Overproduction of vascular endothelial growth factor (VEGF) seems to contribute to the pathogenesis, still unclear, of POEMS Syndrome. Our study retrospectively reviewed the clinical and VEGF data from a multicenter Italian cohort of patients affected by POEMS syndrome who underwent to autologous peripheral blood stem cell transplantation (aPBSCT) in order to find an impact on clinical improvement or outcome. Patients with VEGF levels higher than 758 pg/mL were at higher risk of relapse, with sensible difference in PFS (p = 0.007). VEGF could be used as a marker of relapse and as a marker of disease intensity in patients with POEMS.

The role of autologous stem cell transplantation (ASCT) in older patients (pts) with multiple myeloma (MM) is being re-evaluated in light of effective anti-CD38-based regimens now available for non-transplant eligible (NTE) pts. In this context, we retrospectively compared outcomes of transplant-eligible (TE) elderly pts receiving ASCT after Dara-VTD induction versus NTE pts treated with anti-CD38-based regimens, evaluating the impact of frailty status on outcomes. We analyzed 122 unselected pts aged 65–75 years (median age 72) with newly diagnosed MM at our institution between April 2016 and December 2024. ASCT eligibility was based on clinical judgment. TE pts received Dara-VTD induction, ASCT, Dara-VTD consolidation and lenalidomide maintenance (ASCT cohort), while NTE pts received anti-CD38-based regimens (no-ASCT cohort). Response rate, progression-free survival (PFS), overall survival (OS), and treatment-related toxicity were assessed. The IMWG frailty score was retrospectively applied to evaluate outcomes according to frailty status. Out of 122 pts recorded, 22 (18%) were ISS stage 3 and 40 (32%) had high risk (HR) cytogenetics. Median age was 68 vs 73 years in ASCT vs no-ASCT cohorts (p<0.0001), while HR cytogenetics and ISS-3 distribution were well balanced between cohorts. Thirty-six (29%) were assigned to the ASCT cohort (5 receiving double ASCT); 86 (71%) constituted the no-ASCT cohort: DRd 54%, D-VMP 16%, Isa-VRd 1%. According to the IMWG frailty score, 27 pts (22%) were classified as fit, 91 (75%) as intermediate-fit (unfit), and 4 (3%) as frail. In the ASCT cohort, 47% were fit and 53% were intermediate-fit. In the no-ASCT cohort, 11% were fit, 84% intermediate-fit, and 5% frail. ORR was 94% in the ASCT cohort vs 91% in the no-ASCT cohort (p=0.7), and ≥VGPR rates were 75% vs 62%, respectively (p=0.5). sCR+CR rates were higher in the ASCT cohort (53% vs 24%, p=0.032). MRD assessed by multiparametric flow cytometry (sensitivity 10⁻⁵) was available in 17 ASCT pts before maintenance, of which 13 (76%) were negative. After a median follow-up of 24 months, PFS was similar between ASCT and no-ASCT (median NR vs 75.5 months; 3-year PFS 83% vs 76%, p=0.55), as was OS (median NR in both cohorts; 3-year OS 93% vs 86%; p=0.41). In the ASCT cohort, PFS was longer in fit pts compared to unfit, although not statistically significant (3-year PFS 94% vs 73%; median NR in both groups; p=0.191). OS showed a similar trend (3-year OS 100% vs 87%; median NR; p=0.208). Among ASCT pts, the subgroup aged >70 years (n=4) showed outcomes comparable to those aged 65–70, with no PFS and OS events reported at the time of analysis. In the no-ASCT cohort, PFS differed significantly according to frailty status (p=0.04): 3-year PFS was 100% in fit pts, 70% in unfit, and 50% in frail; median PFS was 80, 75, and 29 months, respectively. OS was not significantly different between groups (p=0.3), with 3-year OS of 100%, 83%, and 100%, and median OS NR, NR, and 45 months, respectively. No significant differences in PFS or OS were observed when comparing pts aged 65–70 and 71–75 years within each treatment cohort. Notably, PFS in unfit pts receiving ASCT was comparable to that observed in the no-ASCT cohort (3-year PFS 73% vs 70%; p=0.891). Grade ≥3 hematologic toxicities were significantly more frequent in the ASCT cohort, with neutropenia in 92% vs 51% (p<0.0001) and thrombocytopenia in 89% vs 16% (p<0.0001). Infections of any grade occurred in 92% of ASCT pts vs 67% in the no-ASCT cohort (p=0.0017), with grade ≥3 infections reported in 64% vs 34% (p=0.0027), respectively. Temporary treatment discontinuation was comparable between groups. However, when considering the temporary discontinuation of at least one drug within the treatment regimen, the rate was significantly higher in the ASCT cohort (67% vs 43%; p=0.028), mainly due to thalidomide-related complications. These findings support the feasibility and effectiveness of ASCT in carefully selected pts aged >70 years. However, modern anti-CD38-based regimens represent a valid alternative in the 65–75 age group, offering comparable outcomes with a more favorable safety profile. The IMWG frailty score emerges as a valuable tool to guide therapeutic decisions regarding treatment intensity and transplant eligibility, particularly in unfit pts, whose outcomes were comparable to those treated with non-intensive regimens.

Functional high-risk (FHR) multiple myeloma (MM) patients, defined as those with early relapse despite optimal initial therapy, represent an unmet clinical need. Diffusion-weighted whole-body MRI (DW-MRI) is increasingly used in MM management due to its high sensitivity in assessing treatment response. The Myeloma Response Assessment and Diagnosis System (MYRADS) established the Response Assessment Category (RAC), a 5-point scale ranging from complete response (RAC 1) to progressive disease (RAC 5), which independently stratifies patients with different outcomes after autologous stem cell transplantation (ASCT). The relative fat fraction (rFF), derived from DW-MRI, provides additional prognostic insights into bone marrow composition. This study aimed to evaluate whether the combined assessment of RAC and rFF could identify FHR MM patients at risk of early relapse, defined as progression within 18 months post-autologous stem cell transplantation (ASCT). Ninety-seven MM patients were retrospectively analyzed after ASCT, before maintenance, with a median follow-up of 47 months. An rFF threshold of 17.2% predicted early relapse with 83% sensitivity and 85% specificity. Patients with rFF >17.2% had significantly improved post-ASCT progression-free survival (PFS, median not reached [NR] vs. 13.7 months, HR 0.18; 95% CI: 0.08-0.43) and overall survival (OS, 3-year rate: 96% vs. 62%, HR 0.12; 95% CI: 0.03-0.45) compared to rFF ≤17.2%. Patients with RAC 1/rFF High had the best outcomes, while RAC ≥2/rFF Low had the worst prognosis (median PFS: NR vs. 12.3 months, HR 0.21; 95% CI: 0.07-0.62). rFF complements RAC for response assessment after ASCT, enabling early identification of FHR patients with poor prognosis.

