RESUMEN
Introduction: Combination of daratumumab (Dara) and lenalidomide (Len) may enhance the function of teclistamab (Tec), potentially resulting in improved antimyeloma activity in a broader population. We present initial safety and efficacy data of Tec-Dara- Len combination in patients with multiple myeloma (MM) in a phase 1b study (MajesTEC-2;NCT04722146). Method(s): Eligible patients who received 1-3 prior lines of therapy (LOT), including a proteasome inhibitor and immune-modulatory drug, were given weekly doses of Tec (0.72-or- 1.5 mg/kg with step-up dosing) + Dara 1800 mg + Len 25 mg. Responses per International Myeloma Working Group criteria, adverse events (Aes) per CTCAE v5.0, and for cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) per ASTCT guidelines, were assessed. Result(s): 32 patients received Tec-Dara- Len (0.72 mg/kg, n = 13;1.5 mg/kg, n = 19). At data cut-off (11 July 2022), median follow-up (range) was 5.78 months (1.0-10.4) and median treatment duration was 4.98 months (0.10-10.35). Median age was 62 years (38-75);87.5% were male. Median prior LOT was 2 (1-3), 18.8% were refractory to Dara and 28.1% refractory to Len. CRS was most frequent AE (81.3% [n = 26], all grade 1/2), 95% occurred during cycle1. Median time to onset was 2 days (1-8), median duration was 2 days (1-22). No ICANS were reported. Frequent Aes (>=25.0% across both dose levels) were neutropenia (75.0% [n = 24];grade 3/4: 68.8% [n = 22]), fatigue (43.8% [n = 14];grade 3/4: 6.3% [n = 2]), diarrhoea (37.5% [n = 12];all grade 1/2), insomnia (31.3% [n = 10];grade 3/4: 3.1% [n = 1]), cough (28.1% [n = 9];all grade 1/2), hypophosphatemia (25.0% [n = 8];all grade 1/2), and pyrexia (25% [n = 8];grade 3/4: 6.3% [n = 2]). Febrile neutropenia frequency was 12.5% (n = 4). Infections occurred in 24 patients (75.0%;grade 3/4: 28.1% [n = 9]). Most common were upper respiratory infection (21.9% [n = 7]), COVID-19 (21.9% [n = 7]), and pneumonia (21.9% [n = 7]). Three (9.4%) had COVID-19 pneumonia. One (3.1%) discontinued due to COVID-19 infection and this patient subsequently died of this infection. Overall response rate (ORR, median follow-up) was 13/13 (8.61 months) at 0.72 mg/kg and 13/16 evaluable patients (less mature at 4.17 months) at 1.5 mg/kg. 12 patients attained very good/better partial response at 0.72 mg/kg dose, and response was not mature for 1.5 mg/kg group. Median time to first response was 1.0 month (0.7-2.0). Preliminary pharmacokinetic concentrations of Tec-Dara- Len were similar as seen with Tec monotherapy. Tec-Dara- Len- treatment led to proinflammatory cytokine production and T-cell activation. Conclusion(s): The combination of Tec-Dara- Len has no new safety signals beyond those seen with Tec or Dara-Len individually. Promising ORR supports the potential for this combination to have enhanced early disease control through the addition of Tec. These data warrant further investigation.
RESUMEN
In phase 1 of CC-92480- MM- 001 (NCT03374085), the recommended phase 2 dose (RP2D) of mezigdomide plus dexamethasone (MEZI-d) was selected at 1 mg once daily for 21/28 days. Here we report preliminary results from the MEZI-d dose-expansion cohort in patients with heavily pretreated RRMM. Key eligibility criteria were: RRMM;>=3 prior lines of therapy;disease progression <=60 days of last myeloma therapy;refractoriness to lenalidomide/pomalidomide, a proteasome inhibitor, a glucocorticoid, and an anti-CD38 monoclonal antibody. Oral mezigdomide 1 mg was given on days 1-21 of each 28-day cycle, plus weekly dexamethasone (40 mg;20 mg if >75 years of age). Primary objective was to evaluate efficacy (overall response rate [ORR]);secondary objectives included safety/tolerability and additional efficacy assessments. Pharmacodynamics was an exploratory objective. As of 16/Sep/2022, 101 patients had received MEZI-d at the RP2D. Median age was 67 (range 42-85) years, median time since initial diagnosis was 7.4 (1.1-37.0) years;39.6% of patients had plasmacytomas and 37/101 patients had high-risk cytogenetics (56/101 not evaluable). Median number of prior regimens was 6 (3-15);prior therapies included stem cell transplantation (77.2%) and anti-BCMA therapy (29.7%). All patients were refractory to last myeloma regimen and triple-class refractory. Median follow-up was 7.5 (0.5-21.9) months, with a median of 4 (1-20) cycles;10.0% of patients continued treatment;progressive disease was the main reason for discontinuation (60.4%). ORR was 40.6% for all patients. Whilst data are not mature yet, median PFS was 4.4 (95% CI 3.0-5.5) months and median duration of response was 7.6 (95% CI 5.4-9.5) months. ORR was 30.0% in patients with plasmacytomas (N = 40) and 50.0% in patients with prior anti-BCMA therapy (N = 30). Ninety-one (91.1%) patients experienced a grade 3/4 treatment-emergent adverse event (TEAE). Most frequent hematologic grade 3/4 TEAEs were neutropenia (75.2%), anaemia (35.6%), and thrombocytopenia (27.7%);34.7% of patients had grade 3/4 infections, including grade 3/4 pneumonia (15.8%) and COVID-19 (7.0%). Occurrence of other grade 3/4 non-hematologic TEAEs was generally low. Due to TEAEs, 76.2% and 29.7% of patients had mezigdomide dose interruptions and reductions, respectively;90.1% of patients discontinued mezigdomide. Mezigdomide induced substrate degradation and increases in activated and proliferating T cells in patients, including those directly refractory to pomalidomide-based therapies. MEZI-d had a manageable safety profile with encouraging efficacy in patients with triple-class refractory RRMM, including patients with prior BCMA-targeted therapies. These results strongly support the continued development of mezigdomide in MM, and especially in combination.
