Charts of all myeloma patients observed at the Hematology Unit of Alessandria Hospital (Italy) in years 2005-2020 have been reviewed. Patients received bisphosphonates according to international guidelines, that recommended shorter and tailored duration of antiresorptive treatment (instead of indefinitively prolonged administration, as advised by older guidelines) after 2006-2007. Out of 210 patients receiving pamidronate or zoledronic acid (or sequences of bisphosphonates) and evaluated for oral health, 7 cases of Osteonecrosis of the Jaw (ONJ) were registered (7/210, 3.3%). However, 5 cases were detected among 41 cases starting antiresorptive treatment before 2006 without preventive visit, and only 2 cases were found among 169 cases receiving dental visit before treatment beginning (2/169, 1.2%). Our data seem confirm efficacy of measures directed to reduce the risk of ONJ in myeloma patients treated with less intensive schedules of bisphosphonates, according to latest recommendations..

Background. Expected survival of myeloma patients increased in recent decades, after introduction of new drugs and strategies. Median survival has been reported about 5 years, but it is very variable, according to age, comorbidities, disease stage, etc. Almost all myeloma patients receive bisphosphonates as antiresorptive treatment (with denosumab recently approved as an alternative) shortly after diagnosis, and 1%-15% of them develop Osteonecrosis of the Jaw (ONJ), within some years of treatment (or observation). Expected survival of myeloma patients can influence the choice of ONJ treatment among possible options. Methods. Charts of myeloma patients receiving bisphosphonates and observed at the Haematology Unit of Alessandria Hospital in years 2005-2020 have been reviewed. Kaplan-Meier actuarial survival was evaluated. Results. Median survival from the start of antiresorptive treatment of 244 patients was 5.36 years - with 79%, 69%, 60%, 52% of patients alive at 2, 3, 4, 5 years. At 7 and 10 years, 41.3% and 30.2% of patients were alive. ONJ occurred in 7 patients, after a median of 6.3 years (range 0.5-13.2) from the start of treatment. Mean survival from the ONJ diagnosis time of those 7 patients was 2.9 years (range 0.5-6.0). Conclusions: Expected survival of myeloma patients in a “real life” setting after the start of antiresorptive treatment is medially long in terms of years, with a large portion of patients exposed at risk of developing ONJ for more than 5 years. A surgical treatment of ONJ is warranted, being expected survival not so short to hamper jawbone surgery.