Autologous peripheral blood stem cell transplantation (aPBSCT) provides optimal outcomes in POEMS syndrome but the definition of the best treatment before aPBSCT remains to be defined because of the rarity of the disease and the heterogeneity of published case series. We collected clinical and laboratory data of patients with POEMS syndrome undergoing aPBSCT from 1998 to 2020 in ten Italian centers. The primary endpoint of the study was to evaluate the impact of prior therapies and mobilization regimen on outcome. We divided the patients into three groups: patients who did not receive any treatment before transplant (15 patients, group A: front-line), patients pre-treated with other agents (14 patients, group B) and patients treated with cyclophosphamide as their mobilizing regimen (16 patients, group C). The three groups did not show differences in terms of demographic and clinical characteristics. All 45 patients underwent aPBSCT after a high-dose melphalan conditioning regimen, with a median follow-up of 77 months (range, 37-169 months). The responses were not statistically different between the three groups (P=0.38). Progression-free and overall survival rates at 6 years were: 70% (95% confidence interval: 55-85%) and 91% (95% confidence interval: 82-99) 65%, respectively, and did not differ between the three groups. The cumulative incidence of transplant-related mortality and relapse was 4% and 36%, respectively. In conclusion, in a relatively large number of patients with POEMS syndrome, undergoing an autologous transplant, pre-treatment and disease status at transplant did not appear to have an impact on major transplant outcomes.

Introduction: Functional high risk (HR) multiple myeloma (MM) patients (pts) (namely, pts in whom the disease progresses within 12 to 18 months despite an optimal initial therapy) represent an unmet clinical need despite the availability of highly effective treatments. Diffusion-weighted whole-body MRI (DW-MRI) is increasingly used in the management of MM pts due to its high sensitivity and information regarding response to treatment. The Myeloma Response Assessment and Diagnosis System (MY-RADS) recommendations have established criteria for Response Assessment Category (RAC) with a 5-point scale defining the range of imaging response after treatment from complete (RAC 1) to progressive disease (RAC 5). Furthermore, the RAC score appears to be able to independently stratify pts with different outcomes after autologous stem cell transplantation (ASCT). More recently, a growing interest is emerging in the evaluation of relative fat fraction (rFF) obtainable from MRI, which provides additional insights into bone disease status. Response to treatment of bone disease increases the rFF through a fatty marrow reconversion in previously active lesions, but data regarding the optimal rFF threshold predictive of outcome in MM are lacking. Aim of this study was to evaluate if the combined assessment of RAC score and rFF could better identify functional HR pts after ASCT. Patients and methods: We retrospectively analyzed the outcome of MM pts newly diagnosed at our institution from January 2018 to December 2022 and who underwent DW-MRI evaluation after ASCT, before maintenance. Post ASCT progression free survival (PFS) was calculated from the day of ASCT (the second one in case of double ASCT) until progression or death from any cause. In addition to the RAC score, the rFF of up to 5 target lesions was evaluated for each patient and pts outcome was analyzed accordingly. ROC curve analysis was performed in order to select the optimal threshold value for rFF predictive for early relapse, defined in our study as clinical relapse within 18 months after ASCT. Marrow MRD evaluation before maintenance was also performed with 8-color FCM (sensitivity 10-5). Results: Out of 97 pts recorded, 33 (34%) were ISS stage 3 and 34 (35%) showed HR cytogenetics. Their median age was 61 years. Pts were treated with the following induction regimens: VTD 58, VRD 6, Dara-VRD 5, Dara-VCD 6, Dara-VTD 21, Isa-KRD 1. Single ASCT with MEL200 conditioning was performed in 56 pts (58%), whereas 41 pts (42%) received double ASCT. Response rates before maintenance were PR 5%, VGPR 33%, CR 43% and sCR 19%. Of 79 pts with available MRD result, 52 (66%) were negative. A complete imaging response was observed in 66 (RAC 1: 68%). A total of 416 areas on DW-MRI before maintenance were drawn and reviewed to calculate rFF values. After a median follow up of 47 months, post ASCT PFS was significantly longer in pts with RAC 1 vs RAC ≥2 (median NR vs 24.6 months, p 0.0009, HR 0.27; 95%CI 0.13-0.58), as well as post ASCT OS (3-year rate 95% vs 73%, p 0.0072, HR 0.24; 95%CI 0.07-0.81). Mean rFF ROC analysis revealed an AUC of 0.84 (95% CI 0.72-0.95, p <0.0001); cut-off threshold of 17.2% for rFF identified early relapse with 83% (95% CI 0.61-0.94) sensitivity, 85% (95% CI 0.75-0.90%) specificity, a PPV of 55% (95% CI 36-74%) and a NPV of 96% (95% CI 91-100%). Post ASCT PFS was significantly superior in pts with rFF >17.2% vs rFF <17.2%, defined below as rFF High vs rFF Low: median NR vs 13.7 months, p < 0.0001, HR 0.18 (95% CI 0.08-0.43), as well as post ASCT OS (3- year rate 96% vs 62%, p < 0.0001, HR 0.12; 95% CI 0.03-0.45). Combining RAC score and rFF, post ASCT PFS was significantly better for patients with RAC 1/rFF High before maintenance, compared to pts with RAC ≥2/rFF Low (median NR vs 12.3 months, p < 0.0001, HR 0.21; 95% CI 0.07-0.62). Intermediate PFS (42 months) was observed for pts with either RAC ≥2/rFF High or RAC1/rFF Low, with a significantly different outcome of the three subgroups (p < 0.0001). With a threshold of 17.2%, high or low rFF before maintenance independently affected post ASCT PFS and OS on a multivariate analysis. Conclusion: rFF can complement the RAC score in the assessment of response after ASCT, representing a powerful tool allowing for early identification of functional HR MM pts with early relapse and particularly poor prognosis.

