ALBERT

Description: Diffuse Large B-Cell Lymphoma (DLBCL) is the most frequent aggressive non-Hodgkin’s Lymphoma (NHL) in adults. Presently, prognostic stratification relies on clinical characteristics and International Prognostic Index (IPI) is currently the most useful tool to identify high-risk patients (pts). Positron Emission Tomography (PET) with fluorodeoxyglucose (18F[FDG]) has been used to assess chemosensitivity in Hodgkin’s lymphoma: we investigated the role of 18F[FDG]-PET as prognostic tool in DLBCL treated with a R-CHOP-like chemotherapy. Forty-two pts with newly diagnosed DLBCL treated in our Institute from February 2006 to February 2008 were enrolled in this prospective study. Median age was 59 years (range 24–80), seventeen pts were male (40%); bulky disease was present in 20 pts (48%). Stage was I–II in 18 (43%) and III–IV in 24 pts (67%); IPI was low in 20 pts, low-intermediate in 12 pts, high-intermediate in 5 pts and high in 4 pts. Twelve pts (29%) had a primary extranodal DLBCL. Pts were treated with 6 cycles of CHOP-like treatment, associated with Rituximab in all but one patient; cycles were repeated every 21 days. An interim 18F[FDG]-PET was performed after three cycles (interim 18F[FDG]-PET) and at the completion of treatment (18F[FDG]-PET6). Interim PET result did not change the planned treatment; response was assessed with 1999 Cheson’s criteria. Four pts received radiotherapy after chemotherapy. Overall, 36 pts obtained a complete response (CR), the remaining six pts failed to obtain a CR. Median follow-up was 15 months (range 5–31 months); eight pts relapsed, and six patients died, two of them in CR. Overall survival (OS) at 2 years was 78%, and event-free survival (EFS) at 2 years was 77%. Interim 18F[FDG]-PET was performed after a median interval from the last therapy of 13 days (range 3–21) and was negative in 28 pts (interval 12 days) and positive in 14 pts (interval 13 days). Six positive and two negative interim 18F[FDG]-PET pts relapsed: sensitivity was 75%, specificity was 76%, positive and negative predictive values were 43% and 93%, respectively. Overall, 18F[FDG]-PET6 was positive in eight pts and negative in 34 pts; six positive and two negative 18F[FDG]-PET6 pts relapsed: sensitivity was 75%, specificity was 94%, positive and negative predictive values were 75% and 94%, respectively. The EFS at 2 years in pts with negative interim 18F[FDG]-PET was 90%, in positive interim 18F[FDG]-PET pts was 55%, which resulted statistically significant at the univariate analysis (p=0.01), as well as 18F[FDG]-PET6 (p=0.00). In all relapsed pts but one a salvage therapy with intensified chemotherapy and autologous stem cells transplantation (ASCT) was planned: four pts progressed during treatment or shortly after ASCT, and in three pts treatment is still ongoing. Interim 18F[FDG]-PET was proposed as a prognostic tool in DLBCL. Our data showed that interim 18F[FDG]-PET was statistically associated with EFS, however, nine pts (64%) with a positive interim 18F[FDG]-PET obtained a CR after induction treatment, and eight of them (89%) did not relapse. Our findings do not support an early intensification of pts with DLBCL with a positive interim 18F[FDG]-PET because of the risk of overtreatment of a large part of these pts; however, we performed interim 18F[FDG]-PET after three cycles of therapy, and this could have influenced the results. A longer follow-up and a greater number of pts could be necessary to draw definitive conclusions.