RESUMEN
Background. Despite extensive studies of human immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and coronavirus disease 2019 (COVID-19) vaccination, research examining protective correlates of vertical transmission following maternal exposure in pregnancy remain limited. Here, we characterized antibody and cytokine responses in maternal and cord blood following infection or vaccination at various timepoints during gestation. Methods. Spike S1 protein-specific binding antibodies and antibodies capable of blocking the interaction between the receptor binding domain (RBD) and the angiotensin converting enzyme 2 (ACE2) were measured in maternal and cord blood by ELISA. Serum concentrations of 74 cytokines/chemokines were measured by multiplex assay. Humoral responses and cytokine levels from matched maternal and fetal cord sera were compared and examined for potential correlations. Results. We observed a highly significant correlation between Spike S1-specific antibody titer and RBD-ACE2 blocking antibody activity between maternal and fetal cord serum (p < 2.2e-16, R > 0.90). Blocking antibody activity was significantly higher for mothers infected during the 3rd trimester compared to earlier trimesters;however, vaccinated mothers developed and transferred higher antibody titers with greater RBD-ACE2 blocking antibody activity to their neonates than infected mothers. Furthermore, vaccine-induced Spike S1 IgG transfer ratios (fetal cord/maternal) were significantly higher than those induced by infection (p = 0.002). Multiplex assay showed significantly elevated levels of 33 cytokines/chemokines, mainly pro-inflammatory in infected maternal serum samples, while the paired fetal cord samples exhibited an anti-inflammatory cytokine predominance. Conclusion. Our data support selective vertical transmission of potentially protective humoral responses against SARS-CoV-2, especially following vaccination in the 3rd trimester. The anti-inflammatory cytokine predominance in cord blood that persists despite maternal SARS-CoV-2 infection may offset the adverse outcomes of inflammation in pregnancy for the neonate.
RESUMEN
Background & aims: COVID19 disproportionately affects the immunosuppressed, but its epidemiology over time is incompletely characterised. We describe Australian experiences of COVID19 in a national observational study of patients with malignancy. Methods: An ongoing multisite prospective cohort study of adult COVID19 patients with active cancer was conducted. Clinical and laboratory data over 28 months (1/3/20-22/7/22) was collated from 15 hospitals. Results: There were 491 patients included. Patients were a median of 63(IQR:50-71) years with majority male (254,52%). Solid organ malignancy was most common (296,60%), followed by haematological malignancy (180,37%), then both (15,4%). Most common solid tumour was breast cancer (74/296,25%);most common haematological cancer was lymphoma (102/180,57%). Majority (275,56%) were undergoing cancer treatment at COVID19 diagnosis. From 2020-2022, patients presented less with lower respiratory tract infections (57%,36%,5%) with increasing outpatient management (26%,50%,67%). Improved mortality was seen (27%,19%,11%). Median inpatient length of stay was 8(4-11) days. Intensive care admission was low (21,4%). For patients who had repeated respiratory PCR testing, median time from first to last positive test was 17(7-25, n = 123) days. Cancer treatment modification occurred in 18(4%) and delay in 74(15%). Conclusion: Despite improvements in outcomes, COVID19 still results in morbidity with impacts on cancer treatment. This preliminary data shows that cancer patients remain a vulnerable group and should be prioritised for public health interventions.
RESUMEN
Background: The bortezomib, lenalidomide, and dexamethasone (VRd) regimen is a standard of care for newly diagnosed multiple myeloma (NDMM). Belantamab mafodotin (belamaf) is a B-cell maturation antigen-binding antibody-drug conjugate that eliminates myeloma cells by a multimodal mechanism: direct cell kill and anti-myeloma tumor immune response. Belamaf has demonstrated deep and durable responses as a monotherapy in the DREAMM-2 study of patients (pts) with relapsed/refractory multiple myeloma (RRMM). Preclinical evidence of belamaf in combination with bortezomib or lenalidomide suggests enhanced anti-myeloma activity, providing rationale for this treatment combination. Aims: To evaluate the safety and tolerability of this combination in adult pts with transplant-ineligible (TI) NDMM and establish the recommended Phase III dose. Methods: DREAMM-9 (NCT04091126) is an ongoing Phase I, open-label, randomized study of belamaf + VRd. The belamaf dose cohorts currently being evaluated are Cohort 1 (1.9 mg/kg Q3/4W), Cohort 2 (1.4 mg/kg Q6/8W), Cohort 3 (1.9 mg/kg Q6/8W), Cohort 4 (1.0 mg/kg Q3/4W), and Cohort 5 (1.4 mg/kg Q3/4W). Belamaf is given with VRd Q3W until Cycle 8, and with Rd Q4W thereafter. After evaluation of safety data for Cohort 1, Cohorts 2-5 were opened in parallel and enrolled pts were randomized 1:1:1:1. Primary endpoint is safety. Secondary endpoints include efficacy, tolerability, and pharmacokinetics (PK). Results: As of data cutoff (07 Dec 2021), 64 pts were analyzed across all cohorts. Median age (range) was 73.0 (51- 88) years, 55% were male, 80% were white, 8% had extramedullary disease, 59% were International Staging System stage II or III, 20% had amp1q, and 17% had high-risk cytogenetics (≥1 of: t(4;14), t(14;16), del17p). The median duration of follow-up varied: Cohort 1 (17.4 months [mo]), Cohort 2 (5.9 mo), Cohort 3 (6.1 mo), Cohort 4 (4.7 mo), Cohort 5 (5.8 mo). Median number of belamaf cycles were: Cohort 1 (6), Cohort 2 (3), Cohort 3 (3.5), Cohort 4 (4.5), and Cohort 5 (5). Most common adverse events (AEs) across cohorts included thrombocytopenia (49%), constipation (43%), diarrhea (32%), and peripheral sensory neuropathy (30%). AEs related to study treatment were experienced by 61 (97%) pts. Belamaf-related grade 3/4 AEs occurred in 24 (38%) pts. Belamaf dose reductions occurred in 11 (18%) pts, with dose delays in 10 (16%) pts. Three pts experienced a fatal severe AE (unrelated to study treatment);2 due to COVID-19 infection, 1 due to pancreatic adenocarcinoma. Early deep responses were observed;67-92% pts achieved ≥very good partial response (VGPR) (Table), with median time to VGPR of 2.1-2.9 months across cohorts. Of pts with ≥VGPR, 17 were minimal residual disease (MRD) negative, 10 in Cohort 1. As of data cutoff, 8-75% of pts achieved best response of complete response (CR) or stringent CR (sCR). Grade 3 corneal exam findings were reported in 25-58% of pts;grade 3 visual acuity changes were reported in 21-75% of pts. No grade 4 corneal exam findings or visual acuity changes were reported in pts receiving belamaf Q6/8W, compared with 0-17% and 0-8%, respectively, in the Q3/4W cohorts. Belamaf PK profile was similar to that in pts with RRMM, accounting for baseline characteristics. Image: Summary/Conclusion: Belamaf + VRd demonstrated high response rates in pts with TI NDMM, with a high rate of MRD negativity indicating deep responses. No new safety signals were observed relative to DREAMM-2. Study is ongoing to evaluate the safety and efficacy of variable dose intensities of belamaf in combination with VRd.