Introduction: The increasing availability of functional imaging techniques has enabled the combined evaluation of MRD in MM within and outside bone marrow (BM). Diffusion-weighted whole-body MRI (DW-MRI) is increasingly used in the management of MM patients (pts) and criteria for Response Assessment Category (RAC) have been established by the Myeloma Response Assessment and Diagnosis System (MY-RADS), with a 5 point scale defining complete imaging response (i.e. RAC 1) or residual-progressive disease after treatment (i.e. RAC 2-5). We compared the results of MY-RADS with those of MRD assessment by flow cytometry (MFC) at different timepoints after autologous stem cell transplant (ASCT) in order to evaluate the agreement of the two techniques and to investigate the predictive role of a dual assessment of response on patients outcome. Methods: we retrospectively assessed MRD in transplant eligible MM pts by performing combined evaluations of BM and DW-MRI at day +100 after ASCT and yearly thereafter. MY-RADS RAC criteria were applied for the evaluation of imaging residual disease, whereas 8-color MFC (sensitivity 10-5) was performed for BM MRD detection. The concordance between DW-MRI and MFC results was calculated and the level of agreement was expressed by Cohen’s kappa statistics. The outcome according to the combined DW-MRI/MFC evaluation after ASCT was also investigated. Results: from 2016 to 2021 we performed 143 combined evaluations of DW-MRI and MFC in 79 pts. MFC was negative in 96 BM samples (67%); according to MY-RADS, a complete imaging response (RAC1) was observed in 107 cases (75%), whereas some residual disease was identified in 36 cases (25%) [RAC2: 24 (17%), RAC3: 6 (4%), RAC4: 3 (2%), RAC 5: 3 (2%) respectively]. The concordance between WB-MRI and BM MFC results was low (68.5%, kappa 0,067: 13% both positive, 55% both negative). MRD assessment at day +100 after ASCT (considering the second ASCT in case of double transplant) was available in 76 patients [27(35%) ISS-3, 29 (38%) high risk cytogenetics]. Pts were treated with the following induction regimens: VTD 56 (74%), DaraVCD 6 (8%), DaraVRD 6 (8%), VRD 6 (8%), KCD 1 (1%), KRD 1 (1%); 37 pts (49%) received double ASCT (MEL200). Response rates were sCR 25%, CR 45%, VGPR 21%, PR 9%. MFC was negative in 48 samples (63%), whereas RAC1 was observed in 52 (68%) pts. Seventy pts (92%) received maintenance therapy with lenalidomide (58), daratumumab-lenalidomide (6), daratumumab-ixazomib (6). After a median follow up of 42 months, PFS was significantly better for patients with DW-MRI RAC1 and MFC negative after ASCT, compared to pts with RAC ≥2 and MFC positive results (PFS NR vs 22.3 months; p <0.0001, HR 0.10 - 95%CI: 0,02-0,43). Intermediate PFS was observed for pts with either imaging or BM positive results (PFS NR), with a significantly different outcome of the three subgroups (p <0.0001). A trend of different OS was also observed, although not statistically significant (3y OS: 95% for double negative pts, 89% for pts with either imaging or BM positive results, 60% for double positive pts, p 0.06). Conclusion: DW-MRI is a powerful tool to evaluate the prognosis of pts treated with ASCT; the low concordance between DW-MRI and MFC highlights the complementarity of the two techniques for the definition and monitoring of response in order to better refine the prognosis of pts achieving CR after ASCT

Multiple Myeloma (MM) is still considered an incurable disease. However, the availability of novel and effective therapies is making the prospect of eradicating the malignant clone and converting MM into a curable disease realistic. In this context, the detection of minimal residual disease (MRD) has become of utmost importance. The high spatial genomic heterogeneity that characterizes MM patients explains the potential persistence of residual disease even in bone marrow (BM) MRD negative patients, highlighting the need of different techniques able to detect the disease within and outside of the BM.1 The prognostic usefulness of both MRD assessment and functional imaging response after treatment have been established.2 The combination of BM and imaging techniques has a direct impact on prognosis, with patients reaching double MRD negativity having the best outcome.3 Recently, sustained BM MRD-negativity and its association with an excellent outcome is emerging in clinical trials.4 Diffusion-weighted whole body MRI (DW-MRI) is increasingly used in the management of MM. It produces images in which the contrast between tissues is based on differences in the motion of water at a cellular level and permits to estimate cell density with the so-called apparent diffusion coefficient (ADC). The Myeloma Response Assessment and Diagnosis System (MY-RADS) recommendations have established criteria for Response Assessment Category (RAC) with a 5-point scale defining the range of imaging response after treatment from complete (RAC 1) to progressive disease (RAC 5).5 We have previously shown that RAC criteria were able to independently stratify patients with different outcomes after autologous stem cell transplantation (ASCT).6 Data regarding the predictive role of sustained imaging MRD-neg assessed by DW-MRI are lacking. With this aim, we implemented DW-MRI and RAC criteria in MM patients both after ASCT and at 1 year during maintenance therapy in order to evaluate the predictive information of sustained imaging MRD negativity on outcome. All transplant-eligible MM patients newly diagnosed at our institution between January 2016 and December 2019 who received maintenance therapy after ASCT were retrospectively analyzed. Treatment response according to IMWG criteria was assessed before maintenance. DW-MRI was performed at day +100 after ASCT, and thereafter at 1 year to monitor imaging-residual-disease. In patients receiving double ASCT, DW-MRI performed at day +100 after the second one was considered. Protocol details and application of RAC criteria in our external validation of MY-RADS guidelines in clinical practice have been previously published. BM samples were also collected for MRD assessment by 8-color multiparametric flow-cytometry (MFC, sensitivity 10−5) at day +100 after ASCT, and thereafter at 1-year in MRD-neg patients in order to assess sustained MRD negativity. We focused on the predictive role of sustained 1-year DW-MRI-neg on progression free survival (PFS) and overall survival (OS). PFS after second-line treatment was also evaluated. Kaplan–Meyer method was used to estimate survival curves and multivariate analysis (Cox proportional hazard models) was performed to evaluate the influence of prognostic factors on outcome. In patients with available 1-year BM MRD evaluation, the concordance between BM and DW-MRI results was calculated (Cohen's kappa statistics). This study has been approved at our institution by the local Ethics Committee and has been done in accordance with the Declaration of Helsinki. We identified 70 newly-diagnosed MM patients who underwent ASCT followed by maintenance therapy and had a DW-MRI scan at day +100 after ASCT and at 1-year. Induction regimens used were: VTD in 55 (79%), VRD in five (7%), Dara-VRD in six (9%), KRD in three (4%), KCD in one (1%). Forty patients (57%) received a single ASCT (MEL200), whereas double ASCT was performed in 30 patients (43%). All patients received lenalidomide maintenance, in combination with daratumumab in six (9%) and with carfilzomib in one (1%). Median follow-up duration was 46 months. Median age was 61 years (40–73), 28 (40%) patients were ISS stage III and 21 (30%) of them had high-risk cytogenetics (t[4;14] and/or t[14;16] and/or del17p and/or 1q gain/amp1q abnormalities). IMWG responses at day +100 after ASCT were: PR 6 (8%), VGPR 15 (21%), CR 38 (54%), and sCR 11 (16%). Complete imaging response according to MY-RADS was achieved after ASCT in 41 patients (RAC 1: 59%), whereas residual disease was observed in 29 patients (RAC >2:41%). BM MFC for MRD detection was available before maintenance in 61 patients and was negative in 39 (64%) patients. At 1-year DW-MRI complete imaging response (RAC 1) was observed in 53 (76%) patients, whereas residual disease was documented in 17 patients (24%). BM MRD evaluation at 1-year was available in 35 patients and was negative in 29 (83%). The concordance between 1-year DW-MRI and BM MFC MRD results was high (85%, kappa 0.46: 8% both positive, 77% both negative). Median PFS was significantly longer for patients with imaging MRD-neg at 1-year (RAC 1) compared to patients with residual disease on DW-MRI (RAC ≥2) (median PFS: 55.4 vs. 28.4 months; 3-years PFS: 91% vs. 30%, respectively [HR 0.12; 95% CI: 0.04–0.35; p < 0.0001]) (Figure 1A). Survival of imaging MRD-neg patients at 1-year was significantly longer for patients with RAC1 versus RAC ≥2 (median OS: NR vs. 63 months; 3-years OS: 100% vs. 82%, respectively [HR 0.13; 95% CI: 0.03–0.66; p 0.0007]) (Figure 1B). Upgrade of imaging response from RAC ≥2 at maintenance start to RAC1 at 1-year was observed in 13 patients (19%) Their outcome was superimposable to that of other MRD-neg patients at 1-years. Fifteen out of 17 RAC ≥2 patients at 1-year after ASCT (88%) were treated with the following second-line therapies at biochemical or clinical relapse: DVD: 6 (40%), KD reinduction and ASCT: 6 (40%), KPD:1 (7%), and PVD in 2 (13%) patients. Their median PFS was 13 months. Notably, of 29 patients in sustained MFC MRD-neg at 1-year, two had imaging-residual-disease on DW-MRI. Both developed aggressive extramedullary relapse, one with CNS involvement. Among the prognostic parameters available at 1-year after transplant in all 70 patients (IMWG response, cytogenetic risk profile, ISS stage and RAC score at 1-year), multivariable analysis showed that both PFS and OS were independently affected only by DW-MRI persistent disease (RAC ≥2): p < 0.001, HR 0.12 (95% CI: 0.05–0.30) for PFS, p = 0.032, HR 0.20 (95% CI: 0.05–0.87) for OS. MRD evaluation, an essential step toward achievement of operational cure in MM, has evolved from a single timepoint assessment to repeated monitoring of MRD over time, since sustained BM MRD-neg appears a better predictor of longer PFS and OS. Few data have been reported to date regarding sustained imaging MRD-negativity during maintenance therapy using PET and ancillary studies are under investigations in clinical trials. To our knowledge, this is the first report describing the prognostic value of sustained imaging MRD-negativity assessed by DW-MRI in MM. Our results highlight the ability of DW-MRI to identify a significant proportion of patients who fail to achieve sustained imaging MRD-negativity at 1-year during maintenance therapy (RAC ≥2: 24%), whose outcome is dismal despite being responsive according to IMWG criteria. Compared to RAC1 patients their PFS was halved and OS was significantly shorter. Moreover, their PFS after salvage with the most effective standard second-line combination therapies available was very short. The retrospective nature of our observations, the relatively low number of patients and the lack of BM MFC evaluation at 1-year in the entire cohort of patients represent major limitations of our study, which requires further confirmation. Nevertheless, they lend support to the use of functional imaging techniques to allow a better dynamic risk assessment in order to identify patients at increased risk of relapse and particularly poor prognosis. For patients failing to achieve sustained DW-MRI MRD-negativity, an earlier use of novel emerging salvage treatments, such as CAR-T cells or bispecific antibodies may be considered. Angelo Belotti designed the research and analyzed data and wrote the paper, Rossella Ribolla collected data and performed research, Claudia Crippa collected data, Marco Chiarini performed the research, Viviana Giustini performed the research, Samantha Ferrari collected data, Annalisa Peli collected data, Chiara Cattaneo collected data, Aldo Roccaro supervised research, Barbara Frittoli performed research, Luigi Grazioli performed research, Giuseppe Rossi analyzed data and wrote the paper, Alessandra Tucci analyzed data and wrote the paper. We thank the patients and staff of the Department of Hematology, Spedali Civili, Brescia. We also thank the Department of Radiology, Spedali Civili, Brescia. AMR: Fondazione AIRC; Fondazione Regionale per la Ricerca Biomedica, ERA-NET TRANSCAN-2. The authors declare no conflict of interest to disclose. The data that support the findings of this study are available from the corresponding author upon reasonable request; the data are not publicly available due to privacy and ethical restrictions.

