Phase 1 Study of Bortezomib, Fludarabine, and Melphalan, With or Without Total Marrow Irradiation, as Allogeneic Hematopoietic Stem Cell Transplant Conditioning for High-risk or Relapsed/Refractory Multiple Myeloma.

OBJECTIVES: We conducted a phase 1 study of a conditioning regimen with or without total marrow irradiation (TMI) before allogeneic hematopoietic stem cell transplantation for patients with high-risk or refractory multiple myeloma. METHODS: Eighteen patients were enrolled on one of 2 strata. Patients with no prior radiation received TMI (900 cGy), fludarabine (FLU), and melphalan (MEL) conditioning, with bortezomib added in the second cohort (stratum I). Patients with prior radiation received FLU, MEL, and bortezomib, without TMI (stratum II). RESULTS: Eight patients were enrolled in the TMI arm (stratum I). One of 3 patients in cohort 1 experienced dose-limiting toxicity (DLT), which led to the expansion to 3 more patients with no DLT. Cohort 2 enrolled only 2 patients due to low accrual, with bortezomib, added at 0.5 mg/m2; neither experienced DLT. Nine patients were enrolled in the non-TMI arm (stratum II). Three patients were enrolled in cohort 1 (bortezomib 0.5 mg/m2) and none experienced DLT. Three were enrolled in cohort 2 (bortezomib 0.7 mg/m2), and 1 experienced DLT; therefore, the cohort expanded to 3 more patients. One more patient experienced DLT. Median overall survival on strata I and II was 44.5 months (95% CI: 1.73-not reached) and 21.6 months (95% CI: 4.1-72.7), respectively. Median progression-free survival on strata I and II was 18.1 months (95% CI: 1.73-not reached) and 8.9 months (95% CI: 2.7-24.4), respectively. CONCLUSIONS: TMI 900 cGy, FLU, and MEL are considered feasible as conditioning for allogeneic stem cell transplantation and may warrant further investigation due to favorable response rates and survival.

Waldenström Macroglobulinemia/Lymphoplasmacytic Lymphoma, Version 2.2024, NCCN Clinical Practice Guidelines in Oncology.

The treatment of Waldenström macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL) has evolved to include several new options. The NCCN Guidelines for WM/LPL provide a framework on which to base decisions regarding diagnosis, treatment, assessment of response to treatment, and follow-up of both newly diagnosed and previously treated WM/LPL.

Multiple Myeloma, Version 2.2024, NCCN Clinical Practice Guidelines in Oncology.

The treatment of relapsed/refractory multiple myeloma (MM) has evolved to include several new options. These include new combinations with second generation proteasome inhibitors (PI); second generation immunomodulators, monoclonal antibodies, CAR T cells, bispecific antibodies, selinexor, venetoclax, and many others. Most patients with MM undergo several cycles of remissions and relapse, and therefore need multiple lines of combination therapies. Selecting treatment options for relapsed/refractory MM requires consideration of resistance status to specific classes, and patient-specific factors such as age and other comorbidities should be considered. The NCCN Guidelines for MM provide a framework on which to base decisions regarding workup, treatment, and follow-up of newly diagnosed and previously treated MM. This manuscript outlines the recommendations from NCCN Guidelines for MM specific to relapsed/refractory disease.

Bendamustine lymphodepletion is a well-tolerated alternative to fludarabine and cyclophosphamide lymphodepletion for axicabtagene ciloleucel therapy for aggressive B-cell lymphoma.

