Matthew Fowler

Results from the LYRA trial (NCT02951819) showed that the combination of daratumumab (Darzalex) with cyclophosphamide, bortezomib, and dexamethasone (CyBorD) induction followed by daratumumab maintenance therapy achieved durable and deep responses in patients with newly diagnosed or relapsed multiple myeloma, regardless of transplant status, according to a presentation given during the 2021 European Hematology Association (EHA) Congress.

The multicenter, single-arm, phase 2 study also produced a safety profile consistent with previously reported data on daratumumab plus CyBorD followed by daratumumab maintenance therapy.

“Daratumumab plus CyBorD induction followed by monthly daratumumab monotherapy maintenance attained deep and durable responses in patients with newly diagnosed or relapsed myeloma,” Robert M. Rifkin, MD, FACP, of the US Oncology Research Network, Rocky Mountains Cancer Centers, in Denver, Colorado, said in his presentation of the data. “The estimated 3-year progression-free survival rate was approximately 70% in newly diagnosed patients, regardless of transplant status.”

A total of 101 patients were enrolled in the study, of whom 86 had newly diagnosed and 14 had relapsed multiple myeloma receiving at least 1 dose of the study treatment. Median follow-up durations were 35.7 months for patients with newly diagnosed and 35.3 months for patients with relapsed multiple myeloma.

At the end-of-study analysis, the overall response rates (ORRs) were 97% in newly diagnosed patients who received a transplant, 83% in newly diagnosed patients who did not receive a transplant, and 86% in relapsed multiple myeloma.

Focusing on newly diagnosed patients with multiple myeloma, those who received autologous stem cell transplant (ASCT) had a very good partial response (VGFR) or better rate of 82.1% and a complete response (CR) or better rate of 48.7% at the end-of-study analysis. For newly diagnosed patients who did not receive a transplant, those rates were 70.2% and 29.8%, respectively.

Patients with relapsed multiple myeloma had a VGPR or better rate of 71.4% by the end of the study, with a CR or better rate of 64.3%.

For newly diagnosed patients regardless of transplant status, the median progression-free survival (PFS) was not reached but estimated rates at 36 months were 69.3% and 72.6% for transplant and non-transplant cases, respectively. The median PFS for patients with relapsed multiple myeloma was 21.7 months.

While median overall survival (OS) rates were not met in any groups, the estimated 36-month OS rates were 94.9%, 84.3% and 50.0% for newly diagnosed patients who received transplant, newly diagnosed patients who did not receive transplant, and patients with relapsed disease, respectively.

Treatment-emergent adverse events (TEAEs) occurring in at least 25% of patients included fatigue (66%), cough (48%), nausea (46%), diarrhea (44%), upper respiratory tract infection (37%), back pain (33%), vomiting (31%), insomnia (30%), dyspnea (30%), constipation (27%), and headache (27%).

Serious TEAEs were reported in 32.6% and 35.7% of patients with newly diagnosed and relapsed disease, respectively. Seven newly diagnosed patients discontinued treatment due to TEAEs, with 1 TEAE leading to death. Patients with relapsed disease had 1 discontinuation, which led to death.

“These data support the recently updated NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®), which, based upon the findings in LYRA, now include daratumumab plus CyBorD as a treatment that may be ‘useful in certain circumstances’ for transplant eligible newly diagnosed multiple myeloma patients and as an ‘other recommended’ therapy for transplant-ineligible newly diagnosed multiple myeloma patients and relapsed multiple myeloma patients,” wrote the investigators in their poster presentation of the data.

The primary analysis of the phase 2 LYRA trial was previously reported after all patients completed 4 cycles of daratumumab plus CyBorD induction therapy. For that analysis, the rate of VGPR or better was 44.2% for patients with newly diagnosed multiple myeloma and 57.1% for patients with relapsed multiple myeloma.

Eligible patients for the LYRA trial were 18 years or older with multiple myeloma defined

by the International Myeloma Working Group criteria, had an ECOG performance score of 0 to 2, and had previously untreated newly diagnosed multiple myeloma or relapsed multiple myeloma which could have been treated 1 time previously.

