Lenalidomide-refractory Multiple Myeloma Research Articles

Efficacy of CARVYKTI in CARTITUDE-4 versus other conventional treatment regimens for lenalidomide-refractory multiple myeloma using inverse probability of treatment weighting.

Aim: The phase III randomized controlled trial (RCT) CARTITUDE-4 (NCT04181827) demonstrated superiority of CARVYKTI (ciltacabtagene autoleucel; cilta-cel) over daratumumab, pomalidomide and dexamethasone (DPd) and pomalidomide, bortezomib and dexamethasone (PVd) for relapsed/refractory multiple myeloma (RRMM) patients who have received one to three prior line(s) of therapy (LOT[s]) including an immunomodulatory agent and a proteasome inhibitor, and are refractory to lenalidomide. These analyses estimate the relative efficacy between cilta-cel and other common treatment regimens, for which no direct comparative evidence is available. Materials & methods: Patient data were available from the CARTITUDE-4, CASTOR, CANDOR and APOLLO RCTs. Imbalances between cohorts on key patient characteristics were adjusted for using inverse probability of treatment weighting (IPTW). Relative efficacies were estimated with response rate ratios (RRs) and 95% confidence intervals (CIs) for overall response rate (ORR), very good partial response or better rate (≥VGPR) and complete response or better rate (≥CR), and with hazard ratios (HRs) and 95% CIs for progression-free survival (PFS). Sensitivity analyses using different analytical methods and additional covariates were explored. Results: Key characteristics were well balanced across cohorts after IPTW. Cilta-cel showed statistically significant benefit in PFS (HRs: 0.11-0.51), ≥VGPR (RRs: 1.51-5.13) and ≥CR (RRs: 2.90-35.24) versus all comparators, and statistically significant improvements in ORR over most comparator regimens (RRs: 1.22-1.90). Results were consistent across sensitivity analyses. Conclusion: Cilta-cel demonstrated benefit over other common treatment regimens, highlighting its potential to become a new standard of care option for lenalidomide-refractory RRMM patients with one to three prior LOT(s). These comparisons help to demonstrate the improved efficacy of cilta-cel in countries where the standard of care may differ from DPd/PVd.

Real-world treatment patterns and outcomes in relapsed/refractory multiple myeloma (1-3 prior lines): Flatiron database

AbstractIn the context of multiple myeloma (MM), early use of the immunomodulatory drug lenalidomide has led to an increased population of patients with lenalidomide-refractory MM in early-line settings, but their outcomes are not well characterized. Herein, we report treatment patterns, survival outcomes, prognostic variables, and attrition rates for patients with proteasome inhibitor–exposed, lenalidomide-refractory MM, treated with 1 to 3 prior lines of therapy (LOT). From 12 767 patients with MM in the Flatiron Health database between January 2016 and April 2022, 1455 met the inclusion criteria. The most common subsequent treatments were triplet combinations (41.6% of patients); daratumumab/pomalidomide/dexamethasone was the most common treatment regimen (13.2%). Median real-world progression-free survival (RW-PFS) and overall survival (OS) were 6.5 months and 44.4 months, respectively. RW-PFS was similar in patients with 1, 2, or 3 prior LOT. International Staging System stage III, Eastern Cooperative Oncology Group performance status of 1, hemoglobin <12 g/dL, high-risk cytogenetics, and refractoriness to anti-CD38 antibody at baseline were associated with worse RW-PFS and OS. Outcomes remained similar for patients who received National Comprehensive Cancer Network–preferred treatments and those who received treatments after 2020. In 561 patients with 1 prior LOT at inclusion, the cumulative attrition rate from LOT 2 to 5 was 85%, which included 25% patients who died and 60% with no further treatment. Patients with lenalidomide-refractory MM who have received 1 to 3 prior LOT have poor outcomes and progress rapidly through available therapies, highlighting the need for more effective treatments early in the disease course, before patients are lost to attrition.

Efficacy and Safety in Patients with Lenalidomide-Refractory Multiple Myeloma and 1–3 Prior Lines Who Received a Single Infusion of Ciltacabtagene Autoleucel As Study Treatment in the Phase 3 Cartitude-4 Trial

Efficacy and Safety in Patients with Lenalidomide-Refractory Multiple Myeloma and 1–3 Prior Lines Who Received a Single Infusion of Ciltacabtagene Autoleucel As Study Treatment in the Phase 3 Cartitude-4 Trial

Cost per Responder Analysis of Patients with Lenalidomide-Refractory Multiple Myeloma Who Received Cilta-Cel from the Cartitude-4 Trial

Cost per Responder Analysis of Patients with Lenalidomide-Refractory Multiple Myeloma Who Received Cilta-Cel from the Cartitude-4 Trial

Cost per Responder Analysis of Patients with Lenalidomide-Refractory Multiple Myeloma Who Received Cilta-Cel from the Cartitude-4 Trial