Fludarabine/cyclophosphamide (Flu/Cy) is established for lymphodepletion (LD) prior to standard-of-care CAR T-cell therapy for lymphoma. There is ongoing need to test alternative LD regimens to preserve efficacy, improve safety, and address challenges including the recent national fludarabine shortage. We retrospectively evaluated outcomes among patients with relapsed/refractory aggressive B-cell lymphoma who received bendamustine (n = 27) or Flu/Cy (n = 42) LD before axicabtagene ciloleucel (axi-cel) at our institution. The median change in absolute lymphocyte count from pre-LD to time of axi-cel infusion was -0.6×109 /L in bendamustine cohort and -0.7×109 /L in Flu/Cy cohort. The best overall response/complete response rates were 77.8% (95% CI: 57.7%-91.4%)/48.1% (95% CI: 28.7%-68.1%) among bendamustine cohort and 81.0% (95% CI: 65.9%-91.4%)/50.0% (95% CI: 34.2%-65.8%) among Flu/Cy cohort. Six-month progression-free survival were 43.8% (95% CI: 24.7%-61.3%) and 55.6% (95% CI: 39.0%-69.3%) in bendamustine and Flu/Cy cohorts, while 6-month overall survival were 81.5% (95% CI: 61.1%-91.8%) and 90.4% (95% CI: 76.4%-96.3%), respectively. Relative to Flu/Cy-treated patients, bendamustine-treated patients did not show an increase in hazards associated with experiencing progression/relapse/death (aHR:1.4 [95% CI: 0.7-2.8]; p = .32) or death (aHR:1.6 [95% CI: 0.5-5.6]; p = .46), after adjusting for baseline number of prior therapies and refractory disease. Any grade/grade ≥3 CRS were observed in 89%/3.7% and 86%/4.8% among bendamustine and Flu/Cy cohorts, while any grade ICANS/grade ≥3 ICANS were observed in 30%/19% and 55%/31% respectively. While more Flu/Cy-treated patients experienced grade ≥3 neutropenia compared with bendamustine-treated patients (100% vs. 68%), grade ≥3 infectious complications were comparable (24% vs. 19% respectively). More patients received bendamustine LD and axi-cel as outpatient than Flu/Cy cohort, without increased toxicities and with shorter median inpatient stays. In conclusion, we observed comparable efficacy and lower any grade ICANS among patients receiving bendamustine relative to Flu/Cy LD, followed by axi-cel.

Ciltacabtagene Autoleucel in Patients With Prior Allogeneic Stem Cell Transplant in the CARTITUDE-1 Study.

BACKGROUND: Patients with prior allogeneic stem cell transplant (alloSCT) are typically excluded from trials of chimeric antigen receptor (CAR) T cell therapies, because their engineered cells may include allogeneic T cells. Ciltacabtagene autoleucel (cilta-cel) demonstrated early, deep, durable responses and manageable safety in heavily pretreated relapsed/refractory multiple myeloma patients. We retrospectively analyzed patients who received alloSCT prior to cilta-cel in CARTITUDE-1. PATIENTS AND METHODS: Patients eligible for CARTITUDE-1 were ≥18 years, had ≥3 prior lines of therapy (LOT) or were double refractory to a proteasome inhibitor (PI) and immunomodulatory drug (IMiD) and had received a PI, IMiD, and anti-CD38 antibody. Patients with active graft-versus-host disease (GVHD) or had alloSCT within 6 months before apheresis were excluded. Patients received cilta-cel 5 to 7 days after lymphodepletion. RESULTS: Patients (N = 7) received median 9 prior LOTs (range, 6-14); median time since alloSCT was 5.1 years (range, 2.7-6.2). At median follow-up 27.7 months after cilta-cel infusion, overall response rate was 85.7% (n = 6). The safety profile was generally consistent with patients without alloSCT as prior therapy (cytokine release syndrome, 85.7% vs. 95.6%, respectively; immune effector cell-associated neurotoxicity syndrome, 14.3% vs. 16.7%). One patient with prior alloSCT had grade 3 movement and neurocognitive treatment-emergent adverse events/parkinsonism. No GVHD cases were reported. Two patients died due to adverse events (treatment-related lung abscess; unrelated liver failure). CONCLUSION: Cilta-cel efficacy and safety were comparable between CARTITUDE-1 patients with and without prior alloSCT. Additional studies are needed to fully elucidate the suitability of CAR-T cell therapy in the post-alloSCT setting.

Results of a Phase II Trial of Allogeneic Hematopoietic Stem Cell Transplantation Using 90Y-Ibritumomab Tiuxetan (Zevalin) in Combination With Fludarabine and Melphalan in Patients With High-Risk B-Cell Non-Hodgkin's Lymphoma.