The eligible population received 4 to 8 cycles of induction therapy of daratumumab plus CyBorD. Specifically, cyclophosphamide 300 mg/m

 was administered orally on days 1, 8, 15, and 22; bortezomib 1.5 mg/m2 was given subcutaneously on days 1, 8, and 15; oral or intravenous (IV) dexamethasone 40 mg was given weekly; daratumumab 8 mg/kg IV was administered on days 1 and 2 of the first cycle, followed by daratumumab 16 mg/kg IV weekly from day 8 of the first cycle through the end of cycle 2, every 2 weeks during cycles 3 to 6, and every 4 weeks thereafter.

The primary end point of the research was the rate of VGPR or better following 4 cycles of daratumumab plus CyBorD induction therapy, with results previously published. Key secondary end points included ORR, time to VGFR or better, time to and duration of response, PFS, and OS at both 1 and 3 years, and safety.

Rifkin RM, Melear J, Faber E, et al. Daratumumab (DARA) Maintenance Therapy Following DARA + Cyclophosphamide, Bortezomib, and Dexamethasone (CyBorD) Induction Therapy in Multiple Myeloma (MM): End-of-Study Analysis of LYRA. Presented at: 2021 European Hematology Association Annual Meeting; June 9-17, 2021; Virtual. Abstract EP969.

Articles

Results from the LYRA trial showed that the combination of daratumumab with cyclophosphamide, bortezomib, and dexamethasone induction followed by daratumumab maintenance therapy achieved durable and deep responses in patients with newly diagnosed or relapsed multiple myeloma, regardless of transplant status.

Daratumumab/CyBorD Followed By Maintenance Leads to Deep Responses in Multiple Myeloma

Daratumumab (Darzalex) plus cyclophosphamide, bortezomib, and dexamethasone (CyBorD) induction followed by daratumumab maintenance therapy achieved durable and deep responses in patients with newly diagnosed or relapsed multiple myeloma, regardless of transplant status, according to data from the LYRA trial (NCT02951819) presented at the 2021 European Hematology Association (EHA) Congress.

The eligible population received 4 to 8 cycles of induction therapy of daratumumab plus CyBorD. Specifically, cyclophosphamide 300 mg/m2 was administered orally on days 1, 8, 15, and 22; bortezomib 1.5 mg/m2 was given subcutaneously on days 1, 8, and 15; oral or intravenous (IV) dexamethasone 40 mg was given weekly; daratumumab 8 mg/kg IV was administered on days 1 and 2 of the first cycle, followed by daratumumab 16 mg/kg IV weekly from day 8 of the first cycle through the end of cycle 2, every 2 weeks during cycles 3 to 6, and every 4 weeks thereafter.

Daratumumab plus cyclophosphamide, bortezomib, and dexamethasone  induction followed by daratumumab maintenance therapy achieved durable and deep responses in patients with newly diagnosed or relapsed multiple myeloma, regardless of transplant status. 

Deep Remission Achieved with Daratumumab Plus CyBorD Followed by Daratumumab Maintenance for Multiple Myeloma

Patients with triple-class exposed relapsed or refractory multiple myeloma demonstrated greater efficacy in terms of response and survival from treatment with ciltacabtagene autoleucel (cilta-cel) in comparison with the standard of care (SOC) in the CARTITUDE-1 trial (NCT03548207), according to findings presented at the 2021 European Hematologic Association (EHA) Congress.

Overall response rate (ORR), complete response (CR) or better rate, progression-free survival (PFS), and overall survival (OS) were all superior with cilta-cel compared with  patients from 3 global trials treated with the anti-CD38 monoclonal antibody daratumumab (Darzalex).

“In the absence of a direct comparison between cilta-cel and treatments used in clinical practice, this analysis demonstrated that cilta-cel offers substantially more clinical benefit than current standard of care therapies for patients with triple-class exposed relapsed and refractory multiple myeloma,” Katja Weisel, MD, of the University Hospital Hamburg, explained in her presentation of the data.

In CARTITUDE-1, eligible patients previously received at least 3 lines of prior therapy, with ECOG performance scores of 0 or 1 and evidence of progressive disease within 12 months of the last line of therapy. The final population of patients from the CARTITUDE-1 trial for this analysis included 97 patients.

The comparative control SOC cohort was comprised of patients from the phase 3 POLLUX (NCT02076009) and CASTOR (NCT02136134) trials and the phase 1b EQUULEUS trial (NCT01998971). A total of 267 patients were included in this cohort since they met the eligibility criteria of the CARTITUDE-1 trial, contributing 378 observations.