INTRODUCTION. The proteasome inhibitor (PI) Ixazomib, approved for the treatment of relapsed/refractory multiple myeloma (MM), represents an appealing option for the management of elderly patients, due to its oral administration and the lack of peripheral neuropathy. We previously presented preliminary results of the phase II EMN10-Unito study investigating Ixazomib in combination with dexamethasone (Id), Cyclophosphamide-dexamethasone (ICd), Thalidomide-dexamethasone (ITd) or Bendamustine-dexamethasone (IBd) as induction therapy followed by single-agent Ixazomib maintenance in transplant-ineligible newly diagnosed (ND) MM patients. Here we present updated results of the study with a longer follow-up. METHODS. Transplant-ineligible NDMM patients ≥65 years were enrolled. Treatment consisted of 9 28-day induction cycles of Ixazomib 4 mg on days 1,8,15 and dexamethasone 40 mg on days 1,8,15,22 or Id plus either Cyclophosphamide 300 mg/m2 orally on days 1,8,15 or Thalidomide 100 mg/day or Bendamustine 75 mg/m2 iv on days 1,8; followed by Ixazomib maintenance (4 mg on days 1,8,15) for up to 2 years. The primary endpoint was the selection of the most effective induction regimen considering a 2-year progression-free survival (PFS) ≥65% as satisfactory; secondary endpoints were very good partial response (VGPR), PFS2, overall survival (OS) and adverse events (AEs) during induction and maintenance. RESULTS. 171 patients (Id 41, ICd 59, ITd 60 and IBd 11) with a median age of 74 years were enrolled and started treatment. Two of the four investigational arms were prematurely closed due to low-enrollment (IBd arm, 11 patients enrolled) and high risk of inefficacy (Id, 41 patients enrolled). Median follow-up was 27 months. After the induction phase, ICd and ITd resulted in higher ≥ PR (75%-84% vs. 57%; p<0.05) and VGPR (46%-48% vs 24%; p<0.05) rates as compared to Id. The median PFS was 10.3 months with Id, 17.9 with ICd, 12.3 with ITd, and 13.8 with IBd, with a 2-year PFS probability of 31%, 39%, 27% and 40%, respectively. Median OS was not reached in either arm, without significant differences in the 2-year OS across arms (Id: 85%; ICd: 75%; ITd: 78%; IBd: 89%). Grade 3-4 non-hematological AEs were more frequent in the ITd arm (45%) as compared to the Id (17%), ICd (17%) and IBd (36%) arms, as well as the risk of treatment discontinuation due to AEs: ITd 17% vs Id 10%, ICd 12%, IBd 9%. Overall, 102 patients (60%) completed the induction phase and proceeded to ixazomib maintenance (median follow-up from start of maintenance: 18 months). The best response during maintenance was PR in 26%, VGPR in 29%, and complete response (CR) in 26% of patients; 18% of patients improved the response obtained during induction by at least one IMWG category. The median PFS from start of maintenance was 15 months. The median duration of maintenance was 12 months. All grades AEs occurred in 39% of patients during maintenance, while grade 3-4 AEs occurred in 10% of patients. Grade 1-2 peripheral neuropathy (PN) was reported in 15% of patients, without grade 3-4 events. Overall, 15% required at least one dose reduction of ixazomib and 12% discontinued ixazomib maintenance due to AEs. CONCLUSIONS. Safety and efficacy data suggest that Id combined with cyclophosphamide was the most promising induction strategy compared to the other investigated combinations. Continuous treatment with single-agent Ixazomib confirmed its efficacy and tolerability in elderly NDMM patients. Disclosures Mina: Amgen: Honoraria; Celgene: Honoraria; Takeda: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Larocca: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; Takeda: Membership on an entity's Board of Directors or advisory committees. Corradini:KiowaKirin: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Sanofi: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other; BMS: Other; Kite: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Daiichi Sankyo: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Incyte: Consultancy; Celgene: Consultancy, Honoraria, Other: Travel and accommodations paid by for; F. Hoffman-La Roche Ltd: Consultancy, Honoraria. Liberati:CELGENE: Honoraria; BIOPHARMA: Honoraria; ARCHIGEN: Honoraria; BEIGENE: Honoraria; BMS: Honoraria; AMGEN: Honoraria; FIBROGEN: Honoraria; INCYTE: Honoraria; VERASTEM: Honoraria, Research Funding; 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; JANSSEN: Honoraria. 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; Jannsen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Boccadoro:Sanofi: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; AbbVie: Honoraria; Mundipharma: Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees. Bringhen:Takeda: Consultancy; 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; Bristol-Myers Squibb: Honoraria; 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. OffLabel Disclosure: The presentation includes discussion of off-label use of a drug or drugs for the treatment of multiple myeloma (including ixazomib, dexamethasone, cyclophosphamide, thalidomide and bendamustine).

