ALBERT

Description: Abstract 3562 Aim of the present study was to evaluate the clinical outcome of a large series of younger patients with symptomatic multiple myeloma (MM) who were enrolled in two subsequent clinical trials of thalidomide-dexamethasone (thal-dex) incorporated into double autologous stem-cell transplantation (ASCT) to support high-dose melphalan (200 mg/m2). In both studies, thal (100 mg/day for the first 14 days and then 200 mg/day) and pulsed dex (between 480 and 160 mg per cycle), were administered from the onset until the second ASCT. The analysis was performed on an intention-to-treat basis on a total of 593 patients who were followed for a median of 36 months. The best VGPR and CR rates were 69% and 35%, respectively. The median duration of CR was 66 months. Median TTP and PFS were 53 and 44 months, respectively. The 5-year projected rates of TTP and PFS were 46% and 38%, respectively, while the corresponding value for OS was 67%. More than 80% of the patients were screened at diagnosis for the presence of cytogenetic abnormalities by FISH analysis. Forty-five percent of patients had del(13q), while t(4;14) and del(17p) were found in 16 % and 7 % of patients, respectively. The presence of del(17p) and/or t(4;14) was associated with a significantly shorter 5-year projected TTP, PFS and OS in comparison with the absence of these abnormalities, indifferently from the presence or absence of del(13q) (TTP: 30% vs 53%, respectively P=0.0000; PFS: 28% vs 45%, respectively, P=0.0000; OS: 53% vs 69%, respectively, P=0.0000). OS and PFS curves of patients carrying del(13q) alone were almost superimposable to those of patients without cytogenetic abnormalities, while TTP was significantly shorter for patients with del(13q) alone (5-year projected rates: 40% vs 53%, respectively, P=0.04). Patients carrying del(17p) in the absence of t(4;14) had similar 5-year projected TTP and PFS as compared with t(4;14) positive but del(17p) negative patients. However, OS was significantly shorter for the subgroup with del(17p) and absence of t(4;14) in comparison with that of patients carrying t(4;14) without del(17p) (5 year projected rates: 18% vs 70%, respectively, P=0.03). In a multivariate analysis, presence of del(17p) and high beta2-m at baseline were the most important variables adversely influencing TTP (HR: 2.3, P=0.001 and HR: 1.8, P=0.002, respectively), PFS (HR: 2.0, P=0.001 and HR: 1.9, P=0.001, respectively), and OS (HR: 3.9, P=0.000 and HR: 2.0, P=0.005, respectively). Additional variables predicting for shorter TTP and PFS were the presence of t(4;14) (HR: 1.8, P=0.004) and of del(13q) (HR: 1.6, P= 0.009). Also the quality of best response to the overall treatment program influenced clinical outcomes. In particular, patients achieving CR had a significantly longer PFS and OS than those achieving a VGPR (PFS: median 68 vs 40 months, respectively, P=0.007; 5-year projected OS rates: 84% vs 70%, respectively, P=0.01). In conclusion, incorporation of thal-dex into double autotransplantation failed to overcome the poor prognosis conferred by del(13 q), t(4;14) and del(17p). In a multivariate Cox regression analysis, del(17p) and high levels of serum beta2-m at diagnosis were the strongest variables adversely influencing PFS and OS. In comparison with the presence of t(4;14) but absence of del(17p), patients carrying del(17p) without t(4;14) had a significantly shorter OS, possibly due to their worst outcome after relapse. Presence of del(13q) alone conferred a significantly shorter TTP, but did not have an adverse impact on OS due to the favorable role of effective salvage therapies incorporating either bortezomib or lenalidomide. Disclosures: Off Label Use: use of first line thalidomide in preparation for ASCT. Cavo:Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau, no; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, no; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau, no.

