: Dara-KRD as induction prior ASCT is safe and allows deep responses in TE NDMM patients with high-risk cytogenetic profile. IFM 2018-04 study is ongoing and longer follow-up is needed to evaluate safety and efficacy of the overall strategy with Dara- KRD induction and consolidation plus double transplant in this subset of HR patients.

[Interest of daratumumab in refractory AL amyloidosis in a 96-year-old patient]. / Intérêt du daratumumab dans l'amylose AL réfractaire chez une patiente de 96ans.

Systemic immunoglobulin light-chain (AL) amyloidosis is characterized by deposition of amyloid fibrils of light chains produced by clonal CD38+plasma cells, resulting in organ dysfunction. Cardiac involvement has a major prognostic value. Antiplasma cell chemotherapy reduces the synthesis of immunoglobulin light chains (precursors of amyloid deposits). We describe a case of AL amyloidosis in a 95-year-old patient. Our patient responded poorly to treatment with rituximab, cyclophosphamide-bortezomib-dexamethasone, and rituximab-bendamustine. Finally, the anti-CD38 antibody daratumumab was associated with the best hematologic responsiveness without significant adverse effects. In conclusion, our case suggests that daratumumab is an effective and well-tolerated alternative to chemotherapy in the treatment af AL amyloidosis in very elderly patients.

CARTITUDE-2 UPDATE: CILTACABTAGENE AUTOLEUCEL, A B-CELL MATURATION ANTIGEN-DIRECTED CHIMERIC ANTIGEN RECEPTOR T-CELL THERAPY, IN LENALIDOMIDEREFRACTORY PATIENTS WITH PROGRESSIVE MULTIPLE MYELOMA AFTER 1-3 PRIOR LINES OF THERAPY

Introduction: Ciltacabtagene autoleucel (cilta-cel) is a chimeric antigen receptor T-cell (CAR-T) therapy expressing two B-cell maturation antigen (BCMA)-targeting, single-domain antibodies. The multicohort, open-label, phase 2 CARTITUDE-2 study (NCT04133636) is assessing cilta-cel in patients (pts) with multiple myeloma (MM) under various clinical settings and evaluating the suitability of outpatient administration. Updated results of CARTITUDE-2 cohort A are presented here. Methods: Cohort A pts had progressive MM after 1-3 prior lines of therapy (LOT;included proteasome inhibitor [PI] and immunomodulatory drug [IMiD]), were lenalidomide-refractory, and had no previous exposure to BCMA-targeting agents. A single cilta-cel infusion at a target dose of 0.75×106 CAR+ viable T cells/kg was given 5-7 d after start of lymphodepletion (cyclophosphamide [300 mg/m2] and fludarabine [30 mg/m2] for 3 d). The primary endpoint was minimal residual disease (MRD) negativity at 10-5 at any time point. Secondary endpoints were overall response rate (ORR), duration of response (DOR), time and duration of MRD negativity, and incidence and severity of adverse events (AEs). Response was assessed per International Myeloma Working Group criteria and AEs were graded by Common Terminology Criteria for Adverse Events version 5.0 (cytokine release syndrome [CRS] and immune effector cell-associated neurotoxicity syndrome [ICANS] by American Society for Transplantation and Cellular Therapy). Results: As of April 15, 2021 (median follow-up of 9.7 mo), 20 pts (65% men;median age 60 y [range 38-75]) received cilta-cel, with 1 pt treated in an outpatient setting. Pts had a median of 2 prior LOT (range 1-3);60% had 1-2 prior LOT and 40% had 3 prior LOT. All pts were exposed to a PI, IMiD, and dexamethasone;95% were exposed to alkylating agents and 65% to daratumumab. 95% of pts were refractory to last LOT;40% were triple-class refractory. ORR was 95% (95% CI 75.1-99.9);85% (95% CI 62.1-96.8) had ≥complete response (CR), and 95% (95% CI 75.1-99.9) had ≥very good partial response (Figure). Median time to first response was 1.0 mo (range 0.7-3.3) and median time to ≥CR was 2.6 mo (range 0.9-7.9). Median DOR was not reached;progression-free survival (PFS) at 6 mo was 90% (95% CI 65.6-97.4). Of 13 MRD-evaluable pts, 92.3% (95% CI 64.0-99.8) were MRD-negative at 10-5. Hematologic AEs (≥20% of pts) were neutropenia (95%;grade [gr] 3/4: 95%), thrombocytopenia (80%;gr 3/4: 35%), anemia (75%;gr 3/4: 45%), lymphopenia (65%;gr 3/4: 60%) and leukopenia (55%;gr 3/4: 55%). 95% of pts had CRS (gr 3/4: 10%);median time to onset was 7 d (range 5-9) and median duration was 4 d (range 2-11). Four pts (20%) had CAR-T neurotoxicity (all gr 1/2). Three pts (15%) had ICANS (all gr 1/2);median time to onset was 8 d (range 7-10) and median duration was 3 d (range 1-3). One pt had facial paralysis (gr 2) with time to onset of 29 d and duration of 51 d. No movement and neurocognitive treatment-emergent adverse events (TEAEs) were reported. One death due to COVID-19 was assessed as treatment-related. Safety was manageable in the pt treated in an outpatient setting. Conclusions: A single cilta-cel infusion led to early and deep responses in pts with MM who had 1-3 prior LOT and were lenalidomide-refractory. No movement and neurocognitive TEAEs occurred, suggesting successful implementation of monitoring and pt management strategies across phase 2/3 studies in the CARTITUDE program.