Description: Abstract 3956 Background: Recently in large randomized studies, the addition of Rituximab to standard chemotherapy in the first-line treatment of follicular lymphoma (FL) demonstrated improvements in long-term outcome in FL. Methods: We compared the outcome of 111 naive FL patients (pts) treated at our institution from 1995 to 2009 with a single alkylating agent in combination or not with Rituximab: 58 pts received Chlorambucil plus Rituximab (R-Chl) and 53 pts Chlorambucil and prednisone (Chl+PDN). The 2 schedules included an induction phase, where Chlorambucil was given at 6mg/mq for 6 consecutive weeks in both groups and the Rituximab in 4 weekly administrations. The maintenance phase was longer in the Chl+PDN group: Chlorambucil was administered 6mg/mq daily 14 days each month for a total of 12-months of treatment versus 14 days with monthly-Rituximab for 4 consecutive months in the R-Chl group. Results: The demographic and prognostic factors are reported in Table 1. At the end of treatment the ORR was 98% in the R-Chl pts and 77% in the Chl+PDN group, with a percentage of complete response of 79% and 55% respectively. No significant incidence of adverse events were reported and only one HBsAg positive patient in R-Chl group discontinued the therapy. One case of myelodysplastic syndrome was described in a Chl+PDN relapsed patient. With a median follow up of 34 months, the OS and the EFS in R-Chl pts is 95% and 76% respectively. Otherwise, with a median observation time of 82 months in the Chl+PDN group 73% are alive and only 28% of pts maintained the response. The median time to subsequent therapy (TTST) is 21 and 15 months respectively in the 2 groups. Conclusions: The addition of Rituximab to alkylating in first-line treatment in previously untreated FL pts improves significantly the EFS and prolongs the time to next antilymphoma therapy compared with alkylating alone. Because of its low toxicity profile, our combination with Rituximab and Chlorambucil could be considered a first-line therapy, especially in FL patients not eligible for aggressive chemotherapy regimens. Disclosures: No relevant conflicts of interest to declare.

Description: Introduction Lenalidomide (Len) and low-dose Dexamethasone (dex) (Rd) in continuous is a new standard of care for elderly newly-diagnosed multiple myeloma (NDMM) patients (pts), as established by FIRST trial (Facon et al, Blood 2018). Methods and results This is a retrospective, multicentric study conducted in Italy with the aim of evaluating efficacy and tolerability of Rd in a real-life population. Thirty-seven centers were involved and data of 429 pts are available. Pts were considered eligible for the study when completing at least 2 cycles of Rd regimen. Table 1 summarizes the characteristics of pts at time of MM diagnosis. Median age was 78 years (range 57-92), 36.6% had an ECOG PS≥2, creatinine clearance (ClCr) was ULN (P=0.01) and ClCr2 still impact on OS (p

Description: In CLL/SLL pts the combination of purine analogue and rituximab represents a well known effective therapy. Human concentrative nucleotide transporter (hCNT1) and human equilibrative nucleotide transporter (hENT1) are proteins involved in uptake of nucleoside analogues into the tumour cells. The aim of this study was to investigate R-2CDA as first line therapy and in pre-treated pts with active CLL and SLL, and to identify, by pharmacogenomic approaches, genetic factors that may predict clinical response to such treatment. 45 pts with active CLL (27 pts) or SLL (18 pts) were treated. The median age was 59 years (31–76). Patients received 4 cycles of rituximab 375 mg/m2 on day 1 and 2-CDA 0.1 mg/kg (subcutaneously) on days 2 to 6. The treatment was repeated every 4 weeks. A CT scan of the abdomen was performed at baseline and at the end of treatment in all pts; CT scan before treatment was abnormal in 42 pts. Minimal residual disease was evaluated by 6-colour flow-cytometry and PCR methods. Treatment outcome was evaluated according to NCI-WG updating guidelines: to confirm a CR the marrow should be free of clonal B-CLL cells by flow-cytometry and a CTscan should be negative. At baseline we investigated, on bone marrow for SLL and on