INTRODUCTION. Bortezomib- and/or lenalidomide-based combinations are standard initial approaches in transplant (ASCT) ineligible NDMM. Different studies confirmed the advantages of continuous treatment. Despite the benefits of bortezomib maintenance, the parenteral administration and the risk of peripheral neuropathy (PN) limit its long-term use. The oral proteasome inhibitor (PI) Ixazomib plus Lenalidomide-dexamethasone was effective and well tolerated at diagnosis or relapse. The need for a convenient and well tolerated PI-based frontline therapy for an extended duration with minimal cumulative toxicity remains an unmet need for the elderly. In this prospective, multicenter, phase II randomized study, we assessed Ixazomib in combination with dexamethasone, Cyclophosphamide, Thalidomide or Bendamustine, followed by Ixazomib maintenance in ASCT-ineligible NDMM. METHODS. NDMM patients (pts) ≥65 years old or younger ASCT-ineligible could be enrolled. Treatment consisted of nine 28-day induction cycles of Ixazomib 4 mg on days 1,8,15 and dexamethasone 40 mg on days 1,8,15,22 (Id) or combined with Cyclophosphamide 300 mg/m2 orally on days 1,8,15 (ICd) or plus Thalidomide 100 mg/day (ITd) or plus Bendamustine 75 mg/m2 iv on days 1,8 (IBd); followed by maintenance with Ixazomib 4 mg on days 1,8,15 until progression. Because the study included the novel drug Ixazomib, dual stopping rules combining efficacy (at least very good partial response [VGPR] rate), and safety (predefined toxicity possibly related to Ixazomib) were planned and analyzed in a cohort of 5 patients in each arm during the first 4 cycles. Here we report the results of the cohort analysis during the first 4 cycles and the efficacy and safety analysis during induction treatment. RESULTS. In February 2017, the protocol was amended due to a low enrolment and the IBd arm, the only one including an iv drug, was closed. After closing this arm, all the other all oral arms continued the enrolment. Overall, 175 pts were enrolled (Id 42, ICd 61, ITd 61, and IBd 11 pts) and 171 pts started treatment. Median age was 74 years, 20% of pts had high risk cytogenetics, 44% were fit, 30% intermediate and 26% frail, according to the IMWG frailty score. Median follow-up was 13.2 months (IQR 8.9-20.7). During the first 4 cycles, at least VGPR rate was 24% with Id, 33% with ICd, 31% with ITd and 18% with IBd. In March 2018, after the analysis of the 4th cohort, the Id arm was closed due to high risk of inefficacy. Overall response rate (ORR) during induction was 73%, VGPR was 39%. ≥VGPR rates were 24% in Id, 48% in ICd, 43% in ITd and 27% in IBd. Median time to first response was 2.4 and to the best response 4 months. Responses were comparable according to cytogenetics: in high risk pts, ORR was 77%, ≥VGPR 46% and ≥nCR 17% as compared to 71%, 36% and 18% in standard risk pts (p=0.53, p=0.33 and p=1, respectively). Response rates were also comparable according to frailty status: in frail pts, ORR was 73%, ≥VGPR 36% and ≥nCR 11% as compared to 75%, 40% and 17% in intermediate and 70%, 40% and 22% in fit pts (p=0.78, p=0.90 and p=0.32, respectively). Median number of induction cycles was 9 (IQR 5-9); 93 (53%) pts completed induction treatment and 14 (8%) pts are still on induction treatment. During the first 4 cycles, hematologic toxicity was limited, and non-hematologic toxicity manageable. The most frequent G3-4 adverse event (AE) was rash in ITd arm (11%); discontinuation rate due to toxicity was 6%. During induction, the rate of at least 1 hematologic G≥3 AE was 11% and at least 1 non-hematologic G≥3 AE was 44%. The most frequent G≥3 AEs were neutropenia (8%), gastrointestinal (9%), infections (11%), neurologic (11%) and dermatologic (6%). G3-4 thrombocytopenia (3%) and PN (5%) were limited. Ixazomib dose reduction due to AEs was required in 15% of pts. The rate of non-hematologic AEs was slightly higher in ITd arm (37% in Id, 37% in ICd, 53% in ITd, 55% in IBd). Early death rate (<60 days from start therapy) was 1%. CONCLUSIONS. ITd and ICd are convenient all-oral induction regimens for ASCT-ineligible NDMM, confirming an improved efficacy of a triplet vs a doublet combination, also in intermediate and frail patients. Id showed lower efficacy, thus suggesting a possible effect of the dose of Ixazomib or the absence of a third drug. Treatment was feasible, with limited toxicity and low discontinuation rate due to AEs, although ITd induced a slightly higher toxicity, but mainly attributable to Thalidomide. Disclosures Larocca: Amgen: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: 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; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Corradini:Servier: Honoraria; Amgen: Honoraria; Gilead: Honoraria, Other: Travel Costs; Takeda: Honoraria, Other: Travel Costs; BMS: Other: Travel Costs; Kite: Honoraria; Novartis: Honoraria, Other: Travel Costs; Roche: Honoraria; Sanofi: Honoraria; KiowaKirin: Honoraria; Jazz Pharmaceutics: Honoraria; Daiichi Sankyo: Honoraria; Janssen: Honoraria, Other: Travel Costs; AbbVie: Consultancy, Honoraria, Other: Travel Costs; Celgene: Honoraria, Other: Travel Costs. Mina:Amgen: Honoraria; Celgene: Honoraria; Janssen: Honoraria. Liberati:Bristol-Myers Squibb: Honoraria; Roche: Other: Clinical trial support; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Clinical trial support; Janssen: Honoraria; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Clinical trial support; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; Celgene: Honoraria, Other: Clinical trial support; Novartis: Other: Clinical trial support. Petrucci:Takeda: 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; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: 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; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees. Patriarca:Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Zambello:Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Belotti:Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Cellini:Amgen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; Janssen: Honoraria. Galli:Takeda: Honoraria; Leadiant (Sigma-Tau): Honoraria; Janssen: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria. 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. De Sabbata:Janssen: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Ballanti:Bristol-Myers Squibb: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Amgen: Honoraria. Offidani: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; Amgen: 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; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Boccadoro:Janssen: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; AbbVie: Honoraria; Mundipharma: Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. Bringhen:Celgene Corporation: 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; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Bristol-Myers Squibb: Honoraria. OffLabel Disclosure: The presentation includes discussion of off-label use of a drug or drugs for the treatment of multiple myeloma.

