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Early morbidity and mortality affect patient outcomes in multiple myeloma. Thus, we dissected the incidence and causes of morbidity/mortality during induction therapy (IT) for newly diagnosed multiple myeloma (NDMM), and developed/validated a predictive risk score. We evaluated 3700 transplant-eligible NDMM patients treated in 2005–2020 with novel agent-based triplet/quadruplet IT. Primary endpoints were severe infections, death, or a combination of both. Patients were divided in a training (n = 1333) and three validation cohorts (n = 2367). During IT, 11.8%, 1.8%, and 12.5% of patients in the training cohort experienced severe infections, death, or both, respectively. Four major, baseline risk factors for severe infection/death were identified: low platelet count (<150/nL), ISS III, higher WHO performance status (>1), and age (>60 years). A risk score (1 risk factor=1 point) stratified patients in low (39.5%; 0 points), intermediate (41.9%; 1 point), and high (18.6%; ≥2 points) risk. The risk for severe infection/death increased from 7.7% vs. 11.5% vs. 23.3% in the low- vs. intermediate- vs. high-risk groups (p < 0.001). The risk score was independently validated in three trials incorporating quadruplet IT with an anti-CD38 antibody. Our analyses established a robust and easy-to-use score to identify NDMM patients at risk of severe infection/death, covering the latest quadruplet induction therapies. Trial registrations: HOVON-65/GMMG-HD4: EudraCT No. 2004-000944-26. GMMG-MM5: EudraCT No. 2010-019173-16. GMMG-HD6: NCT02495922. EMN02/HOVON-95: NCT01208766. GMMG-HD7: NCT03617731.

Minimal residual disease (MRD) by multiparameter flow cytometry (MFC) is the most effective tool to define a deep response in multiple myeloma (MM). We conducted an MRD correlative study of the EMN02/HO95 MM phase III trial in newly diagnosed MM patients achieving a suspected complete response before maintenance and every 6 months during maintenance. Patients received high-dose melphalan (HDM) versus bortezomib-melphalan-prednisone (VMP) intensification, followed by bortezomib-lenalidomide-dexamethasone (VRd) versus no consolidation, and lenalidomide maintenance. Bone marrow (BM) samples were processed in three European laboratories, applying EuroFlow-based MFC protocols (eight colors, two tubes) with 10−4−10−5 sensitivity. At enrollment in the MRD correlative study, 76% (244/321) of patients were MRD-negative. In the intention-to-treat analysis, after a median follow-up of 75 months, 5-year progression-free survival was 66% in MRD-negative versus 31% in MRD-positive patients (HR 0.39; p < 0.001), 5-year overall survival was 86% versus 69%, respectively (HR 0.41; p < 0.001). MRD negativity was associated with reduced risk of progression or death in all subgroups, including ISS-III (HR 0.37) and high-risk fluorescence in situ hybridization (FISH) patients (HR 0.38;). In the 1-year maintenance MRD population, 42% of MRD-positive patients at pre-maintenance became MRD-negative after lenalidomide exposure. In conclusion, MRD by MFC is a strong prognostic factor. Lenalidomide maintenance further improved MRD-negativity rate.

Contains fulltext : 219520.pdf (Publisher’s version ) (Closed access)

Contains fulltext : 219520.pdf (Publisher’s version ) (Closed access)

Contains fulltext : 219520.pdf (Publisher’s version ) (Closed access)

