BCMA CAR-T induces complete and durable remission in refractory plasmablastic lymphoma.

Plasmablastic lymphoma (PBL) is a rare subtype of aggressive large B-cell lymphoma, with a dismal prognosis despite aggressive therapies. New approaches are needed for those with refractory disease. PBL expresses antigens similar to multiple myeloma (MM), including B-cell maturation antigen (BCMA). Chimeric antigen receptor T-cell (CAR-T) therapy directed against BCMA has shown efficacy for the treatment of heavily pretreated MM with low rates of grades 3 and 4 cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) in a phase Ib/II trial (A Study of JNJ-68284528, a CAR-T Directed Against BCMA in Participants With Relapsed or Refractory Multiple Myeloma (CARTITUDE-1), NCT03548207). However, data for the use of BCMA CAR-T for treating PBL are lacking.We report a challenging case of multiple refractory PBL that emerged from B-cell acute lymphoblastic leukemia in an adolescent who failed to respond to an allogeneic hematopoietic cell transplant. The patient developed rapidly advancing disease despite withdrawal of immunosuppression, treatment with etoposide, ibrutinib, and daratumumab, prompting consideration of BCMA CAR-T (under emergency investigational new drug (eIND)). The patient achieved a complete remission (CR), without recurrent acute graft versus host disease (GVHD), CRS or ICANS after BCMA CAR-T therapy. BCMA CAR-T expansion was detected in vivo, peaking on day 15. The patient remains in CR for more than a year post CAR-T therapy, supporting consideration of immunotherapy for future patients with refractory PBL, a disease with few treatment options.

Efficacy and safety of cilta-cel in patients with progressive multiple myeloma after exposure to other BCMA-targeting agents.

B-cell maturation antigen (BCMA)-targeting therapies, including bispecific antibodies (BsAbs) and antibody-drug conjugates (ADCs), are promising treatments for multiple myeloma (MM), but disease may progress after their use. CARTITUDE-2 is a phase 2, multicohort study evaluating the safety and efficacy of cilta-cel, an anti-BCMA chimeric antigen receptor T therapy, in various myeloma patient populations. Patients in cohort C progressed despite treatment with a proteasome inhibitor, immunomodulatory drug, anti-CD38 antibody, and noncellular anti-BCMA immunotherapy. A single cilta-cel infusion was given after lymphodepletion. The primary end point was minimal residual disease (MRD) negativity at 10-5. Overall, 20 patients were treated (13 ADC exposed; 7 BsAb exposed; 1 in the ADC group also had prior BsAb exposure). Sixteen (80%) were refractory to prior anti-BCMA therapy. At a median follow-up of 11.3 months (range, 0.6-16.0), 7 of 20 (35%) patients were MRD negative (7 of 10 [70.0%] in the MRD-evaluable subset). Overall response rate (95% confidence interval [CI]) was 60.0% (36.1-80.9). Median duration of response and progression-free survival (95% CI) were 11.5 (7.9-not estimable) and 9.1 (1.5-not estimable) months, respectively. The most common adverse events were hematologic. Cytokine release syndrome occurred in 12 (60%) patients (all grade 1-2); 4 had immune effector cell-associated neurotoxicity syndrome (2 had grade 3-4); none had parkinsonism. Seven (35%) patients died (3 of progressive disease, 4 of adverse events [1 treatment related, 3 unrelated]). Cilta-cel induced favorable responses in patients with relapsed/refractory MM and prior exposure to anti-BCMA treatment who had exhausted other therapies. This trial was registered at www.clinicaltrials.gov as NCT04133636.

Comparative effectiveness of ciltacabtagene autoleucel in CARTITUDE-1 versus physician's choice of therapy in the Flatiron Health multiple myeloma cohort registry for the treatment of patients with relapsed or refractory multiple myeloma.