Klebsiella pneumoniae is the most common Klebsiella species infecting animals and is one of the causing agents of mastitis in cows. The rise of antimicrobial resistance in K. pneumoniae, particularly in strains producing extended-spectrum β-lactamases (ESBLs) and/or carbapenemases, is of concern worldwide. Recently (Regulation UE No 2022/1255), carbapenems and cephalosporins in combination with β-lactamase inhibitors have been reserved only to human treatments in the European Union. The aim of this study was to investigate the role of cattle as carrier of human pathogenic carbapenem-resistant (CR) and ESBL-producing K. pneumoniae. On this purpose, a study involving 150 dairy farms in Parma province (Northern Italy) and 14 non replicate K. pneumoniae isolates from patients admitted at Parma University-Hospital was planned. Four multidrug resistant (MDR) K. pneumoniae strains were detected from 258 milk filters collected between 2019 and 2021. One carbapenemase KPC-3-positive K. pneumoniae ST307 (0.4 %; 95 % CI - 0.07 - 2.2) was detected in milk filters. The isolate also harboured OXA-9, CTX-M-15 and SHV-106 determinants, together with genes conferring resistance to aminoglycosides (aac(3')-IIa, aph (3″)-Ib, aph (6)-Id), fluoroquinolones (oqxA, oqxB, qnrB1), phosphonic acids (fosA6), sulphonamides (sul2), tetracyclines (tet(A)6) and trimethoprim (dfrA14). One KPC-3-producing K. pneumoniae ST307 was identified also among the human isolates, thus suggesting a possible circulation of pathogens out of the clinical settings. The remaining three bovine isolates were MDR ESBL-producing K. pneumoniae characterized by different genomic profiles: CTX-M-15, TEM-1B and SHV-187 genes (ST513); CTX-M-15 and SHV-145 (ST307); SHV-187 and DHA-1 (ST307). Occurrence of ESBL-producing K. pneumoniae in milk filters was 1.2 % (95 % CI 0.4-3.4). All the isolates showed resistance to aminoglycosides, 3rd-generation cephalosporins, and fluoroquinolones. Among the human isolates, two multidrug resistant ESBL-producing K. pneumoniae ST307 were found, thus confirming the circulation of this high-risk lineage between humans and cattle. Our findings suggest that food-producing animals can carry human pathogenic microorganisms harboring resistance genes against carbapenems and 3rd-generation cephalosporins, even if not treated with such antimicrobials. Moreover, on the MDR K. pneumoniae farms, the antimicrobial use was much higher than the Italian median value, thus highlighting the importance of a more prudent use of antibiotics in animal productions.