Introduction: Ciltacabtagene autoleucel (cilta-cel) is a chimeric antigen receptor-T cell (CAR-T) immunotherapy approved for patients with relapsed or refractory multiple myeloma (RRMM). In the phase 3 trial, CARTITUDE-4 (NCT04181827), cilta-cel demonstrated better efficacy than physician's choice (daratumumab plus pomalidomide and dexamethasone [DPd] or pomalidomide plus bortezomib and dexamethasone [PVd]) with an overall response rate (ORR) of 84.6% versus 67.3% and ≥complete response (CR) of 73.1% versus 21.8% (San-Miguel et al. New Engl J Med. 2023). The present analysis assessed the value of cilta-cel and physician's choice treatments within the CARTITUDE-4 trial from a US combined commercial and Medicare payer perspective using a novel cost per responder (CPR) model that incorporates efficacy and total treatment costs. Methods: A CPR analysis was conducted from a mixed payer perspective (67.7% commercial, 23.3% Medicare), comparing the direct medical cost per patient receiving cilta-cel versus physician's choice (87% DPd and 13% PVd, per distribution in the trial) over 25.4 months, the maximum observed period for the physician's choice arm in the CARTITUDE-4 trial. The model was developed using progression-free survival (PFS), overall survival (OS), time to next treatment, CR, stringent CR (sCR), and ORR endpoints from the CARTITUDE-4 trial to inform health status. A standard parametric approach was taken to extrapolate the PFS and OS beyond the trial period for each arm for analysis scenarios with longer follow-up. Resource use and costs associated with the administration process for each treatment were included: apheresis, bridging therapy, pre-conditioning treatment, infusion, drug acquisition, other medications (infection prophylaxis, antihistamine, and antipyretic), and monitoring (eg, labs, vital sign assessment, hematologist visit) for CAR-T; drug acquisition, administration, other medications, and monitoring for physician's choice. The base case assumed CAR-T infusion was entirely administered in the inpatient setting, and an additional scenario was included that considered the outpatient infusion setting (70% inpatient and 30% outpatient). Costs of managing grade 3 to 4 AEs and grade 1 to 4 AEs for cytokine release syndrome (CRS) and neurotoxicity were included. Costs of subsequent therapies were assigned following disease progression, and costs of terminal care were also considered upon death events. Model outcomes included total cost per treated patient, total cost per complete responder, and cost per month in PFS compared between cilta-cel and physician's choice of therapy. All costs were adjusted to 2023 US dollars based on the consumer price index for medical care. Results: The total cost (PFS and post-progression survival [PPS] combined) per treated patient was estimated as $693,009 for cilta-cel and $1,028,444 for physician's choice over 25.4 months. Total estimated costs per treated patient were lower for cilta-cel than physician's choice during PFS and PPS separately ($581,108 vs $765,169 and $111,901 vs $263,275, respectively). Treatment acquisition and subsequent treatment costs are key drivers of the total costs during PFS and PPS, respectively ($451,318 and $103,101 for cilta-cel; $726,356 and $249,005 for physician's choice). Total cost per complete responder was estimated to be lower for cilta-cel compared with physician's choice ($948,029 vs $4,717,634) (Figure). Total estimated cost per month in PFS was $30,814 for cilta-cel versus $58,113 for physician's choice (Figure). Scenario analysis with a lower percentage of patients receiving CAR-T infusion in inpatient settings led to lower cost per complete responder and lower cost per month in PFS for cilta-cel (70% inpatient and 30% outpatient, $940,431 and $30,520, respectively). Conclusions: Overall, cilta-cel offers substantial clinical and economic benefit for patients with RRMM. The CPR analysis of data from CARTITUDE-4 estimated that, for patients with RRMM, cost per complete responder, and cost per month in PFS for cilta-cel were remarkably lower compared to physician's choice (DPd or PVd). Treatment acquisition and subsequent treatment costs appear to be key drivers for total direct medical costs.

Selinexor, Daratumumab and Dexamethasone for Patients with Multiple Myeloma Previously Treated with Lenalidomide at First Relapse: A Real-World Study