Description: Background: Several biological parameters define patients with multiple myeloma (MM) at high-risk of progression or death. The well-known International Staging System (ISS), as well as age per se, are insufficient to explain differences of overall survival (OS) in patients over 65 years, who are 2/3 of newly diagnosed (ND) MM patients. We have recently showed that a frailty score combining age, functional status (Activity of Daily Living and Instrumental Activity of Daily living scores) and comorbidities (Charlson index) defines 3 categories of patients - fit, intermediate-fitness, frail - with significantly differences in OS and progression-free survival (Larocca A, et al. Blood 2013 122:687). Here we assess the causes of the different mortality in intermediate-fitness and frail groups compared to fit ones and present a final prognostic score based on the combination of ISS and frailty scores. Methods: NDMM patients over 65 years enrolled in 3 clinical trials, receiving either lenalidomide, bortezomib or carfilzomib were included in the analysis. Details on treatment regimens and results of these studies have previously been reported (Palumbo A, et al. Blood 2013 122:536; Larocca A, et al. Blood 2013 122:539, Bringhen S et al. Blood 2014 Jul 3;124(1):63-9). The cumulative incidences of discontinuation and toxicities were calculated using the Fine & Gray model. The frailty score was combined with ISS with the CHi-squared Automatic Interaction Detector method used as an iterative decision tree. Results: 869 patients (median age 74 years) were included in the analysis; 260 (30%) were frail, 269 (31%) intermediated-fitness and 340 (39%) fit. The 3-year OS was 57% in frail, 76% in intermediated-fitness and 84% in fit patients. Overall, 143 patients (16%) died, 70 (27%) frail, 39 (14%) intermediate-fitness and 34 (10%) fit. The causes of death were: disease progression [35 (13%) in frail, 22 (8%) in intermediate-fitness and 18 (5%) in fit patients] and toxicity [21 (8%), 10 (4%) and 11 (3%), respectively]. The higher risk of death for progression was related with the lower dose-intensity due to the higher rate of drug discontinuation and/or dose reduction. The average dose intensity was lower in frail (74%, p=0.0006) and intermediate-fitness patients (80%, p=0.07) compared with fit patients (85%). The cumulative incidence of drug discontinuation for any cause, excluding progression and death, was higher in frail (25%; HR 2.21, p

Description: Introduction : a formal comparison between Lenalidomide-Dexamethasone (Rd) and Lenalidomide-Prednisone plus Melphalan (MPR) or Cyclophosphamide (CPR) has not been performed yet. We compared Rd vs. MPR vs. CPR in newly diagnosed multiple myeloma (NDMM) patients ≥65 years old in a multicenter phase III trial. Per protocol, upfront dose reductions of Dexamethasone, Melphalan and Cyclophosphamide were performed, according to patients age ( ≤75 years vs. 〉75 years). The primary endpoint was progression-free survival (PFS). Methods : 662 patients with NDMM were randomized to receive nine 28-day cycles of Rd (n=222), MPR (n=218) or CPR (n=222). Rd: lenalidomide 25 mg/day for 21 days; dexamethasone 40 mg on days 1,8,15,22 in patients 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 patients 65-75 years old and 0.13 mg/Kg in patients 〉75 years; prednisone 1.5 mg/Kg for 4 days; CPR: lenalidomide 25 mg/day for 21 days; cyclophosphamide orally 50 mg/day for 21 days in patients 65-75 years old and 50 mg every other day in patients 〉75 years; prednisone 25 mg every other day. After induction, patients were randomized to receive maintenance with lenalidomide alone (R) or with prednisone (RP). Results : Patients characteristics were well balanced. Eighty-three (37%) patients in the Rd, 86 (39%) in the MPR and 80 (36%) in the CPR groups were older than 75 years. In intention to treat analysis, after a median follow-up of 31 months, no difference in PFS and overall survival (OS) was observed. Median PFS was 23 months in Rd, 27 months in MPR and 23 months in CPR (Rd vs MPR p=0.216; Rd vs CPR p=0.872; MPR vs CPR p=0.148). Median OS was not reached and was 73% in Rd, 67% in MPR and 72% in CPR at 3 years (Rd vs MPR p=0.663; Rd vs CPR p=0.754; MPR vs CPR p=0.448). A subgroup analysis, according to age was performed. No difference in response rate was observed. In patients ≤75 years, median PFS was 23 in Rd, 30 in MPR and 23 months in CPR (Rd vs MPR, p 75 years (MPR vs Rd/CPR p〈 0.0001). No difference was observed in extra-hematologic adverse events: 25% in Rd, 24% in MPR and 25% in CPR patients ≤75 years; 29% in Rd, 35% in MPR, 34% in CPR patients 〉75 years. Conclusion : this trial compared for the first time Rd, MPR and CPR in elderly NDMM. In all patients, the addition of alkylating agent to Lenalidomide-steroid combination did not show any advantage on PFS and OS. In a subgroup analysis, safety and efficacy data suggest that triplet regimens may be indicated in patients ≤75 years, while a doublet regimens for those 〉75 years. The MPR combination showed a PFS advantage in patients ≤75 years, with a higher incidence of hematologic toxicity and SPM. In patients 〉75 years an OS advantage was reported with Rd, mainly due to a higher efficacy of salvage treatments. Updated results will be presented at the meeting. Disclosures Off Label Use: Use of Lenalidomide as off label. Bringhen:Onyx: Consultancy; Merck Sharp & Dohme: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Janssen and Cilag: Honoraria; Celgene: Honoraria. Offidani:Mundipharma: Honoraria; Sanofi: Honoraria; Janssen and Cilag: Honoraria; Celgene: Honoraria; Amgen: Honoraria. Patriarca:Merck Sharp & Dohme: Honoraria; Janssen and Cilag: Honoraria; Celgene: Honoraria. Hajek:Janssen: Honoraria; Celgene: Consultancy, Honoraria; Merck: Consultancy, Honoraria. Boccadoro:Onyx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen and Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Palumbo:Onyx Pharmaceuticals: Consultancy, Honoraria; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Genmab A/S: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Sanofi: Honoraria; Amgen: Consultancy, Honoraria; Array BioPharma: Honoraria.