peripheral blood for CLL, the expression of human concentrative nucleotide transporter (hCNT1) and human equilibrative nucleotide transporter (hENT1) using ABI PRISM 7000 Real Time RT-PCR platform in 24 pts. 42 pts (26 untreated) were fully evaluable for response.LDH and beta2microglobulins were abnormal in 14% and 30% of pts respectively. The percentage of neoplastic cells in the bone marrow was more than 70% in 17% of pts. The overall response rate was 88% (26% CR and 62% PR), with 21% of untreated pts and 5% of pre-treated pts achieving a CR. Severe neutropenia (grade 4) developed in 7% of pts. 4 pts developed pneumonia, 1 with neutropenia. 1 pt had reactivation of herpes zoster virus and 1 pt experienced febrile neutropenia of unknown origin. The median TTP was 41 months. There was not statistically significant difference in terms of duration of response between untreated and pre-treated pts (TTP: 44 vs 35 months, p=0.1814). Pts achieving a CR had a longer response duration than pts with PR (p=0.0047). Low serum lactate dehydrogenase levels, a lower (〈 70%) neoplastic marrow infiltration at baseline and a normal CT scan at the end of therapy (independent of response) predicted a longer response duration (p=0.0145, p=0.0164 and p=0.008 respectevely). The pharmacogenomic analysis showed a difference (p=0.8345) in terms of hCNT1 expression levels between patients achieving a CR and pts with PR or NR. Pts in CR had higher levels of hCNT1 expression and the increase of 1 unit of the expression level of hCNT1 is associated with a reduced risk of PD by 33%. The refractory pts had lower levels of hCNT1 than non refractory pts but the difference was not statistically significant. There was no statistically significant difference in terms of hCNT1 expression between CLL and SLL pts. The combination of 2-CDA and rituximab induces a high response rate, including CR in pre-treated pts. The treatment is well tolerated with acceptable toxicity also in pts over 70 years. The achievement of a CR is important to obtain durable response. The correlation between the levels of expression of hCNT1 and the response to therapy needs to be confirmed in larger studies.

Description: Here we present the clinical results and the outcomes of 143 consecutive newly-diagnosed follicular lymphoma (FL) patients (pts) treated with 3 different modalities of treatment in our institution from 1994 until 2007. During this period, from 1994 to 2002, 55 pts received Chlorambucil and Prednisone (Chl+PDN), subsequently 31 pts Rituximab with Chlorambucil (R-Chl) and 57 pts a 4-weekly standard-dose of Rituximab alone (R). Chlorambucil was given in an induction phase at 10mg/day for 6 consecutive weeks followed by a longer maintenance phase in the first group: 2-week pulses of 10 mg daily with 2-week intervals for a total of 12-months of treatment versus four 2-week pulses with monthly-Rituximab. In the single agent R group 36 pts received maintenance with at least 4-bimonthly administrations. The 3 groups were comparable for demographic and prognostic factors: median age at diagnosis was 55 yrs, over 60% of pts were in advanced stages and mainly asyptomatic (about 90%) and over 50% of pts in each group were low-risk FLIPI. A third of pts in both Rituximab-based treatment groups had bone marrow involvement and bulky disease. In terms of ORR 78% of pts treated with Chl+PDN, 97% with R-Chl and 72% with R single agent, obtained a clinical response, with a percentage of complete response of 58%, 90% and 47% respectively. No significant incidence of adverse events were reported and none discontinued the therapy because of toxicity. One case of myelodysplatic syndrome was described in a relapsed patient of the Chl-PDN group. With a median follow up of 72, 56 and 27 months in the 3 groups evaluated, the CR rate was maintained in 29%, 74% and 37% of pts respectively with a median duration of response of 36, 40 and 24 months. Rituximab as first-line in FL pts seems safe, feasible and able to induce a high rate of clinical response similar to those achieved with standard chemotherapy alone. On the other hand, the immunochemotherapy seems to confirm its superiority in terms of response rate and duration of response.