CONCLUSIONS As lenalidomide becomes increasingly established standard of care for patients with newly diagnosed multiple myeloma (NDMM), a significant number of patients may develop resistance to lenalidomide in their treatment, representing a clinically important population in need of effective therapies. Lenalidomide-refractory patients, who relapse quickly and have very poor outcomes, constitute a population with unmet medical needs. Selinexor is a selective inhibitor of exportin-1, leading to the accumulation of tumor suppressor proteins and growth regulator proteins in the nucleus. This results in reduced expression of several oncoproteins, leading to cell cycle arrest and apoptosis of cancer cells. Previous data indicate that the biology associated with resistance to the monoclonal antibody daratumumab is linked to sensitivity to selinexor (ASH 2021), and selinexor conbombined with daratumumab and dexamethasone (SDd) is a well-tolerated and effective option for patients with relapsed/refractory multiple myeloma (RRMM) (Gasparetto C, 2020). Here, we present the safety and preliminary efficacy findings from the first study of SDd combination therapy in Chinese patients with multiple myeloma who refractory to lenalidomide at first relapse (NCT05559788). This study is a single-arm, prospective, non-interventional, real-world study that enrolled pts who had previously received one-line anti-myeloma treatment. Subjects were treated with selinexor (60 mg QW) in combination with daratumumab (16 mg/kg per label) and dexamethasone (40 mg QW) in 28-day cycles until PD, death or patients' withdrawal. Data collected included treatment response, patient characteristics such as age, sex, multiple myeloma features (cytogenetics by fluorescence in situ hybridization, type, stage, anti-myeloma treatment, and stem cell transplantation [SCT] status), and patients' survival. Between Feb 1, 2023, and May 30, 2023, a total of 8 RRMM pts were enrolled and received treatment at The First Affiliated Hospital of Soochow University. The median age was 63 years (range 44-78), with all pts (100%) had R-ISS stage II/III disease. Among them, 6 (75%) pts were classified as high risk or above by mSMART risk stratification, and 4 (50%) pts had extramedullary disease (EMD). All 8 (100%) pts were refractory to lenalidomide, and 7（87.5%）have received autologous stem cell transplantation (ASCT) (Table 1). At the end of one course, 6 patients (75%) achieved remission (3 very good partial responses [VGPR] and 3 partial responses [PR]). Among the 4 pts with EMD, 1 pt showed progressive disease (PD) after two courses, 1 pt showed stable disease (SD), and 2 pt achieved PR and VGPR but progressed after four and two courses, respectively. The data suggests that SDd combination therapy brings about rapid remission in EMD patients, while the duration of response may be shorter. Therefore, for these patients, it is crucial to closely monitor and plan for the next steps of treatment after achieving rapid remission. All four remaining non-EMD pts achieved remission, three of whom are continuing treatment (one died of COVID-19). Four patients were infected with COVID-19 during the treatment process. One pt was asymptomatic and detected positive with virus infection by antigen test screening. Among the three pts with symptoms, one had fever, cough, and pneumonia, and one had multiple organ failure (MOF). Three pts received antiviral medication (two with Paxlovid and one with Molnupiravir), and three recovered, but the one with MOF died. The SDd treatment was interrupted in all four pts, with a median time of 18 days (range: 12 to 21 days), until COVID-19 turned negative. The most common grade 3 adverse events (AEs) were thrombocytopenia (25%), anemia (13%), and neutropenia (13%). Non-hematological AEs were mainly grade 1-2. Three patients had dose reductions due to myelosuppression. This real-world study demonstrates that SDd combination therapy led to early, deep responses in lenalidomide-refractory multiple myeloma patients at their first relapse. Considering that patients with extramedullary disease had limited benefit from SDd treatment, future study designs may restrict the recruitment of such patients.

Patient-Reported Outcomes in the Phase 3 CARTITUDE-4 Study of Ciltacabtagene Autoleucel Vs Standard of Care in Patients with Lenalidomide-Refractory Multiple Myeloma after 1-3 Lines of Therapy

Introduction: The phase 3 CARTITUDE-4 trial (NCT04181827) in patients with multiple myeloma (MM) after 1-3 lines of therapy compared ciltacabtagene autoleucel (cilta-cel) with standard of care (SOC; pomalidomide, bortezomib, and dexamethasone or daratumumab, pomalidomide, and dexamethasone). In the primary analysis, a single cilta-cel infusion significantly improved progression-free survival (hazard ratio [HR], 0.26; P&amp;lt;0.0001) and increased the rate and depth of response vs SOC. Here, we present adjusted comparisons of patient-reported outcomes (PROs) from patients randomized to cilta-cel vs SOC in CARTITUDE-4. Methods:419 patients with lenalidomide-refractory MM and 1-3 prior lines of therapy, including a proteasome inhibitor and an immunomodulatory drug, were randomized (intent-to-treat [ITT] population) to receive cilta-cel (N=208) or SOC (N=211). European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30; 100-point scale), EuroQoL 5-Dimension 5-Level (EQ-5D-5L; 100-point scale), and Multiple Myeloma Symptom and Impact Questionnaire (MySIm-Q; 5-point scale) questionnaires were administered to all patients until disease progression. PRO compliance was calculated as the number of patients whose PROs were received divided by the number whose PROs were expected (ie, all patients on study pre disease progression and before subsequent therapy for each time point). Mixed-model for repeated measures analyses were performed on the ITT population to analyze changes from baseline for each arm and included the baseline PRO score and prognostic characteristics as covariates to balance arms and to adjust for confounders. Assessments after the start of subsequent therapy were excluded. Time to symptom worsening, defined as a clinically meaningful increase (≥0.5 standard deviation of pooled baseline values) without a subsequent reduction in MM symptoms, was assessed using the Kaplan-Meier method. Results: At clinical cut-off on November 1, 2022, 99 patients in the cilta-cel arm and 66 in the SOC arm had both baseline and 12-month PRO assessments, representing data prior to progression. PRO compliance was 100% at baseline and decreased with subsequent visits to 74% in the cilta-cel arm and 81% in the SOC arm at month 12. Patients reported improved functioning and symptom reduction from baseline in the cilta-cel arm, while PRO scores in the SOC arm trended towards worsening or lower degrees of improvement from baseline for most domains and symptoms. The average improvement from baseline to month 12 (least squares [LS] mean change) for patients who received cilta-cel exceeded clinically meaningful thresholds for global health status (10.1 points), pain (-10.2 points), and the visual analogue scale (8.0 points); improvements in fatigue (-9.1 points) and emotional functioning (9.5 points) neared clinically meaningful thresholds (Table). For all other EORTC QLQ-C30 domains, results numerically favored cilta-cel. On the MySIm-Q total symptom scale, the median time until MM symptom worsening in the cilta-cel arm was 23.7 months (95% CI, 22.1-not estimable) and was 18.9 months (95% CI, 16.8-not estimable) in the SOC arm (HR, 0.42). Conclusions:Patients with lenalidomide-refractory MM who had 1-3 prior lines of therapy demonstrated clinically meaningful improvements in health-related quality of life and meaningful reductions in disease-specific symptoms on multiple PRO endpoints after a single cilta-cel infusion. Improvements in health-related quality of life were numerically greater with cilta-cel than with continuously administered SOC treatments across all scales. With previously reported data showing that cilta-cel significantly improves PFS, response rate, and depth of response, these results strengthen the potential for cilta-cel to be a new SOC for patients with lenalidomide-refractory MM after first relapse.