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (alloHCT) is potentially curative for relapsed/refractory (r/r) B-cell non-Hodgkin's lymphoma (B-cell NHL). However, relapse remains a major cause of treatment failure, especially in patients with either positron emission tomography (PET)-positive and/or chemoresistant disease prior to alloHCT. 90Y-ibritumomab tiuxetan (Zevalin) is a radiolabeled anti-CD20 antibody which is a safe and effective therapy in multiple histologic subtypes of B-cell NHL and has also been incorporated in both autologous HCT (autoHCT) and alloHCT conditioning regimens. OBJECTIVES: The purpose of this study was to evaluate the efficacy and confirm the safety of the radiolabeled anti-CD20 antibody ibritumomab tiuxetan (Zevalin) combined with the reduced intensity conditioning (RIC) regimen of fludarabine and melphalan (Flu/Mel) in patients with high-risk B-cell NHL. STUDY DESIGN: We conducted a phase II trial (NCT00577278) of Zevalin with Flu/Mel in patients with high-risk B-cell NHL. We enrolled 41 patients from October 2007 to April 2014, all of whom had either a fully matched sibling or 8/8 or 7/8 matched unrelated donor (MUD). Patients received 111In-Zevalin (5.0 mCi) on day -21 pre-HCT, followed by 90Y-Zevalin (0.4 mCi/kg) on day -14. Fludarabine (25 mg/m2 daily) was given from days -9 to -5 and melphalan (140 mg/m2) was administered on day -4. All patients received rituximab 250 mg/m2 on day +8 and an additional dose on either day +1 or -21 depending on the baseline rituximab level. Patients with a low rituximab level were given rituximab on days -21 and -15. All patients received tacrolimus/sirolimus (T/S) with or without methotrexate (MTX) for graft-versus-host disease (GVHD) prophylaxis starting on day -3, and stem cells were infused on day 0. RESULTS: The 2-year overall survival (OS) and progression-free survival (PFS) for all patients were 63% and 61%, respectively. The incidence of relapse at 2 years was 20%. Nonrelapse mortality (NRM) at day +100 and 1 year were 5% and 12%, respectively. The overall cumulative incidence of grade II-IV and III-IV acute GVHD (aGVHD) were 44% and 15%, respectively. Extensive chronic GVHD (cGVHD) occurred in 44% of patients. On univariate analysis, histology (diffuse large B cell lymphoma (DLBCL) vs. others) was negatively predictive for OS (P = .0013) and PFS (P = .0004), while histology (DLBCL vs. others, P = .0128) predicted for relapse. PET positivity pre-HCT did not correlate with any of the efficacy endpoints. CONCLUSION: Addition of Zevalin to Flu/Mel is safe and effective in high-risk NHL and met the prespecific endpoint. Results were suboptimal in patients with DLBCL.

Use of monoclonal antibody therapy in hematologic patients with mild-to-moderate COVID-19: A retrospective single-center experience.

INTRODUCTION: In November 2020, the FDA issued an emergency use authorization (EUA) for monoclonal antibody (mAb) therapy in patients with mild-to-moderate COVID-19 at high risk for disease progression. METHODS: We retrospectively reviewed 38 adult hematology patients who received mAbs from 11/2020 to 2/2021. RESULTS: Thirty (79%) patients received bamlanivimab and 8 (21%) casirivimab-imdevimab. Four (11%) patients were hospitalized due to COVID-19, two (5%) progressed to severe disease and one patient (3%) died within 30 days from COVID-19 disease. Most patients (n = 34, 89%) ultimately tested negative for SARS-CoV-2, with 34% (n = 13) clearing the virus within 14 days after mAb infusion. The median time to clearance of viral shedding was 25.5 days (range: 7-138). After mAb infusion, most patients with hematological malignancies (HM) (n = 10/15; 67%) resumed therapy for underlying disease with a median delay of 21.5 days (range: 12-42). We observed a significant difference in hospitalization among patients who received a HCT versus non-HCT (0% n = 0/26 and 36% n = 4/11, respectively; p < 0.01). CONCLUSIONS: This study demonstrates that SARS-CoV-2 specific mAb was safe and may reduce hospitalization compared to what is reported in malignant hematology patients at high risk for disease progression. Our HCT cohort patients had less hospitalization rate compared with HM cohort patients.