Description: 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 (

Description: Introduction: The randomized phase 3 ENDEAVOR trial demonstrated superior progression-free survival (PFS), overall survival (OS), and health-related quality of life in patients with relapsed or refractory multiple myeloma (RRMM) for patients treated with carfilzomib (56 mg/m2) and dexamethasone (Kd56) compared with bortezomib and dexamethasone (Vd). In patients with relapsed MM, the time of therapy initiation might impact treatment outcome. Prior studies have demonstrated a median of 5 months between the presence of biochemical and symptomatic relapse (Lopez. Leuk Res Rep. 2015;4:64-69). Herein, we report a post hoc subgroup analysis from the ENDEAVOR study to evaluate the impact of initiating Kd56 therapy upon biochemical relapse. Methods: Adults with RRMM who previously received 1-3 lines of therapy and had measurable disease were eligible to participate in the ENDEAVOR trial. Symptomatic disease was not required for eligibility. Kd56 patients received carfilzomib on days 1, 2, 8, 9, 15, and 16 as a 30-minute intravenous infusion and dexamethasone (20 mg) on days 1, 2, 8, 9, 15, 16, 22, and 23 of a 28-day cycle. Vd patients received bortezomib (1.3 mg/m2; intravenous bolus or subcutaneous injection) on days 1, 4, 8 and 11 and dexamethasone (20 mg) on days 1, 2, 4, 5, 8, 9, 11, and 12 of a 21-day cycle. Treatment continued until disease progression, physician decision, unacceptable toxicity, withdrawal of consent, or death. This post hoc subgroup analysis evaluated PFS, OS, and safety in subgroups defined according to the presence of symptoms at the time of enrollment. Patients with RRMM who experienced biochemical progression without CRAB symptoms (hypercalcemia, renal impairment, anemia, or bone lesions) upon relapse were considered asymptomatic, whereas symptomatic patients were those who had CRAB symptoms upon relapse. In each subgroup, PFS and OS were compared between treatment arms using an unstratified Cox proportional hazards model. Results: Of the 929 patients enrolled and randomized in ENDEAVOR, 117 (12.6%) were asymptomatic (Kd56, n=60; Vd, n=57) and 812 (87.4%) were symptomatic (Kd56, n=404; Vd, n=408). In the asymptomatic group, the median PFS was not estimable (NE) for Kd56 vs 13.7 months for Vd (hazard ratio [HR]: 0.462; 95% confidence interval [CI]: 0.232-0.922), and the median OS was NE for either treatment arm (HR: 0.768; 95% CI: 0.350-1.683) (Table). In the symptomatic group, median PFS was 17.7 months for Kd56 vs 8.8 months for Vd (HR: 0.539; 95% CI: 0.439-0.662), and median OS was 44.0 months for Kd56 vs. 36.8 months for Vd (HR: 0.801; 95% CI: 0.653-0.982) (Table). Kaplan-Meier PFS and OS curves are shown in the Figure. The rate of grade ≥3 treatment-emergent adverse events (Kd56 vs Vd) was 78.3% vs 58.9% in the asymptomatic group and 81.9% vs 72.8% in the symptomatic group (Table). Conclusions: Kd56 demonstrated superior survival outcomes compared with Vd in patients with RRMM, regardless of presence of CRAB symptoms at study randomization. As expected, outcomes were improved when Kd56 was initiated early in the disease course, before CRAB symptoms occurred. The small size of the subgroups in this study is a limitation. However, the findings warrant further investigation. The safety profile of Kd56 in both subgroups was consistent with that in the overall population as previously reported (Dimopoulos. Lancet Oncol. 2016;17:27-38; Siegel, Clin Lymphoma Myeloma Leuk. 2017;17:e142). Overall, Kd56 had a favorable benefit-risk profile in both patients with biochemical and symptomatic relapse. Disclosures Moreau: Amgen: 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; 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. Siegel:Merck: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau. Goldschmidt:Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; ArtTempi: Honoraria; Novartis: Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Mundipharma: Research Funding; Adaptive Biotechnology: Consultancy; Amgen: Consultancy, Research Funding. Niesvizky:Takeda: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Amgen Inc.: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Bringhen:Takeda: Consultancy; Janssen: Honoraria, Other: Advisory Board; Amgen: Honoraria, Other: Advisory Board; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria. Orlowski:Spectrum Pharma: Research Funding; BioTheryX: Research Funding; Amgen: Consultancy, Research Funding; Takeda: Consultancy; Sanofi-Aventis: Consultancy; Janssen: Consultancy; Bristol-Myers Squibb: Consultancy; Celgene: Consultancy; Kite Pharma: Consultancy. Blaedel:Amgen: Employment, Equity Ownership. Yang:Amgen Inc.: Employment, Equity Ownership. Dimopoulos:Takeda: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; Amgen: Honoraria.

