This information is intended for US healthcare professionals to access current scientific information about Janssen products. It is prepared by Janssen Medical Information and is not intended for promotional purposes, nor to provide medical advice.
SUMMARY
- LEGEND-2 was a first-in-human, phase 1, single-arm, open-label study evaluating the safety and efficacy of LCAR-B38M chimeric antigen receptor T (CAR-T) cells in patients with relapsed/refractory multiple myeloma (RRMM).1,2
- A total of 74 patients with RRMM were treated across 4 centers in China (57 patients at the Xi’an site; 17 patients each at the Ruijin, Changzheng and Jiangsu sites).2
- ≥5-Year Follow-Up
- At a median follow-up of 65.4 months (≥5 years after the last patient was dosed), treatment-emergent adverse events (TEAEs) were reported by all patients during the first month of treatment. Cytokine release syndrome (CRS) was the most common TEAE, occurring in 91.9% of patients.3
- Median progression free survival (PFS) and median overall survival (OS) were 18.0 and 55.8 months, respectively. The 5-year PFS and 5-year OS rates across all treated patients were 21.0% (95% confidence interval [CI], 12.2-31.4) and 49.1% (95% CI , 37.2-60.0), respectively.3
- The median duration of response (DOR) was 23 months.3
- 4-Year Follow-Up
- At a median follow-up of 47.8 months, grade ≥3 adverse events (AEs) occurred in 60.8% of patients: most commonly, leukopenia (25.7%), aspartate aminotransferase (AST) elevation (20.3%), and thrombocytopenia (18.9%). CRS occurred in 91.9% of patients, of which most were of grade 1 (47.3%) and grade 2 (35.1%).2
- Median PFS and median OS across all treated patients were 18.04 months and not estimable (NE), respectively. The 24-month OS across all treated patients was 63.4-months.2
- The median DOR was 23.26 months.2
- The efficacy of LCAR-B38M was evaluated in a subgroup of 22 patients with RRMM and extramedullary disease (EMD) at a median follow-up of 47.8 months. In patients with EMD vs without EMD, ORR was 81.8% vs 90.4% and complete response (CR) was 54.5% vs 80.8%.2
CLINICAL DATA
LEGEND-2 (clinicaltrials.gov identifier: NCT03090659) was an investigator-initiated, first-in-human, phase 1, single-arm, open-label study evaluating the safety and efficacy of LCAR-B38M CAR-T cells in 74 patients with RRMM. The study was conducted at 4 sites in China (57 patients at the Xi’an site; 17 patients at the Ruijin [n=5], Changzheng [n=3] and Jiangsu [n=9] sites).2,4
Study Design/Methods
- Key inclusion criteria: patients aged 18-80 years, International Myeloma Working Group (IMWG) diagnosis of multiple myeloma (MM) with documented disease progression ≤12 months of most recent anti-MM medication treatment or autologous hematopoietic stem-cell transplant, ≥3 prior lines of therapy.2,4
- Lymphodepletion and dosing: each study site had its own protocol for lymphodepletion and variable CAR-T infusion methods (split vs single infusion).2,4
- Lymphodepletion was performed using cyclophosphamide 300 mg/m2 or cyclophosphamide 250 mg/m2 plus fludarabine 25 mg/m2. LCAR-B38M CAR-T cells were infused over 3 split infusions (n=65) or as a single infusion (n=9).2,4
- Xi’an site: patients received cyclophosphamide 300 mg/m2 daily for 3 days on days -5 to -3. Patients received split infusions of LCAR-B38M CAR-T cells on day 1, 3, and 7 (20%, 30%, and 50% of the total dose, respectively) administered over 7 days.2,4
- Ruijin and Changzheng sites: patients received cyclophosphamide 250 mg/m2 plus fludarabine 25 mg/m2 daily for 3 days on days -5 to -3. Patients received split infusions of LCAR-B38M CAR-T cells on day 0, 3, and 6 (20%, 30%, and 50% of the total dose, respectively).2,5
- Jiangsu site: patients received cyclophosphamide 300 mg/m2 day daily for 3 days on days -5 to -3. Patients received single dose infusions of LCAR-B38M CAR-T cells on day 0.2,5
- CAR-T cells were successfully manufactured for all patients and infused at a median dose of 0.513 × 106 cells/kg (range, 0.07-2.10x106). Some patients received a below-target dose of LCAR-B38M.2
- Primary objective: safety of LCAR-B38M CAR-T cells2,4
- Secondary objective: antimyeloma activity based on IMWG response criteria.2,4
Patient Characteristics
- Overall, 74 patients (Xi’an site, n=57; Rujin site, n=5; Changzhen site, n=3; and Jiangsu site, n=9) who underwent leukapheresis were included.2
- At the clinical cut-off date of May 25, 2021, 39 patients were continuing the study, 34 patients had died, and 1 patient was lost to follow-up.2
- Baseline patient demographics and disease characteristics of 74 patients enrolled in the study have been presented in Table: LEGEND-2: Baseline Patient Demographics and Clinical Relevance.