Systemic Light Chain Amyloidosis, Version 2.2023, NCCN Clinical Practice Guidelines in Oncology.

Primary systemic light chain amyloidosis (SLCA) is characterized by production of light chains that get converted to amyloid fibrils with an affinity for visceral organs and causing organ dysfunction. The therapy for SLCA is directed to recovering the function of the affected organs by targeting the abnormal plasma cell clone and slowing deposition of amyloid fibrils. The NCCN Guidelines for SLCA provide recommendations for workup, diagnosis, and treatment of primary as well as previously treated SLCA.

Ethical Challenges with Multiple Myeloma BCMA Chimeric Antigen Receptor T Cell Slot Allocation: A Multi-Institution Experience.

Chimeric antigen receptor T cell (CAR-T) therapies are Food and Drug Administration (FDA)-approved for patients with triple refractory multiple myeloma (MM). Real-world access to CAR-T therapy remains challenging owing to supply chain limitations impacting manufacturing. The goal of this study was to evaluate the extent of this issue and how major centers are handling the challenges of CAR-T manufacturing slot allocation. MM CAR-T physician leaders at each CAR-T treatment center across the United States were surveyed. We received responses from 17 of 20 centers. A median of 1 slot is allocated per month per center, and the median number of patients per center on the waitlist since the FDA's approval of idecabtagene vicleucel is 20 (range, 5 to 100). As a result, patients remain on the waitlist for a median of 6 months (range, 2 to 8 months) prior to leukapheresis. For patient selection, all centers reported using a committee of experienced CAR-T physicians to ensure consistency. To ensure transparency, 15 centers make selection criteria, selection timelines, and priority scores readily available for CAR-T providers. Centers also reported using ethical values for selection: (1) equal treatment: time spent on waiting list (n = 12); (2) priority to the worst-off: limited therapeutic options (n = 14), MM burden (n = 11), high Hematopoietic Cell Transplantation Comorbidity Index (n = 5); (3) maximize benefit: most likely to complete apheresis (n = 13) or infusion (n = 13) or to achieve response (n = 8); and (4) social value: younger patients (n = 3). Maximizing benefit was considered the most important criterion by 10 centers. This study is the first attempt to evaluate existing issues with CAR-T access for patients with MM and the variability and challenges in patient selection. Integrating ethical resource allocation strategies, similar to those described here, into formal institutional policies would help streamline access to CAR-T therapy and protect the needs of both current and future patients and physicians.

Allogeneic BCMA-targeting CAR T cells in relapsed/refractory multiple myeloma: phase 1 UNIVERSAL trial interim results.

ALLO-715 is a first-in-class, allogeneic, anti-BCMA CAR T cell therapy engineered to abrogate graft-versus-host disease and minimize CAR T rejection. We evaluated escalating doses of ALLO-715 after lymphodepletion with an anti-CD52 antibody (ALLO-647)-containing regimen in 43 patients with relapsed/refractory multiple myeloma as part A of the ongoing first-in-human phase 1 UNIVERSAL trial. Primary objectives included determination of the safety and tolerability of ALLO-715 and the safety profile of the ALLO-647-containing lymphodepletion regimen. Key secondary endpoints were response rate and duration of response. Grade ≥3 adverse events were reported in 38 (88.0%) of patients. Cytokine release syndrome was observed in 24 patients (55.8%), with 1 grade ≥3 event (2.3%) and neurotoxicity in 6 patients (14%), with no grade ≥3 events. Infections occurred in 23 patients (53.5%), with 10 (23.3%) of grade ≥3. Overall, 24 patients (55.8%) had a response. Among patients treated with 320 × 106 CAR+ T cells and a fludarabine-, cyclophosphamide- and ALLO-647-based lymphodepletion regimen (n = 24), 17 (70.8%) had a response including 11 (45.8%) with very good partial response or better and 6 (25%) with a complete response/stringent complete response. The median duration of response was 8.3 months. These initial results support the feasibility and safety of allogeneic CAR T cell therapy for myeloma.