RESUMEN
Background: The bortezomib, lenalidomide, and dexamethasone (VRd) regimen is a SoC for NDMM. Belamaf, a B-cell maturation antigen (BCMA)-targeting antibody-drug conjugate, demonstrated durable responses in patients with relapsed/refractory multiple myeloma. Preclinical studies of belamaf in combination with bortezomib/ lenalidomide suggest enhanced antimyeloma activity. We report preliminary findings of belamaf + VRd for patients with TI NDMM. Materials and Methods: DREAMM-9 (NCT04091126) is an ongoing Phase I, open label, randomized, dose and schedule evaluation trial. Adults with TI NDMM and ECOG status 0-2 are eligible. VRd is administered Q3W until Cycle 8, followed by lenalidomide + dexamethasone (Rd) Q4W. Belamaf + VRd is administered until Cycle 8, and with Rd thereafter. The currently evaluated belamaf dose cohorts are: Cohort 1 (1.9 mg/kg Q3/4W), Cohort 2 (1.4 mg/kg Q6/8W), Cohort 3 (1.9 mg/ kg Q6/8W), Cohort 4 (1.0 mg/kg Q3/4W), and Cohort 5 (1.4 mg/kg Q3/4W). Primary endpoint is safety. Secondary endpoints include efficacy, tolerability, and pharmacokinetics (PK). Results: Overall 36 patients were treated across the 5 cohorts. The median (range) age was 74.0 (63-80) years;56% patients were male, 17 (47%) had stage 2 disease, 3 (8%) had extramedullary disease, 6 (17%) patients had high risk cytogenetic abnormalities;the median number of belamaf cycles ranged from 1-9. No new safety signals were observed. Across Cohorts 1-5, all patients experienced AEs related to study treatment;1 patient in Cohort 1 died due to COVID-19 infection. The most common AEs leading to dose modification were thrombocytopenia, neutropenia, and corneal events. Patients in Cohort 2 and 3 had the lowest number of Grade ≥3 corneal events (3 and 2 events, respectively). All 12 patients in Cohort 1, all 6 in Cohorts 3 and 5, and 5/6 patients in Cohorts 2 and 4 have responded to the treatment;≥half of patients in each cohort achieved very good partial response or better. As of data cut-off, 3/12 patients in Cohort 1, 2/6 in Cohort 4, and 1/6 patients each in Cohorts 3 and 5 remained in complete response. Belamaf PK profile was similar to that observed in patients with RRMM taking into consideration baseline patients characteristics. Conclusions: Preliminary data suggest addition of belamaf to VRd did not reveal new safety signals and demonstrates high response rates, albeit with short follow-up. The trial is ongoing to confirm safety and evaluate the efficacy of belamaf + VRd. .
RESUMEN
INTRODUCTION: Management of the airway in the perioperative period for patients requiring major head and neck ablative surgery has commonly included the performance of elective surgical tracheostomy. This has been standard practice in most maxillofacial units across the UK, including ours. However, the COVID-19 pandemic and emerging guidelines on aerosol-generating procedures required us to revisit the need for a perioperative tracheostomy. METHODS: We present our series of 29 consecutive cases, cared for during the first wave of the COVID-19 pandemic, that were managed either using surgical tracheostomy or overnight tracheal intubation. RESULTS: Out of 29 patients 3 received a surgical tracheostomy. The average duration of tracheostomy use was 8 days. Twenty patients were managed using a period of overnight tracheal intubation. Average duration of tracheal intubation was 1.2 days, with an average intensive care unit stay of 1.7 days. The average duration of hospital stay was 15.8 days for patients managed with overnight tracheal intubation and 30.1 days for patients who received a surgical tracheostomy. The return to theatre rate was 13.8% for reasons including flap failure and neck space infection. There were no airway issues reported in this series of patients. CONCLUSIONS: Our findings suggest that overnight tracheal intubation can be a safe alternative to surgical tracheostomy in the majority of cases.