INTRODUCTION:Early toxic death (≤60 days of diagnosis) in elderly multiple myeloma (MM) patients is attributable to active disease, age and co-morbidities. Rate of early toxic deaths is 10% with conventional chemotherapy mainly due to infection and renal failure. Novel agents have improved MM outcome at the expense of newer toxicity.METHODS:We analyzed 1146 individual patient data to assess toxic deaths during induction treatment with first-generation novel agents thalidomide, lenalidomide, bortezomib.RESULTS:During first-line therapy, 119/1146 patients (10%) died for any cause, and 47/1146 (4%) due to toxicity, including 12/1146 (1%) early deaths. The 24-month cumulative incidence was 4.1% without any difference between bortezomib (18/503 patients, 4%) and lenalidomide (29/643patients, 5%; p = 0.31). Toxic deaths occurred in 34/1039 (3%) patients <80 years and 13/107 (12%) patients ≥80 years. Causes were cardiac events (28%), infections (26%) and vascular complications (15%). In a multivariate analysis, older age and unfavorable ISS stage increased the risk of death.CONCLUSION:First-generation novel agents significantly reduced toxic deaths compared to conventional chemotherapy. One third of deaths during first-line therapy were due to cumulative drug-related toxicities, thus supportive approaches and prevention strategies should be optimized. The higher mortality rate for toxicity in octogenarians confirms the need for a careful frailty assessment.

The recent randomized trial, published by Raje et al., on Lancet Oncology is potentially practice changing. It proposes that denosumab is a valid alternative to zoledronic acid in the treatment of myeloma patients. However, several points need further data and more details, such as information on incidence, diagnosis, and follow-up of osteonecrosis of the jaw (ONJ) cases, observed among treated patients. Adopted definition to adjudicate ONJ cases, type of registration of potential ONJ cases, length of observation are possible causes of potential underestimation of ONJ incidence in their study. Future updated evaluations with longer follow-up, and including actuarial estimation, are required for final judgment on ONJ risk in myeloma patients receiving denosumab, and comparison with ONJ risk by zoledronic acid.