Scopo del progetto era identificare le migliori strategie terapeutiche ed i possibili fattori prognostici predittivi di outcome nel contesto di trials clinici sperimentali condotti dall’Istituto di Ematologia “Seragnoli”. L’attenzione è stata focalizzata sul protocollo EMN02/HO95MM, uno studio multicentrico, internazionale di fase III, riservato a pazienti con mieloma all’esordio, volto a ridefinire ruolo e corretto timing del trapianto autologo di cellule staminali (ASCT) nell’era dei nuovi farmaci. Secondo il disegno dello studio i pazienti venivano randomizzati post induzione a ricevere intensificazione con bortezomib-melphalan-prednisone (VMP) o chemioterapia ad alte dosi ed ASCT. Per i centri con una policy di doppio trapianto la randomizzazione era pianificata in rapporto 1:1:1 tra VMP, singolo (ASCT-1) o doppio trapianto (ASCT-2). Endpoint primario dello studio era comparare l’efficacia in termini di PFS di VMP versus ASCT. Tra gli endpoint secondari vi era il confronto tra singolo e doppio ASCT. Per intenzione di trattamento, con un follow-up mediano di 38 mesi, l’analisi ha dimostrato che ASCT consente un significativo prolungamento di PFS rispetto a VMP (HR=0.76, 95%CI=0.63-0.90, p=0.002). Il vantaggio è stato confermato in analisi multivariata ed in sottogruppi di pazienti sia a basso che ad alto rischio prognostico. L’OS è risultata del tutto sovrapponibile tra i due gruppi di trattamento, mentre un vantaggio significativo è stato osservato in pazienti ad alto rischio per profilo citogenetico ed alto stadio R-ISS sottoposti ad ASCT. Il trapianto upfront si conferma al momento gold standard terapeutico per il paziente giovane con malattia all’esordio. Per quanto riguarda il confronto tra singolo e doppio trapianto, la randomizzazione ad ASCT-2 è risultata correlare con un significativo prolungamento sia di PFS (HR=0.70; CI=0.50-0.98; p=0.040) che di OS (HR=0.52, CI=0.31-0.86, p=0.011). Tale beneficio appare particolarmente evidente in pazienti con caratte, High-dose melphalan with autologous stem-cell transplantation (ASCT) has been traditionally considered the standard of care for young newly diagnosed multiple myeloma (NDMM) patients. Nevertheless, remarkable activity of novel agent-based therapies has recently questioned the role of upfront ASCT. The EMN02/HO95 randomized, international, multicenter, phase 3 trial was designed to primarily compare upfront high-dose intensification therapy followed by ASCT vs standard-dose intensification therapy with bortezomib-melphalan-prednisone (VMP). In centers with a policy of double ASCT, patients were randomized in a 1:1:1 ratio to receive either VMP, single (ASCT-1) or tandem ASCT (ASCT-2). A primary study endpoint was PFS comparison between VMP and ASCT arms; a secondary endpoint was to assess efficacy of ASCT-1 vs ASCT-2. A total of 1192 patients were included in the analysis: 497 patients were allocated to VMP arm, 695 received ASCT. On an intention-to-treat basis, with a median follow up of 38 months, upfront ASCT was associated with a significant improvement in PFS vs VMP in the overall patient population (median not reached vs 44 months, 3-years estimates of 64% vs 57%; HR=0.76, 95%CI=0.63-0.90, p=0.002). PFS benefit with ASCT was retained across prespecified subgroups of patients at standard- and high-risk, and in a multivariate analysis. Although no OS difference between the two treatment groups was seen in the overall population, ASCT significantly prolonged the OS of patients with poor prognosis, including those with R-ISS stage 3 disease and who carried a high-risk cytogenetic profile. Upfront ASCT continues to be the reference treatment choice for NDMM patients, even in the novel agent era. Restricting the analysis to patients enrolled in centers with a double transplantation policy, randomization to ASCT-2 proved to significantly prolong PFS (HR=0.70; CI=0.50-0.98; p=0.040) and OS (HR=0.52, CI=0.31-0.86, p=0.011) in comparison to ASCT-1. Clinical benefits were