Efficacy and Safety in Patients with Lenalidomide-Refractory Multiple Myeloma after 1-3 Prior Lines Who Received a Single Infusion of Ciltacabtagene Autoleucel As Study Treatment in the Phase 3 CARTITUDE-4 Trial

Introduction: CARTITUDE-4 (NCT04181827) is a randomized, phase 3 trial comparing ciltacabtagene autoleucel (cilta-cel), a BCMA-directed CAR-T cell therapy, with standard of care (SOC; pomalidomide, bortezomib, and dexamethasone [PVd] or daratumumab, pomalidomide, and dexamethasone [DPd]) in patients (pts) with lenalidomide (len)-refractory multiple myeloma (MM). The trial recently showed that pts in the cilta-cel arm experienced significantly improved progression-free survival (PFS) vs SOC (HR, 0.26; P&amp;lt;0.0001) and a significantly higher rate of complete response (CR) or better and overall response rate (ORR) in the intent-to-treat (ITT) set (San-Miguel et al, New Engl J Med 2023). We report efficacy and safety in pts who received cilta-cel as study treatment (‘as-treated’ set) in the experimental (cilta-cel) arm of the study. Methods: Pts had 1-3 prior lines of therapy (LOT), including a proteasome inhibitor and immunomodulatory drug. A single cilta-cel infusion (target dose, 0.75×10 6 CAR+ viable T cells/kg) was administered after apheresis, bridging therapy (DPd [28-day cycles] or PVd [21-day cycles]), and lymphodepletion. Treatment responses and disease progression were assessed per IMWG criteria; minimal residual disease (MRD) negativity at 10 -5 was assessed by next-generation sequencing starting at day 56 post infusion; time-to-event endpoints were analyzed using the Kaplan-Meier method. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity (ICANS) were graded per ASTCT criteria; other adverse events (AEs) were graded per NCI-CTCAE criteria. Results: As of Nov 1, 2022, 176 of 208 pts randomized to the cilta-cel arm had received cilta-cel as study treatment (median age, 61 years; 34% with 1 prior LOT; 6% ISS stage III; 60% with high-risk cytogenetic profile; 17% with soft tissue plasmacytoma; 13% with high tumor burden; 11% triple-class refractory). Baseline characteristics were consistent with those of the ITT set. In the as-treated set, median follow-up from randomization was 16 months (mo), and 22% of pts had received 1 bridging therapy cycle, 59% 2 cycles, and 18% 3 cycles. Disease burden was effectively controlled in the as-treated set during bridging therapy. Median PFS was not reached and the 12-mo PFS rate from infusion was 85%; 12-mo overall survival rate from infusion was 92%. 175 of 176 pts who received cilta-cel as study treatment responded (99% ORR), including 86% who achieved ≥CR. Median time from randomization to first response was 2.1 mo and responses deepened over time; 2% of pts achieved ≥CR by 2 mo post randomization, and rates increased to 40% by 6 mo and 80% by 12 mo (Figure A). Median duration of response was not reached. 72% of the as-treated set (88% of 144 MRD evaluable) achieved MRD negativity at any time. 111 of 144 MRD-evaluable pts (77%) achieved both MRD negativity and ≥CR. These pts had improved PFS vs pts who remained MRD positive and/or had &amp;lt;CR (HR, 0.36; 95% CI, 0.15-0.88; P=0.0196); respective 12-mo PFS rates were 89% and 71% (Figure B). The most common CAR-T cell-related toxicity was CRS (76% any grade [gr]; 1% gr 3). The overall CAR-T cell neurotoxicity rate was 21% (3% gr 3/4). ICANS occurred in 5% of pts (no gr 3/4). Other neurotoxicities occurred in 17% of pts (2% gr 3/4); these included cranial nerve palsy (CNP) in 9% (1% gr 3/4), peripheral neuropathy in 3% (1% gr 3/4), and 1 pt with gr 1 movement/neurocognitive treatment-emergent AEs (MNT). By clinical cut-off, CRS and ICANS had resolved in all pts; CNP and peripheral neuropathy had resolved in all but 2 pts; and the 1 MNT case had not yet resolved. Conclusions: This analysis of the as-treated set in CARTITUDE-4 shows potent effects of cilta-cel in pts with len-refractory MM after 1-3 LOT. The PFS rate of 85% at 12 mo post infusion (89% in pts with MRD-negative ≥CR) compares favorably with real-world data in similar populations (12-mo PFS rate &amp;lt;50%; Lecat et al, Front Oncol 2021). Effective bridging therapy during the CAR-T manufacturing period may help ensure that pts can receive cilta-cel. In the context of longer-term data from cohort A of the CARTITUDE-2 study (Hillengass et al, ASH 2023, submitted) in a similar pt population, these results support the potential for prolonged disease control and the benefit of cilta-cel for pts with MM as early as after first relapse.

