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The combination of elotuzumab, lenalidomide, and dexamethasone (EloRd) enhanced the clinical benefit over Rd with a manageable toxicity profile in the ELOQUENT-2 trial, leading to its approval in relapsed/refractory multiple myeloma (RRMM). The present study is a 3-year follow-up update of a previously published Italian real-life RRMM cohort of patients treated with EloRd. This revised analysis entered 319 RRMM patients accrued in 41 Italian centers. After a median follow-up of 36 months (range 6-55), 236 patients experienced disease progression or died. Median progression-free survival (PFS) and overall survival (OS) were 18.4 and 34 months, respectively. The updated multivariate analyses showed a significant reduction of PFS and OS benefit magnitude only in cases with ISS stage III. Major adverse events included grade 3/4 neutropenia (18.5%), anemia (15.4%), lymphocytopenia (12.5%), and thrombocytopenia (10.7%), while infection rates and pneumonia were 33.9% and 18.9%, respectively. No new safety signals with longer follow-up have been observed. Of 319 patients, 245 (76.7%) reached at least a partial remission. A significantly lower response rate was found in patients previously exposed to lenalidomide. In conclusion, our study confirms that EloRd is a safe and effective regimen for RRMM patients, maintaining benefits across multiple unfavorable subgroups. This article is protected by copyright. All rights reserved.

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The lack of a randomized trial comparing carfilzomib (K) versus elotuzumab (Elo) associated with lenalidomide and dexamethasone (Rd) prompted us to assess the relative usefulness of one triplet over the other. Five independent retrospective cohorts of 883 relapsed/refractory multiple myeloma (RRMM) patients, including 300 EloRd and 583 KRd cases, outside clinical trials, entered this non-randomized comparison. KRd cohort accounted for a higher incidence of younger patients, cases with ≥3 lines of therapy, already exposed to lenalidomide, International Staging System (ISS) stage III, and abnormal lactic dehydrogenase (LDH) level compared with EloRd cohort. Moreover, cytogenetic risk categories, detected in roughly one-third of cases, were equally distributed between the two therapy arms. The probability of CR+VGPR response was significantly higher in KRd (n = 314, 53.9%) than in EloRd patients (n = 111, 37.0%). Likewise, the cumulative incidence function of CR+VGPR, taking into account the competitive risk of death, was significantly higher in KRd arm patients than those in the EloRd arm (p = .003). Moreover, KRd treatment significantly reduced the progression or death risk by 46% in an adjusted multivariate analysis (HR: 0.54, 95% CI 0.42-0.69, p .0001). Finally, in an adjusted illness-progression/death model, the effect of KRd versus EloRd was of higher magnitude among those who achieved CR+VGPR (-39% hazard ratio reduction, p = .02) than among those who achieved VGPR (-29% hazard ratio reduction, p = .007). With limitations characteristic to any retrospective analysis, this current clinical practice study's overall results demonstrated potential benefits of KRd therapy compared with EloRd. This observation may help the daily clinical practice.

Background Clinical decision-making in patients with relapsed refractory multiple myeloma (RRMM) is challenging and identification of patients who can benefit the most from a given therapy is of critical importance. The International Myeloma Working Group (IMWG) index is one of the most robust scores to evaluate frailty, and it has been validated for patients with newly diagnosed MM. However, little is known on its applicability in the setting of RRMM and of its relationships with patient-reported health-related quality of life (HRQoL). Objectives The primary objective of this study was to investigate whether the IMWG frailty score is able to detect distinct patient-reported HRQoL profiles in the setting of RRMM. A secondary objective was to assess the prevalence of patient-reported clinically important symptoms by frailty groups (ie., fit, intermediate-fit, and frail). Patients and Methods This was an international (Italy and UK) prospective cohort observational study that consecutively enrolled patients from 30 centers. The patients were eligible if they had received at least 1 prior therapy (but no more than 5) and had RRMM according to IMWG criteria. An additional inclusion criterion at the time of study entry was the availability of all variables incorporated into the IMWG frailty score to allow classification of patients in the following three groups: fit, intermediate-fit and frail. Baseline assessment of HRQOL was mandatory to be included in this study and patients completed a set of well-validated measures including the EORTC QLQ-C30 and its myeloma module (QLQ-MY20). The scores from EORTC QLQ-C30 and MY20 questionnaires were summarized by means and standard deviations, overall and by frailty group. Unadjusted differences in mean scores were compared between frailty groups. We also estimated the adjusted mean differences in HRQoL scores of respectively fit and intermediate groups vs frail patients, using a multivariable linear regression model, adjusting for a number of key potential confounders including: sex, education, time since diagnosis, number of previous lines of therapy, previous transplantation, currently receiving therapy, myeloma status (refractory vs relapsed only) and type of MM at diagnosis (secretory vs else). We also assessed the prevalence of clinically important symptoms, based on previously published evidence-based thresholds, by IMWG frailty group. Results Overall, 365 RRMM patients were enrolled between November 2017 and December 2018. Median age was of 69.7 years (IQR, 62.7-75.0) and 296 had received at least two previous lines of therapy. According to the IMWG frailty score evaluation at study entry, 192 (53%), 85 (23%) and 88 (24%) patients were classified as fit, intermediate-fit and frail. Each group was associated with a clearly distinct patient-reported HRQoL profile with both fit and intermediate-fit groups reporting statistically and clinically meaningful better outcomes (ie., improved functional status and lower symptom burden) than frail patients in the majority of the scales from the EORTC QLQ-C30 and QLQ-MY20. For example, mean scores of the EORTC QLQ-C30 physical functioning scale were 71.2, 62.2, and 47.5 for fit, intermediate-fit and frail patients, respectively (p Conclusions: In the setting of RRMM, the IMWG frailty score is able to detect clearly distinct patient-reported HRQoL profiles. Current findings may lay the groundwork for the development of a patient-centered frailty index, which also incorporates HRQoL data, to be used in patients with RRMM treated in real-life. Figure 1 Figure 1. Disclosures Efficace: Janssen: Consultancy; Abbvie: Consultancy, Other: Grants (to Institution); Amgen: Consultancy, Other: Grants (to Institution); Takeda: Consultancy. Gaidano: Incyte: Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astrazeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Petrucci: BMS: Honoraria, Other: Advisory Board; Takeda: Honoraria, Other: Advisory Board; Amgen: Honoraria, Other: Advisory Board; GSK: Honoraria, Other: Advisory Board; Karyopharm: Honoraria, Other: Advisory Board; Janssen-Cilag: Honoraria, Other: Advisory Board; Celgene: Honoraria, Other: Advisory Board. Tafuri: Celgene: Research Funding; Roche: Research Funding; Novartis: Research Funding. Larocca: Amgen: Honoraria; Bristol-Myers Squibb: Honoraria, Other: Advisory Board; Celgene: Honoraria, Other: Advisory Board; Janssen: Honoraria, Other: Advisory Board; GSK: Honoraria; Takeda: Other: Advisory Board. Molica: Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Astrazeneca: Honoraria. Gozzetti: Janssen: Honoraria; AbbVie: Honoraria. Vignetti: Amgen: Consultancy, Honoraria; Incyte: Honoraria; Novartis: Honoraria. Cavo: Novartis: Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Accommodations, Speakers Bureau; Adaptive Biotechnologies: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GlaxoSmithKline: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Speakers Bureau; Bristol-Myers Squib: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Background. Infections represent a major cause of toxicity in newly diagnosed multiple myeloma (NDMM) patients, and their incidence is higher during the first 4 months of therapy (Dumontet, Leukemia 2018). The use of prophylactic levofloxacin for the first 3 months of therapy demonstrated to reduce rates of infections (Dryson, Lancet Hematol 2019). However, factors predicting the risk of infections in patients treated with novel agents and the need for antimicrobial prophylaxis for all vs selected patients remain under debate. We investigated the incidence of severe infections and associated baseline risk-factors in NDMM patients. Methods. Data from Italian patients enrolled in clinical trials and receiving carfilzomib-based (IST-CAR-506, IST-CAR-561), bortezomib-based (EMN02) and lenalidomide-based (EMN01, RV-MM-PI-0752, RV-MM-EMN-441) treatment were pooled together and analyzed. The primary aim of the analysis was to evaluate the incidence of severe infections, defined as any grade (G) 3-5 event or G2 if involving the lung/lower respiratory tract (CTCAE version 4.0). The rate of early severe infections (i.e. infections occurring during the first 4 months of treatment) was also analyzed. Secondary goals were to identify baseline factors associated with an increased risk of early severe infections and to evaluate the impact of early severe infections on treatment outcome. Results. A total of 1892 patients were included in the analysis. Median age was 65 years, 970 (51%) patients were transplant eligible (TE) and 922 (49%) transplant ineligible (NTE). Overall, 1059 (56%) patients received IMiD-based induction therapy and 833 (44%) a PI-based induction therapy. Median follow-up was 68 months. We recorded 898 infections of any grade, of which 436 (49%) were considered severe. Most frequent severe infections included lung/lower respiratory tract infection (50%), febrile neutropenia (23%) and sepsis/septic shock (10%). Overall, severe infections occurred when myeloma response to treatment was ≤PR in 62% of cases, VGPR in 29% and sCR/CR in 9%. 654 (35%) patients reported at least 1 infection of any grade and 377 (20%) patients at least one severe infection. Early infections (first 4 months) occurred in 243 patients (13%) and early severe infections in 129 patients (6.8%). Overall, 21 patients (1.1%) died due to infection, of whom 6 during the first 4 months. In a multivariate analysis (Table), main factors associated with increased risk of early severe infections were ISS stage 3 (OR 2.14, 95% CI 1.32-3.48), presence of del17p by FISH (OR 1.80, 95% CI 1.1-2.96), intermediate fit status (OR 1.88 95% CI 1.1-3.21) and frail status (OR 2.12, 95% CI 1.08-4.18) according to IMWG frailty score (Palumbo, Blood 2015). No difference in risk of early severe infections was observed according to induction treatment with PI vs IMiD (OR 1.10, 95%CI 0.68-1.78). In a time-dependent Cox regression analysis adjusted for potential confounders (age, RISS stage and performance status), the risk of disease progression/death was significantly higher in patients who had an early severe infection compared to patients without early severe infection (median PFS 21.3 months vs 31.3 months, HR 1.32, 95% CI 1.07-1.63, p Conclusions. We found that 34% of patients experiencing severe infections had the event during the first 4 months of therapy. Patients with aggressive disease and elderly frail patients are at higher risk of early severe infections, hampering treatment adherence and efficacy, and eventually affecting PFS and OS. Identifying patients more susceptible to severe infections through easily available parameters could pave the way for the evaluation of risk-adapted antimicrobial prophylaxis in clinical trials. Table 1 Disclosures D'Agostino: GSK: Membership on an entity's Board of Directors or advisory committees. Offidani:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; BMS: Consultancy, Honoraria. Petrucci:BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Liberati:JANSSEN: Honoraria; AMGEN: Honoraria; CELGENE: Honoraria; ROCHE: Honoraria, Research Funding; PFIZER: Honoraria, Research Funding; ONCOPEPTIDES AB: Honoraria, Research Funding; TAKEDA: Honoraria, Research Funding; MORPHOSYS: Honoraria, Research Funding; ONCONOVA: Honoraria, Research Funding; ABBVIE: Honoraria, Research Funding; NOVARTIS: Honoraria, Research Funding; KARYOPHARM: Honoraria, Research Funding; BMS: Honoraria; BEIGENE: Honoraria; ARCHIGEN: Honoraria; BIOPHARMA: Honoraria; FIBROGEN: Honoraria; INCYTE: Honoraria; VERASTEM: Honoraria, Research Funding. Benevolo:Amgen: Honoraria; Celgene: Honoraria; Novartis: Honoraria. Gaidano:Sunesys: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astrazeneca: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Galli:Takeda: Honoraria; Janssen: Honoraria; Celgene: Honoraria; BMS: Honoraria. Corradini:Janssen: Consultancy, Honoraria; Incyte: Consultancy; Gilead: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Daiichi Sankyo: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Amgen: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Sanofi: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other; BMS: Other; KiowaKirin: Consultancy, Honoraria; Kite: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Other: Travel and accommodations paid by for; F. Hoffman-La Roche Ltd: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: Travel and accommodations paid by for. Conticello:Amgen, Takeda, Janssen: Honoraria. Cavo:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GlaxoSmithKline: Honoraria, Speakers Bureau; Karyopharm: Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Speakers Bureau. Sonneveld:Skyline Dx: Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding. Boccadoro:Mundipharma: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria. Bringhen:Bristol-Myers Squibb: Honoraria; Takeda: Consultancy; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: The presentation includes discussion of off-label use of a drug or drugs for the treatment of multiple myeloma (including carfilzomib, cyclophosphamide, dexamethasone, bortezomib, melphalan, prednisone and lenalidomide).