Description: Abstract 5030 Treatment for multiple myeloma is dramatically changed over the past 5 years. Thalidomide containing regimen is now widely accepted as standard treatment for multiple myeloma in first line. The mechanism of action and the toxicity profile of Thalidomide, make this drug suitable for combination with chemotherapeutic agents. We report clinical results in terms of efficacy and safety of an antracycline containing regimen [liposomal doxorubicin (Myocet), Dexamethasone and Thalidomide (ThalDoDex)] In multiple myeloma before autologous transplantation. From June 2007 to June 2010, ThalDoDex was delivered to 28 previously untreated multiple myeloma patients. Median age was 59 years (range 42–71); 5 patients were staged IIA and 21 patients staged IIIA and 2 IIIB; 15, 8 and 5 patients were ISS I, II, III respectively. Fifteen patients presented IgG monoclonal immunoglobuline, 6 IgA, 5 patients light chains myeloma, 1 patient plasma cell leukaemia and one other secretory multiple myeloma. Treatment schedule was as follows: Thalidomide 100 mg/day for 14 days then 200mg/day until the end of induction; Dexamethasone 40 mg days 1à4; Liposomal Antracycline (MYOCET) 50 mg/sqm day 1 for 4 cycles at 4 weekly intervals. LMWH 100UI/kg/day was added to all patients for DTV prophylaxis. All patients were considered for a peripheral blood stem cell transplantation program according to age and clinical outcome. Twenty-five patients are evaluable for response. Fifteen patients (60%) achieved a CR (1 pt) or a nCR (5 pts), or a VGPR (9 pts) with an overall response rate of 80% (CR, nCR, VGPR, PR). Six patients developed transient febrile neutropenia which solved with antibiotics. During neutropenia two patients developed pneumonia treated with appropriate antimicrobial therapy. No major haematological toxicity was observed. No neurological toxicity or thrombotic event was reported. Our experience suggests that ThalDoDex is effective and safe as induction phase in newly diagnosed multiple myeloma patients. The clinical results are similar to those reported with other Thalidomide containing regimens. Liposomal doxorubicin in combination with Thalidomide and steroid may induce an important rate of CR and nCR as requested for the best clinical result of subsequent autologous transplant procedure. Our combination regimen avoiding alkylating agents and proteosome inhibitors may deserve the use at eventually subsequent relapse. Disclosures: No relevant conflicts of interest to declare.

Description: Background: Survival rates of multiple myeloma (MM) patients (pts) has improved over the past few years, but patients inevitably relapse and become more resistant to subsequent treatments. Carfilzomib and Pomalidomide were both approved for the treatment of relapsed/refractory MM (RRMM). Combinations including a proteasome inhibitor (PI) plus an immunomodulator (IMiD), such as Bortezomib-Lenalidomide-Dexamethasone (VRD) or Carfilzomib-Lenalidomide-Dexamethasone (CRD), showed a very high response rate with an acceptable toxicity. Moreover, in the CHAMPION1 study (Berenson et al Blood 2016), the weekly infusion of Carfilzomib showed to be as effective as the twice schedule. In this phase I/II study we assessed for the first time weekly Carfilzomib plus Pomalidomide and low dose Dexamethasone (wKPd) for the treatment of RRMM. Here we report preliminary results. Methods: the primary objective of the phase I part of the trial was to determine the maximum tolerated dose (MTD) of wKPd combination. The primary objective of the phase II was to determine the rate of partial response (PR). Patients with RRMM, who received 1-3 prior lines of treatments and were refractory to Lenalidomide were eligible. Treatment consisted of 28-day cycles of oral Pomalidomide at fixed dose of 4 mg on days 1-21 (1 week off), oral or intravenous (iv) Dexamethasone 40 mg on days 1,8,15,22 and iv Carfilzomib at escalating doses on days 1,8,15. Escalation started at the dose of 36 mg/m2 (0 level) and used a standard 3+3 schema based on dose-limiting toxicities (DLTs) occurring in cycle 1. Treatment was continued until relapse or intolerance. Results: A total of 57 patients were enrolled in 6 Italian centers. Fifty-two patients could be evaluated for this analysis (5 patients did not complete the first cycle yet). The median age was 62 years with a median time from diagnosis of 4 years. 