Introduction: Ciltacabtagene autoleucel (cilta-cel) is a novel chimeric antigen receptor T-cell therapy that is being evaluated in the CARTITUDE-1 trial (NCT03548207) in patients with relapsed or refractory multiple myeloma (RRMM) who received as part of their previous therapy an immunomodulatory drug, proteasome inhibitor, and an anti-CD38 monoclonal antibody (i.e., triple-class exposed). Given the absence of a control arm in CARTITUDE-1, this study assessed the comparative effectiveness of cilta-cel and physician's choice of treatment (PCT) using an external real-world control arm from the Flatiron Health multiple myeloma cohort registry. Methods: Given the availability of individual patient data for cilta-cel from CARTITUDE-1 and PCT in Flatiron, inverse probability of treatment weighting was used to adjust for unbalanced baseline covariates of prognostic significance: refractory status, cytogenetic profile, International Staging System stage, time to progression on last regimen, number of prior lines of therapy, years since diagnosis, and age. Comparative effectiveness was estimated for progression-free survival (PFS), time to next treatment (TTNT), and overall survival (OS). A range of sensitivity analyses were conducted. Results: Baseline characteristics were similar between the two cohorts after propensity score weighting. Patients with cilta-cel had improved PFS (HR: 0.18 [95% CI: 0.12, 0.27; p < 0.0001]), TTNT (HR: 0.15 [95% CI: 0.09, 0.22; p < 0.0001]), and OS (HR: 0.25 [95% CI: 0.13, 0.46; p < 0.0001]) versus PCT. Cilta-cel treatment benefit was robust and consistent across all sensitivity analyses. Conclusion: Cilta-cel demonstrated significantly superior effectiveness over PCT for all outcomes, highlighting its potential as an effective therapy in patients with triple-class exposed RRMM.

Matching-Adjusted Indirect Treatment Comparison to Assess the Comparative Efficacy of Ciltacabtagene Autoleucel in CARTITUDE-1 Versus Belantamab Mafodotin in DREAMM-2, Selinexor-Dexamethasone in STORM Part 2, and Melphalan Flufenamide-Dexamethasone in HORIZON for the Treatment of Patients With Triple-Class Exposed Relapsed or Refractory Multiple Myeloma.

INTRODUCTION: This study estimated the comparative efficacy of ciltacabtagene autoleucel (cilta-cel; CARTITUDE-1), a chimeric antigen receptor (CAR)-T-cell therapy, versus 3 non-CAR-T therapies (belantamab mafodotin [DREAMM-2], selinexor plus dexamethasone [STORM Part 2], and melphalan flufenamide plus dexamethasone [HORIZON]), each with distinct mechanisms of action, for the treatment of patients with relapsed or refractory multiple myeloma (RRMM) who were triple-class exposed to an immunomodulatory drug, proteasome inhibitor, and an anti-CD38 monoclonal antibody. PATIENTS AND METHODS: Pairwise matching-adjusted indirect treatment comparisons (MAICs) were conducted using patient-level data for cilta-cel from CARTITUDE-1 and summary level data for each comparator (2.5 mg/kg cohort in DREAMM-2, modified intention-to-treat population in STORM Part 2, and triple-class refractory patients in HORIZON). Treated patients from CARTITUDE-1 who satisfied the eligibility of the comparator trial were included. MAICs adjusted for imbalances in important prognostic factors between CARTITUDE-1 and the comparator populations. Comparative efficacy of cilta-cel versus each therapy was estimated for overall response rate, complete response or better rate, progression-free survival, and overall survival. RESULTS: After adjustment, patients treated with cilta-cel demonstrated at least a 3.1-fold and at least a 10.3-fold increase in the likelihood of achieving an overall response or complete response or better, respectively, at least a 74% reduction in the risk of disease progression or death, and at least a 47% reduction in the risk of death. These results were statistically significant. CONCLUSION: Cilta-cel showed improved efficacy over each comparator for all outcomes, demonstrating its potential as an efficacious treatment for patients with triple-class exposed RRMM.

LocoMMotion: a prospective, non-interventional, multinational study of real-life current standards of care in patients with relapsed and/or refractory multiple myeloma.