Efficacy of Carvykti in CARTITUDE-4 Versus Other Conventional Treatment Regimens for Lenalidomide-Refractory Multiple Myeloma Patients Using Inverse Probability of Treatment Weighting

Introduction: CARTITUDE-4 is a phase 3 randomized controlled trial (RCT) assessing the efficacy and safety of CARVYKTI (ciltacabtagene autoleucel; cilta-cel) versus pomalidomide, bortezomib and dexamethasone (PVd) or daratumumab, pomalidomide and dexamethasone (DPd) in patients with relapsed and refractory multiple myeloma (RRMM) who have received one to three prior line(s) of therapy that included an immunomodulatory agent (IMiD) and a proteasome inhibitor (PI), and who are refractory to lenalidomide. CARTITUDE-4 demonstrated superiority of cilta-cel over PVd and DPd on progression-free survival (PFS) and response rates (overall response rate [ORR], very good partial response [VGPR] or better, and complete response [CR] or better [CR or stringent CR]). Other available therapies for the treatment of this patient population where individual patient data was available for analysis include: daratumumab in combination with bortezomib and dexamethasone (DVd), bortezomib in combination with dexamethasone (Vd), carfilzomib in combination with daratumumab and dexamethasone (DKd) or dexamethasone alone (Kd), and pomalidomide in combination with dexamethasone (Pd). This analysis aims to compare efficacy outcomes in patients randomized to the cilta-cel arm (i.e., patients apheresed or infused with cilta-cel) in CARTITUDE-4 vs each of these regimens in the same target population. Methods: Individual patient data were collected from the CARTITUDE-4 (cilta-cel), CASTOR (DVd and Vd), CANDOR (DKd and Kd), and APOLLO (Pd) RCTs. Patients who met CARTITUDE-4 eligibility criteria were identified from the above mentioned RCTs. As no patients in the comparative trials had prior treatment with anti-CD38, patients with prior exposure to anti-CD38 therapies in the cilta-cel cohort were excluded. Key prognostic baseline covariates including refractory status, ISS stage, presence of extramedullary disease, and time to progression on prior line, were adjusted for using inverse probability of treatment weighting (IPTW), with average treatment effect in the treated weights. Differences in baseline characteristics were assessed using standardized mean differences. PFS, ORR, VGPR or better, and CR or better were compared between patients in the cilta-cel arm and the comparator regimens. Relative efficacy of cilta-cel vs comparator regimens were estimated with hazard ratios (HRs) and 95% confidence intervals (CIs) from weighted Cox proportional hazards models for PFS, and response rate ratios (RRs) and 95% CIs from weighted logistic regression models for ORR, VGPR or better, and CR or better. Sensitivity analyses using alternative statistical approaches and including additional covariates were explored. Results: After the exclusion of 53 patients with prior exposure to an anti-CD38 therapy, 155 patients in the cilta-cel arm remained. Across the comparative trials, 44 patients treated with DVd, 46 patients treated with Vd, 98 patients treated with DKd, 46 patients treated with Kd, and 92 patients treated with Pd met the inclusion criteria of CARTITUDE-4. Baseline covariates were similar across the cohorts after IPTW. Patients randomized to the cilta-cel arm showed significant improvements in PFS (adjusted HRs from 0.11 vs Vd to 0.51 vs DKd), VGPR or better (adjusted RRs from 1.51 vs DKd to 5.13 vs Vd), and CR or better rate (adjusted RRs from 2.90 vs DKd to 35.24 vs Pd) (Table). Improvements in ORR were also observed against all comparator regimens (adjusted RRs from 1.22 vs DKd to 1.90 vs Pd), though were marginally not statistically significant vs DVd and Kd. Treatment with DKd consistently yielded the best results out of all comparator regimens, but results were still in favor of cilta-cel. Results of cilta-cel benefit were consistent across sensitivity analyses, yielding adjusted HRs below 1.00 and RRs above 1.00 in all cases against other comparator regimens. Conclusions: Data from CARTITUDE-4 and these analyses demonstrate the benefit of cilta-cel over additional regimens commonly used in clinical practice, highlighting its potential to become a new standard of care option for patients with RRMM, who have received one to three prior lines(s) of therapy, including an IMiD and a PI, and who are refractory to lenalidomide. These comparisons provide valuable information to contextualize the efficacy of CARVYKTI in countries where standard of care may be different from DPd/PVd.