LEGEND-2: Baseline Patient Demographics and Clinical Relevance3
|
|
|
|
|
---|
Median age, years (range)
| 54.5 (27-74)
| 52.5 (35-68)
| 55.0 (27-74)
| 0.5654
|
ECOG performance status, n (%)
|
0
| 30 (40.5)
| 8 (66.7)
| 22 (35.5)
| 0.0144
|
1
| 32 (43.2)
| 1 (8.3)
| 31 (50.0)
|
2
| 12 (16.2)
| 3 (25.0)
| 9 (14.5)
|
Myeloma subtype, n (%)
|
IgG
| 33 (44.6)
| 9 (75.0)
| 24 (38.7)
| 0.0206
|
IgA
| 21 (28.4)
| 3 (25.0)
| 18 (29.0)
| 1.0000
|
IgD
| 1 (1.4)
| 0
| 1 (1.6)
| 1.0000
|
Kappa
| 7 (9.5)
| 0
| 7 (11.3)
| 0.5901
|
Lambda
| 12 (16.2)
| 0
| 12 (19.4)
| 0.1953
|
ISS staging, n (%)
|
I
| 33 (44.6)
| 8 (66.7)
| 25 (40.3)
| 0.3824
|
II
| 14 (18.9)
| 1 (8.3)
| 13 (21.0)
|
III
| 21 (28.4)
| 3 (25.0)
| 18 (29.0)
|
Unknown
| 6 (8.1)
| 0
| 6 (9.7)
|
Durie-Salmon system, n (%)
|
IIA
| 8 (10.8)
| 2 (16.7)
| 6 (9.7)
| 0.5751
|
IIB
| 1 (1.4)
| 0
| 1 (1.6)
|
IIIa
| 3 (4.1)
| 0
| 3 (4.8)
|
IIIA
| 44 (59.5)
| 7 (58.3)
| 37 (59.7)
|
IIIB
| 9 (12.2)
| 0
| 9 (14.5)
|
Unknown
| 9 (12.2)
| 3 (25.0)
| 6 (9.7)
|
Extramedullary plasmacytoma, n (%)
|
Yes
| 22 (29.7)
| 0
| 22 (35.5)
| 0.0139
|
No
| 52 (70.3)
| 12 (100.0)
| 40 (64.5)
|
Cytogenetic abnormalities, n
| 42
| 8
| 34
|
|
Standard risk, n (%)
| 9 (21.4)
| 1 (12.5)
| 8 (23.5)
| 0.6622
|
High risk, n (%)
| 33 (78.6)
| 7 (87.5)
| 26 (76.5)
|
t(4;14)
| 5 (11.9)
| 1 (12.5)
| 4 (11.8)
| |
t(14;16)
| 0
| 0
| 0
| |
t(14;20)
| 0
| 0
| 0
| |
del(17p)
| 11 (26.2)
| 2 (25.0)
| 9 (26.5)
| |
gain(1q)
| 29 (69.0)
| 7 (87.5)
| 22 (64.7)
| |
Double-hitb
| 10 (23.8)
| 3 (37.5)
| 7 (20.6)
| |
Triple-hitc
| 1 (2.4)
| 0
| 1 (2.9)
| |
Serum β2-microglobulin (mg/L)
|
Mean (SD)
| 5.8 (4.7)
| 4.1 (2.4)
| 6.1 (4.9)
| 0.1039
|
Median (range)
| 3.9 (1.7-31.7)
| 3.7 (1.9-9.0)
| 4.3 (1.7-31.7)
|
Time from initial MM diagnosis (years)
|
Mean (SD)
| 3.9 (2.1)
| 3.5 (2.2)
| 4.0 (2.0)
| 0.3445
|
Median (range)
| 4.0 (1-9)
| 3.0 (1-9)
| 4.0 (1-9)
|
Number of prior lines of therapy, n (%)
|
Mean (SD)
| 3.2 (1.8)
| 2.8 (1.5)
| 3.3 (1.8)
| 0.2797
|
Median (range)
| 3.0 (1-9)
| 2.0 (1-6)
| 3.0 (1-9)
|
Median total CAR-T cells, ×106/kg, range
| 0.5 (0.1-2.1)
| 0.4 (0.2-1.6)
| 0.5 (0.1-2.1)
| 0.7204
|
Infusion mode, n (%)
|
Unfractionated infusion
| 9 (12.2)
| 0
| 9 (14.5)
| 0.3392
|
Fractionated infusion
| 65 (87.8)
| 12 (100.0)
| 53 (85.5)
|
Preconditioning therapy, n (%)
|
Cyclophosphamide
| 66 (89.2)
| 8 (66.7)
| 58 (93.5)
| 0.0204
|
Fludarabine + cyclophosphamide
| 8 (10.8)
| 4 (33.3)
| 4 (6.5)
|
Abbreviations: CAR, chimeric antigen receptor; ECOG, Eastern Cooperative Oncology Group; Ig, immunoglobulin; ISS, International Staging System; MM, multiple myeloma; PD, progressive disease; SD, standard deviation. aThe Duric-Salmon staging of the 3 patients could not be further stratified due to unavailability of serum creatinine levels at baseline. b,cMM disease having any 2 of the high-risk cytogenetic abnormalities including t(4;14), t(14;16), t(14;20), del(17p), and gain(1q) is defined as double-hit MM and having any 3 as triple-hit MM. Note: P values were calculated by t-test or Fisher’s exact test.