Background: Proteasome inhibitor (PI)-based induction and consolidation proved to be effective in newly diagnosed multiple myeloma (NDMM) patients (pts) eligible for melphalan 200 mg/m2-autologous stem cell transplant (MEL200-ASCT). High response rates have been reported with the second-generation PI Carfilzomib in combination with Lenalidomide-dexamethasone (KRd) or Cyclophosphamide-dexamethasone (KCd). Aims: The primary aim was to evaluate the efficacy and safety of KRd induction-ASCT-KRd consolidation (KRd-ASCT-KRd) vs 12 cycles of KRd (KRd12) vs KCd induction-ASCT-KCd consolidation (KCd-ASCT-KCd). Methods: NDMM pts ≤65 years were randomized (1:1:1; stratification ISS and age) to: KRd-ASCT-KRd: 4 28-day cycles with KRd induction (Carfilzomib 20/36 mg/m2 IV days 1,2,8,9,15,16; Lenalidomide 25 mg days 1-21; dexamethasone 20 mg days 1,2,8,9,15,16) followed by MEL200-ASCT and 4 KRd consolidation cycles; KRd12: 12 KRd cycles; KCd-ASCT-KCd: 4 28-day induction cycles with KCd (Carfilzomib 20/36 mg/m2 IV days 1,2,8,9,15,16; Cyclophosphamide 300 mg/m2 days 1,8,15; dexamethasone 20 mg days 1,2,8,9,15,16) followed by MEL200-ASCT and 4 KCd consolidation cycles. Thereafter, pts were randomized to maintenance with Lenalidomide alone or plus Carfilzomib. Centralized minimal residual disease (MRD) evaluation - 8-color second generation flow cytometry, sensitivity 10-5 - was performed in pts achieving ≥very good partial response (VGPR). Endpoints were pre-maintenance stringent complete response (sCR) and MRD negativity in intention-to-treat (ITT) analysis. Data cut-off was May 30, 2018. Results: 474 NDMM pts were randomized (KRd-ASCT-KRd, n=158; KRd12, n=157; KCd-ASCT-KCd, n=159) and analyzed. Pts characteristics were well balanced. Median follow-up was 20 months. Depth of response improved during treatment (Figure). By ITT analysis, rates of pre-maintenance sCR was similar between KRd-ASCT-KRd (41%) and KRd12 (42%), and significantly higher than with KCd-ASCT-KCd (30%; P value KRd-ASCT-KRd vs KCd-ASCT-KCd=0.047; P value KRd12 vs KCd-ASCT-KCd=0.028). Similarly, rate of ≥CR was 49% with KRd-ASCT-KRd, 52% with KRd12 and 38% with KCd-ASCT-KCd (P value KRd-ASCT-KRd vs KCd-ASCT-KCd=0.041; P value KRd12 vs KCd-ASCT-KCd=0.014) and rate of ≥CR+unconfirmed CR (missing immunofixation confirmation) raised to 60% vs 63% vs 46% in the 3 groups, respectively; rate of ≥VGPR was 88% with KRd-ASCT-KRd, 86% with KRd12 and 74% with KCd-ASCT-KCd (P value KRd-ASCT-KRd vs KCd-ASCT-KCd=0.002; P value KRd12 vs KCd-ASCT-KCd=0.008). In multivariate analysis, the main factor affecting probability of achieving ≥VGPR, ≥CR or sCR was treatment with KRd-ASCT-KRd or KRd12 vs KCd, with no significant impact of ISS Stage or FISH abnormalities. In ITT analysis (MRD missing [31/395 VGPR pts, 8%] and <VGPR were considered as MRD positive), MRD negativity was again similar with KRd-ASCT-KRd (58%) and KRd12 (54%) and significantly higher than with KCd-ASCT-KCd (41%; P value KRd-ASCT-KRd vs KCd-ASCT-KCd=0.004; P value KRd12 vs KCd-ASCT-KCd=0.023); 82% vs 78% vs 88% of pts in the 3 groups, respectively, could maintain extended MRD negative status with 2 MRD negative results obtained apart ≥6 months (either pre-ASCT and post consolidation or post consolidation and during maintenance). During treatment (excluding ASCT) the most frequent grade 3-4 AEs were neutropenia (KRd-ASCT-KRd 20%, KRd12 10%, KCd-ASCT-KCd 16%), thrombocytopenia (KRd-ASCT-KRd 15%, KRd12 8%, KCd-ASCT-KCd 13%) and infections (KRd-ASCT-KRd 14%, KRd12 12%, KCd-ASCT-KCd 13%). Grade 3-4 dermatologic AEs (KRd-ASCT-KRd, 5% with KRd12 12%, KCd-ASCT-KCd 1%), increase in liver enzymes (KRd-ASCT-KRd 9%, KRd12 10%, KCd-ASCT-KCd 1%) and hypertension (KRd-ASCT-KRd 3%, KRd12 8%, KCd-ASCT-KCd 3%) were more frequent with KRd12. Rates of grade 3-4 cardiac AEs (KRd-ASCT-KRd 3%, KRd12 2%, KCd-ASCT-KCd 4%) and thrombosis (KRd-ASCT-KRd 1%, KRd12 2%, KCd-ASCT-KCd 2%) were below 5% in all arms. Discontinuation for AEs was similar in the 3 arms (KRd-ASCT-KRd 6%, KRd12 8%, KCd-ASCT-KCd 7%). Conclusions: Rates of MRD negativity, sCR, ≥CR, ≥VGPR were significantly higher with KRd-ASCT-KRd and KRd12 vs KCd. At present, no differences in MRD and overall best response (sCR, ≥CR, ≥VGPR) were noticed between KRd-ASCT-KRd and KRd12; longer follow-up is needed to evaluate survival. Treatment was well tolerated. Updated data will be presented at the meeting. Figure. Figure. Gay: Roche: Other: Advisory Board; Seattle Genetics: Other: Advisory Board; Bristol-Myers Squibb: Honoraria; Janssen: Honoraria; Celgene: Honoraria, Other: Advisory Board; Amgen: Honoraria; Takeda: Honoraria, Other: Advisory Board. Galli:Sigma-Tau: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria. Belotti:Celgene: Other: Advisory Board; Amgen: Other: Advisory Board. Zamagni:BMS: 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; 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. Angelucci:Novartis: Honoraria, Other: Chair Steering Committee TELESTO protocol in MDS; Celgene: Honoraria, Other: Chair DMC proptocol BELIEVE 1 and BELIVE 2 in Thalassemia; Vertex Pharmaceuticals Incorporated (MA) and CRISPR Therapeutics AG (CH): Other: Chair DMC CRISPR CAS9 in Hemoglobinopathies; Jazz Pharmaceuticals Italy: Other: Local (national) advisory board on AML; Roche Italia: Other: Local (national) advisory board on biosimilars. Annibali:Celgene; Takeda; Amgen, Janssen Cilag: Honoraria. Offidani:Amgen: Honoraria, Other: Advisory Board; Takeda: Honoraria, Other: Advisory Board; Janssen: Honoraria, Other: Advisory Board; Celgene: Honoraria, Other: Advisory Board; Bristol-Myers Squibb: Honoraria, Other: Advisory Board. Palumbo:Takeda: Employment. Musto:Amgen: Honoraria; BMS: Honoraria; Takeda: Honoraria; Janssen: Honoraria; Celgene: Honoraria. Cavo: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; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; 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; 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; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Boccadoro:Bristol-Myers Squibb: Honoraria, Research Funding; Mundipharma: Research Funding; Sanofi: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; AbbVie: Honoraria.