Background. High-dose melphalan followed by autologous stem cell transplantation is a standard of care in transplant-eligible newly diagnosed multiple myeloma (NDMM) patients and is also an option at relapse. Therefore, since the minimum number of CD34+ cells required to ensure adequate bone marrow recovery after myeloablative chemotherapy is 2x10^6/kg, an adequate upfront stem-cell collection is necessary in MM patients. Approximately 5-15% of MM patients mobilized with granulocyte colony-stimulating factor (G-CSF) or G-CSF+cyclophosphamide (G-CSF/CY) fail stem-cell collection ( Methods. NDMM patients undergoing stem-cell mobilization with cyclophosphamide (2-4 g/m2) and G-CSF (5-10 mcg/kg/day), with on-demand plerixafor according to clinical practice ( Results. At the data cut-off (09 June 2020), a total of 252 patients had been enrolled: of these, 192 patients (59, 29-72 years) were available for the analysis. The median number of induction cycles before mobilization was 4 (range 1-7); median time from diagnosis to mobilization was 6 months (IQR 5-8). Induction therapy consisted of a bortezomib-based regimen in 171 (90%), carfilzomib/lenalidomide-based regimen in 14 (7%), lenalidomide-based regimen in 3 patients (2%). 187/192 (97%) patients successfully collected ≥2 x 10^6/Kg CD34: of these, 153/192 (80%) collected with G-CSF/CY, 29/192 (15%) required the administration of plerixafor. The PM rate was 5/192 (2.5%): of these, 3/5 did not receive plerixafor in addition to G-CSF/CY, while 2/5 failed stem-cell collection despite the use of plerixafor. The median number of CD34 collected was 9.8x10^6/Kg (6.7-14.2). The median number of CD34/Kg collected with or without plerixafor was 5.1 (4.3-9.1) and 10.6 (8.1-14.4), respectively. The median number of apheresis days was 1 (IQR 1-2), with a stem-cell collection efficiency (CD34 number collected/ days of apheresis) equal to 7.7 x10^6 CD34/kg/day. The median number of apheresis days was 1 without plerixafor and 2 with plerixafor, with a stem-cell collection efficiency (CD34 number collected/ days of apheresis) equal to 8.8 without plerixafor and 3 with plerixafor. In patients who received plerixafor, the median number of CD34/ul pre-apheresis was 16 (10-19.5); after the administration of plerixafor, the median number of CD34/ul pre-apheresis increased to 46 (21-81). Non hematological AEs within 30 days after mobilization occurred in 8% of patients (grade 3-4: 2%); all grade and grade 3-4 infections occurred in 2% of patients each. In a multivariate analysis, main factors predicting the use of plerixafor were ISS 3 (vs. 1, OR 4.43; p=0.008), bone marrow plasma cells at diagnosis >60% (OR 3.85; p=0.006), white blood cell (WBC) count pre-mobilization (OR 6.66; p Conclusion. "On-demand" plerixafor combined with G-CSF/CY is a safe and effective rescue strategy for stem-cell collection in MM, reducing the PM rate to 2.5%. Extensive bone marrow plasmacytosis, ISS 3 disease at diagnosis, use of lenalidomide during induction and a low WBC count pre-mobilization predicted the use of plerixafor. Thus, pre-emptive administration of plerixafor in patients presenting one or more risk factors for poor mobilization might help in further reducing the PM rate. Disclosures Mina: Amgen: Honoraria; Celgene: Honoraria; Takeda: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Petrucci:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees. Lemoli:AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; BerGenBio ASA: Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding. Offidani:BMS: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Musto:Amgen: Honoraria; Celgene: Honoraria. Corradini:F. Hoffman-La Roche Ltd: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Celgene: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Daiichi Sankyo: Consultancy, Honoraria; Incyte: Consultancy; Novartis: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Other: Travel and accommodations paid by for; KiowaKirin: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other; BMS: Other; Sanofi: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Kite: Consultancy, Honoraria. Cavo:BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Speakers Bureau; GlaxoSmithKline: Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Karyopharm: Honoraria. Boccadoro:GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; AbbVie: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Research Funding; Mundipharma: Research Funding; Novartis: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. Larocca:Takeda: Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria. OffLabel Disclosure: The presentation includes discussion of off-label use of a drug or drugs for the treatment of patients with multiple myeloma (including cyclophosphamide, G-CSF and plerixafor).

The Multiple Myeloma (MM) is a plasma cells hematological malignancy with a median age of 69 years at diagnosis. The autologous stem cell transplantation is the standard of care for this disease but less than half of newly diagnosed patients are assessed for this treatment due to comorbidities or complications of disease. The management of transplant ineligible MM patients is based on the balance safety and efficacy of the new available regimen and a careful assessment of the frailty status is mandatory to define the goals. In this review we discuss of the clinical dilemmas in the management and define how to manage them based on the evidence from clinical trials and “real life” experience.

In recent years, with the aim of reducing transplant-related mortality, new conditioning regimens have been explored in patients not eligible for conventional haemopoietic stem cell transplantation. In this setting, we investigated safety and feasibility of the treosulfan-fludarabine-thiotepa combination prior to allogeneic haemopoietic stem cell transplantation in patients with advanced lympho-proliferative diseases and at high transplant risk. Twenty-seven consecutive patients, median age 43 years (range 19-60), entered this study. All of them were affected by lympho-proliferative disease in advanced phase and have been heavily pre-treated. The median haemopoietic stem cell transplant co-morbidity index was 1 (range 0-3). Twenty-five patients had regular engraftment, while the remaining two patients were not evaluable for early deaths. Non-haematological toxicity was limited. No patient developed veno-occlusive disease. The estimated probability of overall survival and progression-free survival with a median follow-up of 40 months was 52% (95% confidence interval 33-73) and 50% (95% confidence interval 30-70) respectively. Six patients have relapsed; all of them were not in remission before transplantation. The treosulfan-fludarabine-thiotepa combination is a reduced toxicity but myeloablative regimen that can be proposed to patients not fitting criteria for conventional myeloablative transplant regimens. Longer follow-up and prospective randomized studies are necessary to evaluate this regimen.