Description: In newly diagnosed multiple myeloma (MM) patients, the combination melphalan, prednisone and thalidomide induces a fast tumor response with a high complete remission rate. In a prospective randomized trial, we compare the efficacy and toxicity of oral MPT and MP. An interim analysis was conducted after the first 200 newly diagnosed myeloma patients, median age 72, range 56–85, entered the study, between January 2002 and June 2004. At present, 116 patients were evaluated for toxicity and 102 patients for response on an intent to treat basis. The MPT regimen included 6 monthly courses of oral melphalan 4 mg/sqm and prednisone 40 mg/sqm for 7 days every month plus thalidomide 100 mg/day continuously until any sign of progressive disease or relapse. The dose of thalidomide was reduced to 50% when grade II toxicity occurred, and suspended for any grade III. On December 2003, the protocol was amended and enoxaparin prophilaxys was added. The MP regimen was as MPT without thalidomide. The end points of the study were: response, EFS, OS and toxicity. The response rate among patients who received MPT was: 25.9% immunofixation negative CR (CR), 5.5% immunofixation positive near CR (nCR) 48.2% partial remission (PR) (M-protein reduction 50–99%), 9.3% stable disease (SD) (M-protein reduction 0–49%) and 11.1% progressive disease (PD). The response rate after MP was 4.2% CR, 0% nCR, 43.6% PR, 23% SD and 29.2% PD. Response was followed by significant improvement of performance status, skeletal pain, anemia and transfusion requirement. After a median follow up of 15 months, 38 patients relapsed: 11 (29%) after MPT and 27 (71%) after MP. The EFS @ 26 months was 67.8% for MPT and 32.4% for MP (P

Description: Key Points Pomalidomide-cyclophosphamide-prednisone is an active combination in multiple myeloma patients who are relapsed/refractory to lenalidomide.