P-295 Efficacy, survival and safety of selinexor, bortezomib and dexamethasone (SVd) in patients with lenalidomide-refractory multiple myeloma: subgroup data from the BOSTON trial

P-295 Efficacy, survival and safety of selinexor, bortezomib and dexamethasone (SVd) in patients with lenalidomide-refractory multiple myeloma: subgroup data from the BOSTON trial

OA-45 Pharmacokinetic and correlative analysis of ciltacabtagene autoleucel in patients with lenalidomide-refractory multiple myeloma in the CARTITUDE-4 trial

OA-45 Pharmacokinetic and correlative analysis of ciltacabtagene autoleucel in patients with lenalidomide-refractory multiple myeloma in the CARTITUDE-4 trial

Cilta-cel or Standard Care in Lenalidomide-Refractory Multiple Myeloma.

Ciltacabtagene autoleucel (cilta-cel), a B-cell maturation antigen (BCMA)-directed CAR T-cell therapy, is effective in heavily pretreated patients with relapsed or refractory multiple myeloma. We investigated cilta-cel in earlier treatment lines in patients with lenalidomide-refractory disease. In this phase 3, randomized, open-label trial, we assigned patients with lenalidomide-refractory multiple myeloma to receive cilta-cel or the physician's choice of effective standard care. All the patients had received one to three previous lines of treatment. The primary outcome was progression-free survival. A total of 419 patients underwent randomization (208 to receive cilta-cel and 211 to receive standard care). At a median follow-up of 15.9 months (range, 0.1 to 27.3), the median progression-free survival was not reached in the cilta-cel group and was 11.8 months in the standard-care group (hazard ratio, 0.26; 95% confidence interval [CI], 0.18 to 0.38; P<0.001). Progression-free survival at 12 months was 75.9% (95% CI, 69.4 to 81.1) in the cilta-cel group and 48.6% (95% CI, 41.5 to 55.3) in the standard-care group. More patients in the cilta-cel group than in the standard-care group had an overall response (84.6% vs. 67.3%), a complete response or better (73.1% vs. 21.8%), and an absence of minimal residual disease (60.6% vs. 15.6%). Death from any cause was reported in 39 patients and 46 patients, respectively (hazard ratio, 0.78; 95% CI, 0.5 to 1.2). Most patients reported grade 3 or 4 adverse events during treatment. Among the 176 patients who received cilta-cel in the as-treated population, 134 (76.1%) had cytokine release syndrome (grade 3 or 4, 1.1%; no grade 5), 8 (4.5%) had immune effector cell-associated neurotoxicity syndrome (all grade 1 or 2), 1 had movement and neurocognitive symptoms (grade 1), 16 (9.1%) had cranial nerve palsy (grade 2, 8.0%; grade 3, 1.1%), and 5 (2.8%) had CAR-T-related peripheral neuropathy (grade 1 or 2, 2.3%; grade 3, 0.6%). A single cilta-cel infusion resulted in a lower risk of disease progression or death than standard care in lenalidomide-refractory patients with multiple myeloma who had received one to three previous therapies. (Funded by Janssen and Legend Biotech; CARTITUDE-4 ClinicalTrials.gov number, NCT04181827.).

Daratumumab-lenalidomide and daratumumab-pomalidomide in relapsed lenalidomide-exposed or refractory multiple myeloma.

