Daratumumab plus pomalidomide and dexamethasone versus pomalidomide and dexamethasone alone in previously treated multiple myeloma (APOLLO): an open-label, randomised, phase 3 trial

Background: In a phase 1b study, intravenous daratumumab plus pomalidomide and dexamethasone induced a very good partial response or better rate of 42% and was well tolerated in patients with heavily pretreated multiple myeloma. We aimed to evaluate whether daratumumab plus pomalidomide and dexamethasone would improve progression-free survival versus pomalidomide and dexamethasone alone in patients with previously treated multiple myeloma. Methods: In this ongoing, open-label, randomised, phase 3 trial (APOLLO) done at 48 academic centres and hospitals across 12 European countries, eligible patients were aged 18 years or older, had relapsed or refractory multiple myeloma with measurable disease, had an Eastern Cooperative Oncology Group performance status of 0–2, had at least one previous line of therapy, including lenalidomide and a proteasome inhibitor, had a partial response or better to one or more previous lines of antimyeloma therapy, and were refractory to lenalidomide if only one previous line of therapy was received. Patients were randomly assigned (1:1) by an interactive web-response system in a random block size of two or four to receive pomalidomide and dexamethasone alone or daratumumab plus pomalidomide and dexamethasone. Randomisation was stratified by number of previous lines of therapy and International Staging System disease stage. All patients received oral pomalidomide (4 mg, once daily on days 1–21) and oral dexamethasone (40 mg once daily on days 1, 8, 15, and 22; 20 mg for those aged 75 years or older) at each 28-day cycle. The daratumumab plus pomalidomide and dexamethasone group received daratumumab (1800 mg subcutaneously or 16 mg/kg intravenously) weekly during cycles 1 and 2, every 2 weeks during cycles 3–6, and every 4 weeks thereafter until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival in the intention-to-treat population. Safety was analysed in all patients who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov, NCT03180736. Findings: Between June 22, 2017, and June 13, 2019, 304 patients (median age 67 years [IQR 60–72]; 161 [53%] men and 143 [47%] women) were randomly assigned to the daratumumab plus pomalidomide and dexamethasone group (n=151) or the pomalidomide and dexamethasone group (n=153). At a median follow-up of 16·9 months (IQR 14·4–20·6), the daratumumab plus pomalidomide and dexamethasone group showed improved progression-free survival compared with the pomalidomide and dexamethasone group (median 12·4 months [95% CI 8·3–19·3] vs 6·9 months [5·5–9·3]; hazard ratio 0·63 [95% CI 0·47–0·85], two-sided p=0·0018). The most common grade 3 or 4 adverse events were neutropenia (101 [68%] of 149 patients in the daratumumab plus pomalidomide and dexamethasone group vs 76 [51%] of 150 patients in the pomalidomide and dexamethasone group), anaemia (25 [17%] vs 32 [21%]), and thrombocytopenia (26 [17%] vs 27 [18%]). Serious adverse events occurred in 75 (50%) of 149 patients in the daratumumab plus pomalidomide and dexamethasone group versus 59 (39%) of 150 patients in the pomalidomide and dexamethasone group; pneumonia (23 [15%] vs 12 [8%] patients) and lower respiratory tract infection (18 [12%] vs 14 [9%]) were most common. Treatment-emergent deaths were reported in 11 (7%) patients in the daratumumab plus pomalidomide and dexamethasone group versus 11 (7%) patients in the pomalidomide and dexamethasone group. Interpretation: Among patients with relapsed or refractory multiple myeloma, daratumumab plus pomalidomide and dexamethasone reduced the risk of disease progression or death versus pomalidomide and dexamethasone alone and could be considered a new treatment option in this setting. Funding: European Myeloma Network and Janssen Research and Development.European Myeloma Network and Janssen Research and Development

Health-related quality of life in patients with relapsed/refractory multiple myeloma treated with pomalidomide and dexamethasone ± subcutaneous daratumumab: Patient-reported outcomes from the APOLLO trial

In the phase 3 APOLLO trial, daratumumab in combination with pomalidomide and dexamethasone (D-Pd) significantly reduced the rate of disease progression or death by 37% relative to Pd alone in patients with relapsed/refractory multiple myeloma (RRMM) who had received ≥1 prior line of therapy including lenalidomide and a proteasome inhibitor. Here, we present patient-reported outcomes (PROs) from APOLLO. Median treatment duration was 11.5 months with D-Pd and 6.6 months with Pd. PRO compliance rates were high and similar in both groups. No changes from baseline were observed for EORTC QLQ-C30 global health status scores in either group, while physical and emotional functioning, disease symptoms, and adverse effects of treatment remained at baseline levels with D-Pd but worsened with Pd. Reductions (p < 0.05) in pain and fatigue were seen at several time points with D-Pd versus Pd. Overall, these results suggest patients' health-related quality of life remained stable when daratumumab was added to Pd, with several results favoring D-Pd versus Pd. These findings complement the significant clinical improvements observed with D-Pd and support its use in patients with RRMM.The APOLLO study was sponsored by the European Myeloma Network (EMN) in collaboration with Janssen Research & Development, LLC. Medical writing and editorial support were provided by Justine Lempart, PhD, and Linda V. Wychowski, PhD, of Eloquent Scientific Solutions and were funded by Janssen Global Services, LL