|
≥5-Year Follow-Up
Xu et al (2024)3 reported the results from the entire population of the LEGEND-2 study at a longer median follow-up of 65.4 months; ≥5 years after the last patient was dosed.
Results
Safety
- All patients experienced TEAEs during the first month of treatment.
- Grade 3/4 neutropenia and thrombocytopenia were observed in 85.3% and 58.8% of patients.
- Six months after the infusion, 47.3%, 44.6%, and 59.5% of patients reached normal leukocyte, hemoglobin, and platelet levels, with median values of 4.7×109/L, 125.3 g/L, and 155.0×109/L, respectively.
- Grade 3/4 hepatic disorder was observed in 38.3% of patients.
- The median levels of AST and alanine aminotransferase (ALT) were 21.0 U/L and 18.5 U/L, respectively.
- There were no significant differences in hematologic and hepatic function recovery between the non- progressive disease (PD) and PD/death groups.
- CRS was the most common TEAE, occurring in 91.9% of patients (n=68); resolving within 30 days post CAR-T cell infusion for most patients.
- Extended CRS was reported in 3 patients which lasted 31, 37, and 51 days, respectively, with no second wave observed.
- Transient Grade 1 immune effector cell-associated neurotoxicity syndrome (ICANS) was reported by 1 patient.
- One patient died by suicide after a psychiatric disorder developed following myeloma progression, with no signs of movement and neurocognitive TEAEs.
- Patients in CR with a normal Ig level did not report serious infections.
- Virus reactivation or infection was noted beyond 6 months of follow-up without severe complications.
- Herpes zoster virus was reported in 3 patients and hepatitis B virus in 1 patient; all recovered with antiviral treatment and Ig administration.
- Of 19 surviving patients with a history of coronavirus disease 2019 (COVID-19), 6 tested negative, and 13 were infected between 2020 and 2022.
- All 13 infected patients had mild symptoms like fever, cough, and fatigue lasting 1-3 days, with no COVID-19 related pneumonia or deaths reported.
- By the cutoff date, 4 patients developed secondary primary malignancies (SPM) of the lung, esophagus, and cervix 8-32 months after LCAR-B38M treatment.
- All patients achieved myeloma remission with no detectable concurrent hematologic malignancies; 3 patients died of SPM.
- One patient, cured of cervical cancer, had a multiple myeloma relapse 50 months after the infusion and achieved CR after bortezomib and lenalidomide treatment.