Despite treatment advances, patients with multiple myeloma (MM) often progress through standard drug classes including proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and anti-CD38 monoclonal antibodies (mAbs). LocoMMotion (ClinicalTrials.gov identifier: NCT04035226) is the first prospective study of real-life standard of care (SOC) in triple-class exposed (received at least a PI, IMiD, and anti-CD38 mAb) patients with relapsed/refractory MM (RRMM). Patients (N = 248; ECOG performance status of 0-1, ≥3 prior lines of therapy or double refractory to a PI and IMiD) were treated with median 4.0 (range, 1-20) cycles of SOC therapy. Overall response rate was 29.8% (95% CI: 24.2-36.0). Median progression-free survival (PFS) and median overall survival (OS) were 4.6 (95% CI: 3.9-5.6) and 12.4 months (95% CI: 10.3-NE). Treatment-emergent adverse events (TEAEs) were reported in 83.5% of patients (52.8% grade 3/4). Altogether, 107 deaths occurred, due to progressive disease (n = 74), TEAEs (n = 19), and other reasons (n = 14). The 92 varied regimens utilized demonstrate a lack of clear SOC for heavily pretreated, triple-class exposed patients with RRMM in real-world practice and result in poor outcomes. This supports a need for new treatments with novel mechanisms of action.

Comparative Efficacy of Ciltacabtagene Autoleucel in CARTITUDE-1 vs Physician's Choice of Therapy in the Long-Term Follow-Up of POLLUX, CASTOR, and EQUULEUS Clinical Trials for the Treatment of Patients with Relapsed or Refractory Multiple Myeloma.

BACKGROUND AND OBJECTIVE: Ciltacabtagene autoleucel (cilta-cel) is a novel agent being investigated in the single-arm CARTITUDE-1 trial (NCT03548207) for patients with relapsed or refractory multiple myeloma who are triple-class exposed to an immunomodulatory drug, proteasome inhibitor, and an anti-CD38 monoclonal antibody. The objective of this study was to evaluate the comparative efficacy of cilta-cel vs physician's choice of treatment, as no head-to-head trials have been conducted. METHODS: An external control arm for CARTITUDE-1 was created from patients in the long-term follow-up for three clinical trials of daratumumab (POLLUX, CASTOR, and EQUULEUS) who satisfied the eligibility criteria of CARTITUDE-1. These patients received physician's choice of treatment following the discontinuation of study drugs. Inverse probability of treatment weighting was used to align the external control and CARTITUDE-1 populations on important baseline characteristics. Overall response rate, complete response or better rate, progression-free survival, time to next treatment, and overall survival were assessed. Several sensitivity analyses were conducted. RESULTS: After propensity score weighting, baseline characteristics were comparable between cohorts. Patients showed improved results with cilta-cel vs physician's choice of treatment: overall response rate (relative risk: 2.95 [95% confidence interval (CI) 2.27, 3.84; p < 0.0001]), complete response or better (relative risk: 111.70 [95% CI 29.08, 429.06; p < 0.0001]), progression-free survival (hazard ratio [HR]: 0.24 [95% CI 0.15, 0.37; p < 0.0001]), time to next treatment (HR: 0.14 [95% CI 0.09, 0.22; p < 0.0001]), and overall survival (HR: 0.21 [95% CI 0.13, 0.35; p < 0.0001]). Results were consistent across all sensitivity analyses. CONCLUSIONS: Cilta-cel showed superior efficacy compared with physician's choice of treatment, making it a promising new treatment option for patients with triple-class exposed relapsed or refractory multiple myeloma.

Placenta Percreta Presents with Neoangiogenesis of Arteries with Von Willebrand Factor-Negative Endothelium.