17/39 (44%) of patients were considered high risk according to cytogenetic abnormalities [at least one among t (4;14) t (14;16) and deletion chromosome 17 (del17) detected by FISH]. In the phase I of the trial 15 patients were enrolled. The first 3 patients at the dose level 0 of Carfilzomib did not experience any DLT. In the next cohort with Carfilzomib 20/45 mg/m2 a G3 hypertension and a sudden death occurred. According to the protocol, 3 more patients were enrolled at dose level 0: 1 patient experienced G3 atrial fibrillation, 2 patients ≥ G3 hypertension. Considering the serious adverse events (SAEs) occurred, the trial was temporary stopped to evaluate the benefit of continuing the study. All the DLTs were cardiologic and occurred in patients with a prior history of cardiac disease. As per protocol, they were evaluated with ECG and echocardiogram before the enrolment and were considered eligible for the study. The safety committee established new procedures for the evaluation of cardiac function of potentially eligible patients, including 24 h continuing pressure monitoring before the enrolment and serial measurement of blood pressure during and after Carfilzomib infusions. Six more patients were enrolled at dose level -1 (Carfilzomib 20/27 mg/m2) and none experienced a DLT. The MTD was established at dose level -1 with Carfilzomib 20/27 mg/m2, Pomalidomide 4 mg and Dexamethasone 40 mg. In the phase II portion of the trial, 42 patients were enrolled. Considering both phase I and II portions of the study, the most frequent drug related, grade ≥ 3 AEs were hematologic (65% of neutropenia and 13% of thrombocytopenia) and cardiologic (17%, mainly hypertension). We recorded only 4% of infection and ≥ G3 peripheral neuropathy. The overall response rate (ORR) of phase I/II portions was 58% (30/52) including 25% (13/52) of ≥ very good partial remission (VGPR). The ORR of high risk patients was 44% (7/16) including 19% (3/16) of ≥ VGPR. With a median follow-up of 10 months, median progression free survival (PFS) was 9.5 months and the median overall survival was not reached. Conclusions: This is the first phase I/II trial that combined weekly Carfilzomib with Pomalidomide and Dexamethasone. This combination was highly effective in RRMM. After a median follow-up of 10 months, wKRd showed a double median PFS in comparison with Pomalidomide-low dose dexamethasone (Sanmiguel et al Lancet Oncology 2013): 9.5 vs 4 months respectively, confirming the efficacy of combining a PI with an IMiD. An updated analysis will be presented at the meeting. Disclosures Bringhen: BMS: Honoraria; Celgene: Honoraria; Janssen-Cilag: Honoraria; Amgen: Other: ADVISORY BOARD; Mundipharma: Other: ADVISORY BOARD; Karyopharm: Other: ADVISORY BOARD. Larocca:Celgene: Honoraria; Janssen-Cilag: Honoraria; Bristol-Myers Squibb: Honoraria; Amgen: Honoraria. Gaidano:Karyopharm: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau; Morphosys: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau. Oliva:Amgen: Honoraria; Celgene: Honoraria; Takeda: Honoraria. Sonneveld:Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding. Palumbo:Janssen Cilag: Honoraria; Takeda: Employment, Honoraria. Boccadoro:Janssen: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Abbivie: Honoraria; Mundipharma: Research Funding; SANOFI: Honoraria, Research Funding; CELGENE: Honoraria, Research Funding.