Efficacy
- As of November 30, 2022, a total of 33 patients (44.6%) were alive; of which, 12 patients (16.2%) were in remission without relapse.
- The longest observed remission was 6.4 years.
- A total of 62 patients experienced PD (n=53 [after partial response or better (≥PR)]) or death.
- A total of 32 patients died due to PD, while 9 patients died due to non-relapse-related events.
- A total of 21 patients with PD had survived after receiving subsequent treatments.
- Median PFS and median OS were 18.0 and 55.8 months, respectively.
- For patients who achieved CR and minimal residual disease (MRD)-negative CR, the median PFS was prolonged to 28.2 and 30.6 months, respectively. Median OS was not reached for those patients.
- For patients who did not achieve ≥CR, the median PFS was 4.4 months and median OS was 7.9 months.
- Median PFS, OS, and DOR in patients achieving CR and MRD-negative CR is presented in Tables: LEGEND-2: PFS, OS, and DOR in Patients With or Without CR and MRD-Negative CR.
- The 5-year PFS and 5-year OS rates across all treated patients were 21.0% (95% CI, 12.2-31.4) and 49.1% (95% CI , 37.2-60.0), respectively.
- The 5-year PFS and 5-year OS rate among the 65 responders were 23.6% and 55.9%, respectively.
- The 5-year PFS and 5-year OS rates of the 54 CR patients were 28.4% and 65.7%, both being significantly higher than those without achieving CR (P<0.0001).
- A total of 24.0% of the MRD-negative responders (12/50) remained in deep remission with sustained responses at data cut off.
- Median DOR for all patients was 23 months, and for MRD-negative responders vs other responders, it was 32.7 months vs 7.5 months (P<0.0001).
- Patients with longer time to best response (≥3.3 months) had longer PFS (P=0.006) and OS (P=0.001) compared with those achieving best response within 3.3 months.
LEGEND-2: PFS, OS, and DOR in Patients With or Without CR and MRD-Negative CR6 |
|
|
|
|
---|
| 28.16 (19.98-38.74)
| 4.44 (1.97-7.85)
| 30.55 (20.76-47.44)
| 6.44 (2.33-8.25)
|
P-Valuea
| <0.0001
| <0.0001
|
| NE (60.29-NE)
| 7.87 (3.84-14.23)
| NE (60.29-NE)
| 9.23 (5.16-16.30)
|
P-Valuea
| <0.0001
| <0.0001
|
| -
| -
| 32.69 (22.34-49.05)
| 7.46 (2.00-8.61)
|
P-Valuea
| -
| <0.0001
|
Abbreviations: CI, confidence interval; CR, complete response; mDOR, median duration of response; mOS, median overall survival; mPFS, median progression-free survival; MRD, minimal residual disease; NE, not estimable. aP value is based on the log-rank test. bIf the patient had only the month and year available for the death date, disease progression date, and subsequent therapy date, day 15 is used for imputation. cIf the patient had only the month and year available for the death date, day 15 is used for imputation.
|
Immunogenicity
- Among the 26 patients achieving CR with available Ig data, 21 had serologically normal Ig levels; the Ig levels of 1 patient normalized at 5.4 years and those of the remaining 20 patients normalized within 5 years.
- The median time to full Ig restoration was 16.7 months, with the earliest recovery observed at 9.1 months post infusion. All patients who remained relapse-free had serum Ig recovery.
- The 5-year OS rate for the 21 CR patients with full Ig recovery was 100%, which was not significantly different from the five patients with abnormal Ig levels (P=0.14).
- Disease relapse occurred at 68.3-, 69.5-, and 62.4-months post infusion in 3 patients who had achieved MRD-negative CR, respectively.
- One patient developed extramedullary lesion without detectable tumor in bone marrow, and 2 patients had an increased level of monoclonal paraprotein. All proceeded with subsequent therapies.
Pharmacokinetics/Pharmacodynamics
- During the observation period up to 180 days post CAR-T cell infusion, the average circulating lymphocyte counts peaked between 14 and 28 days and gradually declined after 1 month.
- Although the non-PD cohort exhibited higher average lymphocyte count peaks compared with PD/death patients during CAR-T cell expansion, a high peak level of LCAR-B38M did not correlate with CR or sustained remission in the 16 patients with available transgene data.