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 After a median follow-up of 11 months, most pts are still on treatment (60,4%), the median number of administered cycles was 7 (range 2-33). Overall response rate (ORR, ≥PR) was 74.5% with 34.1% of pts obtaining at least a VGPR. Clinical Benefit Rate (CBR, including minimal responses) was 83.3%. Responses were rapid with median time to first and to best response respectively of 1.8 (range 1-8) and 5 (1-26) months. Median OS and PFS were not reached with a 1-y and 2-y OS of 84.8 and 73.8% and a 1-y and 2-y PFS of 78.6 and 65%. Median EFS was 19.8 months. In univariate analysis, factors significatively impairing ORR were frailty (fit/unfit/frail 91.2/77/55.9%, p2 81.7/61.6%, p upper level of normal (ULN) (65.8 vs 77%, p=0.034). 1-y PFS is significantly shorter in pts with lower ECOG (0-1 vs 2, 66.5 vs 84.8%, pULN (66.4 vs 83.2%, p=0.02), lower ClCr (50 57.2/81.3/80.1%, P=0.01), presence of t(14;16) (42.9 vs 80.4% p=0.01) and amp(1q) (63.5 vs 85.6%, p=0.01); factor impairing OS are ECOG (0-1/>2 93.4 vs 69.4%, pULN (75.1 vs 97.1, p=0004), impaired ClCr (50 64/83.7/88.2%, p2 74.2 vs 47.3%, p In multivariate analysis ORR is significantly correlated with ECOG>2 (p=0.05), LDH >ULN (p=0.005) and presence of amp1q (p=0.006); PFS was significantly affected by R-ISS III (p=0.04), LDH >ULN (P=0.01) and ClCr2 still impact on OS (p Dose reduction of Len or dex was required respectively in 20.7% and 22.1% and 39.2% needed cycle delay for adverse events (AEs). Grade 3-4 (G3-4) AEs occurred in 52% of pts with 30.9 and 36.6% having at least a hematological or extra-hematological G3-4 AE. In particular, 17.9 and 16.6% of pts had severe neutropenia and anemia while the most common non-hematological AEs were infections (25.8%, G3-4 12.2%), mainly involving respiratory tract (71.2%). Gastroenteric and cutaneous AEs were quite common (22.1 and 19.2%), mainly diarrhea and itching, but in the vast majority were mild. G3-4 asthenia was present in 22.8% of pts. Although 99% of pts was given antithrombotic prophylaxis, 8.5% had a thromboembolic event, a third of severe entity. G-CSF and EPO analogs were required in 27.4 and 26% of pts. Conclusion Real-life data confirm efficacy and tolerability of Rd in elderly NDMM pts. Performance status by ECOG and IMWG frailty score and severe renal impairment but not age itself act as limiting factors affecting outcome. These data must be confirmed by longer follow-up. Disclosures Conticello: Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Mangiacavalli:Janssen cilag: Consultancy; celgene: Consultancy; Amgen: Consultancy. Zambello:Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Belotti:Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Molteni:Celgene: Membership on an entity's Board of Directors or advisory committees. Aquino:Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Del Fabro:Janssen: Consultancy. Galli:Leadiant (Sigma-Tau): Honoraria; Janssen: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Celgene: Honoraria.

Introduction: The phase 3 GIMEMA-MMY-3006 trial comparing bortezomib-thalidomide-dexamethasone (VTD) versus thalidomide-dexamethasone (TD) as induction therapy before, and consolidation after, double autologous stem cell transplantation (ASCT) for newly diagnosed multiple myeloma (MM) provided the first demonstration of increased CR rate, the primary study endpoint, and prolonged PFS with VTD (Cavo M et al, Lancet 2010). However, updating trial results with longer follow-up than earlier reported is needed to assess the effects of treatment interventions on OS and to identify factors predicting for favorable long term outcomes. Aims: We performed a post-hoc analysis of that study to evaluate long term results and construct a prognostic index of survival. Methods: 474 patients were enrolled, 236 randomized to VTD and 238 to TD. Median follow-up for surviving patients was 124 months (IQR: 117-131). Analyses were performed on an intention-to-treat basis. Semi-parametric Cox regression analysis was used to construct the prognostic index. To assess the evolution of prognosis over time, conditional survival CS(t|s) estimate for PFS was calculated as the probability of surviving without progression a further 2 (t) years (yrs) after having already survived s yrs. Results: Estimates of PFS and OS at 10 yrs for the VTD arm were 34% (HR=0.62; 95% CI=0.50-0.77; p Conclusions: With a follow up of 10 yrs, the final analysis of the GYMEMA MMY-3006 trial comparing VTD versus TD showed a persistent PFS benefit translating into extended OS for the VTD arm. A prognostic model based on cytogenetic, ISS stage and achievement of CR, identified three risk groups with statistically different long-term survival probabilities. Both IR and HR groups significantly benefited from VTD. A PFS time of 78 months predicted for long term survival outcomes in the LR and IR groups. Disclosures Tacchetti: Celgene: Honoraria; Janssen: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Di Raimondo:Takeda: Honoraria, Research Funding; Celgene: Honoraria. Zamagni:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Bringhen:Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Amgen: Honoraria, Other: Advisory Board; Janssen: Honoraria, Other: Advisory Board; Takeda: Consultancy. Offidani:Celgene: Honoraria, Other: Advisory Board; Janssen: Honoraria, Other: Advisory Board; Amgen: Honoraria, Other: Advisory Board; Bristol-Myers Squibb: Honoraria, Other: Advisory Board; Takeda: Honoraria, Other: Advisory Board. Montefusco:Celgene: Other: Advisory Board; Amgen: Other: Advisory Board; Janssen: Other: Advisory Board. Cavo:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Background: Hodgkin Lymphoma (HL) is a neoplastic hematologic disease that requires treatment with standard chemo-radiotherapy and, in relapsed patients, intensification with hematopoietic s cell transplantation (HCT). Introduction: Insertion of a Peripheral Insertion Central Venous Catheter (PICC) instead of a Peripheral Venous Catheter (PVC) could simplify HL patients management and allow a safer therapy, according to their outpatient care. Methods: Since the 2007, a PICC team, consisting of an hematology physician and two dedicated nurses has carried out a prospective study to evaluate complication rate and usefulness of PICC device in the hematology clinical practice, particularly in HL patients. Inclusion criteria included all HL inpatient and outpatient who needed program of chemo-radiotherapy, support treatment and HSCT, regardless of white blood cells (WBC) and platelets (PLT) counts. All patients underwent a previous evaluation of arms vascular anatomy by ultrasonography. All implantation procedures were performed under ultrasound guide with radiographic control following insertion. Results: From March 2007 to January 2018, 228 attempts of PICC implantation were performed in 202 HD patients (104 male and 90 females). Median age was 35 years, range 16-85. Catheter insertion was successful in 220 cases (96.5 %) in 194 patients, whilst in 8 cases (3.5%) PICC insertion was not possible; 96 PICC were inserted in patients treated with a previous chemotherapy. Two hundred and seven PICC (94%) were used for chemo-radiotherapy courses, five (2.3%) for support treatment, 7 (3.2%) for autologous HSCT, 1 (0.5%) for allogenic HSCT. At the time of this analysis 7 out of 220 PICC (3.5%) are still in situ and in use, 180 (81.5%) were removed for end of therapy and 10 (4.5%) for accidental withdrawals. Only 23 PICC (10.5%) were removed because of catheter related complications: 2 (0.9%) for catheter rupture, 4 (1.8 %) for malfunctioning, 7 (3.2%) for occlusions, 4 (1.8%) for local infection, 6 (2.7%) for suspected PICC-related sepsis. Only 3 episode of confirmed PICC-related septicemia (1.4 %; 0.1/1000 days/PICC) were recorded and Staphylococcus was isolated. There were only 5 episodes (2.3% ; 0.14/1000 days/PICC) of symptomatic PICC-related thrombotic complications, without need of removal. Two cases (0.9%) of delayed abnormal dislocation were recorded, fixed with subsequent replacement with guide. PICC median life was 157 days (range 1-396) for a total of 34,764 days. The 365-day cumulative incidence of catheter removal for end of therapy (PICC life) was 95,5%±1.7%. No significant difference was found in patients underwent previous chemotherapy course (95.1±2.6 vs 95.8±2.1%, p=NS). Neither stage of disease WBC or PLT count had influenced on PICC life. Conclusions. These data encourage the use of PICC as standard of care in the management of HD patients because of easy insertion, safety of use, duration of life and low rate of complication. Disclosures Angelucci: Celgene: Honoraria, Other: Chair DMC; Novartis: Honoraria, Other: Chair Steering Comiittee TELESTO Protocol; Vertex Pharmaceuticals Incorporated (MA) and CRISPR CAS9 Therapeutics AG (CH): Other: Chair DMC; Jazz Pharmaceuticals Italy: Other: Local ( national) advisory board; Roche Italy: Other: Local (national) advisory board.

Introduction Elotuzumab (Elo), an immunostimulatory monoclonal antibody targeting signaling lymphocytic activation molecule F7 (SLAMF7), received marketing approval in Italy for relapsed or refractory multiple myeloma (RRMM), in combination with lenalidomide (R) and dexamethasone (d) (EloRd) in April 2017. Here we report preliminary data of an Italian real-life experience on EloRd as salvage therapy for RRMM patients treated outside of controlled clinical trials. The primary objectives of this study were to assess the toxicity profile and the efficacy of EloRd administered as salvage therapy in a real-world setting. Methods Retrospective data collection received approval from local ethic committee. The cohort included 180 RRMM patients from 28 Italian centers who received at least one cycle of EloRd as salvage treatment between April 2017 and June 2018. Patients were treated with EloRD according to marketing approval as follows: Elo 10 mg/kg i.v. on days 1, 8, 15, and 22 during the first two cycles and then on days 1 and 15 of each following cycle, R 25 mg on days 1 to 21 of each cycle and d at a dose of 40 mg during the week without Elo, and 36 mg on the day of Elo administration. Responsive patients had to reach at least a partial remission (PR). Results Baseline characteristics are shown in Table 1. Median age of the 180 patients was 72 years (range 48-89 years); 53.9% were males (Table 1). The median number of previous therapy regimens was 1 (range 1-7); 69 patients (38.3%) received a previous autologous stem cell transplantation (ASCT). One hundred and ten patients (61.1%) showed a symptomatic relapse, 36 (20%) a biochemical relapse, and 34 cases (18.9%) were refractory to the last therapy, including bortezomib in 12.8% of patients. Forty-four patients (24.4%) had creatinine clearance ≤60 mL/min. Among the 138 cases evaluable for International Scoring System (ISS), 54 (39.1%) had stage I, 56 (40.6%) stage II, and 28 (20.3%) stage III. At last data collection (June 2018), 164 cases were evaluable for response. The median number of courses administered so far was 5 (range 1-18). The overall response rate (ORR) was 78%, with 9 complete remissions (CRs) (5.5%) and 49 very good partial remissions (VGPRs) (35.4%). A significant higher ORR was observed in patients who had received only 1 previous line of therapy than those who had received >1 line (64% vs 37.5%; p=0.004). Age ( After a median follow-up of 6 months (range 1-18 months) 33 patients stopped treatment due to disease progression and 4 due to toxicity (2 cases after 1 cycle for pneumonia, 1 after 1 cycle for dexamethasone-related psychosis, and 1 after 2 cycles for lenalidomide-related severe skin rash). A total of 17 patients died (7 patients from progressive disease; 2 from an infection; 1 from a second neoplasia; 7 from causes unrelated to therapy). Follow-up data regarding PFS and overall survival are not sufficiently mature to be analyzed. Common grade 3 or 4 adverse events were fatigue (18.9%), anemia (17%), neutropenia (16.5%), lymphocytopenia (15.9%), and pneumonia (15.9%). Infusion reactions occurred in 13 patients (7.2%) and were always of grade 1 or 2. Infusion reactions resolved in all patients and no case discontinued treatment. Conclusions Our real world preliminary data confirm that EloRd is an effective and safe regimen for RRMM patients, particularly if used as first salvage regimen, basically resembling results obtained in controlled clinical trials. Table 1. Table 1. Disclosures Galli: Celgene: Honoraria; Janssen: Honoraria; Sigma-Tau: Honoraria; Bristol-Myers Squibb: Honoraria. Giuliani:Janssen Pharmaceutica: Other: Avisory Board, Research Funding; Celgene Italy: Other: Avisory Board, Research Funding; Takeda Pharmaceutical Co: Research Funding. Mangiacavalli:Janssen: Consultancy; Celgene: Consultancy; Cilag: Consultancy. Ballanti:Celgene: Honoraria; Janssen: Honoraria; Amgen: Honoraria; BMS: Honoraria. Montefusco:Celgene: Other: Advisory Board; Amgen: Other: Advisory Board; Janssen: Other: Advisory Board. Bringhen:Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Amgen: Honoraria, Other: Advisory Board; Janssen: Honoraria, Other: Advisory Board; Takeda: Consultancy. Zamagni:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees. Patriarca:Celgene: Other: Advisory Role; Travel, accommodations, expenses; Janssen: Other: Advisory role; Jazz: Other: Travel, accommodations, expenses; Medac: Other: Travel, accommodations, expenses; MSD Italy: Other: Advisory Role. Di Raimondo:Takeda: Honoraria, Research Funding; Celgene: Honoraria. Petrucci:Takeda Oncology; Amgen; Celgene; BMS; Janssen Cilag: Honoraria, Other: Advisory Board. Offidani:Bristol-Myers Squibb: Honoraria, Other: Advisory Board; Amgen: Honoraria, Other: Advisory Board; Takeda: Honoraria, Other: Advisory Board; Janssen: Honoraria, Other: Advisory Board; Celgene: Honoraria, Other: Advisory Board.