CONTINUOUS THERAPY WITH CARFILZOMIB-LENALIDOMIDE-DEXAMETHASONE (KRD): A MULTICENTRIC EXPERIENCE IN REAL-LIFE

The irreversible proteasome inhibitor Carfilzomib has a proven efficacy in doublet and triplet combinations for the treatment of patients with relapsed or refractory multiple myeloma (RRMM) as shown in the ENDEAVOR and ASPIRE trials. Here we retrospectively analyzed a series of RRMM patients treated with KRd regimen over 18 cycles to evaluate efficacy and tolerability of continuous treatment (Table 1). Data were elaborated using SPSS Statistics Version 26. Overall survival (OS) was calculated from the time of the beginning of treatment until the date of death for any cause or last follow-up visit. Progression free survival (PFS) was defined as the time from the beginning of treatment to documented progression. OS and PFS were analysed by the Kaplan-Meier test. The statistical significance level was set at the 95th percentile. 36 patients were enrolled at one Calabrian and three Sicilian centres on behalf of the Sicilian Myeloma Network from June 2016 to November 2021. 24 of them were on first relapse (66,6%). Median number of cycles was 31.5 (range 18-61). Overall response rate (ORR) at first response to KRd was 92%: 3 patients (8%) achieved a complete response (CR), 14 patients (39%) achieved a very good partial response (VGPR), 16 (45%) achieved PR, 2 (5%) a minimal response (MR) and 1 (3%) had a stable disease (SD). ORR at best response was 97% (56% CR, 30% VGPR, 4% PR), 1 patient (3%) had SD. At last follow up ORR was 53%: (36% CR, 8% VGPR, 8% PR), one (3%) had a SD. Progression disease (PD) occurred in 16 patients (44%), 15 of them were exposed to another treatment, among them 9 patients were exposed to at least two more treatments including novel agents (Daratumumab, Pomalidomide, Belantamab- Mafodotin). Median PFS was not reached and so was median OS calculated from the beginning of KRd. 9 patients (25%) reported grade 3-4 hematological AEs, 13 patients experienced (36%) grade 3-4 nonhematological AEs, only 3 (8%) cardiovascular AEs. Lenalidomide was reduced in 21 (58%), interrupted in 9 (25%) patients due to serious adverse events (SAEs). During Sars-Cov-2 pandemic waves, to reduce hospital admission, 8 patients who achieved at least VGPR continue halved Carfilzomib administration schedule (total dose 27 mg/m2 once every 2 weeks instead of twice) maintaining previous response except for 1 patient who experienced PD (at cycle 32, after one more year of KRD treatment). Real-world experiences often significantly diverge from randomized clinical trials for patients selection resulting into differences in terms of efficacy and tolerability. In our study KRd combination deepened response over time without relevant toxicity as showed also in a subgroup analysis of ASPIRE and ENDEAVOR. In addition, schedule modification during Sars-Cov-2 pandemic reduced the number of hospital admissions without losing quality of response, thus opening the question of which is the best administration regimen of Carfilzomib as maintenance. (Table Presented).