Patient Perceptions Regarding Ciltacabtagene Autoleucel Treatment: Qualitative Evidence From Interviews With Patients With Relapsed/Refractory Multiple Myeloma in the CARTITUDE-1 Study.

INTRODUCTION: Ciltacabtagene autoleucel (cilta-cel), a novel chimeric antigen receptor T (CAR-T) cell therapy, has demonstrated early, deep, and durable clinical responses in heavily pretreated patients with relapsed/refractory multiple myeloma (RRMM), and improvements in health-related quality of life (HRQoL) in CARTITUDE-1 (NCT03548207). Patient perspectives on treatment provide context to efficacy outcomes and are an important aspect of therapeutic evaluation. METHODS: Qualitative interviews were conducted in a subset of CARTITUDE-1 patients (n = 36) at screening, Day 100, and Day 184 post cilta-cel on living with MM, therapy expectations, and treatment experiences during the study. RESULTS: Patients most wanted to see change in symptoms with the greatest impact on HRQoL: pain (85.2%) and fatigue (74.1%). The primary treatment expectation was achieving remission (40.7%), followed by extended life expectancy (14.8%). Patients most often defined meaningful change as improvement in symptoms (70.4%) and return to normalcy (40.7%). The percentage of patients reporting symptoms (pain, fatigue, bone fracture, gastrointestinal, neuropathy, and weakness) decreased from 85.2% to 22.2% across symptom types at baseline to 29.2% to 0% on Day 184 after cilta-cel. Improved symptoms and positive sentiments corresponded with improved perception of overall health status and reduced pain level, respectively. Most patients reported that their expectations of cilta-cel treatment had been met (70.8%) or exceeded (20.8%) at Day 184, and 70.8% of patients considered cilta-cel therapy better than their previous treatments. CONCLUSION: Overall HRQoL improvements and qualitative interviews showed cilta-cel met patient expectations of treatment and suggest the long treatment-free period also contributed to positive sentiments.

Ciltacabtagene Autoleucel, an Anti-B-cell Maturation Antigen Chimeric Antigen Receptor T-Cell Therapy, for Relapsed/Refractory Multiple Myeloma: CARTITUDE-1 2-Year Follow-Up.

PURPOSE: CARTITUDE-1, a phase Ib/II study evaluating the safety and efficacy of ciltacabtagene autoleucel (cilta-cel) in heavily pretreated patients with relapsed/refractory multiple myeloma, yielded early, deep, and durable responses at 12 months. Here, we present updated results 2 years after last patient in (median follow-up [MFU] approximately 28 months), including analyses of high-risk patient subgroups. METHODS: Eligible patients had relapsed/refractory multiple myeloma, had received ≥ 3 prior lines of therapy or were double refractory to a proteasome inhibitor and immunomodulatory drug and had received prior proteasome inhibitor, immunomodulatory drug, and anti-CD38 therapy. Patients received a single cilta-cel infusion 5-7 days after lymphodepletion. Responses were assessed by an independent review committee. RESULTS: At a MFU of 27.7 months (N = 97), the overall response rate was 97.9% (95% CI, 92.7 to 99.7); 82.5% (95% CI, 73.4 to 89.4) of patients achieved a stringent complete response. Median duration of response was not estimable. Median progression-free survival (PFS) and overall survival (OS) were not reached; 27-month PFS and OS rates were 54.9% (95% CI, 44.0 to 64.6) and 70.4% (95% CI, 60.1 to 78.6), respectively. Overall response rates were high across all subgroups (95.1%-100%). Duration of response, PFS, and/or OS were shorter in patients with high-risk cytogenetics, International Staging System stage III, high tumor burden, or plasmacytomas. The safety profile was manageable with no new cilta-cel-related cytokine release syndrome and one new case of parkinsonism (day 914 after cilta-cel) since the last report. CONCLUSION: At approximately 28 months MFU, patients treated with cilta-cel maintained deep and durable responses, observed in both standard and high-risk subgroups. The risk/benefit profile of cilta-cel remained favorable with longer follow-up.

