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In de gerandomiseerde fase III- CASSIOPEIA-studie werd het effect van het toevoegen van daratumumab aan de standaardbehandeling met bortezomib, thalidomide en dexamethason onderzocht bij 1.074 patiënten met nieuw gediagnosticeerd multipel myeloom (MM). De patiënten ontvingen zes cycli (vier inductiecycli, twee consolidatiecycli) van 28 dagen, bestaande uit subcutaan (SC) bortezomib (1,3 mg/m2 dagen 1, 4, 8, 11), oraal thalidomide (100 mg per dag), dexamethason (20–40 mg) (VTD) en, afhankelijk van de onderzoeksgroep, daratumumab intraveneus (IV). Deze studie is geregistreerd onder EudraCT-nummer NCT02541383. Met resultaten in het voordeel van dara-VTD werd dit regime vervolgens goedgekeurd door EMA voor gebruik bij nieuw gediagnosticeerd MM en zal in de nabije toekomst in Nederland als standaardbehandeling worden geïmplementeerd. Polyneuropathie (PNP) is een veel voorkomende bijwerking tijdens de behandeling van MM. De incidentie van PNP-graad 2–4 (CTCAE-gradering) werd in de CASSIOPEIA-studie geanalyseerd. In totaal ontwikkelden 394/1.074 (37%) patiënten graad 2-PNP en 105/1.074 (10%) graad 3. Significante risicofactoren geassocieerd met PNP-graad 2 waren graad 1-neuropathie in de voorgeschiedenis en overgewicht (BMI >25). In deze studie is de hoge incidentie van PNP-graad 2–4 gedurende MM-behandeling bevestigd. Hiermee wordt de noodzaak van screening op risicofactoren, frequente beoordeling van PNP en strikte naleving van de richtlijnen benadrukt om de incidentie van ernstige PNP te verminderen.

PURPOSE To address the role of consolidation treatment for newly diagnosed, transplant eligible patients with multiple myeloma in a controlled clinical trial. PATIENTS AND METHODS The EMN02/HOVON95 trial compared consolidation treatment with two cycles of bortezomib, lenalidomide, and dexamethasone (VRD) or no consolidation after induction and intensification therapy, followed by continuous lenalidomide maintenance. Primary study end point was progression-free survival (PFS). RESULTS Eight hundred seventy-eight eligible patients were randomly assigned to receive VRD consolidation (451 patients) or no consolidation (427 patients). At a median follow-up of 74.8 months, median PFS with adjustment for pretreatment was prolonged in patients randomly assigned to VRD consolidation (59.3 v 42.9 months, hazard ratio [HR] = 0.81; 95% CI, 0.68 to 0.96; P = .016). The PFS benefit was observed across most predefined subgroups, including revised International Staging System (ISS) stage, cytogenetics, and prior treatment. Revised ISS3 stage (HR, 2.00; 95% CI, 1.41 to 2.86) and ampl1q (HR, 1.67; 95% CI, 1.37 to 2.04) were significant adverse prognostic factors. The median duration of maintenance was 33 months (interquartile range 13-86 months). Response complete response (CR) after consolidation versus no consolidation before start of maintenance was 34% versus 18%, respectively (P < .001). Response >= CR on protocol including maintenance was 59% with consolidation and 46% without (P < .001). Minimal residual disease analysis by flow cytometry in a subgroup of 226 patients with CR or stringent complete response or very good partial response before start of maintenance demonstrated a 74% minimal residual disease-negativity rate in VRD-treated patients. Toxicity from VRD was acceptable and manageable. CONCLUSION Consolidation treatment with VRD followed by lenalidomide maintenance improves PFS and depth of response in newly diagnosed patients with multiple myeloma as compared to maintenance alone. (C) 2021 by American Society of Clinical Oncology