This phase 2 trial evaluated three low-dose intensity subcutaneous bortezomib-based treatments in patients ⩾75 years with newly diagnosed multiple myeloma (MM). Patients received subcutaneous bortezomib plus oral prednisone (VP, N=51) or VP plus cyclophosphamide (VCP, N=51) or VP plus melphalan (VMP, N=50), followed by bortezomib maintenance, and half of the patients were frail. Response rate was 64% with VP, 67% with VCP and 86% with VMP, and very good partial response rate or better was 26%, 28.5% and 49%, respectively. Median progression-free survival was 14.0, 15.2 and 17.1 months, and 2-year OS was 60%, 70% and 76% in VP, VCP, VMP, respectively. At least one drug-related grade ⩾3 non-hematologic adverse event (AE) occurred in 22% of VP, 37% of VCP and 33% of VMP patients; the discontinuation rate for AEs was 12%, 14% and 20%, and the 6-month rate of toxicity-related deaths was 4%, 4% and 8%, respectively. The most common grade ⩾3 AEs included infections (8–20%), and constitutional (10–14%) and cardiovascular events (4–12%); peripheral neuropathy was limited (4–6%). Bortezomib maintenance was effective and feasible. VP, VCP and VMP regimens demonstrated no substantial difference. Yet, toxicity was higher with VMP, suggesting that a two-drug combination followed by maintenance should be preferred in frail patients.

Bortezomib (bort) has improved overall survival in patients with multiple myeloma (MM), but the majority of them develop drug resistance. In this study, we demonstrate that bone marrow (BM) fibroblasts (cancer-associated fibroblasts; CAFs) from bort-resistant patients are insensitive to bort and protect the RPMI8226 and patients' plasma cells against bort-induced apoptosis. Bort triggers CAFs to produce high levels of interleukin (IL)-6, IL-8, insulin-like growth factor (IGF)-1 and transforming growth factor (TGF) β. Proteomic studies on CAFs demonstrate that bort resistance parallels activation of oxidative stress and pro-survival autophagy. Indeed, bort induces reactive oxygen species in bort-resistant CAFs and activates autophagy by increasing light chain 3 protein (LC3)-II and inhibiting p62 and phospho-mammalian target of rapamycin. The small-interfering RNA knockdown of Atg7, and treatment with 3-methyladenine, restores bort sensitivity in bort-resistant CAFs and produces cytotoxicity in plasma cells co-cultured with CAFs. In the syngeneic 5T33 MM model, bort-treatment induces the expansion of LC3-II(+) CAFs. TGFβ mediates bort-induced autophagy, and its blockade by LY2109761, a selective TβRI/II inhibitor, reduces the expression of p-Smad2/3 and LC3-II and induces apoptosis in bort-resistant CAFs. A combination of bort and LY2109761 synergistically induces apoptosis of RPMI8226 co-cultured with bort-resistant CAFs. These data define a key role for CAFs in bort resistance of plasma cells and provide the basis for a novel targeted therapeutic approach.

Bendamustine is an old bi-functional alkylating agent which, thanks to its extended efficacy and good tolerability, is living a second youth with growing use in several lympho-proliferative maligna...

Introduction : Rd and MPR showed to be effective combinations in elderly newly diagnosed multiple myeloma (NDMM) patients (pts). Cyclophosphamide is a less toxic alkylating alternative agent. EMN01 is the first trial to formally compare these three different Lenalidomide-based combinations. Maintenance with Lenalidomide has been recently approved in patients eligible for autologous stem cell transplant (ASCT). Few data are available about the best combination as maintenance in patients not eligible for ASCT. Methods : 662 pts with NDMM were randomized to receive 9 28-day cycles of Rd (lenalidomide 25 mg/day for 21 days; dexamethasone 40 mg on days 1,8,15 and 22 in pts 65-75 years old and 20 mg in those >75 years), MPR (lenalidomide 10 mg/day for 21 days; melphalan orally 0.18 mg/Kg for 4 days in pts 65-75 years old and 0.13 mg/Kg in >75 years pts; prednisone 1.5 mg/Kg for 4 days) or CPR (lenalidomide 25 mg/day for 21 days; cyclophosphamide orally 50 mg/day for 21 days in pts 65-75 years old and 50 mg every other day in >75 years pts; prednisone 25 mg every other day). After induction, pts were randomized to receive maintenance with lenalidomide alone (R; 10 mg/day for 21 days) or with prednisone (RP; R, 10 mg/day for 21 days and P, 25 mg every other day), until disease progression. Results : Pts characteristics were well balanced in all groups; 217 pts in Rd, 217 in MPR and 220 in CPR arms could be evaluated. After a median follow-up of 63.7 months, median PFS was 23.2 months in MPR, 18.9 months in CPR and 18.6 months in Rd (MPR vs CPR p=0.02; MPR vs Rd p=0.08). Median overall survival (OS) was 79.9 months in MPR, 69.4 months in CPR and 68.1 months in Rd (MPR vs CPR p=0.98; MPR vs Rd p=0.64). The most common grade ≥3 adverse event (AEs) was neutropenia: 64% in MPR, 29% in CPR and 25% in Rd pts (p Conclusion : This phase III trial compared 2 different Lenalidomide-containing induction regimens and 2 different Lenalidomide-containing maintenance regimens in an elderly community-based NDMM population. MPR prolonged PFS by approximately 5 months, yet the higher incidence of hematologic toxicity should be carefully considered. The addition of low-dose prednisone to standard lenalidomide maintenance reduced the risk of death/progression by 20%, with a good safety profile. Updated results will be presented at the meeting. Disclosures Bringhen: Mundipharma: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Celgene: Honoraria; Bristol Myers Squibb: Honoraria; Karyipharm: Membership on an entity's Board of Directors or advisory committees. Offidani: celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Musto: Celgene: Honoraria; Janssen: Honoraria. Gaidano: Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Roche: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. De Sabbata: Celgene: Membership on an entity's Board of Directors or advisory committees. Palumbo: Sanofi: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Binding Site: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Genmab A/S: Consultancy, Honoraria, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Employment, Equity Ownership, Honoraria, Research Funding. Hájek: Amgen, Takeda, BMS, Celgene, Novartis, Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Honoraria; Pharma MAR: Consultancy, Honoraria. Boccadoro: Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; AbbVie: Honoraria; Mundipharma: Research Funding; Sanofi: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding.