In placenta percreta cases, large vessels are present on the precrete surface area. As these vessels are not found in normal placentation, we examined their histological structure for features that might explain the pathogenesis of neoangiogenesis induced by placenta accreta spectrum disorders (PAS). In two patients with placenta percreta (FIGO grade 3a) of the anterior uterine wall, one strikingly large vessel of 2 cm length was excised. The samples were formalin fixed and paraffin-embedded. Gomori trichrome staining was used to evaluate the muscular layers and Weigert-Van Gieson staining for elastic fibers. Immunohistochemical staining of the vessel endothelium was performed for Von Willebrand factor (VWF), platelet endothelial cell adhesion molecule (CD31), Ephrin B2, and EPH receptor B4. The structure of the vessel walls appeared artery-like. The vessel of patient one further exhibited an unorderly muscular layer and a lack of elastic laminae, whereas these features appeared normal in the vessel of the other patient. The endothelium of both vessels stained VWF-negative and CD31-positive. In conclusion, this study showed VWF-negative vessel endothelia of epiplacental arteries in placenta accreta spectrum. VWF is known to regulate artery formation, as the absence of VWF has been shown to cause enhanced vascularization. Therefore, we suppose that PAS provokes increased vascularization through suppression of VWF. This process might be associated with the immature vessel architecture as found in one of the vessels and Ephrin B2 and EPH receptor B4 negativity of both artery-like vessels. The underlying pathomechanism needs to be evaluated in a greater set of patients.

Upstream process optimization and micro- and macrocarrier screening for large-scale production of the oncolytic H-1 protoparvovirus.

The oncolytic virus H-1PV is a promising candidate for various cancer treatments. Therefore, production process needs to be optimized and scaled up for future market release. Currently, the virus is produced with minimum essential medium in 10-layer CellSTACK® chambers with limited scalability, requiring a minimum seeding density of 7.9E3 cells/cm2. Production also requires a 5% fetal bovine serum (FBS) supplementation and has a virus yield up to 3.1E7 plaque-forming units (PFU)/cm2. Using the animal-free cell culture medium VP-SFM™ and a new feeding strategy, we demonstrate a yield boost by a mean of 0.3 log while reducing seeding density to 5.0E3 cells/cm2 and cutting FBS supplementation by up to 40% during the production process. Additionally, FBS is completely removed at the time of harvest. Eleven commercial micro- and macrocarriers were screened regarding cell growth, bead-to-bead transfer capability, and virus yield. We present a proof-of-concept study for producing H-1PV on a large scale with the microcarrier Cytodex® 1 in suspension and a macrocarrier for a fixed-bed iCELLis® bioreactor. A carrier-based H-1PV production process combined with an optimized cell culture medium and feeding strategy can facilitate future upscaling to industrial-scale production. KEY POINTS: • Virus yield increase and FBS-free harvest after switching to cell culture medium VP-SFM™. • We screened carriers for cell growth, bead-to-bead transfer capability, and H-1PV yield. • High virus yield is achieved with Cytodex® 1 and macrocarrier for iCellis® in Erlenmeyer flasks.

Full or intensity-reduced high-dose melphalan and single or double autologous stem cell transplant with or without bortezomib consolidation in patients with newly diagnosed multiple myeloma.

OBJECTIVE: A post hoc subgroup analysis of two phase III trials (NCT00416273, NCT00416208) was carried out to investigate the influence of 100/140 and 200 mg/m² melphalan as well as single/double autologous stem cell transplantation (ASCT) on progression-free survival (PFS). Additionally, the effect of bortezomib consolidation on PFS was analyzed. METHODS: Following induction therapy and high-dose melphalan with subsequent ASCT, patients with newly diagnosed multiple myeloma (NDMM) were randomized 1:1 to either four 35-day cycles of bortezomib consolidation (1.6 mg/m² IV on days 1, 8, 15, 22) or observation. RESULTS: Of the 340 patients included in this analysis, 13.5% received 1 × MEL100/140, 22.9% 2 × MEL100/140, 31.2% 1 × MEL200, and 32.4% 2 × MEL200. With higher cumulative melphalan dose, PFS improved (P = .0085). PFS curves of patients treated with 2 × MEL100/140 and 1 × MEL200 were very similar. The superior dose effect of MEL200 over MEL100/140 was non-existent in the bortezomib consolidation arm but pronounced in the observation arm (P = .0015). Similarly, double ASCT was only beneficial in patients without bortezomib consolidation (P = .0569). CONCLUSIONS: Full dose melphalan and double transplantation seem advantageous only as long as patients are not receiving bortezomib consolidation afterwards.