Introduction: sustained minimal residual disease (MRD) negativity assessed by bone marrow (BM) techniques is emerging as a surrogate biomarker of patients' outcome in Multiple Myeloma (MM). Moreover, spatial genomic heterogeneity that characterizes MM patients explains the persistence of residual disease within and outside the BM in patients with hematological complete response. Therefore the combined evaluation of BM MRD and functional imaging assessment is required to examine MM eradication. Diffusion-weighted whole-body MRI (DW-MRI) is increasingly used in the management of MM patients, but few data are available regarding the predictive information obtainable from this technique. The Myeloma Response Assessment and Diagnosis System (MY-RADS) recommendations have established criteria for Response Assessment Category (RAC) with a 5 point scale defining complete imaging response (i.e. RAC 1) or some residual-progressive disease after treatment (i.e. RAC 2-5). We performed DW-MRI in MM patients after autologous stem cell transplantation (ASCT) and at 1 year during maintenance therapy in order to evaluate the predictive information of sustained imaging MRD negativity on outcome. Patients and methods: We analyzed the outcome of 70 newly diagnosed consecutive MM patients (median age 60 years) diagnosed at our institution from January 2015 to December 2020 receiving maintenance therapy after ASCT. Patients underwent DW-MRI evaluation according to MY-RADS criteria at day +100 after ASCT, before maintenance, and after 1 year with the aim of monitoring imaging MRD. BM samples were collected for MRD assessment by 8-color FCM (sensitivity 10-5) at day +100 after ASCT and after 1 year. We focused on sustained 1-year DW-MRI negativity according to RAC response, and its predictive role at that timepoint on progression free survival (PFS) and overall survival (OS); PFS of second line treatment was also evaluated. In patients with available 1-year BM MRD evaluations, concordance between BM and DW-MRI results was calculated and the level of agreement was expressed by Cohen's kappa statistics. Results: Out of 70 patients, 28 (40%) were ISS stage 3 and 16 (23%) showed high risk cytogenetics. Patients were treated with the following induction regimens: VTD 55, VRD 5, Dara-VRD 7, KRD 2, KCD 1. Single ASCT with MEL200 conditioning was performed in 40 patients (57%), whereas 30 patients (43%) received double ASCT. Subsequent maintenance was performed with lenalidomide (60 patients, 86%) or daratumumab-lenalidomide (10 patients, 14%). Response rates after ASCT were PR 8%, VGPR 22%, CR 54% and sCR 16%. After a median follow of 42 months, no difference in PFS and OS was observed according to ISS stage, whereas superior PFS and OS were observed for patients with standard risk cytogenetics, compared to patients with high risk profile: median PFS 50.6 vs 36,2 months, p 0,002, HR 0,33 (95% CI 0,12-0,83); 3-year OS 94% vs 78%, p 0,04, HR 0,27 (95% CI 0,06-1,23). Imaging MRD negativity (RAC1) before maintenance was observed in 41 patients (58%), whereas long term 1 year imaging MRD negativity during maintenance was observed in 53 patients (76%). The 17 (24%) patients with imaging residual disease (RAC ≥2) at 1 year showed a worse prognosis both in terms of PFS and OS (RAC 1 vs RAC ≥2: median PFS NR vs 28,4 months, p <0,0001, HR 0,11 - 95% CI: 0,03-0,33; 3-year OS 100% vs 81%, p < 0,0002, HR 0,15 (95% CI: 0,03-0,78). This subgroup of lenalidomide refractory patients received the following second line treatment: DVD (6), KD reinduction followed by ASCT (6), KPD (1), PVD (2); suboptimal median PFS of 13 months was observed. BM MRD at 1-year timepoint was available in 32 patients and was negative in 29 (90%) cases. Concordance between 1-year DW-MRI and BM FCM results was high (85%, kappa 0,46: 8% both positive, 77% both negative). Of note, the 2 patients with negative BM and positive imaging MRD at 1 year developed aggressive extramedullary relapse, one with CNS disease. Conclusion: Sustained imaging MRD negativity assessed by DW-MRI has strong predictive relevance for survival in newly diagnosed MM patients on maintenance therapy after ASCT. Moreover, given the high rates of CR seen in patients with MM with novel effective treatment combinations, the detection of imaging residual disease during lenalidomide-based maintenance can help the physician to early identify patients with a high risk of relapse and poor response to second line treatments.

Abstract Background Diffusion‐weighted whole‐body MRI (DW‐MRI) is increasingly used in the management of multiple myeloma (MM) patients, but data regarding the prognostic role of DW‐MRI imaging response after treatment are lacking. The Myeloma Response Assessment and Diagnosis System (MY‐RADS) imaging recommendations recently proposed the criteria for response assessment category (RAC) with a 5‐point scale in order to standardize response assessment after therapy, but this score still needs to be validated. Methods We investigated the prognostic role of RAC criteria in 64 newly diagnosed MM patients after autologous stem cell transplantation (ASCT), and we combined the results of MY‐RADS with those of minimal residual disease (MRD) assessment by multiparametric flow cytometry (MFC). Results Superior post‐ASCT PFS and OS were observed in patients with complete imaging response (RAC1), with respect to patients with imaging residual disease (RAC≥2): median PFS not reached (NR) versus 26.5 months, p = 0.0047, HR 0.28 (95% CI: 0.12–0.68); 3‐year post‐ASCT OS 92% versus 69% for RAC1 versus RAC ≥2, respectively, p = 0.047, HR 0.24 (95% CI: 0.06–0.99). Combining MRD and imaging improved prediction of outcome, with double‐negative and double‐positive features defining groups with excellent and dismal PFS, respectively (PFS NR vs. 10.6 months); p = 0.001, HR 0.07 (95%CI: 0.01–0.36). Conclusion The present study supports the applicability of MY‐RADS recommendations after ASCT; RAC criteria were able to independently stratify patients and to better predict their prognosis and the combined use of DW‐MRI with MFC allowed a more precise evaluation of MRD.

This study reports on 382 COVID-19 patients having undergone allogeneic ( n = 236) or autologous ( n = 146) hematopoietic cell transplantation (HCT) reported to the European Society for Blood and Marrow Transplantation (EBMT) or to the Spanish Group of Hematopoietic Stem Cell Transplantation (GETH). The median age was 54.1 years (1.0–80.3) for allogeneic, and 60.6 years (7.7–81.6) for autologous HCT patients. The median time from HCT to COVID-19 was 15.8 months (0.2–292.7) in allogeneic and 24.6 months (−0.9 to 350.3) in autologous recipients. 83.5% developed lower respiratory tract disease and 22.5% were admitted to an ICU. Overall survival at 6 weeks from diagnosis was 77.9% and 72.1% in allogeneic and autologous recipients, respectively. Children had a survival of 93.4%. In multivariate analysis, older age ( p = 0.02), need for ICU ( p < 0.0001) and moderate/high immunodeficiency index ( p = 0.04) increased the risk while better performance status ( p = 0.001) decreased the risk for mortality. Other factors such as underlying diagnosis, time from HCT, GVHD, or ongoing immunosuppression did not significantly impact overall survival. We conclude that HCT patients are at high risk of developing LRTD, require admission to ICU, and have increased mortality in COVID-19.