Daratumumab is an anti-CD38 mAb, used frequently in combination with lenalidomide and pomalidomide. No studies compared daratumumab plus lenalidomide and dexamethasone (DRd) to daratumumab plus pomalidomide and dexamethasone (DPd) in lenalidomide-exposed multiple myeloma. We identified 504 consecutive multiple myeloma patients who received daratumumab at Mayo Clinic between January 2015 and April 2019. We excluded patients who received daratumumab in the first line, received more than four lines of therapy prior to daratumumab use, did not receive lenalidomide prior to daratumumab, or had an unknown status of lenalidomide exposure, and patients who received daratumumab combinations other than DRd or DPd. We examined the impact of using DRd compared to DPd on progression-free survival (PFS) and overall survival (OS) in patients with relapsed/refractory multiple myeloma. Out of 504 patients, 162 received DRd or DPd and were included; 67 were lenalidomide-exposed and 95 were lenalidomide-refractory. DRd was used in 76 (47%) and DPd in 86 (53%) patients. In lenalidomide-exposed multiple myeloma, there was no difference in median PFS; 34.2 months [95% confidence interval (CI), 22.8-44.6] for DRd compared to 25.2 months (95% CI, 4.9-35.3) for DPd, P = 0.2. In lenalidomide-refractory multiple myeloma, there was no difference in median PFS; 18.6 months (95% CI, 13-32) for DRd compared to 9 months (95% CI, 5.2-14.6) for DPd, P = 0.09. No difference in median OS was observed in DRd compared to DPd. Our study shows combining daratumumab with lenalidomide in patients with prior lenalidomide use is a viable and effective treatment option.

How to Manage Patients with Lenalidomide-Refractory Multiple Myeloma

Although lenalidomide-based combinations, such as lenalidomide plus a proteasome inhibitor or an anti-CD38 monoclonal antibody, improve the overall response rate, progression-free survival, and overall survival of patients with relapsed/refractory multiple myeloma (RRMM), there is a tendency to use these regimens as a frontline treatment. This strategy has led to the development of refractoriness early in the disease course, usually after the patient's first treatment. Since lenalidomide-free regimens have so far shown limited efficacy in lenalidomide-refractory patients, there is an unmet need for other treatment options. In this review, we discuss the therapeutic options available to treat the general population of lenalidomide-refractory patients (mono, double and triple refractory) and the subpopulation of patients with other high-risk features such as renal failure, extramedullary disease, and high-risk cytogenetics. Moreover, new promising individual therapies and the possible impact of immunotherapy in RRMM patients are debated.

Poster: MM-498 Addition of Carfilzomib as a Third Agent in Lenalidomide-Refractory Multiple Myeloma: Switching From Doublet to Triplet

Poster: MM-498 Addition of Carfilzomib as a Third Agent in Lenalidomide-Refractory Multiple Myeloma: Switching From Doublet to Triplet

MM-498 Addition of Carfilzomib as a Third Agent in Lenalidomide-Refractory Multiple Myeloma: Switching From Doublet to Triplet

Carfilzomib is a second generation epoxyketone proteasome inhibitor, proven to be effective and safe in relapsed and refractory multiple myeloma (rrMM), in combination with dexamethasone or lenalidomide and dexamethasone. In this retrospective observational trial, we evaluated efficacy and safety of carfilzomib, in combination with lenalidomide-dexamethasone (KRD) as salvage regimen in patients with rrMM, refractory to lenalidomide, where lenalidomide-based regimens have no proven efficacy. 41 patients (23 M/18 F), with rrMM, median age at diagnosis 63.7 years (r. 43-82), median age at start of treatment 67 years (r. 48-84) previously treated with several lines of treatments (median 3, r. 2-11), underwent KRD regimen (ASPIRE trial schedule) for a median of 8 treatment cycles (r 2-18). 61% (19/31) of them had undergone at least one ASCT. ORR was 68.2% (28/41: 9 CR, 12 VGPR, 7 PR) with 5 progressive diseases (PD) and 8 patients in stable disease (SD). This is an impressive result in this subset of rrMM patients, refractory to lenalidomide. In particular, for 11 patients, KRD was, after having achieved at least a PR, a bridge to second/third autologous SCT. Median time to response was 1.3 months (r.1-4), median OS from diagnosis was 62 months (r. 9-170), median OS from start of carfilzomib was 11 months (r. 2-18). Carfilzomib was well tolerated, with grade 2 anemia in 39% (16/41) of patients, successfully managed by ESAs, without needing blood transfusions; 29% (12/41) grade 3-4 neutropenia (pegfilgrastim in primary prophylaxis was given, no hospitalization was required, no septic shock was observed); 34% (14/41) grade 2, 21% (9/41) grade 3 and 12% (5/41) grade 4 thrombocytopenia, without hemorrhagic events and transfusion-dependency. Moreover, pneumonia was observed in 39% (16/41) of patients, treated by common antibiotic drugs and always solved. A cardiac monitoring was performed for all patients: hypertension (grade 2-3) in 34% (14/41) of patients; fatigue in 39% (16/31). KRD has shown significant efficacy in a particularly severe setting of patients, relapsed and refractory to all available therapeutic resources, including lenalidomide, and it could be considered as a bridge to a second autologous or allogenic SCT.