Matching-adjusted indirect comparison of efficacy outcomes for ciltacabtagene autoleucel in CARTITUDE-1 versus idecabtagene vicleucel in KarMMa for the treatment of patients with relapsed or refractory multiple myeloma.

OBJECTIVE: This study estimated the comparative efficacy of ciltacabtagene autoleucel (cilta-cel) versus the approved idecabtagene vicleucel (ide-cel) dose range of 300-460 × 106 CAR-positive T-cells for the treatment of patients with relapsed or refractory multiple myeloma (RRMM) who were previously treated with a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody (i.e. triple-class exposed) using matching-adjusted indirect treatment comparisons (MAICs). METHODS: MAICs were performed with individual patient data for cilta-cel (CARTITUDE-1; NCT03548207) and published summary-level data for ide-cel (KarMMa; NCT03361748). Treated patients from CARTITUDE-1 who satisfied the eligibility criteria for KarMMa were included in the analyses. The MAIC adjusted for unbalanced baseline covariates of prognostic significance identified in the literature and by clinical expertise. Comparative efficacy was estimated for overall response rate (ORR), complete response or better (≥CR) rate, duration of response (DoR), progression-free survival (PFS), and overall survival (OS). RESULTS: Cilta-cel was associated with statistically significantly improved ORR (odds ratio [OR]: 94.93 [95% confidence interval [CI]: 21.86, 412.25; p < .0001]; relative risk [RR]: 1.34), ≥CR rate (OR: 5.49 [95% CI: 2.47, 12.21; p < .0001]; RR: 2.21), DoR (hazard ratio [HR]: 0.50 [95% CI: 0.29, 0.87; p = .0137]), and PFS (HR: 0.37 [95% CI: 0.22, 0.62; p = .0002]) when compared with ide-cel. For OS, the results were in favor of cilta-cel and clinically meaningful but with a CI overlapping one (HR: 0.55 [95% CI: 0.29, 1.05; p = .0702]). CONCLUSIONS: These analyses demonstrate improved efficacy with cilta-cel versus ide-cel for all outcomes, highlighting its therapeutic potential in patients with triple-class exposed RRMM.

Designing an eHealth Coaching Solution to Improve Transitional Care of Seniors' with Heart Failure: End-User Needs.

Based on scientific studies, heart failure is the principal cause of hospitalization among seniors. More than 50% of elderly with heart failure are readmitted to hospital within six months. Readmission is linked with poor compliance with medical treatment and recommendations, emphasizing the need for a tool to help seniors better comply with post-discharge measures. The goal of this study was to identify end-user needs for the development of a coaching solution aiming to support elderly patients but also formal and informal caregivers. End-user needs were identified through interviews with the three end-user profiles: seniors with heart failure and formal and informal caregivers. The results present six categories of needs: daily treatment follow-up; healthcare network communication; transfer of information; synchronization with current digital tools; information access; and psychosocial support. The identified needs will help to develop an eHealth solution to improve care management and coaching after discharge.

[Work-Related Medical Rehabilitation in Patients with Musculoskeletal Disorders: a Propensity-Score-Analysis]. / Medizinisch-beruflich orientierte Rehabilitation bei Rehabilitanden mit muskuloskelettalen Erkrankungen: eine Propensity-Score-Analyse.