Safety and Efficacy of Apixaban as Thromboprophylaxis in Multiple Myeloma Patients Receiving Chemotherapy: A Prospective Cohort Study

Apixaban 2.5 mg twice-daily replaced low-molecular-weight-heparin as thromboprophylaxis (TP) for multiple myeloma (MM) patients receiving outpatientbased chemotherapy considered to be high-risk of venous thromboembolism (VTE) on 1st November 2019 in our regional centre. This prospective cohort study aimed to assess the safety and efficacy of apixaban as thromboprophylaxis in highthrombotic risk patients with MM. Data were systematically collected from the electronic noting system for service evaluation, retrospectively for the historic cohort (1st Nov 2018-1st Nov 2019) prior to the introduction of the novel thromboprophylactic strategy, and prospectively (1st Nov 2019-1st Nov 2020) following the change of local guidelines to include apixaban as TP in high-thrombotic risk patients with MM. Exclusion criteria included antithrombotic treatment other than thromboprophylaxis or contraindication to thromboprophylaxis such as thrombocytopenia or doxorubicin use (due to possible drug-drug interaction with apixaban leading to reduced levels). Data collected included previous VTE history, thromboprophylactic agent, thrombosis and bleeding events while on chemotherapy. Primary outcomes included thrombotic and bleeding events. Table 1 demonstrates patient characteristics and results. There were 102 MM patients in the historic and 147 in the prospective cohort. VTE prophylaxis was prescribed in 82 out of 102 (80%) of the historic cohort and 114 out of 147 (78%) of the prospective cohort. In patients not prescribed thromboprophylaxis, the chemotherapy regimen contained Daratumumab in 65% in the historic and 76% in the prospective cohort. After the introduction of the amended thromboprophylactic strategy, prescriptions of apixaban increased from 22out of 82 (27%) to 60 out of 114 (53%), while aspirin prescriptions fell from 51out of 82 (62%) to 47 out of 114 (41%). After the introduction of apixaban as recommended thromboprophylaxis for high thrombotic risk patients, thrombotic events reduced from 3% (3/102) to 1.4% (2/147). All thrombotic events (two deep vein thrombosis [DVT], one pulmonary embolism) in the historic cohort occurred despite aspirin as thromboprophylaxis and on a pomalidomidecontaining regimen. In the prospective cohort, the thrombotic events were a proximal DVT while on aspirin TP and a peripherally inserted central catheter (PICC)-associated thrombosis occurring on no TP. There were no thrombotic events in patients receiving prophylactic apixaban in either cohort. There were five bleeding events in the historic cohort. This included one major bleeding event of a traumatic subdural haematoma (on apixaban TP). There were two clinically relevant non-major bleeding (CRNMB): an episode of frank haematuria and a per rectum bleed secondary to haemorrhoids (aspirin as TP), and two minor bleeds. In the prospective cohort, there was one major bleeding event which was a gastrointestinal bleed requiring a two-unit blood transfusion (aspirin as TP). One CRNMB event included haemoptysis secondary to COVID-19 (apixaban as TP) and eight minor bleeding events, two of which occurred on no TP. Overall, major bleeding occurred in 1.2% (1/82) and CRNMB in 1.2% (1/82) patients on prophylactic apixaban across both cohorts. These data add further support to the use of apixaban rather than LMWH as thromboprophylaxis for myeloma patients is considered to be at high thrombotic risk, with very low rates of thrombosis and acceptably low rates of major and CRNMB..