Description: In vitro evidences suggest that bisphosponates (BP) may exert some anti-myeloma activities. Indeed, the use of BP has been associated with better survival in selected subgroups of myeloma patients. We have previously reported that pamidronate, a second generation BP, is not useful to prevent or to delay the need of chemo-radiotherapy in patients with early stage or smouldering myeloma, who do not require specific treatments at diagnosis, although such a therapy may reduce skeletal events at the time of disease progression (Musto et al, Leuk Lymphoma2003; 44: 1545). Based on this limited evidence, the recently updated ASCO guidelines still not recommend the use of BP in this specific setting of patients (Kyle et al, J Clin Oncol2007; 25: 2464). On June, 2001, we started a randomised clinical trial comparing zoledronate (ZOL), a third generation, more potent BP, vs simple observation in patients with monoclonal gammopathy fulfilling the diagnostic criteria of stage IA, IIA or smouldering myeloma, not requiring further treatments. These criteria substantially correspond to the current definition of “asymptomatic myeloma”, recently suggested by the International Myeloma Working Group (IMWG, Br J Haematol2003; 121: 749). Accrual was completed on June, 2004. One-hundred-sixty patients were enrolled and randomised (1:1) to receive (n. 80) or not (n. 80) ZOL (Zometa, Novartis Pharmaceuticals. Origgio, Italy) for one year, on an out-patient basis, at the dose of 4 mg as 15′ i.v. single monthly infusion. The two groups were comparable at baseline for time from diagnosis, levels and type of M-component and percentage of bone marrow plasma cells. The most frequent adverse effects observed in ZOL-treated patients were moderate, not clinically relevant hypocalcemia (15 patients: all received oral substitutive therapy and continued the treatment) and fever (7 patients, one of whom stopped drug administration after two cycles). One patient developed reversible osteonecrosis of the jaw, none evidenced renal failure under ZOL therapy. Eight patients (two in the ZOL-treated group and six within controls) died due to unrelated reasons or were lost at follow-up after 6–26 months. No significant reduction of M-component (〉 25%) was observed throughout the study in both groups. After a median follow-up of 55 months (range 36–72), there were 35 (46%) progressions to “symptomatic” myeloma in the ZOL group and 37 (50%) within the controls (p n.s.). Median time-to-progression was 42.2 and 40.7 months, respectively (p n.s.). Bone lesions and/or hypercalcemia at the time of progression were significantly lower (17/35, 48.5%) in ZOL-treated patients than in controls (30/37, 81%) (p 〈 0.02). These mature data suggest that the monthly use of ZOL for one year in patients with early-stage, asymptomatic myeloma is safe, reduces the development of skeletal events at progression, but does not decrease the number of evolutions and does not prolong the time to transformation into “overt” myeloma.

Description: Abstract 128 Background. In newly diagnosed myeloma patients the combination of bortezomib with melphalan-prednisone (VMP) was superior to MP. In relapsed-refractory patients the 4 drug combination bortezomib-melphalan-prednisone-thalidomide (VMPT) induced a high proportion of complete responses (CR). Aims. This prospective, randomized, phase III trial, compared VMPT with a maintenance regimen including bortezomib and thalidomide with VMP without a maintenance regiment. The primary end point was PFS. Methods. Patients (N=511) older than 65 years were randomly assigned to receive VMPT followed by maintenance with bortezomib and thalidomide (N=254) or VMP (N=257). Initially, patients were treated with nine 6-week cycles of VMPT (induction: bortezomib 1.3 mg/m2 days 1,4,8,11,22,25,29,32 in cycles 1–4 and days 1,8,22,29 in cycles 5–9; melphalan 9 mg/m2 days 1–4; prednisone 60 mg/m2 days 1–4 and thalidomide 50 mg days 1–42; maintenance: bortezomib 1.3 mg/m2 every 15 days and thalidomide 50 mg/day) or VMP (bortezomib, melphalan and prednisone at the same doses and schedules previously described without maintenance). In March 2007, the protocol was amended: both VMPT and VMP induction schedules were changed to nine 5-week cycles and bortezomib schedule was modified to weekly administration (1.3 mg/m2 days 1,8,15,22 in cycles 1–9). Results. All patients have been evaluated in intention-to-treat. Patient characteristics were similar in both groups, median age was 71 years. The response rates were always superior in the VMPT group: at least PR rate (86% vs 79%, p=0.02), at least VGPR rate (55% vs 47%, p=0.07) and CR rate (34% vs 21% p=0.0008), respectively. Maintenance treatment did not increase the best response achieved during VMPT induction. After a median follow-up of 17.8 months, the 2-year PFS was 70.0% in the VMPT group and 58.2% in the VMP group (HR=0.62, 95% CI 0.44–0.88, p=0.008). The achievement of CR significantly prolonged PFS in both VMPT (p