INTRODUCTION: Elderly patients with newly diagnosed multiple myeloma (NDMM) are highly heterogeneous and their outcome is influenced by many factors: beside age, also comorbidities, general physical fitness, and cognitive function play a crucial role. The IMWG frailty score combines age, functional status, and comorbidities, and it identifies fit, intermediate-fit and frail patients, with different risk of toxicity, treatment discontinuation, and mortality (Palumbo A et al. Blood 2015). Until now, evidence-based tailored treatments according to patients' frailty are still lacking. Therefore, this phase III study investigated the efficacy and feasibility of dose/schedule-adjusted lenalidomide-dexamethasone therapy followed by lenalidomide maintenance (Rd-R) versus continuous lenalidomide-dexamethasone (Rd) in elderly, intermediate-fit NDMM patients.

Background :Proteasome inhibitor-based induction is currently considered standard of care in newly diagnosed multiple myeloma (NDMM) patients (pts) eligible for high-dose therapy and transplant (MEL200-ASCT). The second-generation proteasome inhibitor Carfilzomib proved to be effective, either in combination with Lenalidomide-Dexamethasone (KRd) or with Cyclophosphamide-Dexamethasone (KCd) (Jakubowiak, Blood 2012; Bringhen, Blood 2014). Aim : The primary objective of this analysis was to compare the efficacy of KRd vs KCd induction in pts eligible for transplantation. The secondary aim was to evaluate the efficacy of KRd vs KCd in different subgroups of pts according to prognostic features, focusing specifically on high-risk pts. Methods : NDMM pts Results : At data cut-off, 309 pts were randomized to KRd vs 154 pts to KCd. Pts characteristics were well balanced: median age was 57 years in both groups, ISS Stage II/III was reported in 48% of pts in KRd and KCd, high-risk chromosomal abnormalities (del(17p) or t(4;14) or t(14;16)) were present in 30% of KRd pts and 34% of KCd pts. After 4 cycles of induction, the rate of ≥partial response (PR) was 96% with KRd vs 92% with KCd; ≥VGPR was 74% with KRd vs 61% with KCd (P=0.01), with 31% vs 20% of pts (P=0.03) achieving ≥near complete response (nCR) and 15% vs 6% (P=0.02) ≥complete response (CR) respectively in KRd and KCd; stable disease was reported in 3% of KRd vs 7% of KCd pts, with only 1% of pts in each group being primary refractory. Subgroup analysis of response rates showed the superiority of KRd vs KCd in terms of ≥VGPR in all the subgroups analyzed (Figure 1 - Panel A). Of interest, the rates of ≥VGPR, ≥nCR and ≥CR were comparable in high- and standard-risk pts treated with KRd (Figure 1 - Panel B). Six-month MRD results were available in a subset of pts (122 KRd and 53 KCd pts): MRD was negative in 66/122 (54%) KRd pts vs 16/53 (30%) KCd pts (P=0.005). Regarding safety, the rate of ≥1 grade 3-4 hematologic adverse events (AEs) was comparable between KRd and KCd (7% vs 6%), the most frequent being neutropenia (KRd 6% vs KCd 5%). The rate of ≥1 Grade 3-4 non-hematologic AEs was higher with KRd (32% vs 16%, P Conclusions :KRd induction showed a higher efficacy of KCd in terms of ≥VGPR, ≥nCR and ≥CR rates, with an acceptable safety profile. The superiority of KRd vs KCd was confirmed in high- and standard-risk groups, with response rates in high-risk pts treated with KRd comparable to the ones in standard-risk, suggesting the high efficacy of this regimen even in this subset of pts representing a current unmet medical need. Updated data will be presented at the meeting. Disclosures Gay: Takeda: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Seattle Genetics: Membership on an entity9s Board of Directors or advisory committees; Roche: Membership on an entity9s Board of Directors or advisory committees; Mundipharma: Membership on an entity9s Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Amgen: Honoraria; Celgene: Honoraria; Bristol Myers Squibb: Honoraria. Offidani: celgene: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity9s Board of Directors or advisory committees. Oliva: Takeda: Honoraria; Celgene: Honoraria. Mancuso: Bristol Myers Squibb: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Celgene: Honoraria. Palumbo: Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Employment, Equity Ownership, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Genmab A/S: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Binding Site: Research Funding. Musto: Janssen: Honoraria; Celgene: Honoraria. Boccadoro: Amgen: Honoraria, Research Funding; Mundipharma: Research Funding; AbbVie: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding.