Ciltacabtagene Autoleucel, a BCell Maturation Antigen-Directed Chimeric Antigen Receptor T-Cell Therapy, in Lenalidomide-Refractory Patients With Progressive Multiple Myeloma After 1-3 Prior Lines of Therapy: Updated Results From CARTITUDE-2 Cohort A

Ciltacabtagene autoleucel (cilta-cel) is a chimeric antigen receptor T-cell (CAR-T) therapy expressing two B-cell maturation antigen (BCMA)-targeting, singledomain antibodies. The multicohort, open-label, phase 2 CARTITUDE-2 study (NCT04133636) is evaluating ciltacel in patients (pts) with multiple myeloma (MM) in various clinical settings and assessing the suitability of outpatient administration. Updated results from CARTITUDE-2 cohort A are presented here. Cohort A pts had progressive MM after 1-3 prior lines of therapy (LOT;included proteasome inhibitor [PI] and immunomodulatory drug [IMiD]), were lenalidomide-refractory, and had no previous exposure to agents targeting BCMA. A single cilta-cel infusion at a target dose of 0.75 × 106 CAR+ viable T cells/kg was given 5-7 days after start of lymphodepletion (cyclophosphamide [300 mg/m2 ] and fludarabine [30 mg/m2 ] for 3 days). The primary endpoint was minimal residual disease (MRD) negativity at 10 -5 at any time point. Secondary endpoints were overall response rate (ORR), duration of response (DOR), time and duration of MRD negativity and adverse events (AEs). Response was assessed by International Myeloma Working Group criteria and AEs were graded by Common Terminology Criteria for Adverse Events version 5.0 (cytokine release syndrome [CRS] and immune effector cell-associated neurotoxicity syndrome [ICANS] by American Society for Transplantation and Cellular Therapy). As of April 15, 2021 (median follow-up 9.7 months), 20 pts (65% men;median age 60 years [range 38-75]) received ciltacel, with 1 pt treated in an outpatient setting. Pts had a median of two prior LOT (range 1-3);60% with 1-2 prior LOT and 40% with three prior LOT. All pts were exposed to a PI, IMiD and dexamethasone;95% were exposed to alkylating agents and 65% to daratumumab. 95% of pts were refractory to last LOT;40% were triple-class refractory. ORR was 95% (95% CI 75.1-99.9);85% (95% CI 62.1-96.8) had ≥complete response (CR), and 95% (95% CI 75.1-99.9) had ≥very good partial response. The median time to first response was 1.0 months (range 0.7-3.3) and the median time to ≥CR was 2.6 months (range 0.9-7.9). The median DOR was not reached;progression-free survival (PFS) at 6 months was 90% (95% CI 65.6-97.4). Of MRD-evaluable pts ( n = 13), 92.3% (95% CI 64.0-99.8) were MRD-negative at 10 -5 . Haematological AEs (≥20% of pts) were neutropenia (95%;grade [gr] 3/4: 95%), thrombocytopenia (80%;gr 3/4: 35%), anaemia (75%;gr 3/4: 45%), lymphopenia (65%;gr 3/4: 60%) and leukopenia (55%;gr 3/4: 55%). Ninety-five percent of pts had CRS (gr 3/4: 10%);median time to onset was 7 days (range 5-9) and median duration was 4 days (range 2-11). Four pts (20%) had CAR-T neurotoxicity (all gr 1/2). Three pts (15%) had ICANS (all gr 1/2);median time to onset was 8 days (range 7-10) and median duration was 3 days (range 1-3). One pt had facial paralysis (gr 2) with time to onset of 29 days and duration of 51 days. No movement and neurocognitive treatment-emergent adverse events (TEAEs) occurred. One death occurred due to COVID-19 (assessed as treatment-related). Safety was manageable in the pt treated in an outpatient setting. Lenalidomide-refractory pts with MM and 1-3 prior LOT showed early and deep responses with a single cilta-cel infusion. No movement and neurocognitive TEAEs were reported, suggesting utilisation of successful monitoring and pt management strategies across phase 2/3 studies in the CARTITUDE program.