The POLLUX study investigated daratumumab plus lenalidomide (Revlimid) and dexamethasone versus lenalidomide and dexamethasone. CASTOR evaluated daratumumab plus bortezomib (Velcade) and dexamethasone versus bortezomib and dexamethasone. The EQUULEUS trial featured daratumumab plus standard multiple myeloma regimens.

Patients in the SOC cohort were treated with physician’s choice of chemotherapy after discontinuing study treatment, with the most common therapies including pomalidomide (Pomalyst; 25.9% of patients), lenalidomide (18%), bortezomib (17.7%), and carfilzomib (Kyprolis; 17.5%).

Median follow-up for patients in the CARTITUDE-1 trial was 18 months and 16.9 months for patients in the SOC population.

Prior to adjusting for a range of clinically important factors, cilta-cel treatment led to a significantly improved ORR at 97.9% compared with SOC ORR at 37.8% (odds ratio [OR], 78.06; 95% CI, 24.20-478.16; 

 < .0001). The same was true for CR or better, finding an 80.4% rate with cilta-cell compared with 1.6% with SOC (OR, 254.53; 95% CI, 105.87-724.78; 

The responses remained true after adjustments to the SOC group, resulting in an ORR of 33.6% (OR, 133.01; 95% CI, 35.71-887.29, 

 < .0001) and CR or better of 0.7% (OR, 754.27; 95% CI, 114.19-35,258.00; 

When examining survival outcomes prior to adjustment, the research found improved PFS and OS for cilta-cel compared with SOC treatment. More, compared with SOC after adjustment, cilta-cel showed a significant reduction in the risk of disease progression or death of about 76%; reduction in the risk of death was about 79%.

Specifically, the median PFS for patients in the SOC group was 5.59 months while the median PFS was just reached for cilta-cel at month 23. More, the OS for patients treated with SOC was 10.9 months, while the median was not reached with cilta-cel.

“Standard of care for patients with triple-class exposed relapsed/refractory multiple myeloma is comprised of a vast and highly heterogeneous set of treatment regimens,” wrote the investigators in their poster presentation of the data. “These analyses provide evidence of superior outcomes with ciltacel versus standard of care in patients with triple-class exposed relapsed/refractory multiple myeloma.”

Weisel K, Martin T, Krishnan A, et al. Comparison of Ciltacabtagene Autoleucel (Cilta-cel) in CARTITUDE-1 Versus Standard of Care in Triple-Class Exposed Multiple Myeloma Patients in Clinical Trials of Daratumumab. Presented at: 2021 European Hematologic Association Congress; Virtual. June 9-17, 2021. Abstract EP977.

Patients with triple-class exposed relapsed or refractory multiple myeloma demonstrated greater efficacy in terms of response and survival from treatment with ciltacabtagene autoleucel in comparison with the standard of care (SOC) in the CARTITUDE-1 trial, according to findings presented at the 2021 EHA Congress.

Cilta-Cel Significantly Improves Responses for Triple-Class Exposed Myeloma Patients

Outcomes for patients with relapsed or refractory multiple myeloma who had previously received a proteasome inhibitor, an immunomodulatory drug (IMiD), and an anti-CD38 monoclonal antibody improved with the use of ciltacabtagene autoleucel (cilta-cel) as compared with conventional therapies, according to findings from propensity score–matched analyses of the CARTITUDE-1 (NCT03548207) and MAMMOTH studies. 

“Our analysis provides evidence of better outcomes with cilta-cel compared with conventional treatments in patients with relapsed/refractory multiple myeloma who had received a proteasome inhibitor, an immunomodulatory drug (IMiD), and an anti-CD38 monoclonal antibody using propensity score matching,” Luciano J. Costa, MD, PhD, of the O’Neal Comprehensive Cancer Center at the University of Alabama at Birmingham, explained in his presentation of the data at the 2021 European Hematologic Association (EHA) Congress.

After 1:1 propensity score matching, the study included 95 patients in the intent-to-treat population (ITT) and 69 patients in the modified ITT (mITT) population from both the CARTITUDE-1 and MAMMOTH trials.