Bendamustine, a bi-functional alkylating agent comprising a purine-like benzimidazole ring an a nitrogen mustard group, exerts a peculiar mechanism of action if compared to most conventional alkylators and this may partially explain its effectiveness in alkylator-resistant cells. In patients with MM several studies demonstrated the efficacy and tolerability of bendamustine as monotherapy or in combination with new drugs, particularly bortezomib that was found to enhance the in vitro sensitivity of MM cells to bendamustine. These observations represented the rationale for our protocol design namely to evaluate the combination bendamustine (70 mg/m2 days 1, 8), bortezomib (1.3 mg/ m2 days 1, 4, 8, 11) and dexamethasone (20 mg days 1-2, 4-5, 8-9, 11-12) (BVD). Cycles were administered every 4 weeks up to four cycles. Patients achieving a response less than a PR were taken off-study. Patients obtaining at least a PR received two additional treatment cycles followed by a 12-months consolidation phase with cycles repeated every 2 months. Therefore, patients with a PR after the induction phase could receive up to 18 months of treatment and up to 12 cycles of BVD. Patients with relapsed/refractory MM of any age, with adequate cardiac, liver and hematological function, not refractory to bortezomib and treated with no more than four previous lines of therapy were enrolled in this prospective, single-arm, open-label, phase II study conducted in 21 Italian centres. The primary endpoint was achievement of a response at least PR after four cycles of BVD and response was assessed according to to IMWG criteria. From March 2011 to June 2012, 75 patients were included. Median age was 68 years (range 41-85), 26.5% had ISS stage 3, 19% IgA myeloma and 9% renal failure. In total, 8 of 36 evaluable patients (22%) had adverse cytogenetics. All patients had received prior treatment with new drugs, including targeted agents such as thalidomide (57%), lenalidomide (54.5%) or bortezomib (46.5%). Patients had received a median of one prior line of therapy (range 1-4), including alkylators (69%), anthracyclines (29%) and ASCT (44%). Twenty-four patients (32%) were refractory to IMIDs. The response rate ≥ PR after four cycles of BVD was 71.5%, including 11 patients with CR (16%), 13 VGPRs (18.5%) and 26 PRs (37%). Also, 14 patients (20%) had disease stabilization while 6 (8.5%) had progressive disease. Median time to response was 1.2 months (range 0.9-1.4 months). Only prior treatment with bortezomib significantly reduced the response rate ≥ PR (54.5% vs 86.5%; P = 0.003). At a median follow-up of 12 months (range 6-24), 30 patients had progressed and 18 had died. Median TTP and PFS were 16.5 months and 15.5 months, respectively while median OS had not been reached and 78% of patients were alive at 1 year. The Cox regression analysis identified prior therapy with bortezomib plus lenalidomide as the only factor that significantly reduced TTP (9 vs 17 months; HR = 4.5; 95% CI = 1.7-12.3; P = 0.005) Grade 3-4 adverse events occurred in 55% of patients leading to therapy reduction in 20% and to protocol discontinuation in 10.5% of patients. The most frequent severe adverse events were thrombocytopenia (30.5%), neutropenia (18.5%), infections (12%), peripheral neuropathy (8%), gastrointestinal and cardiovascular events (both 6.5%). Compared with younger, patients aged > 70 years had a significantly higher incidence of grade 3-4 thrombocytopenia (22% vs 37%; p=0.042) and severe infections (7 vs 19%; p=0.047) and consequently a higher rate of therapy reduction (9% vs 34.5%; p=0.007) and therapy discontinuation (7% vs 15.5%; p=0.043). Moreover, 4/5 early deaths occurred in patients aged more than 70 years. BVD combination is an effective regimen in relapsed-refractory MM patients since it elicits rapid, high (> 70%) and good quality of response (more than a third of patients achieved CR + VGPR). Moreover, BVD combination is a feasible and well tolerated regimen provided that adapted therapy and adequate antibiotic prophylaxis are employed in patients older than 70 years. Disclosures: Offidani: Mundipharma: Honoraria, Research Funding. Off Label Use: Bendamustine.

INTRODUCTION:The aim of this report is to evaluate feasibility, safety and activity of a new procedure of computed tomography (CT) - guided percutaneous screw fixation (PSF) plus cementoplasty for treatment of mielomatous osteolytic lesions with refractory pain and fracture or to prevent impending pathological fractures. The association of scew fixation with cementoplasty allows, compared to cementoplasty alone, a better augmentation of the bone and reduces the risk of cement leakage through a selective injection of the of polymethylmethacrylate (especially in case of lytic lesion of vertebral pedicle). METHODS: From September 2014 to May 2016 thirteen (13) consecutive patients (eight men and five women, median age 67 years, range 48-78 years) with Multiple Myeloma who had developed painful and symptomatic bone lytic lesions in the pelvis and vertebrae were submitted to the procedure (three patients underwent multiple interventions). This consisted of PSF followed by percutaneous bone-cement injection with an solution of polymethylmethacrylate (PMMA) in eighteen sessions. The procedures were performed into the thoracic vertebrae (three interventions), lumbar vertebrae (nine interventions), pelvis (five interventions, bilateral in one instance) and into a paravertebral mass which involved the fifth and sixth thoracic vertebrae. For the osteosynthesis we used cannulated screws with lateral holes, that allow to selectively inject the cement through the screw avoiding undesired leakage. After the screw insertion, to obtain a better augmentation of the bone, from 8 to 22 ml of PMMA in all the lesions. In two cases, before the PSF and PMMA injection, in order to reduce the volume of the tumor a radiofrequency ablation was performed. All the procedures were performed using local anesthesia, conscious sedation in all patients and antibiotic prophylaxis with ceftriaxone 2 gr i.v. Pain was measured by visual analogue scale (range 0-10), mobility by functional mobility score system with a range from 1 (normal mobility) to 4 (bedridden). Statistical analysis was performed using the test of Wilcoxon. RESULTS:Technical success was achivied in all patients. The CT scan acquired immediately after the procedure didn't demonstrate any complications such as leakage of cement or incorrect positioning of the screws or undesired burning during thermal ablation. No additional bone fractures occurred during a median follow-up of 19 months (range 3-23 months). Pain relief occurred in all the patients within one month. Median VAS score was 7 (range 4-9), 3 (range1-4) and 1 (range 1-2) before, at one and six months after procedure respectively (p Only three patients needed opioid therapy after the procedure. CONCLUSION:The PSF plus cemetoplasty of the pelvis and vertebrae is safe and effective in patients affected by myelomatous localizzations. The procedure is minimally invasive and allows to stabilize the fracture and prevent pathological fractures with significant pain relief and good recovery of walking ability. Further controlled studies with large series of patients are warranted to confirm these preliminary results. Disclosures No relevant conflicts of interest to declare.

Only limited data are available regarding myocardial iron overload in adult patients with transfusion dependent acquired anemias. To address this topic using MRI T2* we studied 27 consecutive chronic transfusion dependent patients with acquired anemias: (22 myelodysplastic syndrome, 5 primary myelofibrosis). Cardiac MRI T2* values obtained ranged from 5.6 to 58.7 (median value 39.8) milliseconds. Of the 24 analyzable patients, cardiac T2* correlated with transfusion burden (p=0.0002). No patient who had received less than 290 mL/kg of packed red blood cells (101 units=20 grams of iron) had a pathological cardiac T2* value (< 20 ms). All patients who had received at least 24 PRBC units showed MRI T2* detectable hepatic iron (liver T2* value

Introduction: Bendamustine, a bifunctional alkylating agent, exerts a mechanism of action different from that of other conventional alkylators despite it remains mostly unknown. In patients with newly diagnosed or relapsed-refractory MM bendamustine has proven to be active either as monotherapy or in combination with new drugs, particularly bortezomib and immunomodulatory agents. Methods: The preliminary results of this prospective, phase II study conducted in 22 Italian centres are recently published (Blood Cancer J. 2013, 3: e162). Here we present the conclusive results of the combination Bendamustine (70 mg/m2 days 1, 8), Bortezomib (1.3 mg/ m2 days 1, 4, 8, 11) and Dexamethasone (20 mg days 1-2, 4-5, 8-9, 11-12) (BVD) administered every 4 weeks in patients with relapsed-refractory MM of any age, with adequate cardiac, liver and hematological function, not refractory to bortezomib and treated with no more than four previous lines of therapy. The primary endpoint of this study was achievement of a response at least PR, as to IMWG criteria, after four cycles of BVD. Patients achieving a response less than a PR were taken off-study. Patients obtaining at least a PR received two additional treatment cycles followed by a 12-months consolidation phase with cycles repeated every 2 months. Therefore, patients with a PR after the induction phase could receive up to 18 months of treatment and up to 12 cycles of BVD. Results: 75 patients were included in the study. Median age was 68 years (range 41-85 years), 26.5% had ISS stage 3, 19% IgA myeloma and 9% renal failure. Eight of 36 evaluable patients (22%) had high-risk cytogenetics. Patients had received a median of one prior line of therapy (range 1-4). All patients had received prior treatment with new drugs, such as thalidomide (57%), lenalidomide (54.5%), bortezomib (46.5%) or both (20%). Twenty-four patients (32%) were refractory to IMIDs. Best response rate was 75%, including 14 CRs (20%), 22 VGPRs (24%) and 27 PRs (31%). Five patients (6.5%) died early. Only prior treatment with bortezomib significantly reduced the response rate ≥ PR (48.5% vs 80%; P = 0.004). At a median follow-up of 27 months (range 18-38), 45 patients had progressed and 43 had died. Median TTP and PFS were 17 and 12.5 months, respectively while median OS was 24 months (40% at 3 years). After longer follow-up, prior therapy with bortezomib plus lenalidomide was confirmed as the only factor that significantly reduced TTP (9 vs 19 months; HR = 2.7; 95% CI = 1.3-5.8; P = 0.009), PFS (9 vs 15 months; HR = 2.1; 95% CI = 1.2-3.8; P = 0.020) and OS (17 vs 32 months; HR = 2.1; 95% CI = 1.2-3.9; P = 0.043). Grade 3-4 adverse events occurred in 55% of patients leading to therapy reduction in 24% and to protocol discontinuation in 11% of patients. The most frequent severe adverse events were thrombocytopenia (28%), neutropenia (20%), infections (12%), peripheral neuropathy (9%), gastrointestinal (5%) and cardiovascular events (4%). Compared with younger, patients aged > 70 years had a significantly higher incidence of grade 3-4 side effects particularly thrombocytopenia and infections with, consequently, a higher rate of therapy reduction and discontinuation. Moreover, 4/5 early deaths occurred in patients aged more than 70 years. Conclusions: BVD combination is an effective and well tolerated regimen in relapsed-refractory MM. Data suggest that the optimal target of BVD maybe patients younger than 70 years who has not previously received both bortezomib and lenalidomide. Disclosures Offidani: Mundipharma, Janssen: Honoraria. Off Label Use: Bendamustine. Corvatta:Janssen: Honoraria. Ballanti:Janssen: Honoraria. Brunori:Janssen: Honoraria.