Machbarkeit und Nutzen von einem 12-Kanal-EKG und einer "Point-of-care" Bestimmung von Myokardnekroseparametern in der prähospitalen Diagnostik von Patienten mit Verdacht auf ein akutes Koronarsyndrom

Beim akuten Koronarsyndrom (ACS) ist Zeit der ein Faktor um Morbidität und Mortalität zu reduzieren. Der Effekt einer erweiterten prähospitalen Diagnostik in Form einer Bestimmung von infarktanzeigenden Serummarkern und der Anfertigung eines 12-Kanal-EKGs im Rettungsdienst auf die Zeit bis zur Therapie intrahospital wurde untersucht. Bei 218 Patienten konnte hierdurch keine Verkürzung der "door-to-balloon"-Zeit erreicht werden. Die Prähospitalzeit verlängerte sich nicht durch die neuen Mittel. Die Prähospitalzeit war, verglichen mit dem Bundesdurchschnitt, kurz. Der verwendete Schnelltest für kardiale Marker eignet sich nicht für die Anwendung im Rettungsdienst in der untersuchten Umgebung. Die Rate an 12-Kanal-EKGs im Rettungsdienst war mit 36,8% zu niedrig. Bei den intrahospitalen Zeitabläufen fanden sich verschiedene Optimierungsmöglichkeiten hinsichtlich des Patientenmanagements. Bei den Patienten mit einer Myokardischämie fiel ein rechtsthorakales Schmerzverteilungsmuster auf

Comparative efficacy of bortezomib, melphalan, and prednisone (VMP) with or without daratumumab versus VMP Alone in the treatment of newly diagnosed multiple myeloma: propensity score matching of ALCYONE and VISTA Phase III studies

Introduction: Bortezomib, melphalan, and prednisone (VMP) is the standard of care for transplant-ineligible newly diagnosed multiple myeloma. The phase III VISTA trial established the bortezomib dosing schedule for VMP. To mitigate bortezomib-associated toxicity, the phase III ALCYONE study of daratumumab plus VMP (D-VMP) versus VMP used modified bortezomib dosing. D-VMP demonstrated improved progression-free survival and overall response rate. Propensity score matching enables indirect comparisons by controlling for differences in baseline covariates. Patients and Methods: The efficacy and safety of both arms of ALCYONE were compared with VISTA VMP using propensity score matching. ALCYONE D-VMP and VMP patients were matched on selected baseline characteristics to VISTA VMP patients, reducing or eliminating systematic differences between treatment groups. Results: After matching, median progression-free survival and overall response rate were comparable for ALCYONE VMP and VISTA VMP, and were significantly improved with ALCYONE D-VMP versus VISTA VMP. Rates of grade 3/4 peripheral sensory neuropathy were significantly lower for both arms of ALCYONE versus VISTA VMP, with or without matching. Conclusion: This propensity score matching analysis demonstrates significant improvements in efficacy with ALCYONE D-VMP versus VISTA VMP and a significantly lower incidence of peripheral sensory neuropathy in both arms of ALCYONE versus VISTA VMP, although safety improvements may be due to different bortezomib administration routes (ALCYONE, subcutaneous; VISTA, intravenous). © 2020 A propensity score-matched analysis compared bortezomib, melphalan, and prednisolone (VMP) in the ALCYONE study (± daratumumab [D]) with VMP in the VISTA study because no direct comparisons are available. Results indicated a lower intensity VMP regimen such as in ALCYONE has a favorable benefit/risk profile compared with the VISTA VMP schedule and D-VMP significantly improves efficacy versus VISTA VMP. © 202

Matching‐adjusted indirect comparison of efficacy and safety of bortezomib, thalidomide, and dexamethasone (VTd) as per label compared with modified VTd dosing schedules in patients with newly diagnosed multiple myeloma who are transplant eligible