Health-related quality of life in patients given ciltacabtagene autoleucel for relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b-2, open-label study.

BACKGROUND: CARTITUDE-1 is a phase 1b-2 study evaluating ciltacabtagene autoleucel (cilta-cel), a chimeric antigen receptor T cell therapy with two B-cell maturation antigen-targeting single-domain antibodies, in patients with relapsed or refractory multiple myeloma. Primary efficacy outcomes have previously been reported. Here, we report health-related quality of life (HRQOL) secondary outcomes evaluated using patient-reported outcomes. METHODS: This single-arm, open-label, phwase 1b-2 study was done at 16 centres in the USA. Patients were aged 18 years or older with diagnosis of multiple myeloma and Eastern Cooperative Oncology Group performance status of 1 or less with three or more previous lines of therapy, or were double refractory to a proteasome inhibitor and immunomodulatory drug, and had received a proteasome inhibitor, immunomodulatory drug, and anti-CD38 antibody. A single cilta-cel infusion (target dose 0·75 × 106 CAR+ T cells per kg) was administered 5-7 days after lymphodepletion. Patient-reported outcomes were assessed using the European Organisation for Research and Treatment of Cancer (EORTC) quality of life questionnaire core 30-item, pre-specified items from the EORTC myeloma module, and EuroQol five-dimensional descriptive system questionnaire. Clinically meaningful changes in patient-reported outcomes were defined by anchor-based minimally important differences. This trial is registered with ClinicalTrials.gov, NCT03548207. This trial is completed but feeding into a long-term follow-up study. FINDINGS: Between July 16, 2018, and Oct 7, 2019, 78 patients were enrolled and underwent apheresis in phase 2 of the study. 68 patients were treated (43 [63%] male, 49 [72%] White), and their patient-reported outcomes assessed (median follow-up 16·9 months, IQR 15·7-17·5). After infusion, a transient decline was observed, followed by improvements in global health status (mean change from baseline to day 464 +8·0 points, SD 20·9), physical (+4·6 points, 21·1), and emotional functional scales (+1·9 points, 23·7) over time, and declines for symptom-based scores (-14·1 pain, SD 31·5 and -15·4 fatigue; SD 29·5), indicating improved patient HRQOL following treatment with cilta-cel. INTERPRETATION: These durable HRQOL improvements are consistent with clinical findings, in which a single cilta-cel infusion led to substantial and durable responses in heavily pre-treated patients with relapsed or refractory multiple myeloma. These results support the use of cilta-cel in patients with relapsed or refractory multiple myeloma. FUNDING: Janssen Research & Development and Legend Biotech USA.

NCCN Guidelines® Insights: Multiple Myeloma, Version 3.2022.

The NCCN Guidelines for Multiple Myeloma provide recommendations for diagnosis, initial workup, treatment, follow-up, and supportive care for patients with various plasma cell neoplasms, including multiple myeloma. These NCCN Guidelines Insights highlight some of the important updates/changes specific to the treatment of patients with multiple myeloma in the 2022 version of the guidelines.

Filanesib plus bortezomib and dexamethasone in relapsed/refractory t(11;14) and 1q21 gain multiple myeloma.