Background sustained MRD negativity is emerging as a surrogate biomarker of patients (pts)’ outcome in clinical trials. We implemented this tool in our clinical practice and we analyzed outcome according to sustained MRD negativity in MM pts treated with autologous stem cell transplantation (ASCT) at our Institution. Methods We retrospectively analyzed the outcome of 77 newly diagnosed MM pts (median age 61 years) diagnosed between January 2015 to December 2019 in ≥ VGPR after ASCT. Bone marrow samples were collected for MRD by 8-color FCM (Sn 10-5) at day +100 after ASCT, before maintenance. Sustained 1 year MRD negativity was also evaluated and the prognostic impact of MRD status on PFS and OS was analyzed. Results out of 77 pts, 28 (36%) were ISS stage 3 and 18 (23%) showed high risk cytogenetics. Patients were treated with the following induction regimens: VTD 51, VRD 5, Dara-VRD 5, KRD 14, KCD 2. Single ASCT with MEL200 conditioning was performed in 49 pts (64%), whereas 28 pts (36%) received double ASCT. Subsequent maintenance was performed with lenalidomide (70), daratumumab-lenalidomide (5), carfilzomib-lenalidomide (2). Response rates were VGPR 26%, CR 61% and sCR 13%. MRD before maintenance was positive in 20 pts (26%) and negative in 57 (74%). Sustained MRD negativity lasting ≥ 1 year was documented in 49 pts (64%), whereas early loss of MRD negative status was observed in 8 (10%) of cases. After a median follow up of 40.2 months, PFS was significantly longer in pts with sustained MRD negativity (≥1 year) compared to MRD positive patients before maintenance: median NR vs 41.4 months, p 0.0002, HR 0.17 (0.044-0.65). The worst PFS (24.7 months) was observed in pts with early loss of MRD negativity (<1 year) and was significantly inferior if compared both to pts with sustained MRD negativity (p<0.0001, HR 0.06; 0.01-0.54) and to MRD positive pts before maintenance (p 0.03, HR 0.35; 0.11-0.16), with significantly different outcome of the three subgroups (p<0.0001). Different OS trend was also observed among the three subgroups: NR in sustained MRD negative pts, 58.5 months in MRD positive pts and 35.3 months in pts with early loss of MRD negativity (p<0.0001), although OS difference between sustained MRD negativity (≥ 1 year) and MRD positive pts was not statistically significant on a direct comparison (p 0.054). The worst OS observed in pts with early loss of MRD negativity (<1 year) was significantly inferior if compared both to pts with sustained MRD negativity (p<0.0001, HR 0.05; 0.003-0.80) and to MRD positive pts before maintenance (p 0.020, HR 0.21; 0.035-1.26). Conclusion we confirm the predictive value of MRD assessment after ASCT and therefore the importance of achieving sustained MRD negativity regardless of different treatment strategies. Moreover, the detection of early loss of MRD negativity can help the physician to identify pts with particularly poor prognosis sustained MRD negativity is emerging as a surrogate biomarker of patients (pts)’ outcome in clinical trials. We implemented this tool in our clinical practice and we analyzed outcome according to sustained MRD negativity in MM pts treated with autologous stem cell transplantation (ASCT) at our Institution. We retrospectively analyzed the outcome of 77 newly diagnosed MM pts (median age 61 years) diagnosed between January 2015 to December 2019 in ≥ VGPR after ASCT. Bone marrow samples were collected for MRD by 8-color FCM (Sn 10-5) at day +100 after ASCT, before maintenance. Sustained 1 year MRD negativity was also evaluated and the prognostic impact of MRD status on PFS and OS was analyzed. out of 77 pts, 28 (36%) were ISS stage 3 and 18 (23%) showed high risk cytogenetics. Patients were treated with the following induction regimens: VTD 51, VRD 5, Dara-VRD 5, KRD 14, KCD 2. Single ASCT with MEL200 conditioning was performed in 49 pts (64%), whereas 28 pts (36%) received double ASCT. Subsequent maintenance was performed with lenalidomide (70), daratumumab-lenalidomide (5), carfilzomib-lenalidomide (2). Response rates were VGPR 26%, CR 61% and sCR 13%. MRD before maintenance was positive in 20 pts (26%) and negative in 57 (74%). Sustained MRD negativity lasting ≥ 1 year was documented in 49 pts (64%), whereas early loss of MRD negative status was observed in 8 (10%) of cases. After a median follow up of 40.2 months, PFS was significantly longer in pts with sustained MRD negativity (≥1 year) compared to MRD positive patients before maintenance: median NR vs 41.4 months, p 0.0002, HR 0.17 (0.044-0.65). The worst PFS (24.7 months) was observed in pts with early loss of MRD negativity (<1 year) and was significantly inferior if compared both to pts with sustained MRD negativity (p<0.0001, HR 0.06; 0.01-0.54) and to MRD positive pts before maintenance (p 0.03, HR 0.35; 0.11-0.16), with significantly different outcome of the three subgroups (p<0.0001). Different OS trend was also observed among the three subgroups: NR in sustained MRD negative pts, 58.5 months in MRD positive pts and 35.3 months in pts with early loss of MRD negativity (p<0.0001), although OS difference between sustained MRD negativity (≥ 1 year) and MRD positive pts was not statistically significant on a direct comparison (p 0.054). The worst OS observed in pts with early loss of MRD negativity (<1 year) was significantly inferior if compared both to pts with sustained MRD negativity (p<0.0001, HR 0.05; 0.003-0.80) and to MRD positive pts before maintenance (p 0.020, HR 0.21; 0.035-1.26). we confirm the predictive value of MRD assessment after ASCT and therefore the importance of achieving sustained MRD negativity regardless of different treatment strategies. Moreover, the detection of early loss of MRD negativity can help the physician to identify pts with particularly poor prognosis

Introduction: The role of minimal residual disease (MRD) in Multiple Myeloma (MM) as a surrogate biomarker of patients' outcome, as well as the prognostic information of functional imaging response after treatment have been established in recent years. Furthermore, the predictive relevance of sustained MRD negativity assessed by marrow and imaging techniques and its association with an excellent outcome is emerging in clinical trials. Diffusion-weighted whole-body MRI (DW-MRI) is increasingly used in the management of MM patients, but data regarding the predictive role of sustained DW-MRI response after treatment are lacking. The Myeloma Response Assessment and Diagnosis System (MY-RADS) recommendations have established criteria for Response Assessment Category (RAC) (Messiou C et al, Radiology 2019) with a 5 point scale defining the probability of complete imaging response (i.e. RAC 1) or progressive disease after treatment (i.e. RAC 5). We implemented the RAC criteria in our clinical practice and DW-MRI at 1-year in MM patients treated with autologous stem cell transplantation (ASCT) followed by maintenance therapy.