Scopo del progetto era identificare le migliori strategie terapeutiche ed i possibili fattori prognostici predittivi di outcome nel contesto di trials clinici sperimentali condotti dall’Istituto di Ematologia “Seragnoli”. L’attenzione è stata focalizzata sul protocollo EMN02/HO95MM, uno studio multicentrico, internazionale di fase III, riservato a pazienti con mieloma all’esordio, volto a ridefinire ruolo e corretto timing del trapianto autologo di cellule staminali (ASCT) nell’era dei nuovi farmaci. Secondo il disegno dello studio i pazienti venivano randomizzati post induzione a ricevere intensificazione con bortezomib-melphalan-prednisone (VMP) o chemioterapia ad alte dosi ed ASCT. Per i centri con una policy di doppio trapianto la randomizzazione era pianificata in rapporto 1:1:1 tra VMP, singolo (ASCT-1) o doppio trapianto (ASCT-2). Endpoint primario dello studio era comparare l’efficacia in termini di PFS di VMP versus ASCT. Tra gli endpoint secondari vi era il confronto tra singolo e doppio ASCT. Per intenzione di trattamento, con un follow-up mediano di 38 mesi, l’analisi ha dimostrato che ASCT consente un significativo prolungamento di PFS rispetto a VMP (HR=0.76, 95%CI=0.63-0.90, p=0.002). Il vantaggio è stato confermato in analisi multivariata ed in sottogruppi di pazienti sia a basso che ad alto rischio prognostico. L’OS è risultata del tutto sovrapponibile tra i due gruppi di trattamento, mentre un vantaggio significativo è stato osservato in pazienti ad alto rischio per profilo citogenetico ed alto stadio R-ISS sottoposti ad ASCT. Il trapianto upfront si conferma al momento gold standard terapeutico per il paziente giovane con malattia all’esordio. Per quanto riguarda il confronto tra singolo e doppio trapianto, la randomizzazione ad ASCT-2 è risultata correlare con un significativo prolungamento sia di PFS (HR=0.70; CI=0.50-0.98; p=0.040) che di OS (HR=0.52, CI=0.31-0.86, p=0.011). Tale beneficio appare particolarmente evidente in pazienti con caratte, High-dose melphalan with autologous stem-cell transplantation (ASCT) has been traditionally considered the standard of care for young newly diagnosed multiple myeloma (NDMM) patients. Nevertheless, remarkable activity of novel agent-based therapies has recently questioned the role of upfront ASCT. The EMN02/HO95 randomized, international, multicenter, phase 3 trial was designed to primarily compare upfront high-dose intensification therapy followed by ASCT vs standard-dose intensification therapy with bortezomib-melphalan-prednisone (VMP). In centers with a policy of double ASCT, patients were randomized in a 1:1:1 ratio to receive either VMP, single (ASCT-1) or tandem ASCT (ASCT-2). A primary study endpoint was PFS comparison between VMP and ASCT arms; a secondary endpoint was to assess efficacy of ASCT-1 vs ASCT-2. A total of 1192 patients were included in the analysis: 497 patients were allocated to VMP arm, 695 received ASCT. On an intention-to-treat basis, with a median follow up of 38 months, upfront ASCT was associated with a significant improvement in PFS vs VMP in the overall patient population (median not reached vs 44 months, 3-years estimates of 64% vs 57%; HR=0.76, 95%CI=0.63-0.90, p=0.002). PFS benefit with ASCT was retained across prespecified subgroups of patients at standard- and high-risk, and in a multivariate analysis. Although no OS difference between the two treatment groups was seen in the overall population, ASCT significantly prolonged the OS of patients with poor prognosis, including those with R-ISS stage 3 disease and who carried a high-risk cytogenetic profile. Upfront ASCT continues to be the reference treatment choice for NDMM patients, even in the novel agent era. Restricting the analysis to patients enrolled in centers with a double transplantation policy, randomization to ASCT-2 proved to significantly prolong PFS (HR=0.70; CI=0.50-0.98; p=0.040) and OS (HR=0.52, CI=0.31-0.86, p=0.011) in comparison to ASCT-1. Clinical benefits were