Filanesib is a first-in-class kinesin spindle protein inhibitor which demonstrated safety and encouraging activity in combination with bortezomib and dexamethasone in relapsed/refractory multiple myeloma in a preliminary analysis of dose-escalation phase results. This multicenter study included first a dose-escalation phase to determine maximum tolerated dose of two schedules of filanesib, bortezomib, and dexamethasone and a subsequent dose-expansion phase using the maximum tolerated doses. In the dose-expansion phase, 28 patients were evaluable for safety and efficacy. The most common grade ≥3 adverse events were neutropenia (21%) and anemia (18%), which were noncumulative and reversible, and hypertension (18%). The overall response rate was 43% with median duration of response not yet reached (range, 2.8-23.7+ months) with median follow-up of 6.3 months. A post hoc analysis incorporated 29 dose-escalation phase patients who received therapeutic filanesib doses, with an overall response rate of 39% and median duration of response of 18.0 months among the 57 total patients with median progression-free survival of 8.5 months. Notably, the PFS of high risk patients was comparable at 8.5 months, driven by the patients with 1q21 gain, characterized by increased MCL-1 expression, with a PFS of 9.1 months versus 3.5 months for the remainder of high risk patients. Patients with t(11;14) also had an encouraging PFS of 15.0 months. The combination of filanesib, bortezomib, and dexamethasone continues to show safety and encouraging activity in relapsed/refractory multiple myeloma, particularly in those patients with 1q21 gain and t(11;14).

Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b/2 open-label study.

BACKGROUND: CARTITUDE-1 aimed to assess the safety and clinical activity of ciltacabtagene autoleucel (cilta-cel), a chimeric antigen receptor T-cell therapy with two B-cell maturation antigen-targeting single-domain antibodies, in patients with relapsed or refractory multiple myeloma with poor prognosis. METHODS: This single-arm, open-label, phase 1b/2 study done at 16 centres in the USA enrolled patients aged 18 years or older with a diagnosis of multiple myeloma and an Eastern Cooperative Oncology Group performance status score of 0 or 1, who received 3 or more previous lines of therapy or were double-refractory to a proteasome inhibitor and an immunomodulatory drug, and had received a proteasome inhibitor, immunomodulatory drug, and anti-CD38 antibody. A single cilta-cel infusion (target dose 0·75 × 106 CAR-positive viable T cells per kg) was administered 5-7 days after start of lymphodepletion. The primary endpoints were safety and confirmation of the recommended phase 2 dose (phase 1b), and overall response rate (phase 2) in all patients who received treatment. Key secondary endpoints were duration of response and progression-free survival. This trial is registered with ClinicalTrials.gov, NCT03548207. FINDINGS: Between July 16, 2018, and Oct 7, 2019, 113 patients were enrolled. 97 patients (29 in phase 1b and 68 in phase 2) received a cilta-cel infusion at the recommended phase 2 dose of 0·75 × 106 CAR-positive viable T cells per kg. As of the Sept 1, 2020 clinical cutoff, median follow-up was 12·4 months (IQR 10·6-15·2). 97 patients with a median of six previous therapies received cilta-cel. Overall response rate was 97% (95% CI 91·2-99·4; 94 of 97 patients); 65 (67%) achieved stringent complete response; time to first response was 1 month (IQR 0·9-1·0). Responses deepened over time. Median duration of response was not reached (95% CI 15·9-not estimable), neither was progression-free survival (16·8-not estimable). The 12-month progression-free rate was 77% (95% CI 66·0-84·3) and overall survival rate was 89% (80·2-93·5). Haematological adverse events were common; grade 3-4 haematological adverse events were neutropenia (92 [95%] of 97 patients), anaemia (66 [68%]), leukopenia (59 [61%]), thrombocytopenia (58 [60%]), and lymphopenia (48 [50%]). Cytokine release syndrome occurred in 92 (95%) of 97 patients (4% were grade 3 or 4); with median time to onset of 7·0 days (IQR 5-8) and median duration of 4·0 days (IQR 3-6). Cytokine release syndrome resolved in all except one with grade 5 cytokine release syndrome and haemophagocytic lymphohistiocytosis. CAR T-cell neurotoxicity occurred in 20 (21%) patients (9% were grade 3 or 4). 14 deaths occurred in the study; six due to treatment-related adverse events, five due to progressive disease, and three due to treatment-unrelated adverse events. INTERPRETATION: A single cilta-cel infusion at the target dose of 0·75 × 106 CAR-positive viable T cells per kg led to early, deep, and durable responses in heavily pretreated patients with multiple myeloma with a manageable safety profile. The data from this study formed the basis for recent regulatory submissions. FUNDING: Janssen Research & Development and Legend Biotech.