Abstract Background The combination of bortezomib, thalidomide, and dexamethasone (VTd) is a standard of care for transplant‐eligible patients with newly diagnosed multiple myeloma (NDMM). Although approved labeling for VTd includes an escalating thalidomide dose up to 200 mg daily (VTd‐label), a lower fixed dose of thalidomide (100 mg daily; VTd‐mod) has become commonplace in clinical practice. To date, no clinical trials comparing VTd‐mod with VTd‐label have been performed. Here, we compared outcomes for VTd‐mod with VTd‐label using a matching‐adjusted indirect comparison. Methods VTd‐mod data were from NCT02541383 (CASSIOPEIA; phase III) and NCT00531453 (phase II); VTd‐label data were from NCT00461747 (PETHEMA/GEM; phase III). To adjust for heterogeneity, baseline characteristics from VTd‐label were weighted to match VTd‐mod. Outcomes included overall survival (OS), progression‐free survival (PFS), postinduction and posttransplant responses, and safety. Results VTd‐mod was noninferior to VTd‐label for OS, postinduction overall response rate (ORR), and very good partial response or better (≥VGPR). VTd‐mod was significantly better than VTd‐label for PFS, posttransplant ORR, and ≥VGPR. VTd‐mod was noninferior to VTd‐label for safety outcomes, and inferior to VTd‐label for postinduction and posttransplant complete response or better. Conclusions Our analysis supports the continued use of VTd‐mod in clinical practice in transplant‐eligible NDMM patients

Comparative efficacy and safety of bortezomib, thalidomide, and dexamethasone (VTd) without and with daratumumab (D‐VTd) in CASSIOPEIA versus VTd in PETHEMA/GEM in transplant‐eligible patients with newly diagnosed multiple myeloma, using propensity score matching

Abstract Background Traditional bortezomib, thalidomide, and dexamethasone (VTd) regimens for patients with newly diagnosed multiple myeloma (NDMM) include doses of thalidomide up to 200 mg/day (VTd‐label). Clinical practice has evolved to use a lower dose (100 mg/day) to reduce toxicity (VTd‐mod), which was evaluated in the phase III CASSIOPEIA study, without or with daratumumab (D‐VTd; an anti‐CD38 monoclonal antibody). We used propensity score matching to compare efficacy and safety for VTd‐mod and D‐VTd with VTd‐label. Methods Patient‐level data for VTd‐mod and D‐VTd from CASSIOPEIA (NCT02541383) and data for VTd‐label from the PETHEMA/GEM study (NCT00461747) were analyzed. Propensity scores were estimated using logistic regression, and nearest‐neighbor matching procedure was used. Outcomes included overall survival (OS), progression‐free survival (PFS), time to progression (TTP), postinduction and posttransplant responses, as well as rate of treatment discontinuation and grade 3/4 peripheral neuropathy. Results VTd‐mod was noninferior to VTd‐label for OS, PFS, TTP, postinduction very good partial response or better (≥VGPR) and overall response rate (ORR). VTd‐mod was significantly better for posttransplant ≥VGPR and ORR versus VTd‐label. VTd‐mod safety was not superior to VTd‐label despite the lower thalidomide dose. D‐VTd was significantly better than VTd‐label for OS, PFS, TTP, postinduction and posttransplant ≥VGPR and ORR, and was noninferior to VTd‐label for safety outcomes. Conclusions In transplant‐eligible patients with NDMM, D‐VTd had superior efficacy compared with VTd‐label. Despite a lower dose of thalidomide, VTd‐mod was noninferior to VTd‐label for safety and was significantly better for posttransplant ≥VGPR/ORR. These data further support the first‐line use of daratumumab plus VTd

Population pharmacokinetics and exposure–response analyses of daratumumab plus pomalidomide/dexamethasone in relapsed or refractory multiple myeloma

Aim: A population pharmacokinetic (PPK) model was developed to characterize pharmacokinetics (PK) of subcutaneous or intravenous daratumumab administration in a new indication (i.e., combination with pomalidomide and dexamethasone [D-Pd] in patients with relapsed or refractory multiple myeloma [RRMM]). Analyses were conducted to explore exposure–response (E-R) relationships for efficacy and select treatment-emergent adverse events (TEAEs). Methods: The PPK analysis included pooled data from the D-Pd cohorts of the phase 3 APOLLO and phase 1b EQUULEUS studies. Covariates were evaluated in the PPK model. Model-predicted exposures to daratumumab were compared between covariate subgroups of interest and used to investigate relationships between daratumumab exposure and efficacy and safety in APOLLO. Results: The PPK analysis included 1146 daratumumab PK samples from 239 patients (APOLLO, n = 140; EQUULEUS, n = 99). Observed concentration–time data of daratumumab were well described by a two-compartment PPK model with first-order absorption and parallel linear and nonlinear elimination pathways. Treatment with D-Pd provided similar daratumumab PK characteristics versus historical daratumumab monotherapy. The E-R dataset contained data from 290 APOLLO patients (D-Pd, n = 140; Pd, n = 150). The PK–efficacy relationship of daratumumab supported improved progression-free survival for patients in the D-Pd group vs. the Pd group. Additionally, TEAEs did not increase with increasing PK exposure in the D-Pd group. Conclusions: The PPK and E-R analyses support the daratumumab subcutaneous 1800 mg dosing regimen in combination with Pd for treatment of patients with RRMM. No dose adjustment is recommended in this indication for any of the investigated factors, none of which had clinically relevant effects on daratumumab PK