In MAMMOTH, which served as the comparative control group for CARTITUDE-1, patients who received a non–CAR T-cell subsequent therapy after becoming refractory to a proteasome inhibitor, IMiD, and anti-CD38 monoclonal antibody while also not having renal failure or meeting the criteria for plasma cell leukemia were in the ITT population. The mITT population included patients who also did not experience death or progression within 47 days from study inclusion to therapy initiation.

The treatments for patients in MAMMOTH included pomalidomide (34% of patients), anti-CD38 monoclonal antibody (24%), carfilzomib (19%), and cytotoxic chemotherapy (35%) as next therapy.

For CARTITUDE-1, the ITT population was defined as patients who underwent apheresis, while the mITT population consisted of patients who also received a cilta-cel infusion.

The research team found that response and survival rates were significantly higher for patients in the CARTITUDE-1 study than patients in the MAMMOTH study. Focusing on the ITT populations, the overall response rate (ORR) was 84% for the CARTITUDE-1 population compared with 28% in the MAMMOTH population (odds ratio [OR], 13.4; 95% CI, 6.6-27.3; 

Survival data in the ITT populations were also significant for CAR T-cell therapy, with a 12-month progression-free survival (PFS) rate of 73% (95% CI, 64%-83%) for patients in the CARTITUDE-1 population and 12% (95% CI, 6%-21%) for patients in the MAMMOTH population. The 12-month overall survival (OS) rate followed suit, with rates of 83% (95% CI, 76%-91%) and 39% (95% CI, 30%-51%) in the CARTITUDE-1 and MAMMOTH populations, respectively.

The mITT analyses produced similar results to that of the ITT populations. The ORR for these patients was 96% in CARTITUDE-1 compared with 30% in MAMMOTH (OR, 50.3; 95% CI, 14.2-178.3; 

The 12-month PFS rate was 79% (95% CI, 69%-90%) in the CARTITUDE-1 population compared with 15% (95% CI, 7%-28%) in the MAMMOTH population (

 < .001). More, the 12-month OS rates were 88% (95% CI, 81%-96%) and 35% (95% CI, 24%-51%), respectively (

“In propensity score–matched analyses of ITT and mITT populations, ORR and 12-month PFS and OS rates were significantly higher in CARTITUDE-1 vs MAMMOTH,” wrote the investigators in their poster presentation of the data.

The CARTITUDE-1 trial treated patients with multiple myeloma who received 3 or more prior therapies or were double refractory to an IMiD and proteasome inhibitor, and who received a proteasome inhibitor, IMiD, and anti-CD38 monoclonal antibody. Eligible patients received a single cilta-cel infusion of 0.75 × 106 CAR-positive viable T cells/kg, which was given 5 to 7 days after starting lymphodepletion.

Eligible patients with multiple myeloma for the MAMMOTH study were previously treated for 4 or more weeks with an anti-CD38 monoclonal antibody regimen.

While the data are useful, the research team notes that study design differences between CARTITUDE-1 and MAMMOTH limit the results. Specifically, CARTITUDE-1 is a prospective clinical study, while MAMMOTH is retrospective and observational in design.

“In the absence of a direct comparator, however, this analysis indicates that cilta-cel outperforms currently available therapies for heavily pretreated patients with multiple myeloma,” concluded the investigators.

Costa LJ, Lin Y, Martin T, et al. Comparison of Ciltacabtagene Autoleucel Versus Conventional Treatment inPatients With Relapsed/Refractory Multiple Myeloma. Presented at: 2021 European Hematologic Association Congress; Virtual. June 9-17, 2021. Abstract EP990.

Outcomes for patients with relapsed or refractory multiple myeloma who had previously received a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody improved with the use of ciltacabtagene autoleucel as compared with conventional therapies, according to findings from propensity score–matched analyses of the CARTITUDE-1 and MAMMOTH studies. 

Matthew Fowler | Authors

Articles

Daratumumab/CyBorD Followed By Maintenance Leads to Deep Responses in Multiple Myeloma

Deep Remission Achieved with Daratumumab Plus CyBorD Followed by Daratumumab Maintenance for Multiple Myeloma

Cilta-Cel Significantly Improves Responses for Triple-Class Exposed Myeloma Patients

Cilta-Cel Outperforms Conventional Therapies in R/R Multiple Myeloma