Asunto(s)
COVID-19 , Traqueostomía , Humanos , Traqueostomía/métodos , COVID-19/epidemiología , Pandemias , Estudios Retrospectivos , Intubación Intratraqueal/métodosRESUMEN
BACKGROUND Bortezomib-based induction (V-IND) approaches are used in >90% of Australian newly diagnosed transplant eligible multiple myeloma (NDTE MM) patients (pts) with a maximum of 4 cycles of V-IND therapy available via the pharmaceutical benefits scheme (PBS) prior to a planned autologous stem cell transplantation (ASCT). However, NDTE MM patients failing V-IND (defined as best response < partial response [PR]) demonstrate shortened survival and continue to represent a sub-group of MM where a clear unmet medical need persists. The ALLG MM21 was designed to evaluate the efficacy of an early response adapted approach with a switch to an intensive Daratumumab-lenalidomide-dexamethasone (DRd)-based salvage-ASCT- consolidation strategy in patients failing V-IND. METHOD We present the results of a planned interim analysis of the multi-centre single arm study MM21 (ACTRN12618001490268). Eligible pts were NDTE MM who had received V-IND pre-ASCT and demonstrated either a sub-optimal response (SOR - defined as <minimal response [MR] after 2 cycles or <PR after 4 cycles of V-IND) or primary refractoriness (1REF - defined as disease progression while on or within 60 days of completing V-IND). Pre-ASCT DRd was DARA 16mg/kg IV days 1, 8, 15 and 22 for cycles 1 (C1) and 2, and on days 1 and 15 of C3 and C4;Lenalidomide 25mg OD D1-21;and, dexamethasone 40mg PO on D 1, 8, 15 and 22 of each 28-day cycle for C1 to C4. Anti-thrombotic and anti-viral prophylaxis was as per individual institutional practice. Between C3 and C4, patients underwent a G-CSF mobilised PBSC collection with a melphalan 200mg/m2 conditioned ACST after C4. Patients underwent D100 post-ASCT disease response assessment including EuroFlow minimal residual disease (MRD) testing. In the absence of disease progression, patients then received 12, 28-day cycles of consolidation comprising DARA IV 16mg/kg on D1, 15 of C1 and C2 and on D1 of C3 to C12, lenalidomide 25mg PO on D1-21 of C1 and C2 and 10mg OD on days 1-28 of C3 to C12;dexamethasone 40mg was weekly from C1 to C12. RESULTS Fifty patients were recruited from 7 Australian sites between March 2019 and July 2020. Median age was 61 years with 66% males. Disease status at study entry was SOR in 72% (<MR n = 9, <PR n = 27) and 1REF in 28%. Data cut-off date was June 30 2021. 45 patients (90%) received 4 complete cycles of salvage DRd. 11/50 (22%) patients did not undergo ASCT and 4 patients failed stem cell collection. Two pts were withdrawn due to treatment related gastrointestinal toxicity - persistent oesophagitis (n =1) and recurrent colitis (n=1). There were two deaths, due to COVID-19 pneumonia (n =1) and septic shock (n =1). Pre-ASCT response was evaluable in 43 patients, overall response rate (ORR) was 70% - complete response (CR) 6%, very good partial response (VGPR) 18%, partial response (PR) 46%, clinical benefit rate (CBR) 83% - MR 11% and stable disease (SD) 2% on Intention to Treat (ITT n = 50) analysis. 33 patients were assessed for MRD - MRD negative 6% on ITT (3/33 9%). Pre-consolidation disease assessment was evaluable in 37 pts, both ORR and CBR were 72% - stringent complete response (sCR) 4%, CR 14%, VGPR 24%, PR 30% ITT analysis. 31 pts were evaluated for MRD - MRD negative 28% ITT (14/31 45%). In 6 patients, MRD was omitted or could not be performed due to pre-analytical issues. Post-C2 consolidation assessment was evaluable in 37 pts, ORR 72% - sCR 2%, CR 24%, VGPR 26%, PR 20%, CBR 74% - SD 2% ITT analysis. To date, 22 patients have been evaluated for MRD with 4 patients awaiting results, MRD negative rate of 38% ITT (10/22 45%). MRD sample collection at this time-point was omitted in 7 patients, potentially skewing MRD negativity on ITT analysis. CONCLUSION Preliminary analysis of the MM21 trial demonstrates early response-adaptive escalation to DRd facilitated ASCT in the majority patients with robust ORR post-autologous stem cell transplant and substantial improvement in disease control, as reflected in improved rates of MRD and disease response to treatment. At both post-ASCT time-p ints there was significant drop off in MRD testing due to testing omission, potential skewing results of MRD analysis. MRD and duration of response analysis following C12 consolidation is planned and will be of interest. Current data suggests this drug combination shows potential for substantial benefit in the study population. (Figure Presented).