Background. Allogeneic hemopoietic stem cell transplantation is the treatment of choice for high and intermediate risk acute myeloid leukemia (AML) and for higher risk myelodysplastic syndrome (MDS). Standards preparative regimens TBI-CY and BU-CY have been widely used and extra hematologic toxicity remains a concern. Even if the combination of intravenous formulation Busulphan-CY has shown lower toxicity and suggested favorable safety and efficacy profile new drugs associations are continuously explored. Recently the association Busulphan-Fludarabine has replaced the Bu-Cy regimen with the aim to further reduce toxicity. In our Institution we started to use this regimen as preparation for allogeneic transplantation in patients with AML and MDS in October 2008 using Busulphan in a single daily infusion with the primary objective of evaluating safety and efficacy. Methods. Since October 2008 to May 2014, 23 consecutive patients (19 males, 4 females) entered this study. Median age was 56 years (range 35-63). Thirteen patients presented with first remission AML, five with first or more advanced relapse or resistant disease and five with intermediate II or high risk MDS. Conditioning consisted of intravenous Busulphan (Busilvex® 9,6 -12,8 mg/kg) given once daily in a 4 hours infusion in association with Fludarabine 160 mg /m2 for 4 consecutive days. Fifteen patients received HSCs from HLA identical siblings, 1 from a family mismatched donor, 7 from matched unrelated donors. Source of stem cells was bone marrow in 13 patients, peripheral blood stem cells in 9 patients, and both in 1 patient. CSA + short MTX was used as GVHD prophylaxis and anti-Lymphocyte globulins (Thymoglobulin® or ATG Fresenius®) was added in case of unrelated donor transplants Toxicity was evaluated by WHO toxicity scale Common Terminology Criteria for Adverse Events (CTCAE) version 3. Acute Graft versus Host Disease was evaluated in patients with engraftment and graded according to the revised Glucksberg scale. Internal review board approved study. All patients gave written informed consent to procedure. Results. All patients regularly engrafted (mean time to neutrophils >500/microliter was 13 days (range 11-15). Seven patients experienced gastro-intestinal toxicity (1 grade III mucositis, 2 grade II mucositis, 4 grade I mucositis); 3 patients had grade II cystitis. Overall grade >II toxicity occurred in a single patient (4%). Acute grade IV gastro-intestinal- GvHD occurred in 1 patient, while 12 patients presented grade I skin GvHD. Cr. GVHD occurred in 4/18 evaluable patients (moderate in 1). CMV reactivation occurred in 15/23 patients (65%), no patient developed life-threatening bacterial or fungal infection. Eight out of 23 patients have died (35%) all but one by recurrent disease and 1 by grade IV acute GvHD. Fifteen patients are alive (65%), 14 in complete remission, with a median follow-up of 8 months (range 2-37 months). Conclusion. This single Centre report, even if with limited number of patients, underlines that the association of intravenous single dose infusion Busulphan plus Fludarabine is a safe and effective conditioning regimen in AML/MDS patients. Intravenous Busulphan administered once daily is convenient, well tolerated and effective. Further prospective studies are warranted. Disclosures No relevant conflicts of interest to declare.

Bendamustine demonstrated synergistic efficacy with bortezomib against multiple myeloma (MM) cells in vitro and seems an effective treatment for relapsed-refractory MM (rrMM). This phase II study evaluated bendamustine plus bortezomib and dexamethasone (BVD) administered over six 28-day cycles and then every 56 days for six further cycles in patients with rrMM treated with ⩽4 prior therapies and not refractory to bortezomib. The primary study end point was the overall response rate after four cycles. In total, 75 patients were enrolled, of median age 68 years. All patients had received targeted agents, 83% had 1–2 prior therapies and 33% were refractory to the last treatment. The response rate⩾partial response (PR) was 71.5% (16% complete response, 18.5% very good PR, 37% partial remission). At 12 months of follow-up, median time-to-progression (TTP) was 16.5 months and 1-year overall survival was 78%. According to Cox regression analysis, only prior therapy with bortezomib plus lenalidomide significantly reduced TTP (9 vs 17 months; hazard ratio=4.5; P=0.005). The main severe side effects were thrombocytopenia (30.5%), neutropenia (18.5%), infections (12%), neuropathy (8%) and gastrointestinal and cardiovascular events (both 6.5%). The BVD regimen is feasible, effective and well-tolerated in difficult-to-treat patients with rrMM.

Background Frail patients represent 30% of the myeloma population, and are more susceptible to adverse events (AEs) with subsequent treatment discontinuations that significantly affect efficacy and dose-intensity. This community-based, phase II, multicenter trial aims to assess the efficacy and safety of 3 reduced-dose intensity subcutaneous (sc) bortezomib-based treatments in newly diagnosed elderly multiple (MM) patients. Methods Patients with symptomatic, measurable MM, older than 75 years were enrolled. No exclusion criteria were planned in the protocol, to avoid patient selection bias. Patients with abnormal cardiac, pulmonary, renal or hepatic function were included. Treatment consisted of nine 28-day cycles with sc bortezomib 1.3 mg/m2 days 1, 8, 15, 22 plus oral prednisone 50 mg every other day (VP) or VP plus oral cyclophosphamide 50 mg every other day (VCP) or oral melphalan 2 mg every other day (VMP) for 28 days, followed by maintenance with sc bortezomib every 2 weeks until progression. A geriatric assessment was performed, including the Charlson index for estimating comorbidities, the Activity of Daily Living (ADL) and the Instrumental Activity of Daily Living (IADL) questionnaires to assess self-care and independence status. Combining these factors with age, patients were classified as fit (80 years or ADL=5, IADL=6-7, Charlson score=1), or frail (unfit patients >80 years or ADL≤4, IADL ≤5 and Charlson score ≥2). Results A total of 152 patients were enrolled, including 51 patients in the VP, 51 in the VCP and 50 in the VMP group. Median age was 78 years and 30% of patients were older than 80 years. Overall, 53%, 47% and 32% of the patients had ISS stage III disease, 21%, 20% and 24% had an unfavourable FISH profile [at least one chromosomal abnormality: del17, or t(4;14), or t(14;16)], and 88%, 84% and 78% were defined as unfit/frail in the VP, VCP, and VMP groups, respectively. Patients received a median of 9 treatment cycles and 44% of patients started maintenance. All three induction regimens exhibited substantial activity, with an overall response rate (≥partial response) of 67% in the VP, 63% in the VCP, and 80% in the VMP group. After a median follow-up of 17 months, median progression-free survival (PFS) was 14, 16 and 16 months and 1-year overall survival (OS) estimates were 80%, 82% and 80% in the VP, VCP and VMP group, respectively. The incidence of Serious Adverse Events (SAEs) was 22%, 20% and 30% and the discontinuation rate due to AEs was 14%, 16% and 26% in the VP, VCP and VMP groups, respectively. The most common non hematologic grade ≥3 AEs were infections (12%), cardiovascular events (8%), and neurologic events (7%), including 5% of peripheral neuropathy. According to the geriatric classification, and specifically in the fit, unfit and frail patients, the overall response rate was 92%, 67% and 65%, the 1 year OS was 100%, 88% and 73%, rate of SAEs was 4%, 22%, 30% and discontinuation due to toxicity was 40%, 58% and 67%, respectively. Conclusions In this community-based population of elderly newly diagnosed MM patients low-dose intensity VP, VCP and VMP showed similar PFS and OS estimates, while SAEs and discontinuations were higher with VMP, suggesting that a melphalan-free regimen should be preferred in these patients. Geriatric assessment is mandatory, since both efficacy and toxicities are significantly different in fit, unfit and frail patients. Disclosures: Larocca: Janssen and Cilag: Honoraria. Cavallo:Janssen-Cilag: Honoraria. Caravita:Janssen-Cilag: Honoraria. Petrucci:Janssen-Cilag: Honoraria. Sonneveld:Janssen-Cilag: Honoraria; Celgene: Honoraria; Onyx: Honoraria; Janssen-Cilag: Research Funding; Millenium: Research Funding; Onyx: Research Funding; Celgene: Research Funding. Boccadoro:Janssen-Cilag: Membership on an entity’s Board of Directors or advisory committees; Janssen-Cilag: Research Funding; Janssen-Cilag: Consultancy. Palumbo:Amgen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen Pharmaceuticals: Consultancy, Honoraria; Millenium: Consultancy, Honoraria; Onyx: Consultancy, Honoraria.

Background The management of high dose chemotherapy followed by autologous or allogeneic hemopoietic stem cell transplantation requires an intravenous line for administrations of high-dose chemotherapy, blood and platelet transfusions, antibiotics and parenteral nutrition. In this context a safe central venous access is a basic tool for patients management. The aim of our phase II prospective study is to evaluate feasibility, safety and cost of the use of peripherally inserted central catheters (PICC) for the management of hemopoietic stem cell transplantation. Methods Inclusion criteria included inpatient who needed program of autologous and allogenic hematopoietic stem cell transplantation regardless the underlined hematological disease or white cells and platelets counts. All patients were submitted to a preliminary evaluation of arms vascular anatomy by ultrasonography. All implantation procedures has been done under ultrasound guide with radiographic control after insertion. The PICC cost analysis was performed on the cost of devices, insertion and daily management and compared with a historical cohort of patients with short term central venous catheter (CVC). The study was approved by institutional review board. All patients provided a written informed consent. Results From March 2007 to July 2013 76 consecutive PICC have been implanted in 74 patients for autologous or allogenic stem cell transplantations. There were 37 male and 37 females. Median age was 55 years, range 22-70. With regard to disease, 11 patients (15%) had Hodgkin Lymphoma, 13 (17.5%) non Hodgkin lymphoma, 9 (12%) acute lymphoblastic leukemia, 35 (47%) multiple myeloma, 4 (5.5%) acute myelogenous leukemia, and 2 (3%) other hematological disease. Fifty-five PICC (72%) have been used for single autologous stem cell transplantation, 10 (13%) for double autologous stem cell transplantation and 11 (15%) for allogenic transplantation. Catheter insertion was successful in all instances. PICC median life was 119 days (1-457) for a total of 10877 days of implanted PICC. At the time of this analysis 4 out of 76 PICC (5%) are still “in situ” and in use and 72 (95%) have been removed. Reason for removal was end of therapy in 58 instances (80.5%), accidental withdrawal in 8 (11%), patient death in 1 (1.5%) and catheter related complication in 5 (7%). Catheter related complications were the following: 2 occlusions, 3 suspected PICC-related sepsis. Only 1 episode of confirmed PICC-related septicemia (0.1/1000 days/PICC) was recorded and S.Aureus was isolated. There were only 2 cases (2.6%) of symptomatic PICC-related thrombotic complications which has requested conservative management. Twenty-five of 76 PICC (33%) were power PICC. No patients presented the need for a additional central venous access. Regarding the economic aspect, the actual daily cost of PICC was 1.98 €/day versus 3.40 €/day of the short term CVC (45% lower). Conclusions These data encourage the use of PICC in the autologous and allogenic stem cell transplantation because of insertion easiness, duration of life, cost and low rate complication. Disclosures: Off Label Use: Bendamustine.