BACKGROUND:With the rapid development of innovative anticancer treatments, the optimization of tools able to accelerate the access of new drugs to the market by the regulatory authority is a major issue. The aim of the project was to propose a reliable methodological pathway for the assessment of clinical value of new therapeutic innovative options, to objectively identify drugs which deserve early access (EA) priority for solid and possibly in other cancer scenarios, such as the hematological ones. MATERIALS AND METHODS:After a comprehensive review of the European Public Assessment Report of 21 drugs, to which innovation had previously been attributed by the Italian Medicines Agency (Agenzia Italiana del Farmaco, AIFA), an expert panel formulated an algorithm for the balanced use of three parameters: Unmet Medical Need (UMN) according to AIFA criteria, Added Benefit (AB) according to the European Society for Medical Oncology's Magnitude of Clinical Benefit Scale (ESMO-MCBS) criteria and Quality of Evidence (QE) assessed by the Grades of Recommendation Assessment, Development and Evaluation (GRADE) method. By sequentially combining the above indicators, a final priority status (i.e. EA or not) was obtained using the skip pattern approach (SPA). RESULTS:By applying the SPA to the non-curative setting in solid cancers, the EA status was obtained by 5 out of 14 investigated drugs (36%); by enhancing the role of some categories of the UMN, additional 4 drugs, for a total of 9 (64%), reached the EA status: 2 and 3 drugs were excluded for not achieving an adequate score according to AB and QE criteria, respectively. For hematology cancer, only the UMN criteria were found to be adequate. CONCLUSIONS:The use of this model may represent a reliable tool for assessment available to the various stakeholders involved in the EA process and may help regulatory agencies in a more comprehensive and objective definition of new treatments' value in these contexts. Its generalizability in other national contexts needs further evaluation.

SummaryBortezomib‐ and lenalidomide‐containing regimens are well‐established therapies in multiple myeloma (MM). However, despite their extensive use, head‐to‐head comparisons have never been performed. Therefore, we compared bortezomib and lenalidomide in fixed‐duration therapies. In this open‐label, phase III study, we randomized MM patients at first relapse to receive either nine cycles of bortezomib plus cyclophosphamide plus dexamethasone (VCD) or lenalidomide plus cyclophosphamide plus dexamethasone (RCD). The primary endpoint was achievement of a very good partial response (VGPR) or better at six weeks after nine treatment cycles. From March 2011 to February 2015, 155 patients were randomized. VGPR or better was achieved by 12 patients (15%) in the VCD arm and 14 patients (18%) in the RCD arm (P = 0·70). Median progression‐free survival (PFS) was 16·3 (95% CI: 12·1–22·4) with VCD and 18·6 months (95% CI: 14·7–25·5) with RCD, and the two‐year overall survival (OS) was 75% (95% CI: 66–86%) and 74% (95% CI: 64–85%) respectively. In subgroup analyses, no differences in PFS were observed in bortezomib‐ and lenalidomide‐naïve patients, nor in patients who received a bortezomib‐based regimen in first line. Adverse events were consistent with the well‐established safety profiles of both drugs. Bortezomib and lenalidomide treatments were equally effective in terms of depth of response, PFS, and OS in MM patients at first relapse.

Consolidation treatment in acute myeloid leukemia (AML) patients achieving complete remission (CR) is warranted. High-dose cytarabine (HDAC) is considered first choice in favorable risk and an option in intermediate-risk AML. However, its optimal dose and schedule, as well as the benefit of additional chemotherapy agents remain controversial. Herein, we report on the long-term outcome of consecutive unselected AML patients treated with repeated courses of HDAC, with the addition of idarubicin, followed by autologous peripheral blood stem cell (PBSC) support, in order to limit toxicity, according to Northern Italy Leukemia Group (NILG) AML-01/00 study (EUDRACT number 00400673). Among 338 patients consecutively diagnosed from 2001 to 2017 at our center, 148 with high-risk AML (adverse cytogenetic, isolated FLT3-internal tandem duplication mutation, refractory to first induction) were addressed to allogeneic stem cell transplant. All other cases, 186 patients (55%), median age 53 (range 19-75), were considered standard-risk and received the NILG AML-01/00 program. After achieving CR, patients were mobilized with cytarabine 8 g/sqm to collect autologous CD34+-PBSC and received three consolidation cycles with HDAC (20 g/sqm) plus idarubicin (20 mg/sqm) per cycle, followed by reinfusion of limited doses of CD34+ PBSC (1-2x106/kg). The program was completed by 160 (86%) patients. Toxicity was acceptable. Neutrophils recovered a median of 10 days. Treatment-related mortality was 3/160 (1.8%). After a median follow-up of 66.4 months, overall survival (OS) and relapse-free survival (RFS) at 5-years were 61.4% and 52.4%, respectively. Twenty-eight selected patients aged >65 had similar outcomes. According to European leukemia net-2010 classification, the OS and RFS at 5-years were 76.4% and 65% in favorable risk, without differences between molecular subgroups, 52.3% and 47.2% in Intermediate-I, 45.2% and 36.5% in Intermediate-II risk patients, respectively. In conclusion, consolidation including repeated courses of high dose cytarabine and idarubicin, with limited PBSC support, proved feasible and very effective in nonhigh risk patients. The incorporation of novel agents in its backbone may be tested to further improve patient's prognosis.