RESUMEN
Introduction: The bortezomib, lenalidomide, and dexamethasone (VRd) regimen is an acceptable standard of care (SoC) for both transplant-eligible and transplant-ineligible newly diagnosed multiple myeloma (TI NDMM). Ongoing development of novel therapies and combinations strive to improve survival outcomes beyond what is expected from SoC. Belantamab mafodotin (belamaf) is a B-cell maturation antigen-binding antibody-drug conjugate that eliminates myeloma cells by a multimodal mechanism and has demonstrated durable responses in patients with relapsed/refractory multiple myeloma (RRMM). Preclinical evidence of belamaf in combination with bortezomib or lenalidomide suggests enhanced anti-myeloma activity, providing rationale for this treatment combination. We report the preliminary findings of belamaf + VRd for TI NDMM patients. Methods: DREAMM-9 (NCT04091126) is an ongoing Phase I, open-label, randomized, dose and schedule evaluation study of belamaf + VRd in patients with TI NDMM. Eligible patients include those ≥18 years old with ECOG status 0-2 and adequate organ system functions. The study evaluates safety and tolerability of belamaf + VRd in up to 8 cohorts, up to 144 patients, to establish the recommended phase 3 dose (RP3D). VRd is administered Q3W until cycle 8, followed by lenalidomide + dexamethasone (Rd) Q4W. Belamaf + VRd is administered until cycle 8, and then in combination with Rd thereafter. The belamaf dose cohorts currently being evaluated are: cohort 1 (1.9 mg/kg Q3/4W), cohort 2 (1.4 mg/kg Q6/8W), cohort 3 (1.9 mg/kg Q6/8W), cohort 4 (1.0 mg/kg Q3/4W), and cohort 5 (1.4 mg/kg Q3/4W). After evaluation of safety data for cohort 1, cohorts 2-5 were opened in parallel and enrolled patients were randomized 1:1:1:1. Safety data, clinical activity, and drug concentrations will be assessed, and used to determine the belamaf RP3D. This analysis reports the preliminary results from cohort 1. Primary endpoints include number of patients with adverse events (AEs). Secondary endpoints include establishing relative dose intensity of lenalidomide and bortezomib in combination with belamaf, cumulative dose of belamaf, pharmacokinetics (PK) profile of belamaf when combined with VRd, overall response rate (ORR), complete response (CR), stringent complete response (sCR), complete response rate ([CRR];% of patients with a confirmed CR or better), and rate of very good partial response or better (≥VGPR). Exploratory endpoints include assessing minimal residual disease (MRD) in patients who achieve ≥VGPR, and safety and efficacy exposure-response relationships. Results: Twelve patients in cohort 1 were included in this preliminary analysis. Eight patients (67%) were male;median age (range) was 72.5 years (63-77). Ten patients (83%) were white and 2 (17%) were Asian. Nine patients (75%), were ISS stage II or III, and 4 (33%) patients had high-risk cytogenetics (consisting of one or more of the following: t(4;14), t(14;16), del17p, 17p13del). AEs related to study treatment were experienced by all 12 patients. Dose reductions occurred in 12 (100%) patients, all of whom also experienced a dose delay. Most common AEs leading to dose modification were thrombocytopenia, neutropenia, and corneal events. Grade 3 or 4 AEs related to belamaf occurred in 9 (75%) patients. During the trial, one patient experienced a fatal severe AE due to COVID-19 infection (unrelated to study treatment;Table). All patients, 100% (n=12;95% CI: 73.5-100) achieved ≥VGPR. Early deep responses were observed;2 (17%) patients achieved VGPR as early as 4 weeks. As of data cut-off, 5 (42%) remain in CR and 3 (25%) in sCR. Based on real-time data captured in the clinical database, 7 out of 9 patients achieved MRD-negative status at the first test after VGPR. Belamaf PK profile was similar to that observed in patients with RRMM taking into consideration baseline patients characteristics. Conclusion: Preliminary data suggest addition of belamaf to VRd did not reveal new safety signals and demonstrates high response rates, albeit with short follow up. The study is ongoing to confirm safety and evaluate the efficacy of belamaf + VRd. Updated data for cohort 1 will be reported at the congress. Funding: GSK (Study 209664);belamaf drug linker technology licensed from Seagen;belamaf monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa. [Formula presented] Disclosures: Usmani: Pharmacyclics: Consultancy, Research Funding;Seattle Genetics: Consultancy, Research Funding;Takeda: Consultancy, Research Funding, Speakers Bureau;Merck: Consultancy, Research Funding;SkylineDX: Consultancy, Research Funding;Sanofi: Consultancy, Research Funding, Speakers Bureau;Janssen: Consultancy, Research Funding, Speakers Bureau;Janssen Oncology: Consultancy, Research Funding;Bristol-Myers Squibb: Research Funding;EdoPharma: Consultancy;GSK: Consultancy, Research Funding;Celgene/BMS: Consultancy, Research Funding, Speakers Bureau;Array BioPharma: Consultancy, Research Funding;Abbvie: Consultancy;Amgen: Consultancy, Research Funding, Speakers Bureau. Quach: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;GlaxoSmithKline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;Janssen/Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Antengene: Consultancy, Membership on an entity's Board of Directors or advisory committees;Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees;CSL: Consultancy, Membership on an entity's Board of Directors or advisory committees. Koh: Pfizer: Consultancy;Jassen: Honoraria;AstraZeneca: Honoraria;Novartis: Honoraria;GSK: Honoraria;Roche: Honoraria;Takeda: Honoraria. Guenther: Novartis: Consultancy;Celgene: Consultancy, Honoraria;Roche: Consultancy;Takeda: Consultancy, Honoraria;Amgen: Consultancy, Honoraria;AbbVie: Consultancy;Jazz Pharmaceuticals: Honoraria;Janssen Pharmaceuticals: Consultancy, Honoraria. Zhou: GlaxoSmithKline: Current Employment. Kaisermann: GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Mis: GlaxoSmithKline: Current Employment. Williams: GlaxoSmithKline: Current Employment. Yeakey: GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Ferron-Brady: GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Figueroa: GlaxoSmithKline: Current Employment. Kremer: GlaxoSmithKline: Current Employment. Gupta: Novartis: Current equity holder in publicly-traded company;GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Janowski: Celgene: Consultancy;AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees;Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees;Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees;BMS: Membership on an entity's Board of Directors or advisory committees.