Description: Abstract 3754 Poster Board III-690 Introduction Follicular lymphoma (FL), one of the most common B-cell non-Hodgkin's lymphoma (NHL), is an indolent disease characterized by a continuous relapse pattern. In the last years the treatment have changed with the introduction of Rituximab, that in combination with chemotherapy prolongs the progression-free survival (PFS) and the overall survival (OS) of FL pts. We report here the results of a regimen containing Rituximab and Chlorambucil (Chl) in untreaed FL pts. Methods Since December 2001 48 pts (22 male and 26 female) with naive FL were treated in first-line with R-Chl. The schedule consisted of an induction phase with four weekly infusion of Rituximab at standard dose and 6 consecutive weeks of Chl at 6mg/mq/daily. Pts were restaged and in absence of disease progression received four cycles of consolidation with a monthly Rituximab infusion and 14 days of Chl each month. Results Median age at diagnosis was 56 years (range 29-79). Ann Arbor stage was I-II in 13 pts and III-IV in 35 pts (73%); 15 pts had bulky disease and 14 pts presented an extranodal localization. B symptoms were present in 8 pts. Histological grading was available in 42 cases, and was 1 in 10 pts, 2 in 26 pts and 3 in 6 pts. FLIPI was evaluable in 46 pts, and was 0-1 in 25 pts (52%), 2 in 12 pts (25%), and 〉2 in 9 pts (18%). After the induction phase overall response rate (ORR) was 98% with 14 pts in complete remission (CR). After the consolidation phase 39 pts (81%) obtained a CR and eight (17%) a partial response (PR); the remaining patient had a stable disease and underwent high-dose chemotherapy and autologous transplantation. All pts but one concluded the planned treatment. The mean daily dose of Chl administered during the induction phase was 10 mg, while 8 mg in the prolonged treatment. Twenty-eight pts (58%) experienced a neutropenia during treatment, and Chl dose was reduced in 22 pts (46%); however, only 11 pts (23%) had a G3-4 neutropenia. The Chl was stopped only in a patient because of a persistent G3 neutropenia after the first consolidation cycle. After a median observation time of 42.5 months (range 7-94) nine pts relapsed (19%), with a median time to relapse of 20 months (range 7-66). Two pts died, one of disease progression and one of a pre-existing ovarian cancer. Conclusions Our results described a safe and feasible combination of immuno-chemotherapy in untreated FL pts. With respect to traditional treatments, our regimen shows a similar efficacy and a lower toxicity, that leads to an easier handling. The schedule including four monthly additional Rituximab administrations confirms the superiority of a prolonged exposure to Rituximab over the standard 4-weekly administrations. In conclusion, our data suggest that this combination may be considered as a valid first-line treatment of FL patients, especially in those not eligible for more aggressive chemotherapy regimens. Disclosures: No relevant conflicts of interest to declare.

Description: Mantle cell lymphoma (MCL) is an aggressive disease, currently incurable with standard-dose chemotherapy. Autologous cell transplantation (ASCT) is frequently considered a therapeutical approach in MCL, despite not generally being curative. In controlled studies upfront ASCT showed a significant event-free survival advantage, that might be improved by the addition of the anti-CD20 monoclonal-antibody (MoAb) (Rituximab®) in the myeloablative regimen. Based on these evidences, we prospectively analysed our patients (pts) affected by MCL, who received a continuous Rituximab administration in course on treatment. From May 2000 to the present we treated 22 pts with histological diagnosis of MCL, including 16 pts (73%) newly diagnosed. The majority were male (15/22) and the median age at diagnosis was 56 years old (range 35–66). Disease was stage III–IV: 21 pts with bone marrow involvement in 60%. Eleven pts presented extranodal involvement. The induction schedule included 2–4 CHOP-like regimen with MoAb (R-ACOD), followed by mobilization chemotherapy with cyclophosphamide, MoAb and G-CSF. Harvest was performed successfully in all pts with a median number of CD34-positive cells of 8.0 x 106/Kg (1.9–22.8 106/Kg). Subsequently the pts received 2 cycles of high-dose, cytarabine-based regimen with MoAb (R-ESHAP). Rituximab injections were given at standard dose (375 mg/mq). Before ASCT, 11 pts (50%) were in complete response (CR); in particularly 5 of them who were pretreated. Eight achieved partial response, while one was in progression. Two pts were not restaged. One patient did not undergo ASCT, because of serious pulmonary infection after high-dose cytarabine. In terms of conditioning regimen all pts received Rituximab (375 mg/mq), Melphalan (180mg/mq) in association with either Idarubicin (15mg/mq for 3 days) in 13 pts and or Novantrone (60 mg/mq for 1 day) in 8 pts. After stem cell reinfusion and G-CSF from Day +5, the median time to recovery (neutrophil counts 〉0.5x103) was 14 days (range 13–28 days) in the first regimen versus 10 days (range 8–11 days) in the more recent regimen. During aplasia the infection rate was low, as a matter of fact we observed just two episodes of pneumonia, that resolved at neutrophil recovery. No toxic death was reported. Response at 3 months after ASCT was evaluable in 19 patients (90%); one was lost at follow-up, while one has been transplanted one month ago. Seventy patients (80%) achieved complete response, maintained in 11 of them after a median time of 23 month (range 10–79) after ASCT; seven of them were in complete response before the transplant procedure. With a median time of 27 months (range 9–46 months) 7 patients progressed and 4 of these died because of lymphoma. Our study supports that ASCT can be considered a valid approach to induce high response rate. To enhance the ASCT outcomes, the addition of Rituximab can be considered a feasible approach associated with its “purging in vivo” effect. Long-term disease control might be reflected upon a plateau in the survival curve, but a randomised study and longer follow up is warranted.