COVID-19 is a severe infectious complication in patients with underlying medical conditions such as having undergone hematopoietic stem cell transplantation (HCT). This prospective survey reports outcome on 272 COVID-19 patients from 19 countries having undergone allogeneic (n = 175) or autologous (n = 97) HCT reported to the EBMT registry or to the GETH. All patients had the diagnosis of SARS-CoV-2 documented by PCR. Patients were included in this analysis if COVID-19 diagnosis was before April 10, 2020. The overall survival was estimate by using the Kaplan Meier methods, considering the death due to any cause as an event and the time from COVID-19 infection to the latest follow-up as survival time; difference between groups were tested by the log-rank test. Univariate and multivariate risk factor analysis for overall survival were performed with the Cox regression model. The median age was 54.4 years (1.0 - 80.3) for allogeneic and 60.9 years (7.7 - 73.4) for autologous HCT patients. 20 patients were children (< 18 years of age; median age 11.3 (1.0 - 16.9)). The median time from HCT to diagnosis of COVID-19 was 13.7 months (0.2 - 254.3) in allogeneic and 25.0 months (-0.9 - 350.3) in autologous recipients. Lower respiratory tract disease (LRTD) developed in 84.8% and 21.5% were admitted to an intensive care unit (ICU). At the time of analysis, 68/238 (28.6%) patients had died (47/155 allogeneic patients; 21/83 autologous patients). No follow-up had been received on 34 patients. The median time from infection to death was 19 days (0-102). Five patients were reported to have other primary causes of death than COVID-19. Of the patients reported to be alive, the median follow-up was 44 days. 144 (84.7%) patients (93 allogeneic; 51 autologous) had virologic resolution of the COVID-19 infection having at least one negative PCR. 26 patients were alive and known to be still COVID-19 positive (15 allogeneic; 11 autologous). For 34 patients the resolution status was unknown. Factors influencing the likelihood of resolution in multivariate analysis were underlying diagnosis (p=.01) and longer time from transplant to diagnosis of COVID-19 (p=.035). Overall survival at 6 weeks from COVID-19 diagnosis was 76.8% and 83.8% in allogeneic and autologous HCT recipients (p =ns), respectively (figure 1). Children (n=20) tended to do better with a 6-week survival of 95.0% although the difference was not significantly different (p =.12). In multivariate analysis of the total population older age (HR 1.26; 95% CI 1.05 - 1.51; p = .01) increased the risk and better performance status decreased the risk for fatal outcome (HR 0.79; 95% CI 0.69 - 0.90; p = .0003). The same factors had significant impact on overall survival in allogeneic HCT recipients (age HR 1.28; 95% CI 1.05 - 1.55; p=.01; performance status HR 0.79; 95% CI 0.68 - 0.92); p=.002) while only age impacted survival among autologous HCT patients (data not shown). Other transplant factors such as underlying diagnosis, time from HCT to diagnosis of COVID-19, graft-vs-host disease, or ongoing immunosuppression did not have a significant impact on overall survival. We conclude that HCT patients are at an increased risk compared to the general population to develop LRTD, require admission to ICU, and have increased mortality in COVID-19. Figure 1 Disclosures Duarte: Incyte Corporation: Other: Has received speaker and advisor fees. Kwon: Jazz: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Mielke: Novartis: Honoraria, Other: received via my institution, Speakers Bureau; Celgene/BMS: Honoraria, Other: received via my institution , Speakers Bureau; Bellicum: Honoraria, Other: received via my institution, Speakers Bureau; Kite/Gilead: Honoraria, Other: received via my institution , Speakers Bureau; Miltenyi: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Other: received via my institution , Speakers Bureau; KIADIS Pharma: Honoraria, Other: received via my institution , Speakers Bureau; DNA Prime: Honoraria, Other: received via my institution , Speakers Bureau. López Jiménez: MSD: Speakers Bureau; Roche: Research Funding, Speakers Bureau; Takeda: Speakers Bureau; Janssen: Research Funding, Speakers Bureau; Abbvie: Research Funding, Speakers Bureau; Gilead: Research Funding, Speakers Bureau.

BackgroundThe phase 3 GIMEMA-MMY-3006 trial, which compared bortezomib, thalidomide, and dexamethasone (VTD) combination therapy with thalidomide and dexamethasone (TD) as induction therapy before and consolidation therapy after double autologous haematopoietic stem-cell transplantation (HSCT) for newly diagnosed multiple myeloma, showed the superiority of the triplet regimen over the doublet in terms of increased complete response rate and improved progression-free survival. We report the results from the final analysis of the study.MethodsIn this randomised, open-label, phase 3 study, patients aged 18–65 years with previously untreated symptomatic multiple myeloma and a Karnofsky Performance Status of 60% or higher were enrolled at 73 centres in Italy. Patients were randomised (1:1) by a web-based system to receive three 21-day cycles of thalidomide (100 mg daily orally for the first 14 days and 200 mg daily thereafter) plus dexamethasone (total 320 mg per cycle; 40 mg on days 1–2, 4–5, 8–9, and 11–12 in the VTD regimen, and 40 mg on days 1–4 and 9–12 in the TD regimen), either alone (TD group) or with bortezomib (1·3 mg/m2 intravenously on days 1, 4, 8, and 11; VTD group). After double autologous HSCT, patients received two 35-day cycles of either the VTD or TD regimen, according to random assignment, as consolidation therapy. The primary outcome was the rate of complete response and near complete response after induction (already reported). In this updated analysis we assessed long-term progression-free survival and overall survival (secondary endpoints of the study) with an extended 10-year median follow-up, and analysed the variables influencing survival. Analysis was by intention to treat. The study is registered with ClinicalTrials.gov, NCT01134484.FindingsBetween May 10, 2006, and April 30, 2008, 480 patients were enrolled and randomly assigned to receive VTD (241 patients) or TD (239 patients). Six patients withdrew consent before start of treatment. 236 (99 [42%] women) in the VTD group and 238 (102 [43%] women) in the TD group were included in the intention-to-treat analysis. The data cutoff date for this analysis was May 31, 2018. Median follow-up for surviving patients was 124·1 months (IQR 117·2–131·7). The 10-year progression-free survival estimate for patients in the VTD group was 34% (95% CI 28–41) compared with 17% (13–23) for the TD group (hazard ratio [HR] 0·62 [95% CI 0·50–0·77]; p<0·0001). 60% (95% CI 54–67) of patients in the VTD group were alive at 10 years versus 46% (40–54) of patients in the TD group (HR 0·68 [95% CI 0·51–0·90]; p=0·0068). VTD was an independent predictor of improved progression-free survival (HR 0·60 [95% CI 0·48–0·76]; p<0·0001) and overall survival (HR 0·68 [0·50–0·91]; p=0·010). The incidence of second primary malignancies per 100 person-years was 0·87 (95% CI 0·49–1·44) in the VTD group compared with 1·41 (0·88–2·13) in the TD group.InterpretationIncorporation of VTD into double autologous HSCT resulted in clinically meaningful improvements in long-term progression-free survival and overall survival, confirming that a regimen including bortezomib and an immunomodulatory drug is the gold standard treatment for patients with newly diagnosed myeloma who are fit for high-dose chemotherapy.FundingSeràgnoli Institute of Haematology, University of Bologna, and BolognAIL.

Autologous stem cell transplantation (ASCT) is feasible and effective in selected older patients with Multiple Myeloma, but specific criteria for evaluating ASCT eligibility in elderly patients are lacking. We evaluated 131 patients aged 65-75 considered for ASCT at our center: The Charlson Comorbidity Index (CCI), Hematopoietic cell transplantation comorbidity index (HCT-CI) and IMWG frailty score were obtained at diagnosis, but the intensity of treatment was left to physician's choice. The scores and age's impact on outcome was analyzed: 85 patients were judged transplant eligible, whereas 46 patients received a less intensive treatment (median follow up 27 months). No patients classified as frail had been considered eligible to ASCT with a worse outcome compared to fit and unfit patients (median PFS (progression free survival): 7.9 vs 32.9 and 29.6 months; P < .001). PFS was superior in the ASCT group (35.6 vs 19.9 months, P .013). In the ASCT group, PFS was better in patients aged 65-69 years than in patients ≥70 (51.5 vs 27.7 months, P.004). Indeed, in unfit patients aged ≥70 the PFS of the ASCT group was comparable to NO ASCT group (18 vs 27 months, P = .33) whereas in unfit patients aged 65-69 PFS was superior in the ASCT group: 43.3 vs 18.4 months, P .01. ISS III and impaired functional status independently affected PFS in a multivariate analysis (P .011 and P .006). While CCI and HCT-CI did not predict different outcome in ASCT patients, the IMWG frailty score would be of help in identifying unfit patients aged 70-75, whose outcome with ASCT selected by clinical judgment was no better than with less intensive treatments.