This is a phase 2 dose escalation trial of carfilzomib in combination with thalidomide and dexamethasone for induction and consolidation in transplant-eligible patients with newly diagnosed multiple myeloma. The results of 4 dose levels are reported. Induction therapy consisted of 4 cycles of carfilzomib 20/27 mg/m2 (n=50), 20/36 mg/m2 (n=20), 20/45 mg/m2 (n=21) and 20/56 mg/m2 (n=20) on days 1, 2, 8, 9, 15, 16 of a 28-day cycle; thalidomide 200 mg on day 1 through 28 and dexamethasone 40 mg weekly. Induction therapy was followed by high dose melphalan and autologous stem cell transplantation and consolidation therapy with 4 cycles of carfilzomib, thalidomide and dexamethasone in the same schedule except a lower dose of thalidomide (50 mg). Very good partial response rate or better and complete response rate or better after induction therapy were 65% and 18% respectively, increasing to 86% and 63% respectively after consolidation therapy. In all cohorts combined, after a median follow-up of 58.7 months, median progression-free survival was 58 months (95% CI 45-67 months). Median overall survival was 83 months (95% CI 83 months-not reached). Grade 3/4 adverse events consisted mainly of infections, respiratory disorders, skin and vascular disorders in 11%, 8%, 9%, and 9% respectively. Only in 1 patient grade 3 polyneuropathy was reported. Cardiac events were limited, grade 3/4 in 5% of patients. Carfilzomib, thalidomide and dexamethasone as induction and consolidation treatment after high dose melphalan and autologous stem cell transplantation is highly efficacious and safe in transplant-eligible patients with newly diagnosed multiple myeloma. This study was registered at http://www.trialregister.nl as #NTR2422.

Introduction This phase 2 dose escalation trial of the European Myeloma Network investigated the combination of Carfilzomib with Thalidomide and dexamethasone (KTd) in newly diagnosed, transplant-eligible patients with multiple myeloma (MM) as induction and consolidation treatment (abstract ASH 2016 # 1141). We investigated the effect of intensified induction with 8 cycles of KTd (56 mg/m2 ) as compared with standard 4 cycles (27 - 56 mg/m2) on depth of response before and after high-dose Melphalan (HDM). Methods In this multicenter, open-label phase 2 trial, patients aged between 18 and 65 years with transplant eligible, newly diagnosed symptomatic MM were included. Four dose levels of Carfilzomib combined with Thalidomide and dexamethasone (KTd) for 4 cycles of induction therapy were used. The dose of Carfilzomib was 20 mg/m2 i.v. on days 1, 2 followed by 27, 36, 45 or 56 mg/m2 on days 8, 9, 15, 16 of cycle 1 and on days 1, 2, 8, 9, 15 and 16 of cycles 2 to 4. Thalidomide dose was 200 mg orally on days 1 through 28 and dexamethasone 40 mg orally on days 1, 8, 15 and 22 of a 28-day cycle. After induction, stem cell harvest was performed after Cyclophosphamide priming (2 to 4 g/m2 ) and G-CSF. Following HDM (200 mg/m2 ) and autologous stem cell transplantation, consolidation treatment consisted of 4 cycles of KTd in the same schedule except for a lower dose of Thalidomide (50mg) (abstract ASH 2016 # 1141). Next we investigated the potential benefit of prolonged induction therapy on response depth prior to and following HDM by using 8 cycles of KTd at the highest dose of Carfilzomib (56mg/m2 ) in the same schedule. The primary endpoint was response after induction therapy, specifically complete response (CR) and very good partial response (VGPR). Other endpoints were safety, progression-free survival (PFS) and overall survival (OS). Results A total of 137 eligible patients were included. We report the response of 26 patients treated with 8 cycles of KTd induction therapy versus 111 patients treated with 4 cycles of KTd induction therapy with different dose levels of Carfilzomib. Median follow-up was 48 months [range 8-81 months]. Median age was 57 years. ISS stages I/II/III were 43%/35%/21% respectively. With 8 KTd, response after induction was CR/sCR in 27%, ≥ VGPR in 92% and ≥ PR in 96%. In contrast, with 4 KTd at 56 mg/m2 (20 patients) response after induction was CR/sCR in 20%, ≥ VGPR in 80% and ≥ PR in 90%. CR/sCR rate with 8 KTd increased to 42% after HDM and to 62% after consolidation treatment. In comparison, with 4 KTd at 56 mg/m2 CR/sCR rate increased to 30% after HDM and 65% after consolidation treatment. All dose levels combined given for 4 induction cycles showed response after induction of CR/sCR in 18%, ≥ VGPR in 65% and ≥ PR in 93%. CR/sCR rate increased to 31% after