Abstract 2971 Introduction: Bendamustine is a bifunctional alkylating agent approved for the treatment of several lymphoproliferative disorders. Studies have evidenced its efficacy in multiple myeloma (MM), but data so far available in this setting are scarce. We performed a retrospective analysis of Italian patients with relapsed/refractory MM, who had received bendamustine as salvage therapy within a national compassionate use program. Patients and methods: Seventy-eight patients (42 males, 36 females) were collected in 19 hematological centers. Mean age was 64.2 years (range 38–84). ISS was equally distributed, with about one third of patents being represented in single stages. Twenty-three of 43 analyzed patients had cytogenetic abnormalities, the most frequent being del13q (14 patients); t(4;14) and t(11;14) were observed in 4 and 2 patients, respectively, while t(6;14), del17p or complex karyotype occurred in single patients. The median number of prior lines of therapy was 4 (range 1–10). Ninety-seven percent of patients had previously received bortezomib, 94% IMIDs, 85% melphalan, 74% cyclophosphamide, 45% anthracyclines, 26% other drugs, 33% radiotherapy. Sixty percent of patients had undergone autologous and 4% allogeneic stem cell transplantation. The last treatment before bendamustine was a bortezomib-based regimen in 31%, an IMIDs-based regimen in 42%, a combined bortezomib/IMIDs-based regimen in 9%, while 18% of patients had received other therapies. Seventy-three percent of patients were resistant to last therapy received, while 27% had relapsed. Median duration of response to last treatment received before bendamustine was 9 months (range 2–46). Median Hb value was 10.1 g/dl (range 7.6–14.9), WBC count 2.700/μl (range 550–15.200), PLT count 130.000/μl (range 6.000–410.000). Serum creatinine, calcium, beta2-microglobulin and LDH levels were increased in 12 (15%), 4 (5%), and 44 (56%) patients, respectively, while albumin levels were decreased in 27 patients (35%). The median percentage of marrow plasma cells (as evaluated in 57 cases) was 60% (range 1–100). Seventy-six percent of patients had osteolytic bone involvement and 78% extramedullary localizations, with 13% showing secondary plasma cell leukemia and 7% documented amyloidosis or proteinuria. Finally, 45% of patients presented with at least one severe comorbidity, mainly cardio-vascular, liver or pulmonary dysfunction, and diabetes. Results: A total of 236 cycles was administered (median 3, range 1–9). In 47% of patients bendamustine was variously associated to bortezomib (23%), or IMIDs (21%), or to a combination of both (3%). In 80% of patients receiving bendamustine +/− steroids, a median dose of 90 mg/sqm for two consecutive days every 28 days was employed; the median dose was 80 mg/sqm when bendamustine was combined with bortezomib, 60 mg/sqm with IMIDs (total range: 40–140 mg/sqm). The remaining patients received single, monthly doses ranging from 60 to 150 mg/sqm. According to IMWG uniform response criteria, 21 out of 73 evaluable patients achieved a response after a median time of 3 months. In particular, there were 16 PR, 1 VGPR, 1 sCR, and 3 CR; overall response rate (ORR) was, therefore, 29%. Response rate was 10% (4/39) in bendamustine single agent +/− steroids, 38% (5/13) in bendamustine + bortezomib and 62% (10/16) in bendamustine + IMIDs subgroups, respectively. Responders had received a lower number of previous treatments than non responders (median 3 vs 4). Response rate was higher in relapsed (12/21, 57%) than in resistant patients (10/57, 17%). The time to best response ranged from 1 to 8 months. After a median follow-up of 8 months, median PFS duration was 6 months, with 13 out of 21 responding patients not yet progressed. Median OS of the entire cohort was 6.2 months (7 months in responders and 4 months in non responders, range 0–27). Grade 3–4 hematological and non-hematological toxicities occurred in 56% and 15% of patients, respectively, causing three interruptions of the treatment. Conclusions: Though with the clear limits due to the high heterogeneity of treatments applied and of population analyzed, our data indicate that bendamustine may be a therapeutic option in heavily pretreated MM, suggesting a possible non cross-resistance with other agents. Its earlier use with appropriate doses and combinations might further improve the results obtained in this study. Disclosures: Musto: Mundipharma: Honoraria. Off Label Use: Bendamustine in relapsed/refractory myeloma. Fragasso:Mundipharma: Honoraria. Baldini:Mundipharma: Honoraria. Storti:Mundipharma: Honoraria.

Abstract 1871 Introduction: In a randomized phase 3 study, the use of VTD as induction therapy prior to and consolidation therapy following double ASCT increased the rate of complete or near complete response (CR/nCR) and extended PFS in comparison with TD given as induction and post-ASCT consolidation therapy in 474 newly diagnosed MM patients (Cavo et al, Lancet 2010). However, the specific impact of VTD consolidation on improved clinical outcomes was not defined. Methods: To address this issue, we performed a per-protocol analysis of 321 patients who received the entire treatment program, including the two pre-planned cycles of consolidation therapy with either VTD (160 of 236 patients, 68%) or TD (161 of 238 patients, 68%). By study design, two 35-d cycles of VTD (V 1.3 mg/m2 on days 1, 8, 15, and 22; T 100 mg/d on days 1–35; D 40 mg on the days of and after each V administration) or TD (at the same doses as in VTD) were given as consolidation therapy to patients randomly assigned to each of the two respective induction regimens. Patient and disease characteristics at baseline were comparable in the two groups of patients. Results: The rates of CR and CR/nCR were significantly higher after consolidation therapy with VTD compared with TD (CR: 61% vs 47%; p=0.012; CR/nCR: 73% vs 61%; p=0.020). The impact of VTD consolidation on post-ASCT enhanced rates of CR and CR/nCR was confirmed by the McNemar test (CR: p=0.0009; CR/nCR: p=0.004) which conversely failed to demonstrate a significant increase in the frequencies of CR (p=0.052) and CR/nCR (p=0.110) with TD consolidation therapy. The absolute probability of upgrading from less than CR before consolidation to CR after consolidation was 31% with VTD and 17% with TD (Pearson chi-square test: p=0.03). Ninety six percent of patients who upgraded from less than CR to CR after VTD consolidation were in nCR (44%) or VGPR (52%) before starting consolidation therapy. A landmark analysis (with the landmark set as the start of consolidation therapy) was performed to compare time to progression (TTP), PFS, and overall survival (OS) between treatment groups. With a median follow-up of 30 months, the estimated 3-year probability of relapse or progression was 38% with VTD and 52% with TD (p=0.039 by Kaplan-Meier analysis) (HR: 0.68, 95% CI: 0.47–0.98, p=0.041). PFS was significantly longer for patients receiving VTD consolidation than for those treated with TD (3-year estimates: 62% vs 46%; p=0.025) (HR: 0.66, 95% CI: 0.46–0.95, p=0.027), a gain particularly evident for patients who failed to achieve CR after ASCT (3-year PFS estimates: 66% vs 43%; HR: 0.54, 95% CI: 0.32–0.91, p=0.022). Superior PFS with VTD vs TD consolidation was retained across poor prognosis subgroups, including patients with t(4;14) and/or del(17q) (HR: 0.44, p=0.004), del(13q) (HR: 0.44, p=0.002), β2-microglobulin >3.5 mg/L (HR: 0.57, p=0.025), lactate dehydrogenase >190 U/L (HR: 0.57, p=0.005), or ISS stage 2 and 3 (HR: 0.57, p=0.021). In a multivariate regression analysis, the most important and independent variables positively correlated with PFS were VTD consolidation therapy (p=0.002), double ASCT (p=0.001), low β2-microglobulin (p Conclusions: In comparison with TD, post-ASCT consolidation therapy with the triplet VTD regimen significantly increased the rates of CR and CR/nCR, and extended landmarked TTP and PFS. Superior PFS with VTD consolidation was maintained across poor prognosis subgroups, including those with advanced ISS stage and/or high-risk cytogenetic profiles. In a multivariate regression analysis VTD consolidation was confirmed to be an independent variable favorably affecting PFS. The superior activity seen with VTD versus TD as induction therapy before ASCT was retained despite the same triplet regimen being used as post-ASCT consolidation. Disclosures: Cavo: Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria; Genzyme: Honoraria. Off Label Use: Bortezomib and Thalidomide as post autotransplantation consolidation therapy in myeloma. Patriarca:Schering-Plough: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Roche: Honoraria. Petrucci:Celgene: Honoraria; Janssen: Honoraria. Di Raimondo:Janssen: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau. Palumbo:Merck: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria. Offidani:Celgene: Honoraria; Janssen: Honoraria. Baccarani:Bristol-Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Abstract 42 We prospectively compared thalidomide-dexamethasone (TD) with bortezomib-thalidomide-dexamethasone (VTD) as induction therapy before, and consolidation after, double autologous stem-cell transplantation (ASCT) in patients with newly diagnosed multiple myeloma (MM). Three 21-d cycles of either VTD (V, 1.3 mg/m2 twice-weekly; T, 200 mg/d through d 1 to 63; D, 320 mg/cycle) or TD were given as induction therapy. Consolidation therapy comprised two 35-d cycles of VTD (V, 1.3 mg/m2 once-weekly; T, 100 mg/d through d 1 to 70; D, 320 mg/cycle) or TD. 474 patients randomized to the VTD (n=236) or TD (n=238) arm were analyzed on an intention-to-treat basis for response rate, PFS and OS. Centrally reassessed CR/nCR rate was significantly higher in the VTD compared with the TD arm after all treatment phases, including induction therapy (30% vs 10%, p Disclosures: Cavo: Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Off Label Use: Use of bortezomib and thalidomide as induction therapy before, and consolidation after, autologous transplantation in newly diagnosed multiple myeloma. Baccarani:NOVARTIS: Honoraria; BRISTOL MYERS SQUIBB: Honoraria.