RESUMEN
Background: High-risk smoldering multiple myeloma (HR-SMM) is associated with a greater risk of progression to symptomatic disease, suggesting the need for early, efficacious therapeutic interventions to improve outcomes. The ongoing, randomized Phase 3 ITHACA study (NCT04270409) is evaluating efficacy and safety of the anti-CD38 monoclonal antibody isatuximab (Isa) in combination with lenalidomide (R) and dexamethasone (d) (Isa-Rd) vs Rd in patients (pts) with HR-SMM. We report here preliminary results from the safety run-in part of this trial. Methods: The primary objective was to confirm the recommended dose of Isa in combination with Rd. Pts were eligible if diagnosed with SMM within 5 years and HR-SMM defined by the Mayo ‘20-2-20’ and/or updated PETHEMA model criteria. Minimal residual disease and imaging by MRI and low-dose whole-body CT/PET-CT will be assessed at fixed time points. Results: As of April 12, 2021, 23 pts (median age, 63 [28–85] years;median time from initial diagnosis, 1.14 [0.1–5.2] years) had received Isa 10 mg/kg once weekly then biweekly (QW-Q2W) in combination with Rd. The median number of cycles was 7 (range, 4–10) and median duration of treatment exposure was 29.7 (range, 16.0–38.0) weeks. Two pts met the Mayo clinical model criteria, 13 pts the PETHEMA model criteria, and 8 pts both models’ criteria for HR-SMM. No pt presented with focal lesions at baseline. Seven (30.4%) pts developed 8 grade ≥3 non-hematologic treatment-emergent adverse events (TEAEs): COVID-19 pneumonia, insomnia (2 each), papular rash, muscle spasm, retinal detachment and hyperglycemia (1 each);no pt experienced a grade 5 TEAE and no pt discontinued treatment due to a TEAE. Serious TEAEs were COVID-19 pneumonia (n=2, grade ≥3) and pneumonia, musculoskeletal chest pain and pyrexia (n=1 each, grade <3). The most common, mostly grade 1–2 TEAEs were insomnia (39%) and constipation, headache, and peripheral edema (22% each). Infusion reactions were reported in 2 pts (8.7%) (grade 2, infusion day 1/cycle 1). By laboratory results, no grade 3–4 anemia or thrombocytopenia was observed;grade 3 neutropenia was reported in 5 pts (21.7%), with no grade 4. Isa exposure and CD38 receptor occupancy were in accordance with other MM studies, reaching target saturation in bone marrow plasma cells. The overall response rate was 86.9%;21.7%, 17.4%, and 4.3% of pts have so far achieved very good partial response (VGPR), complete response (CR) and stringent CR (sCR), respectively. Conclusions: Addition of Isa 10 mg/kg QW-Q2W to Rd was associated with a favorable safety profile in pts with HR-SMM, which compares well with Rd literature data in the same patient population. Isa-Rd has shown encouraging preliminary efficacy (21.7% sCR/CR and 43.4% ≥VGPR rates) in pts with HR-SMM. These results confirm the recommended dose of Isa for the randomized part of the Phase 3 ITHACA study, which will further evaluate efficacy and safety of Isa-Rd in HR-SMM. Funding: Sanofi.
RESUMEN
Introduction: The randomized, open-label, multicenter, phase 3 CANDOR study compared carfilzomib, dexamethasone, and daratumumab (KdD) to carfilzomib and dexamethasone (Kd) in patients with multiple myeloma who have relapsed after 1-3 prior lines of therapy (ClinicalTrials.gov, NCT03158688). In the previously reported primary analysis (Dimopoulos et al, Lancet 2020), a significant progression-free survival (PFS) benefit was demonstrated in patients treated with KdD vs patients treated with Kd (hazard ratio [HR], 0.63 [95% CI, 0.46-0.85];two-sided P=0.0027). However, after a median follow-up of 16.9 months, median PFS was not reached in the KdD arm. Here, we report updated efficacy and safety outcomes from the CANDOR study. Methods: Adult patients with relapsed or refractory multiple myeloma (RRMM) received 28-day cycles of KdD or Kd (randomized 2:1). In the primary analysis, PFS was the primary endpoint and overall survival (OS) a key secondary endpoint. In this prespecified interim OS analysis, statistical testing was based on the actual number of OS events observed by the data cutoff (approximately 36 months after enrollment of the first patient);PFS was summarized descriptively. Disease progression was determined locally by investigators in an unblinded manner and centrally by the sponsor using a validated computer algorithm (Onyx Response Computer Algorithm [ORCA]) in a blinded manner. PFS and OS were compared between the KdD and Kd arms using a stratified log-rank test, and HRs were estimated by a stratified Cox proportional-hazards model. Results: Patients were randomized to KdD (n = 312) and Kd (n = 154). Of all randomized patients, median age was approximately 64 years;42% received previous lenalidomide, and 33% were lenalidomide refractory;90% received previous bortezomib, and 29% were bortezomib refractory. At the data cutoff date of June 15, 2020, 199 (63.8%) patients in the KdD arm and 88 (57.1%) in the Kd arm remained on study. Among patients treated with KdD and Kd, 140 (44.9%) and 85 (55.2%) had PFS events, respectively;median follow-up was 27.8 months (KdD) and 27.0 months (Kd). Median PFS by ORCA was 28.6 months for the KdD arm versus 15.2 months for the Kd arm (HR, 0.59 [95% CI, 0.45-0.78];Figure). OS data were not mature and will be updated at a future prespecified analysis. Median treatment duration was 79.3 weeks with KdD versus 40.3 weeks with Kd. Grade ≥3 adverse events (AEs) occurred in 87.0% and 75.8% of patients in the KdD and Kd arms, respectively, and fatal AEs occurred in 8.8% and 4.6%;one fatal AE in the KdD arm (due to arrhythmia) and one fatal AE in the Kd arm (due to COVID-19 