Curable hematologic tumors but not multiple myeloma (MM) benefit from risk-adapted therapy. Intensified treatments such as autologous stem cell transplantation (ASCT) and continuous therapy (CT) improve patients (pts) outcome. A better evaluation of pts prognosis based on the revised international staging system (R-ISS) is now available. We evaluated the impact of ASCT and CT in pts with different baseline prognosis.

BACKGROUND. The genomic heterogeneity that characterizes all Multiple Myeloma (MM) patients (pts) is the consequence of an evolutionary process operating during the pre-neoplastic phase of the disease. Whatever genomic event occurs, it accounts for the de-regulated expression of either one of the cyclin D or other key regulators of cell cycle progression. Therefore, a deficient regulation of cell cycle control is considered as a hallmark of MM. Moreover, among the MM genomic heterogeneity, several lesions are recurrent and their presence significantly impacts the prognosis.

Abstract Disclosures No relevant conflicts of interest to declare.

Bisphosphonates (BPs) are administered to Multiple Myeloma (MM) patients with bone lytic lesion. Osteonecrosis of the Jaw (ONJ) is a complication reported since 2003 in patients treated with intravenous (IV) BPs such as zoledronic acid and pamidronate, with 6%–26.3% frequency in early literature series, before some preventive measures were recommended. We evaluated the occurrence of ONJ with and without dental preventive measures in MM patients treated with BPs in our centre between 1996 and 2015. Since 2005, MM patients (already under treatment or before treatment) underwent a baseline mouth assessment (dental visit, Rx orthopantomography, and eventual tooth avulsion or dental care if necessary) and were followed by a multidisciplinary team. We reviewed the charts of 119 MM patients receiving IV BPs, classified into 3 groups: (a) “historic group” (21 patients who had started BP treatment in years before the awareness of ONJ); (b) “screening group” (20 patients starting BPs without baseline evaluation); and (c) “prevention group” (78 patients starting therapy only after baseline preventive assessment and eventual dental care measures). ONJ was observed in 3/21 patients (14.2%) from group a, in 2/20 patients (10%) from group b, and in no patients from group c (0%). Notably, the median number of IV BP administrations decreased after 2005. Our data confirmed a meaningful reduction of ONJ risk in MM patients treated with BPs if preventive measures are applied. Both implementation of prevention measures and reduction of cumulative doses of IV BPs could have contributed to a decreased incidence of ONJ.

Introduction. The fludarabine, cyclophosphamide, rituximab (FCR) regimen is associated with high complete response (CR) rates and a negative residual disease status in a significant proportion of cases and is considered the optimal front-line treatment for fit patients with chronic lymphocytic leukemia (CLL). In addition, long-term follow-up of patients treated with FCR at the MD Anderson Cancer Center, in the multicenter German CLL8 study and at Italian institutions indicate that a sizable fraction of patients characterized by a favorable biologic profile remains free from progression in excess of 10 years. FC combined with ofatumumab (FC-O), a human monoclonal antibody which targets an epitope of the CD20 molecule, has also been associated with a high CR rate. The aim of this study was to evaluate whether a double dose of ofatumumab (O2) combined with FC could improve the CR rate in young (≤65 yrs) and fit patients with CLL.

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...

Background: Expression of p190 BCR-ABL mRNA is generally considered to be confined to patients with acute lymphoid or more rarely myeloid leukemias, whereas p210 BCR-ABL mRNA is the hallmark of CML. In reality it is not uncommon the presence of p190 m-RNA in p210 CML in chronic phase, due to alternative or missplicing1. Its presence seems to have no impact on prognosis in the pre-TKI era, although it may be expression of genomic instability.

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.