Subcutaneous daratumumab plus pomalidomide and dexamethasone versus pomalidomide and dexamethasone in patients with relapsed or refractory multiple myeloma (APOLLO):extended follow up of an open-label, randomised, multicentre, phase 3 trial

Background: The primary analysis of the APOLLO trial, done after a median follow-up of 16·9 months, showed that daratumumab plus pomalidomide and dexamethasone significantly improved progression-free survival versus pomalidomide and dexamethasone. Here, we report the final overall survival and updated safety results from APOLLO. Methods: APOLLO was an open-label, randomised, phase 3 trial conducted at 48 academic centres and hospitals across 12 countries in Europe, that included adults aged 18 years or older with relapsed or refractory multiple myeloma who had an ECOG performance status score of 0–2, had received at least one previous line of therapy, including lenalidomide and a proteasome inhibitor, had a partial response or better to one or more previous lines of antimyeloma therapy, and were refractory to lenalidomide if they had received only one previous line of therapy. An interactive web-response system was used to randomly assign patients (1:1) to receive daratumumab plus pomalidomide and dexamethasone or pomalidomide and dexamethasone; patients were stratified by the number of previous lines of therapy and International Staging System disease stage. Oral pomalidomide (4 mg once daily; days 1–21) and dexamethasone (40 mg once daily; days 1, 8, 15, and 22) were given in 28-day cycles until disease progression or unacceptable toxicity. Daratumumab (1800 mg subcutaneously or 16 mg/kg intravenously) was administered weekly (cycles 1–2), every 2 weeks (cycles 3–6), and every 4 weeks thereafter. The primary endpoint of progression-free survival, which has previously been reported, and the pre-planned secondary endpoint of overall survival were assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT03180736) and is no longer enrolling patients. Findings: Between June 22, 2017, and June 13, 2019, 304 patients were randomly assigned: 151 to the daratumumab plus pomalidomide and dexamethasone group and 153 to the pomalidomide and dexamethasone group. The median age was 67 years (IQR 60–72); 143 (47%) patients were female and 161 (53%) were male, and 272 (89%) were White. At a median follow-up of 39·6 months (IQR 37·1–43·7), median overall survival was 34·4 months (95% CI 23·7–40·3) in the daratumumab plus pomalidomide and dexamethasone group versus 23·7 months (19·6–29·4) in the pomalidomide and dexamethasone group (hazard ratio [HR] 0·82 [95% CI 0·61–1·11]; p=0·20). The most common grade 3–4 treatment-emergent adverse events were neutropenia (103 [69%] of 149 with daratumumab plus pomalidomide and dexamethasone vs 76 [51%] of 150 with pomalidomide and dexamethasone), anaemia (27 [18%] vs 32 [21%]), and thrombocytopenia (27 [18%] vs 28 [19%]). Serious treatment-emergent adverse events occurred in 80 (54%) of 149 patients in the daratumumab plus pomalidomide and dexamethasone group and in 60 (40%) of 150 patients in the pomalidomide and dexamethasone group, the most common of which was pneumonia (23 [15%] of 149 vs 13 [9%] of 150). Treatment-emergent adverse events resulting in death occurred in 13 (9%) of 149 patients in the daratumumab plus pomalidomide and dexamethasone group and in 13 (9%) of 150 patients in the pomalidomide and dexamethasone group, with 4 (3%) of 151 adverse events leading to death within 30 days of the last treatment dose thought to be related to study treatment in the daratumumab plus pomalidomide and dexamethasone group (septic shock [n=1]; sepsis [n=1]; bone marrow failure, campylobacter infection, and liver disorder [n=1]; and pneumonia [n=1]) and none in the pomalidomide and dexamethasone group. Interpretation: Although the difference in overall survival observed between treatment groups was not significant, the safety profile results with long-term follow-up reported here continue to support the use of daratumumab plus pomalidomide and dexamethasone in patients with relapsed or refractory multiple myeloma. Funding: European Myeloma Network and Janssen Research &amp; Development.</p