- The prognostic relevance of long duration of the transgene persistence (Tlast) is presented in Table: LEGEND-2: Prognostic Relevance of Tlast.
- As of the cut-off date, CAR-T cells remained detectable in 1 patient who had maintained MRD-negative CR for 5.6 years at the last follow-up.
LEGEND-2: Prognostic Relevance of Tlast3
|
|
|
|
---|
Best response
| 53
|
|
|
VGPR or better
| 47
| 421.0 (389.78)
| 0.032
|
PR or worse
| 6
| 141.8 (193.07)
|
Time to best response
| 51
|
|
|
<3.3 months
| 25
| 261.6 (389.89)
| 0.001
|
≥3.3 months
| 26
| 535.3 (333.81)
|
Long-term outcome
| 53
|
|
|
Durable remission
| 9
| 541.1 (593.63)
| 0.372
|
Progression or death
| 44
| 358.3 (324.25)
|
Abbreviations: PR, partial response; SD, standard deviation; Tlast, transgene persistence; VGPR, very good partial response. aP values were calculated by Wilcoxon rank-sum test.
|
4-Year Follow-Up
Zhao et al (2022)2 reported the results from the entire population of the LEGEND-2 study at a median follow-up of 47.8 months (range, 0.4-60.7).
Results
Safety
- All patients experienced ≥1 acute AEs within 100 days after infusion and grade ≥3 AEs were reported in 45 patients (60.8%). See Table: LEGEND-2: Summary of AEs Occurring in ≥15% of Patients.
- CRS occurred in 68 patients (91.9%). The median time to CRS onset was 9 days (range, 1-19) and median duration of CRS was 9 days (range, 3-57).
- The maximum CRS grade observed in patients was: grade 1: 47.3%, grade 2: 35.1%, grade 3: 8.1%, grade 4: no events, grade 5: 1 event.
- CRS was managed using tocilizumab (44.6%), oxygen supply (36.5%), and vasopressor therapy (9.5%).
- Symptom resolution occurred in 66 patients but persisted in 2 patients.
- Reversible grade 1 central nervous system (CNS) toxicity manifested by aphasia, agitation, and seizure-like activity was reported in 1 patient. No patient reported signs or symptoms of parkinsonism.
- The most common chronic AE observed was B cell aplasia.
- Viral activation was reported in 4 patients (herpes zoster virus infection [n=3; at 7, 26, and 46 months after infusion, respectively] and hepatitis B virus activation [n=1; at 7 months after infusion). All viral infections resolved with antiviral drug therapy and supporting treatment.
- Second primary non-hematologic tumors with undetectable myeloma cells were reported in 4 patients. All cases were considered unrelated to LCAR-B38M therapy.
- Lung cancer was diagnosed at 8 months after infusion in 1 patient who underwent surgery followed by chemotherapy, but eventually died of pneumonia.
- Lung cancer was detected at 32 months after infusion in 1 patient who survived.
- Esophageal cancer developed at 15 months after infusion in 1 patient who eventually died.
- Cervical cancer was reported at 8 months after infusion in 1 patient who responded to standard anti-tumor treatment.
- In total, 34 deaths were reported. The causes of deaths were as follows:
- Disease progression (n=28)
- CRS and tumor lysis syndrome (n=1, day 13)
- Pulmonary embolism and potential acute coronary syndrome (n=1, day 22)
- Respiratory failure associated with subsequent therapy (n=1, day 436)
- Esophageal carcinoma (n=1, day 493)
- Infection (n=2, days 157 and 529, respectively)
LEGEND-2: Summary of AEs Occurring in ≥15% of Patients2
|
|
---|
|
|
---|
Any AE
| 74 (100)
| 45 (60.8)
|
Hematologic
|
Leukopenia
| 32 (43.2)
| 19 (25.7)
|
Thrombocytopenia
| 31 (41.9)
| 14 (18.9)
|
Anemia
| 22 (29.7)
| 11 (14.9)
|
Non‑hematologic
|
Pyrexia
| 68 (91.9)
| 11 (14.9)
|
Increased AST
| 28 (37.8)
| 15 (20.3)
|
Hypotension
| 14 (18.9)
| 4 (5.4)
|
Increased ALT
| 13 (17.6)
| 0
|
Cough
| 13 (17.6)
| 1 (1.4)
|
CRS
| 68 (91.9)
| 7 (9.5)a
|
Neurotoxicity
| 1
| 0
|
Abbreviations: AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CRS, cytokine release syndrome. aOne patient died 13 days after treatment due to grade 5 CRS.
|
Efficacy
- Efficacy outcomes are summarized in Table: LEGEND-2: Best Responses in All Patients. Survival outcomes are summarized in Table: LEGEND-2: Survival Outcomes. The median times to initial response and best response were 1.02 months (range, 0.43.5) and 3.32 months (range, 0.43-28.52) respectively.