HDM and to 64% after consolidation treatment. See Table 1. Response based on risk status by ISS/FISH with 8 KTd showed a difference in CR/sCR rate after consolidation between standard risk (10/13, 77%) and high risk (3/8, 38%). High risk was defined as t(4;14) and/or del17p and/or add1q and/or ISS3. With 4 KTd at 56 mg/m2 CR/sCR rate in standard and high risk patients was 100% (7/7) and 50% (5/10) respectively. In all dose levels combined given for 4 induction cycles CR/sCR rate was 70% (32/46) and 58% (25/43) in standard and high risk patients respectively. Cardiac events grade 3 and 4 in patients treated with 8 KTd occurred in 2 patients (8%, heart failure). In comparison with 4 KTd at 56 mg/m2 heart failure grade 3 was reported in one patient (5%). In all dose levels combined given for 4 induction cycles cardiac events grade 3 and 4 included three patients with heart failure and 1 patient with chest pain (4%). In patients treated with 8 KTd PFS and OS at 12 months was 100%. With 4 KTd at 56 mg/m2 PFS and OS were 95% and 100% respectively and in all dose levels combined given for 4 induction cycles PFS and OS were 90% and 95% respectively at 12 months. Before ASH we will update results of PFS and OS. Conclusions Treatment with 8 induction cycles of KTd resulted in a deeper response before HDM and autologous stem cell transplantation. However, depth of response was comparable after consolidation treatment between patients treated with 4 and 8 induction cycles. Effect on survival will be analyzed when longer follow-up is available. (Table Presented).

BackgroundThe EMN02/HO95 trial is the largest multicenter, randomized, phase 3 study conducted in the novel agent era and aimed to prospectively compare (randomization 1, R1) autologous stem cell transplantation (ASCT) vs proteasome inhibitor-based intensification therapy, and (randomization 2) consolidation therapy vs no consolidation, followed by lenalidomide maintenance for newly diagnosed MM.MethodsAfter 3 to 4 cycles of bortezomib-based induction therapy and subsequent PBSC collection, patients aged ≤65 years were randomized (R1, stratification by ISS stage) to receive high-dose intensification treatment with melphalan at 200 mg/m2 (HDM) plus ASCT or standard-dose intensification treatment with bortezomib-melphalan-prednisone (VMP) for 4 additional 42-day cycles (each including 8 doses of bortezomib). Progression-free survival (PFS) from R1 was the primary study end point for R1. The preplanned second interim analysis of ASCT vs VMP was performed in July 2017 when at least 66% of required events had occurred, and results are herein reported.ResultsA total of 1503 patients were registered and 1192 were eligible for R1. Based on the allocation ratio for R1 depending on the single (1:1) vs double (1:1:1) HDM policy of each center, 695 patients were randomly assigned to ASCT and 497 patients to VMP. Median age was 58 years in both groups; ISS stage III was 20% in ASCT arm and 21% in VMP arm. FISH analysis of CD138+ bone marrow plasma cells was available in approximately 75% of patients in both groups. According to IMWG criteria, a high-risk (HiR) cytogenetic profile defined by t(4;14) ± t(14;16) ± del(17p) positivity (HiR-cyto) was detected in 25% of patients in both groups. Median follow-up from R1 was 38 (IQR: 29-47) months for the overall patient population and for each of the two treatment groups. On an intention-to-treat basis, median PFS was not yet reached in the ASCT group and was 44 months in the VMP group; 3-year estimate of PFS was 64% vs 57%, respectively (HR=0.76; 95% CI=0.64-0.91; P=0.002), which represented a 24% reduced risk of progression or death in the ASCT group compared with the VMP group. Prespecified subgroup analyses of PFS confirmed that the benefit associated with ASCT was not influenced by revised ISS (R-ISS) disease stage (stage II: P=0.006; stage III: P55 years: P=0.027; ≤55 years: P=0.038). The probability of achieving ≥ best VGPR was 84% in the ASCT group and was 75% in the VMP group (odds ratio=1.79; CI=1.32-2.35; P