PURPOSE: Work-related medical rehabilitation is a multimodal interdisciplinary approach to reduce health-related discrepancies between work capacity and job demands in order to achieve work participation, especially for patients with severely more restricted work ability. The study tested the effects of a work-related medical rehabilitation program, implemented in routine care, compared with common medical rehabilitation in patients with musculoskeletal disorders. METHODS: Data were assessed in 2014 and 2015 and were analyzed by an as-treated analysis. By means of propensity-score-matching, participants of work-related medical rehabilitation (intervention group, IG) were compared with similar participants of common medical rehabilitation (control group, CG). The primary outcome was a positive work status one year after discharge of rehabilitation. Treatment effects were analyzed by logistic regressions and absolute risk reductions (ARR) were calculated. RESULTS: 312 patients (156 in the IG) were included in the analysis one year after rehabilitation. Propensity-score-matching achieved balanced sample characteristics. Work-related medical rehabilitation increased a positive work status by 11 points (ARR=0.11; 95% CI: 0.02, 0.20; p=0.020) compared to common medical rehabilitation. CONCLUSION: Work-related medical rehabilitation leads to better work participation outcomes after one year compared with common medical rehabilitation.

Recurrent stress across life may improve cognitive performance in individual rats, suggesting the induction of resilience.

Depressive symptoms are often accompanied by cognitive impairments and recurrent depressive episodes are discussed as a potential risk for dementia. Especially, stressful life events are considered a potent risk factor for depression. Here, we induced recurrent stress-induced depressive episodes over the life span of rats, followed by cognitive assessment in the symptom-free period. Rats exposed to stress-induced depressive episodes learned faster than control rats. A high degree of stress-induced depressive-like behavior early in the paradigm was a predictor of improved cognitive performance, suggesting induction of resilience. Subsequently, exposure to lorazepam prior to stress-induced depressive episodes and cognitive testing in a nonaversive environment prevented the positive effect. This indicates a beneficial effect of the stress-associated situation, with the existence of individual coping abilities. Altogether, stress may in some have a beneficial effect, yet for those individuals unable to tackle these aversive events, consecutive unpleasant episodes may lead to worse cognitive performance later in life.

Bortezomib consolidation following autologous transplant in younger and older patients with newly diagnosed multiple myeloma in two phase III trials.

OBJECTIVE: A post hoc analysis of two phase III trials was carried out to explore the influence of age and treatment factors on the effect of bortezomib consolidation on progression-free survival (PFS) post autologous stem cell transplantation (ASCT). METHODS: Patients with newly diagnosed multiple myeloma were assigned to one of two trials (ClinicalTrials.gov IDs: NCT00416273, NCT00416208), which were conducted in parallel, based on age (18-60 or 61-75 years, respectively). Following induction and ASCT, patients were randomized 1:1 to four 35-day cycles of bortezomib consolidation (1.6 mg/m2 IV on days 1, 8, 15, 22) or observation only. RESULTS: Median PFS with bortezomib consolidation vs observation was 33.6 vs 29.0 months (P = 0.3599) in patients aged 18-60 years (n = 202), and 33.4 vs 26.4 months (P = 0.0073) in patients aged 61-75 years (n = 155), respectively. Bortezomib consolidation post-ASCT appeared to equalize outcomes between older and younger patients who received prior treatment of differing intensity. This suggests that the effect of consolidation may be relative and may depend on the composition and intensity of induction and high-dose therapy. CONCLUSION: Older patients receiving less intensive prior treatment could experience a larger PFS benefit from bortezomib consolidation.

Physicians in the pharmaceutical industry: their roles, motivations, and perspectives.

Although physicians occupy a significant number of key positions in the pharmaceutical industry, practicing clinicians are often unaware of the variety of career paths within this industry, or of the structure of a pharmaceutical company. Here, we address questions that practicing clinicians frequently ask their colleagues in the pharmaceutical industry. In addition to providing an overview of the common roles occupied by physicians in pharma, we also describe the various motivations for transitioning into the industry and discuss different scenarios regarding the timing of the career change. Furthermore, we outline the characteristics and skills that enable physicians to have a successful career in pharma.

Re-view and view on maturation disorders in the placenta.