pneumonia) had occurred since the primary analysis. Carfilzomib treatment discontinuation rates due to AEs were 26.0% with KdD and 22.2% with Kd. Exposure-adjusted AE rates per 100 patient years were: 171.2 and 151.9 for grade ≥3 AEs and 6.9 and 5.6 for fatal AEs in the KdD and Kd arms, respectively. Updated data by key subgroups will be presented. Conclusion: With approximately 11 months of additional follow-up, a 13.4-month improvement in median PFS was observed in patients treated with KdD (28.6 months) versus patients treated with Kd (15.2 months;HR, 0.59 [95% CI, 0.45-0.78]). Safety was consistent with previously reported results. KdD continues to show a favorable benefit-risk profile and represents an efficacious treatment option for patients with RRMM. [Formula presented] Disclosures: Dimopoulos: Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau;BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees;Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau;Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau;Celgene: Consultancy, Ho oraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Speakers Bureau. Quach: GlaxoSmithKline, Karyopharm, Amgen, Celgene, Janssen Cilag: Consultancy;Amgen, Celgene, karyopharm, GSK, Janssen Cilag, Sanofi.: Membership on an entity's Board of Directors or advisory committees;Amgen, sanofi, celgene, Karyopharm, GSK: Research Funding;GlaxoSmithKline, Karyopharm, Amgen, Celgene, Janssen Cilag: Honoraria. Mateos: EDOMundipharma: Consultancy;Adaptive: Consultancy;Pharmamar: Consultancy;GlaxoSmithKline: Consultancy;AbbVie: Consultancy;Takeda: Consultancy;Amgen: Consultancy;Celgene: Consultancy;Janssen: Consultancy. Landgren: Pfizer: Consultancy, Honoraria;Merck: Other;Cellectis: Consultancy, Honoraria;Juno: Consultancy, Honoraria;Glenmark: Consultancy, Honoraria, Research Funding;BMS: Consultancy, Honoraria;Binding Site: Consultancy, Honoraria;Celgene: Consultancy, Honoraria, Research Funding;Pfizer: Consultancy, Honoraria;Karyopharma: Research Funding;Merck: Other;Janssen: Consultancy, Honoraria, Other: Independent Data Monitoring Committees for clinical trials, Research Funding;Takeda: Other: Independent Data Monitoring Committees for clinical trials, Research Funding;Glenmark: Consultancy, Honoraria, Research Funding;Juno: Consultancy, Honoraria;Seattle Genetics: Research Funding;Cellectis: Consultancy, Honoraria;Seattle Genetics: Research Funding;Takeda: Other: Independent Data Monitoring Committees for clinical trials, Research Funding;BMS: Consultancy, Honoraria;Adaptive: Consultancy, Honoraria;Amgen: Consultancy, Honoraria, Research Funding;Celgene: Consultancy, Honoraria, Research Funding;Binding Site: Consultancy, Honoraria;Janssen: Consultancy, Honoraria, Other: Independent Data Monitoring Committees for clinical trials, Research Funding;Karyopharma: Research Funding. Leleu: Incyte: Honoraria;Merck: Honoraria;Novartis: Honoraria;Amgen: Honoraria;GSK: Honoraria;Sanofi: Honoraria;BMS-celgene: Honoraria;Janssen: Honoraria;Oncopeptide: Honoraria;AbbVie: Honoraria;Carsgen: Honoraria;Karyopharm: Honoraria. Siegel: Janssen: Consultancy, Honoraria, Speakers Bureau;Merck: Consultancy, Honoraria, Speakers Bureau;Amgen: Consultancy, Honoraria, Speakers Bureau;Celulatiry: Consultancy;Karyopharma: Consultancy, Honoraria;Takeda: Consultancy, Honoraria, Speakers Bureau;BMS: Consultancy, Honoraria, Speakers Bureau. Weisel: Takeda: Consultancy, Honoraria;Amgen: Consultancy, Honoraria, Research Funding;Karyopharm: Consultancy, Honoraria;Adaptive: Consultancy, Honoraria;Bristol-Myers Squibb: Consultancy, Honoraria;GlaxoSmithKline: Honoraria;Sanofi: Consultancy, Honoraria, Research Funding;Janssen: Consultancy, Honoraria, Research Funding;Celgene: Consultancy, Honoraria, Research Funding;Abbvie: Consultancy, Honoraria;Roche: Consultancy, Honoraria. Gavriatopoulou: Takeda: Consultancy, Honoraria;Janssen: Consultancy, Honoraria;Genesis Pharma: Consultancy, Honoraria;Karyopharm: Consultancy, Honoraria;Amgen: Consultancy, Honoraria. Oriol: Janssen: Consultancy;Celgene: Consultancy, Speakers Bureau;Amgen: Consultancy, Speakers Bureau. Rabin: Janssen, BMS/Celgene, Takeda, Karyopharm, Amgen: Consultancy;Janssen, BMS/Celgene, Takeda: Other: Travel;Jansse, BMS/Celgene, Takeda: Speakers Bureau. Nooka: GlaxoSmithKline: Consultancy, Honoraria, Other: Personal Fees: Travel/accomodations/expenses, Research Funding;Karyopharm Therapeutics, Adaptive technologies: Consultancy, Honoraria, Research Funding;Spectrum Pharmaceuticals: Consultancy;Celgene: Consultancy, Honoraria, Research Funding;Amgen: Consultancy, Honoraria, Research Funding;Oncopeptides: Consultancy, Honoraria;Janssen: Consultancy, Honoraria, Research Funding;Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding;Sanofi: Consultancy, Honoraria;Adaptive Technologies: Consultancy, Honoraria;Takeda: Consultancy, Honoraria, Research Funding. Ding: Amgen: Current Employment. Zahlten-Kumeli: Amgen: Current Employment, Current equity holder in publicly-traded compan . Usmani: Celgene: Other;GSK: Consultancy, Research Funding;Pharmacyclics: Research Funding;Array Biopharma: Research Funding;Seattle Genetics: Consultancy, Research Funding;Merck: Consultancy, Research Funding;Incyte: Research Funding;SkylineDX: Consultancy, Research Funding;Takeda: Consultancy, Honoraria, Other: Speaking Fees, Research Funding;Sanofi: Consultancy, Honoraria, Research Funding;Abbvie: Consultancy;BMS, Celgene: Consultancy, Honoraria, Other: Speaking Fees, Research Funding;Amgen: Consultancy, Honoraria, Other: Speaking Fees, Research Funding;Janssen: Consultancy, Honoraria, Other: Speaking Fees, Research Funding.