Description: Background Despite an improvement in treatment response, high-risk multiple myeloma (MM) patients (pts) experience early relapse and short disease-free survival. Together with more validated high-risk features, high levels of circulating plasma cells (high CPC) have been considered a marker of aggressive disease and poor outcome (F. Gay et al, ASH 2019; W.I. Gonsalves et al, Am J Hematol 2020). To date, there are no uniform data on the optimal cut-off predictive of clinical outcome. No prospective data on CPC are available in the setting of novel-drug clinical trials with comprehensive baseline evaluation and minimal residual disease (MRD) assessment. Aims 1) To identify the best cut-off for CPC to predict progression-free survival (PFS); 2) to assess the impact of high CPC levels on the clinical outcome of newly diagnosed (ND)MM pts in the context of concomitant risk features and MRD evaluation. Methods In the multicenter randomized FORTE clinical trial, 474 NDMM pts ≤65 years were randomized (R1) to receive either: carfilzomib-lenalidomide-dexamethasone (KRd) induction-autologous stem-cell transplant-KRd consolidation (KRd_ASCT); KRd for 12 cycles (KRd12); or carfilzomib-cyclophosphamide-dexamethasone (KCd) induction-ASCT-KCd consolidation (KCd_ASCT). Thereafter, pts were randomized (R2) to maintenance treatment with lenalidomide alone (R) or plus carfilzomib (KR). MRD was assessed by 2nd-generation multiparameter flow cytometry (MFC, sensitivity 10-5) in pts who achieved ≥very good partial response before maintenance and then every 6 months. At diagnosis, single-platform FC was used to sort and count CPC. Receiver Operating Characteristic (ROC) analysis was used to define a cut-off based on PFS at 36 months as outcome. Correlations between high CPC and the most important baseline prognostic features (age, International Staging System (ISS), lactate dehydrogenase (LDH), chromosomal abnormalities (CA) by FISH [(del17p, t(4;14), t(14;16), t(11;14), amp1q, del1p, del13], Revised-ISS (R-ISS)) were explored. Hence, we performed a multivariate (MV) analysis to assess the impact of high CPC on the achievement of MRD negativity, on PFS and OS. Finally, we evaluated the impact of baseline CPC and MRD achievement. Results CPC analysis was performed in 401/474 pts at diagnosis; median follow-up was 44.2 months (39.6-47.9) and baseline features were similar to those reported in the overall FORTE population. Median CPC were 0.02% (IQR 0-0.14). The optimal CPC cut-off to predict PFS (ROC analysis) was 0.07% (5 cells/ul, 0.005 x109/l) and was consistent with a cut-off previously identified as a predictor of sustained MRD negativity (MRDsus12; L. Bertamini et al, EHA 2020). High-CPC pts (〉0.07%) were 130/401 (32%), while 271/401 (68%) had low CPC (≤0.07%). The proportion of high-CPC pts was comparable among treatment arms. Baseline features significantly associated with high CPC in a MV analysis were: ISS II/III, high LDH, amp1q, t(4;14), t(14;16) and bone marrow plasma cells (〉60%). Regarding PFS, in a MV analysis adjusted for R-ISS and R1 treatment, including all the baseline features, high CPC were associated with a lower PFS (HR 2.49, 95% CI 1.76-3.51, P