- CR rates were comparable between patients with high vs standard cytogenetic risk (80% vs 66.7%) and no significant difference was observed in survival outcomes.
- ORR and CR rates were comparable among various subgroups differentiated by age, time from disease diagnosis to CAR-T cell therapy, disease stage, number of prior therapies, and prior proteasome inhibitor (PI)/immunomodulatory drug exposure.
- The longest PFS without maintenance treatment was 60 months (observed in a patient with λ light-chain-type MM and extensive EMD).
- PD developed in 43 of 65 patients who had achieved ≥PR. The median OS of patients with PD was 36.14 months (95% CI, 21.13-NE).
- Death was reported in 22 patients with PD. The median OS in the 21 surviving patients was 19.68 months after receiving subsequent line of therapy.
LEGEND-2: Best Responses in All Patients2
|
|
---|
ORRa, %
| 87.8
|
CR
| 54 (73)
|
MRD-negativeb
| 50 (67.6)
|
VGPR
| 5 (6.8)
|
PR
| 6 (8.1)
|
| 5 (6.8)
|
| 1 (1.4)
|
| 3 (4.1)
|
Abbreviations: CR, complete response; CRS, cytokine release syndrome; MRD, minimal residual disease; NE, not evaluable; ORR, overall response rate; PD, progressive disease; PR, partial response; SD, stable disease; TLS, tumor lysis syndrome; VGPR, very good partial response. aIncludes patients with ≥PR. b8-color flow cytometry with cell count up to 500,000 cells. MRD negativity was assessed at a sensitivity threshold of 10-4. cOne patient died of pulmonary embolism/acute coronary syndrome prior to evaluation, 1 patient died on day 13 due to CRS and TLS, and 1 patient received chemotherapy prior to first assessment and was censored.
|
LEGEND-2: Survival Outcomes2
|
|
|
|
---|
Median OS (95% CI), months
| NE (24.44-NE)
| NE (NE-NE)
| 7.87 (3.84-14.23)
|
24-month OS, %
| 63.4
| 77.5
| 25.0
|
Median PFS (95% CI), months
| 18.04 (10.61-25.56)
| 28.16 (19.91-38.74)
| 4.44 (1.97-7.85)
|
Median DOR (95% CI), months
| 23.26 (13.04-32.69)
| 29.14
| 5.03
|
Abbreviations: CI, confidence interval; CR, complete response; DOR, duration of response; NE, not evaluable; OS, overall survival; PFS, progression-free survival.
|
Pharmacokinetics/Pharmacodynamics
- The median Tlast was 280 days (range, 81466).
- Patients with Tlast >280 days had a longer OS than patients with Tlast <280 days (P=0.010); however, no such correlation was observed with PFS or DOR.
- No significant difference was detected in Tlast between the cyclophosphamide + fludarabine (n=7) vs cyclophosphamide alone (n=46) groups. Although the number of patients were small and not proportional; overall Tlast did not differ between patients with and without PD (287.5 vs 231 days; P=0.921).
- Serum soluble B-cell maturation antigen (sBCMA) was detected in all of the 47 evaluable patients. A mean decrease of 94.2% from baseline was observed in 37 patients.
- The median time to nadir sBCMA was 155 days (range, 3-1444).
- sBCMA levels rebounded higher in 11 evaluable patients who relapsed vs 14 evaluable patients who did not relapse (median 38,909 pg/mL vs 17,357.5 pg/mL, P=0.002).
- Patients with >80% decline in sBCMA from baseline had a longer OS (P<0.001) and PFS (P=0.01) than patients with a mild decrease in sBCMA.
- No correlation between sBCMA levels and DOR was observed.
- Positive antidrug antibodies (ADAs) were reported in 34 of 55 (62%) evaluable patients with the mean time to ADA positivity being 229.6 days (range, 13-905).