Objective: Value frameworks in oncology have not been validated for the assessment of treatments in haematological malignancies, but to avoid overlaps and duplications it appears reasonable to build up experience on existing value frameworks, such as the European Society for Medical Oncology—Magnitude of Clinical Benefit Scale (ESMO-MCBS). Methods: Here we present the results of the first feasibility testing of the ESMO-MCBS v1.1 for haematological malignancies based on the grading of 80 contemporary studies for acute leukaemia, chronic leukaemia, lymphoma, myeloma and myelodysplastic syndromes. The aims were (1) to evaluate the scorability of data, (2) to evaluate the reasonableness of the generated grades for clinical benefit using the current version and (3) to identify shortcomings in the ESMO-MCBS v1.1 that require amendments to improve the efficacy and validity of the scale in grading new treatments in the management of haematological malignancies. Results: In general, the ESMO-MCBS v1.1 was found to be widely applicable to studies in haematological malignancies, generating scores that were judged as reasonable by European Hematology Association (EHA) experts. A small number of studies could either not be graded or were not appropriately graded. The reasons, related to the differences between haematological and solid tumour malignancies, are identified and described. Conclusions: Based on the findings of this study, ESMO and EHA are committed to develop a version of the ESMO-MCBS that is validated for haematological malignancies. This development process will incorporate all of the usual stringencies for accountability of reasonableness that have characterised the development of the ESMO-MCBS including field testing, statistical modelling, evaluation for reasonableness and openness to appeal and revision. Applying such a scale will support future public policy decision-making regarding the value of new treatments for haematological malignancies and will provide insights that could be helpful in the design of future clinical trials.

OBJECTIVE: Value frameworks in oncology have not been validated for the assessment of treatments in haematological malignancies, but to avoid overlaps and duplications it appears reasonable to build up experience on existing value frameworks, such as the European Society for Medical Oncology-Magnitude of Clinical Benefit Scale (ESMO-MCBS). METHODS: Here we present the results of the first feasibility testing of the ESMO-MCBS v1.1 for haematological malignancies based on the grading of 80 contemporary studies for acute leukaemia, chronic leukaemia, lymphoma, myeloma and myelodysplastic syndromes. The aims were (1) to evaluate the scorability of data, (2) to evaluate the reasonableness of the generated grades for clinical benefit using the current version and (3) to identify shortcomings in the ESMO-MCBS v1.1 that require amendments to improve the efficacy and validity of the scale in grading new treatments in the management of haematological malignancies. RESULTS: In general, the ESMO-MCBS v1.1 was found to be widely applicable to studies in haematological malignancies, generating scores that were judged as reasonable by European Hematology Association (EHA) experts. A small number of studies could either not be graded or were not appropriately graded. The reasons, related to the differences between haematological and solid tumour malignancies, are identified and described. CONCLUSIONS: Based on the findings of this study, ESMO and EHA are committed to develop a version of the ESMO-MCBS that is validated for haematological malignancies. This development process will incorporate all of the usual stringencies for accountability of reasonableness that have characterised the development of the ESMO-MCBS including field testing, statistical modelling, evaluation for reasonableness and openness to appeal and revision. Applying such a scale will support future public policy decision-making regarding the value of new treatments for haematological malignancies and will provide insights that could be helpful in the design of future clinical trials.