P-236: Addition of carfilzomib as a third agent in lenalidomide-refractory multiple myeloma: switching from doublet to triplet

P-236: Addition of carfilzomib as a third agent in lenalidomide-refractory multiple myeloma: switching from doublet to triplet

Addition of carfilzomib as a third agent in lenalidomide-refractory multiple myeloma: Switching from doublet to triplet.

e20002 Background: Carfilzomib is an epoxyketone proteasome inhibitor of second generation, proved to be effective and safe in relapsed and refractory Multiple Myeloma (rrMM), in combination with dexamethasone or lenalidomide and dexamethasone. In this retrospective observational trial, it has been evaluated efficacy and safety of carfilzomib, in combination with lenalidomide-dexamethasone (KRD) as salvage regimen in patients with rrMM, refractory to lenalidomide, where lenalidomide-based regimens have no proven efficacy. Methods: 41 patients (23 M/18 F), with rrMM, median age at diagnosis 63.7 years (r. 43-82), median age at start of treatment 67 years (r. 48-84) previously treated with several lines of treatments (median 3, r. 2-11), underwent to KRD regimen (ASPIRE trial schedule) for a median treatment cycles of 8 (r 2-18). ISS was equally distributed, and all patients had previously been treated with bortezomib and IMIDs, and were refractory to this agents. 61% (19/31) of them had undergone at least to a single ASCT. Results: According to IMWG criteria, after a median follow-up of 9 months (r. 2-18), ORR was 68,2% (28/41: 9 CR, 12 VGPR, 7 PR) with 5 progressive diseases (PD) and 8 patients in stable disease (SD): this can be considered as an impressive result in this subset of rrMM patients, refractory to lenalidomide. In particular, for 11 patients, KRD was, after having achieved at least a PR, a bridge to second/third autologous SCT. Median time to response was 1.3 months (r.1-4), median OS from diagnosis was 62 months (r. 9-170), median OS from start of Carfilzomib was 11 months (r. 2-18). Carfilzomib was well tolerated, with grade 2 anemia in 39%(16/41) of patients, successfully managed by ESAs, without necessity of blood transfusions; 29% (12/41) grade 3-4 neutropenia (pegfilgrastim in primary prophylaxis was given, no ospedalization was required, no septic shocks were observed); 34% (14/41) grade 2, 21% (9/41) grade 3 and 12% (5/41) grade 4 thrombocytopenia, without hemorrhagic events and transfusion-dependency. Moreover, it was observed pneumonia in 39% (16/41) of patients, treated by common antibiotic drugs and always solved. A cardiac monitoring was performed for all patients: hypertension (grade 2-3) in 34% (14/41) of patients; fatigue in 39% (16/31) of patients. Conclusions: Carfilzomib-Lenalidomide-Dexamethasone has shown significant efficacy in a particularly severe setting of patients, relapsed and refractory to all available therapeutic resources, also lenalidomide, and it could be considered as a bridge to a second autologous or allogenic SCT. Clinical trial information: A108.

Oral ixazomib-dexamethasone vs oral pomalidomide-dexamethasone for lenalidomide-refractory, proteasome inhibitor-exposed multiple myeloma: a randomized Phase\ufeff 2 trial

Multiple myeloma (MM) patients typically receive several lines of combination therapy and first-line treatment commonly includes lenalidomide. As patients age, they become less tolerant to treatment, requiring convenient/tolerable/lenalidomide-free options. Carfilzomib and/or bortezomib-exposed/intolerant, lenalidomide-refractory MM patients with ≥2 prior lines of therapy were randomized 3:2 to ixazomib-dexamethasone (ixa-dex) (n = 73) or pomalidomide-dexamethasone (pom-dex) (n = 49) until progression/toxicity. Median progression-free survival (mPFS) was 7.1 vs 4.8 months with ixa-dex vs pom-dex (HR 0.847, 95% CI 0.535–1.341, P = 0.477; median follow-up: 15.3 vs 17.3 months); there was no statistically significant difference between arms. In patients with 2 and ≥3 prior lines of therapy, respectively, mPFS was 11.0 vs 5.7 months (HR 1.083, 95% CI 0.547–2.144) and 5.7 vs 3.7 months (HR 0.686, 95% CI 0.368–1.279). Among ixa-dex vs pom-dex patients, 69% vs 81% had Grade ≥3 treatment-emergent adverse events (TEAEs), 51% vs 53% had serious TEAEs, 39% vs 36% had TEAEs leading to drug discontinuation, 44% vs 32% had TEAEs leading to dose reduction, and 13% vs 13% died on study. Quality of life was similar between arms and maintained during treatment. Ixa-dex represents an important lenalidomide-free, oral option for this heavily pretreated, lenalidomide-refractory, proteasome inhibitor-exposed population.Trial registration: ClinicalTrials.gov number, NCT03170882.

Planned withdrawal of dexamethasone after pomalidomide low-dose dexamethasone induction for lenalidomide-refractory multiple myeloma (ALLG MM14).

Not available.