Background High-dose chemotherapy (HDT) with autologous stem cell transplant improves outcome of multiple myeloma (MM) patients in comparison to conventional chemotherapy. The incorporation of new drugs into induction, consolidation and maintenance therapy is changing the treatment paradigm and is questioning the role of HDT in newly diagnosed MM (NDMM) patients <65 years. Previous finding have been presented (Boccadoro, ASCO 2013) and this analysis provides a longer follow-up. Aims To compare in a prospective randomized trial melphalan-prednisone-lenalidomide (MPR) with tandem melphalan (200 mg/m2) (MEL200) both followed by maintenance with lenalidomide or no maintenance in NDMM patients. Methods A 2x2 factorial randomized trial was designed. The induction treatment consisted of four 28-day cycles of lenalidomide (25 mg d 1-21) and low-dose dexamethasone (40 mg d 1,8,15,22) (Rd). As consolidation, patients were randomized to MPR (N=202) [six 28-day cycles of melphalan (0.18 mg/k g d 1-4), prednisone (2 mg/kg d 1-4) and lenalidomide (10 mg d 1-21)] or MEL200 (N=200)[tandem melphalan 200 mg/m2 with stem-cell support]. Patients were further randomized, within each group, to receive lenalidomide maintenance (10 mg, days 1-21, N=198) or no maintenance (N=204). Primary study endpoint was progression free survival (PFS). The secondary study endpoints included response rates, safety and overall survival (OS). Data were analyzed in the intent-to-treat (ITT) population. Results From November 2007 to July 2009, 402 patients with NDMM <65 years of age were enrolled. All patients were stratified according to International Staging System (ISS) and age. Patient characteristics were well balanced in all groups. In the MPR group, the Very Good Partial Response (VGPR) rate was 50% with 13% of Complete Response (CR) while the VGPR rate was 52% including 19% of CR in the MEL200 group. In the MPR group the CR rate improved from 13% after consolidation to 17% after maintenance. In the MEL200 group the CR rate improved from 19% after consolidation to 25% after maintenance. After a median follow-up of 48 months, the median PFS was 24.2 months in MPR group and 38.6 months in MEL200 group ( P< 0.0001). A multivariate analysis confirms the PFS benefit associated with MEL200 across all subgroups of patients defined by stratification factors and baseline characteristics. The 5-year OS rate was similar between MPR (62%) and MEL200 (71%; P= 0.27). In a landmark analysis, lenalidomide maintenance significantly extended PFS from the start of maintenance (median 42,7 months) compared with no maintenance (median 17.5 months; P<.0001). The 4-year OS rate from the start of maintenance was higher in patients who received lenalidomide maintenance (80%) compared with patients who did not (62%; P= 0,01). No significant interaction was detected between MPR/MEL200 (P=0.704) and maintenance/observation (P=0.984) effects. During consolidation, the incidence of grade 3-4 adverse events (AEs) between MPR and MEL200 were as follow: neutropenia (50% vs. 90%), thrombocytopenia (8% vs. 89%), infections (1% vs. 15%) and gastrointestinal (0% vs. 18%), with complications being higher with MEL200. During the maintenance phase, grade 3-4 hematologic AEs were reported in 17% of patients receiving lenalidomide (16% neutropenia). For individual group comparisons during maintenance, grade 3-4 hematologic AEs were observed in 20% of patients receiving MPR plus lenalidomide maintenance compared with 15% receiving MEL200 plus lenalidomide maintenance. Second primary malignancies were observed in 11 patients (3%), and were mainly solid tumors. Four solid tumors were observed in the MEL200 group and one in the MPR group in the maintenance arm, while three solid tumors were observed in the MEL200 group and three in the MPR group in no maintenance arm. Conclusion The administration of MPR was significantly inferior to MEL200 in terms of PFS. Toxicities were significantly higher in MEL200 group, but manageable. OS is similar between MPR and MEL200. Lenalidomide maintenance significantly reduced the risk of progression and of death independently from the previous treatment. Disclosures: Gay: Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Cavallo:Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Caravita:Celgene: Honoraria, Research Funding. Boccadoro:Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Palumbo:Amgen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen Pharmaceuticals: Consultancy, Honoraria; Millenium: Consultancy, Honoraria; Onyx: Consultancy, Honoraria.

Monitoring of Epstein–Barr virus (EBV) load and pre‐emptive rituximab is an appropriate approach to prevent post‐transplant lymphoproliferative disease (PTLD) occurring after hematopoietic stem cell transplantation (HSCT). This pre‐emptive approach, based on EBV‐DNA monitoring through a quantitative polymerase chain reaction, was applied to 101 consecutive patients who underwent allo HSCT at our Institute (median age 50). A single infusion of rituximab was administered to 11 of 16 patients who were at high risk for progression to PTLD, defined as a DNA value >10 000 copies/mL. All patients cleared EBV DNAemia, without any recurrences. Main factors significantly associated with high risk for PTLD were as follows: (i) unrelated vs. sibling (26% vs. 7%; p = 0.011); (ii) T‐cell depletion (29% vs. 6%; p = 0.001); (iii) graft versus host disease (GVHD; 30% vs. 7%; p = 0.002); and (iv) cytomegalovirus (CMV) reactivation (29% vs. 4%; p = 0.001). Multivariate analysis showed that CMV reactivation was the only independent variable associated with EBV reactivation. We conclude that: (i) a single infusion of rituximab is able to prevent the risk of progression into EBV‐related PTLD; and (ii) CMV reactivation is strongly associated with EBV reactivation; therefore, an intensive EBV monitoring strategy could be advisable only in case of CMV reactivation.