Until delivery, the placenta plays an important mediator role between mother and fetus. This unit is affected by peristatic conditions, such as acute or chronic maternal diseases, malnutrition, drugs, and others. But also genetic factors and fetal malformations due to embryonic developmental disorders may contribute to macroscopically visible changes and functional disorders of the placenta. In a constantly ongoing progress of maturation, the placenta records and saves changes due to fetal distress partly as maturation disorders. Understanding of maturation disorders might, therefore, be an important contribution to a better understanding of influences on villous differentiation and might improve follow up and fetal outcome to reduce recurrence risk. However, an internationally unified classification system of maturation disorders does not exist. In this review, terminology, trials, and classifications of villous maturation disorders are summed up and compared, to pinpoint the need of agreement on an international unified and reproducible classification of maturation disorders.

Identification and quantification of ethylene oxide in sterilized medical devices using multiple headspace GC/MS measurement.

This manuscript, based on the ISO 10993-7 approach, describes a multiple HS-GC measurement of residual EO present in sterilized plastic samples. The quantification of EO is done, according to the ISO standard, by addition of EO amounts extracted for each repeated extraction. During the method development, the specificity of the detection of EO regarding acetaldehyde (structural isomer of EO) which may be formed from EO has been ensured and different tests were performed to check a possible influence of the sample preparation. Assays to maximize EO extraction were performed for different materials (Cyclo-olefine Copolymer (COC), Cyclo-olefine Polymer (COP), Silicon, Polyurethane (PUR)) changing extraction temperatures and times for the headspace and the pre-thermal treatment. Results highlight that depending on the material, EO can be more or less retained and thus thermal extraction conditions to maximize the amount of extractible EO from plastics may change accordingly. For COC syringes a validation according to ICH guidelines and an inter-laboratories study were performed. The method has been used for a market survey of EO sterilized medical devices, results obtained are reported in this manuscript.

Comparative Efficacy of Daratumumab Monotherapy and Pomalidomide Plus Low-Dose Dexamethasone in the Treatment of Multiple Myeloma: A Matching Adjusted Indirect Comparison.

BACKGROUND: Daratumumab (a human CD38-directed monoclonal antibody) and pomalidomide (an immunomodulatory drug) plus dexamethasone are both relatively new treatment options for patients with heavily pretreated multiple myeloma. A matching adjusted indirect comparison (MAIC) was used to compare absolute treatment effects of daratumumab versus pomalidomide + low-dose dexamethasone (LoDex; 40 mg) on overall survival (OS), while adjusting for differences between the trial populations. MATERIALS AND METHODS: The MAIC method reduces the risk of bias associated with naïve indirect comparisons. Data from 148 patients receiving daratumumab (16 mg/kg), pooled from the GEN501 and SIRIUS studies, were compared separately with data from patients receiving pomalidomide + LoDex in the MM-003 and STRATUS studies. RESULTS: The MAIC-adjusted hazard ratio (HR) for OS of daratumumab versus pomalidomide + LoDex was 0.56 (95% confidence interval [CI], 0.38-0.83; p = .0041) for MM-003 and 0.51 (95% CI, 0.37-0.69; p < .0001) for STRATUS. The treatment benefit was even more pronounced when the daratumumab population was restricted to pomalidomide-naïve patients (MM-003: HR, 0.33; 95% CI, 0.17-0.66; p = .0017; STRATUS: HR, 0.41; 95% CI, 0.21-0.79; p = .0082). An additional analysis indicated a consistent trend of the OS benefit across subgroups based on M-protein level reduction (≥50%, ≥25%, and <25%). CONCLUSION: The MAIC results suggest that daratumumab improves OS compared with pomalidomide + LoDex in patients with heavily pretreated multiple myeloma. IMPLICATIONS FOR PRACTICE: This matching adjusted indirect comparison of clinical trial data from four studies analyzes the survival outcomes of patients with heavily pretreated, relapsed/refractory multiple myeloma who received either daratumumab monotherapy or pomalidomide plus low-dose dexamethasone. Using this method, daratumumab conferred a significant overall survival benefit compared with pomalidomide plus low-dose dexamethasone. In the absence of head-to-head trials, these indirect comparisons provide useful insights to clinicians and reimbursement authorities around the relative efficacy of treatments.