Complete response (CR) is an important objective of autologous stem-cell transplantation (ASCT) in multiple myeloma (MM). In comparison with conventional induction treatments, newer combinations of novel agents may effect increased rates of CR and near CR (nCR), a benefit potentially translating into even higher frequencies of CR/nCR after ASCT and improved clinical outcome. We designed a phase III study to detect an increase in CR+nCR rates from 10–15% with conventional Thalidomide-Dexamethasone (TD) to 20–30% with Velcade added to TD (VTD) in newly diagnosed MM. Both TD and VTD were given as three 21-day cycles in preparation for double ASCT. In the present analysis, CR+nCR rates by the two induction treatments were examined in relationship to baseline prognostic variables in 399 evaluable pts aged ≤65 years, of whom 199 randomized to VTD and 200 to TD. All analyses were intent to treat. In comparison with TD, VTD effected higher rates of CR+nCR (12% vs 33%, P190 U/L (33% vs 9%, P10 g/dL (P=0.01). In the VTD arm, a positive correlation was observed with del(13) (P=0.006) and t(4;14) (P=0.02). Response to first ASCT with melphalan 200 mg/m2 could be evaluated in 297 pts, of whom 145 randomized to VTD and 152 to TD. Randomization to VTD was closely associated with increased CR+nCR rates (54% vs 29% with TD, P

Wide experience have been reported on vertebroplasty in multiple myeloma patients. Much less experience is available for the treatment of osteolytic lesions in other critical sites. The aim of this report is to evaluate feasibility, safety and efficacy of transcutaneous femoroplasty, ileoplasty and sacroplasty in advanced multiple myeloma patients with severe osteolytic lesions. From November 2004 to May 2008 8 consecutive advanced myeloma patients (3 males and 5 females, median age 75 years, range 50–78) with pelvis and femora bone lytic lesions entered the study. They received percutaneous bone-cement injection with a solution of 8 to 22 polymethylmethacrylate (PMMA) into supracetabular (4 cases), sacral (2 cases) and femoral bone cavities (2 cases). Lesion approach was performed by 10 g bone biopsy needle under Computed Tomography (CT) and fluoroscopic guidance. In two cases, characterized by large extraosseous lesions, tumour termoablation with radiofrequency was done before PMMA injection. Procedures were performed under local anaesthesia, conscious sedation and antibiotic profilaxis with intravenous ceftriaxone in all patients. Immediate complications were studied with post procedure CT control. Efficacy was evaluated in term of pain relief and mobility recovery. Pain and mobility were assessed by visual analogue scale score (VAS) system (grading 0–10) and functional mobility score system (grading 1–4) respectively (according with “CT-guided percutaneous vertebroplasty: personal experience in the treatment of osteoporotic fractures and dorsolumbar metastases” Radiol med (2008) 113:114–133). Evaluation was performed before and at determined time points after the procedure (at 24 hours, one week, one month and every 3 months). Technical success was achieved in all patients. No complication was recorded. Before the osteoplasty pain assessment by VAS score showed a median value of 6 (range 4–8) and all patients were on analgesic therapy with oppioids and NSAIDs before the procedure. The VAS score decreased to median value 0 (range 0–1.5) within 24 hours after the procedure. The score remained unmodified during the rest of follow-up (median 17.5 months range 2–43). Seven patients were pain free (VAS score 0). Persistence of mild pain was documented in a single patient (score 1,5). Functional mobility score before osteoplasty was 4 in all patients (all were unable to autonomous deambulation). Score became 1 in all (autonomous mobility) within one week after procedure and remained stable during the follow up. Percutaneous osteoplasty is a feasible and safe procedure in patients affected by multiple myeloma with pelvis and femora osteolytic painful lesions. The methylmetacrylate injection is a minimally invasive procedure providing immediate improvement of quality of life. This intervention can contribute to treatment of the multiple myeloma in association with conventional therapy.

The availability of novel drugs such as immunomodulatory drugs, IMiDs, and proteasome inhibitors, PI, for the front line treatment of Multiple Myeloma (MM) has dramatically changed patients’ outcomes, significantly prolonging progression free survival (PFS) and translating into an extended overall survival (OS). Despite these impressive results, concerns have been raised regarding the possibility that IMiDs (lenalidomide and thalidomide) might increase the risk of developing SPMs, especially when associated with alkylating agents such as melphalan (MEL). It has long been known that the use of MEL can result in an increased incidence of SPMs, and this risk seems to be increased by the association with IMiDs. By the opposite, the use of PI in newly diagnosed MM (NDMM) patients (pts) was not associated with an increased risk of SPMs in a phase III study aimed at comparing BOR, MEL and prednisone (MP) vs MP.[1] Despite these results, the full impact of an upfront treatment containing both a PI and an IMiD in association with high dose MEL still has to be investigated. To address this issue, we have evaluated the incidence of SPMs in pts enrolled in the GIMEMA 26866138-MMY-3006 multicentre phase III study aimed at comparing BOR, thalidomide and dexamethasone (VTD) versus TD as induction before, and consolidation after, a double course of high dose MEL. The trial, conducted in Italy from 2006 to 2008, enrolled 480 transplant eligible NDMM, of which 474 received assigned treatment. Data on the incidence of SPMs are available for 299 pts (63%, 148 VTD and 151 TD). With a median follow up of 73 months, 25/299 pts (8%) developed a SPM: 7 (2%) SPMs were hematologic and 18 (6%) were non hematologic. The median time from trial entry to development of the SPM was 36 months (range 8.4-69.0). The number of pts developing a SPM was lower in VTD arm (5%) compared to TD arm (11%, p=0.068). Among pts developing a SPM, the proportion of solid malignancies was similar between treatment arms (75% and 71% in VTD and TD, respectively). Similarly, the percentages of hematologic SPMs was 25% for VTD pts and 29% for TD. On the overall population, the incidence rate (IR) of developing a SPM was 1% at 1 year and 9.9% at 6 years (yrs). This incidence was significantly lower for patients randomised to VTD compared with patients receiving TD (6% vs 13% at 6 yrs, p=0.037). When looking at the IR of solid tumours we noticed that only 5% of VTD-treated patients developed a solid SPM, as compared to 9.6% in TD; similarly, less hematologic SPMs were observed in the BOR arm (1% vs 4% at 6 yrs for VTD and TD, respectively). When the analysis was performed according to SPMs type, no statistical significance could be demonstrated. Our data compare favourably with data previously reported on the incidence of developing SPMs in NDMM treated with BOR frontline in association with MEL. With a follow up of 6 years, we were able to confirm that treatment with PI is associated with a low risk of developing SPM. Interestingly our data suggest that treatment with PI might decrease the risk of developing a SPM compared to IMiDs based treatment. Randomised trials with PI and IMiDs treatment should prospectively evaluate this issue. References 1. San Miguel, J.F., et al., Persistent overall survival benefit and no increased risk of second malignancies with bortezomib-melphalan-prednisone versus melphalan-prednisone in patients with previously untreated multiple myeloma. J Clin Oncol, 2013. 31(4): p. 448-55. Disclosures Musto: Janssen: Honoraria; Celgene: Honoraria. Cavo:Onyx: Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Millenium Pharm: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau.

Abstract 2811 Poster Board II-787 Introduction The recurrent translocation t(4;14)(p16;q32) occurs in less than 20% of patients with newly diagnosed Multiple Myeloma (MM) and is associated with a poor clinical outcome following either conventional or high-dose chemotherapy. Recently, it has been reported that patients carrying t(4;14) are prognostically heterogeneous and that the novel agents bortezomib and lenalidomide may overcome the poor prognosis related to this cytogenetic abnormality. In the present study, we analyzed the gene expression profile of patients who carried or not t(4;14) and were primarily treated with a bortezomib-based regimen. Patients and methods Two hundred thirty six patients with MM who received a combination of bortezomib-thalidomide-dexamethasone (VTD) as first-line therapy were evaluated for the presence at diagnosis of t(4;14). Of these, 41 patients (17.3%) were t(4;14) positive. On an intention-to-treat basis, the rate of CR and near CR (nCR) to VTD induction therapy among patients carrying t(4;14) was 41%, a value higher than the 29% observed among t(4;14) negative patients. In 218 patients for whom data on t(4;14), del(13q) and del(17p) were available, the differential gene expression of CD138+ enriched plasma cells was evaluated by means of expression microarray using the Affymetrix platform. The analysis was performed in t(4;14) negative patients and patients carrying t(4;14), either alone or combined with other abnormalities; t(4;14) negative patients included those with del(13q) alone and with any of these abnormalities. Results In 27 patients, t(4;14) was associated with either del(13q) (24 patients) or del(17p) (3 patients); the remaining 14 patients carried t(4;14) alone. The expression profiles of patients carrying either t(4;14) alone or t(4;14) combined with del(13q) significantly clustered apart when compared with those of cytogenetic negative patients. Similarly, the expression profiles of patients with del(13) alone clustered with those of cytogenetic negative patients. De-regulated expression of similar molecular pathways was demonstrated in patients carrying t(4;14) alone or combined with del(13q). Thus, the analysis of gene expression profiles according to response or no response to VTD was performed in two subgroups of patients, including those carrying t(4;14) alone or combined with del(13q) and those carrying either del(13q) alone or without cytogenetic abnormalities. By comparing the lists of genes differentially expressed (P '0.05) in patients who responded (e.g. those who achieved CR+nCR) and failed to respond (NR) to VTD according to the presence or absence of t(4;14), we found that the differential expression of 3719 genes characterized CR+nCR vs NR patients in the t(4;14) positive subgroup. At the opposite, the differential expression of 3182 genes characterized CR+nCR vs NR patients in the t(4;14) negative subgroup. 271 genes which were common to the two groups of genes were excluded from the list of genes found to be differentially expressed in t(4;14) positive patients who responded to VTD. Among these patients, we observed the de-regulated expression of genes involved in cell cycle progression (e.g. MDM2, CDK6 and SMAD2), Wnt signalling pathway (e.g. FZD7, WNT10A, MMP7,WNT2B, WNT6, WNT9A and DAAM2), and Hedgehog signalling pathway (GAS1, STK36 and GLI1). Overall, genes involved in cell cycle progression resulted over-expressed, thus suggesting a more aggressive phenotype of t(4;14) positive plasma cells of responder patients; nevertheless, the overall down-regulation of genes involved in Wnt and Hedgehog signalling pathways (known to be involved in the maintenance of a putative tumoral stem cell compartment) might mitigate this phenotype and predispose t(4;14) positive plasma cells to more favourably respond to VTD induction therapy. Supported by: BolognAIL, Fondazione Carisbo, Progetto di Ricerca Finalizzata (M.C). Disclosures: No relevant conflicts of interest to declare.