- The appearance of ADAs was less frequent in the cyclophosphamide + fludarabine group compared to the cyclophosphamide alone group (28.6% vs. 66.7%).
- No significant difference was observed in ADA positivity between single-dose infusion (66.7%) and split infusion (60.9%).
- No difference in median Tlast was observed between patients with (n=32) vs without (n=18) ADA positivity (339 vs 137 days, P=0.104).
- The presence of ADAs had no impact on DOR, PFS, or OS.
Clinical Data - Subgroup Analysis: Patients with RRMM and EMD
Zhao et al (2022)2 conducted a subgroup analysis of patients with vs without EMD in the LEGEND-2 study at a median follow-up of 47.8 months.
Results
- Of the 74 study patients, 22 patients (Xi’an site, n=17; East China, n=5) had baseline EMD, including EMD not adjacent to bone (n=15; 2 of whom had concomitant plasma cell leukemia) and bone-based EMD (n=7).
- No significant differences were observed in gender, age, or number of prior lines of therapy in patients with EMD vs without EMD. However, in patients with EMD, the light-chain MM subtype was more frequent than the immunoglobulin G (IgG) or immunoglobulin A (IgA) subtypes.
- Efficacy outcomes by EMD status are summarized in Table: Efficacy Outcomes by EMD Status.
- Extramedullary relapse was reported in 18 of 22 patients with baseline EMD, of whom 1 patient died due to infection, 1 patient was nonresponsive to LCAR-B38M, and 2 patients have not relapsed.
Efficacy Outcomes by EMD Status2
|
|
|
---|
ORR, %
| 81.8
| 90.4
|
CR, %
| 54.5
| 80.8
|
Median PFS (95% CI, P value), months
| 8.9 (5.85-10.61)
| 26.58 (56.8-81.5, P<0.001)
|
Median OS (95% CI), months
| 14.28 (8.87-29.27)
| NR (NA)
|
Abbreviations: CI, confidence interval; CR, complete response; EMD, extramedullary disease; NA, not available; NR, not reached; OS, overall survival; ORR, overall response rate; PFS, progression-free survival.
|
Literature Search
A literature search of Ovid MEDLINE®, Embase®, BIOSIS Previews®, and Derwent Drug File (and/or other resources, including internal/external databases) was conducted on 03 July 2024.
1 | Zhao WH, Liu J, Wang BY, et al. A phase 1, open-label study of LCAR-B38M, a chimeric antigen receptor T cell therapy directed against B cell maturation antigen, in patients with relapsed or refractory multiple myeloma. J Hematol Oncol. 2018;11(1):141. |
2 | Zhao WH, Wang BY, Chen LJ, et al. Four-year follow-up of LCAR-B38M in relapsed or refractory multiple myeloma: a phase 1, single-arm, open-label, multicenter study in China (LEGEND-2). J Hematol Oncol. 2022;15(1):86. |
3 | Xu J, Wang BY, Yu SH, et al. Long-term remission and survival in patients with relapsed or refractory multiple myeloma after treatment with LCAR-B38M CAR T cells: 5-year follow-up of the LEGEND-2 trial. J Hematol Oncol. 2024;17(1):23. |
4 | Wang B, Zhao W, Liu J, et al. Long-term follow-up of a phase 1, first-in-human open-label study of LCAR-B38M, a structurally differentiated chimeric antigen receptor T (CAR-T) cell therapy targeting B-cell maturation antigen (BCMA), in patients (pts) with relapsed/refractory multiple myeloma (RRMM). presented at: 61st American Society of Hematology (ASH) Annual Meeting & Exposition; December 7-10, 2019; Orlando, FL. |
5 | Chen L, Xu J, Fu W, et al. Updated phase 1 results of a first-in-human open-label study of LCAR-B38M, a structurally differentiated chimeric antigen receptor T (CAR-T) cell therapy targeting B-cell maturation antigen (BCMA). Poster presented at: 61st American Society of Hematology (ASH) Annual Meeting & Exposition; December 7-10, 2019; Orlando, FL. |
6 | Xu J, Wang BY, Yu SH, et al. Supplement to: Long-term remission and survival in patients with relapsed or refractory multiple myeloma after treatment with LCAR-B38M CAR T cells: 5-year follow-up of the LEGEND-2 trial. J Hematol Oncol. 2024;17(1):23. |