RESUMEN
[Formula presented] Introduction Daratumumab, when added to standard of care regimens in relapsed and untreated myeloma, has consistently demonstrated significant improvements in response rates, induction of MRD negative responses and progression-free survival (PFS) while proving highly tolerable with minor increases in overall regimen toxicity. In non-transplant eligible patients daratumumab has been added in randomized studies to lenalidomide and dexamethasone (Rd) and bortezomib, melphalan and prednisolone (VMP) backbones, but not to the VCD regimen. Furthermore, the randomized studies excluded a significant proportion of patients with comorbidities so the benefit of daratumumab in a frail, elderly myeloma population remains untested. Methods Inclusion criteria included untreated patients with symptomatic myeloma who were considered ineligible for high-dose chemotherapy with autologous stem cell transplantation due to either age >65years or the presence of comorbidities. Any degree of renal impairment, including dialysis dependence, was allowed as were patients with a prior history of systemic malignancy that had been disease-free for 2 years. Patients were randomized 1:1 to receive VCD or VCDD. VCD consisted of nine 5-week cycles of V 1.3 mg/m2 SC on Days 1, 8, 15 and 22;C 300mg/m2 PO on Days 1, 8, 15 and 22 and D 20 mg PO on Days 1, 8, 15 and 22. VCDD consisted of nine 5-week cycles of VCD plus daratumumab 16 mg/kg IV on Days 1, 8, 15 and 22 of cycles 1 and 2, Days 1 and 15 of cycles 3 to 6 and Day 1 of cycles 7 to 9, followed by daratumumab maintenance 16 mg/kg IV every 4 weeks until progression. The primary endpoint was PFS with secondary endpoints being response rates, MRD, overall survival, toxicity and quality of life. Results A total of 129 patients were randomized, but 7 did not commence intended therapy. The following modified ITT analysis is based on the 122 randomized patients, 58 in the VCD group and 64 in the VCDD group, who received therapy. Baseline characteristics were balanced between the two arms. Median age was 76 years (range, 62-91yrs), with 19% being ≥80 years of age. 30% were female. ECOG performance status was 0 (34%),1 (26%), 2 (16%) and unknown (25%). ISS stage was I (16%), II (36%), III (23%) and unknown (24%). The estimated median potential follow-up is 12.6 months. At the time of this report, the COVID-19 pandemic had impacted collection of site data. As a result, the following outcome data is provisional with a full data set to be available for presentation of the formal pre-planned interim analysis by the time of the ASH meeting. Overall response rate was 86% for VCD and 93% for VCDD. There was no significant difference between response rates after 4 cycles of induction for the VCD and VCDD arms: CR 3% vs 2%, VGPR 31% vs 41%, PR 51% vs 50%, MR 11% vs 7%, PD 3% vs 0%. Median PFS for the entire cohort (Fig A) was 21.8 months (95%CI 17.1-31.6 months). Median PFS for those treated with VCD was 18.9 months (95%CI 15.3-NR) and was 26.3 months (95%CI 17.1-31.6 months) for those treated with VCDD. In both arms combined, median PFS was 26.3 vs 21.9 months for those aged <75 vs ≥75 yrs, and not reached, 21.8 months and 19.9 months for those with ISS stage I, II and III, respectively. 19% of patients in the VCD group and 16% of patients in the VCDD group ceased therapy early, predominantly due to adverse events or death. SAEs during the induction period occurred in 44% and 52% of patients in the VCD and VCDD arms, respectively. There were 13 patients with SAEs due to infection in the VCD group and 20 in the VCDD group. Grade 3 or 4 peripheral neuropathy was uncommon, with only one case in the VCD arm. Conclusions The VCD schedule as detailed in this study appears efficacious, well tolerated and deliverable to an elderly myeloma population. The addition of daratumumab does not compromise chemotherapy delivery and may improve PFS. Formal interim analysis of the trial data will be presented at the meeting. [Formula presented] Disclosures: Mollee: Amgen: Membership on an entity's Board of D rectors or advisory committees;BMS/Celgene: Membership on an entity's Board of Directors or advisory committees;Takeda: Membership on an entity's Board of Directors or advisory committees;Pfizer: Membership on an entity's Board of Directors or advisory committees;Caelum: Membership on an entity's Board of Directors or advisory committees;Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Reynolds: Novartis AG: Current equity holder in publicly-traded company. Janowski: Janssen: Membership on an entity's Board of Directors or advisory committees;BMS/ Celgene: Membership on an entity's Board of Directors or advisory committees;Amgen: Membership on an entity's Board of Directors or advisory committees;AstraZenica: Consultancy. Quach: Amgen, Celgene, karyopharm, GSK, Janssen Cilag, Sanofi.: Membership on an entity's Board of Directors or advisory committees;GlaxoSmithKline, Karyopharm, Amgen, Celgene, Janssen Cilag: Honoraria;GlaxoSmithKline, Karyopharm, Amgen, Celgene, Janssen Cilag: Consultancy;Amgen, sanofi, celgene, Karyopharm, GSK: Research Funding. Campbell: Amgen, Novartis, Roche, Janssen, Celgene (BMS): Research Funding;AstraZeneca, Janssen, Roche, Amgen, CSL Behring, Novartis: Consultancy. Gibbs: Janssen, BMS/Celgene, Amgen, Takeda, Pfizer, Caelum, Abbvie and Eidos: Membership on an entity's Board of Directors or advisory committees. D'Rozario: Abbvie: Membership on an entity's Board of Directors or advisory committees;BMS/ Celgene: Membership on an entity's Board of Directors or advisory committees. Wallington-Beddoe: Amgen: Membership on an entity's Board of Directors or advisory committees. Weber: Amgen: Membership on an entity's Board of Directors or advisory committees. Spencer: Celgene, Janssen and Takeda: Speakers Bureau;AbbVie, Celgene, Haemalogix, Janssen, Sanofi, SecuraBio, Specialised Therapeutics Australia, Servier and Takeda: Consultancy;Amgen, Celgene, Haemalogix, Janssen, Servier and Takeda: Research Funding;AbbVie, Amgen, Celgene, Haemalogix, Janssen, Sanofi, SecuraBio, Specialised Therapeutics Australia, Servier and Takeda: Honoraria. OffLabel Disclosure: Daratumumab as initial treatment of myeloma