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: Abstract 2877 Poster Board II-853 Background and Objective: In newly diagnosed multiple myeloma (MM) patients, treatment with lenalidomide plus high-dose dexamethasone (RD) was superior to high-dose dexamethasone in terms of both response rates and 1-year progression-free survival (PFS) (Zonder JA et al, Blood 2007;110:77). Preliminary results suggest that the combination lenalidomide plus low-dose dexamethasone (Rd) compared to the RD regimen yields significantly better 2-year overall survival (OS) (Rajkumar SV et al, J Clin Oncol 2008;26:8504). The combination of melphalan, prednisone, and lenalidomide (MPR) has been investigated in a phase I/II study showing promising results (Palumbo A et al, J Clin Oncol 2007; 25:4459-4465). The goal of this case –control study was to compare the efficacy and the toxicity of the lenalidomide/dexamethasone (len/dex) combination vs MPR as primary therapy for newly diagnosed elderly MM patients, to determine the additive value of melphalan compared to a regimen of lenalidomide plus corticosteroid. Patients and methods: Data from 51 newly diagnosed MM patients enrolled in Italy in a phase I/II dose-escalating trial, from January to October 2005, with MPR, were analyzed. For comparison of their outcome, 37 patients were identified among newly diagnosed patients seen at the Mayo Clinic from March 2005 to December 2008 who received len/dex as primary therapy and were enrolled in phase II or III trials. Patients treated with MPR received 9 monthly cycles of oral melphalan (doses ranging from 0.18 to 0.25 mg/kg on days 1-4), prednisone (2 mg/kg on days 1-4) and lenalidomide (doses ranging from 5 to 10 mg/day on days 1-21). After 9 cycles, patients started maintenance with lenalidomide alone (10 mg, days 1-21) until relapse or progression. Patients treated with len/dex received oral lenalidomide (25 mg/day, days 1-21) plus dexamethasone, either at low-dose (n=17) (40 mg orally days 1, 8, 15, 22) or at high-dose (n=21) (40 mg orally on days 1-4, 9-12, and 17-20). Treatment was continued until progression, relapse or unacceptable toxicity, or could be stopped at the physician's discretion. Patients (n=13) were allowed to receive transplant if they wished and were deemed eligible. Outcome was analyzed on an intention-to-treat basis. The Chi-square or the rank sum tests were used to compare variables. Time-to-event analysis was performed using the Kaplan-Meier method and comparisons were determined by the log-rank test and the Cox proportional hazards model. Results: On intention-to-treat analysis, 15.7% versus 23.7% patients, respectively in the MPR and in the len/dex group, (p=0.342) achieved a complete response, and 43.2% vs 47.4%, (p=0.691) achieved at least a very good partial response. Time-to-progression (TTP) (median: 24.7 vs 27.5 in MPR and len/dex groups, respectively; HR 1.04; 95% CI 0.55-1.98; p=0.903), PFS (median: 24.7 vs 27.5 in MPR and len/dex groups, respectively; HR 1.03; 95% CI 0.55-1.92; p=0.926) and OS (2-year OS: 86.2% in MPR group vs 89.1% in len/dex, HR 0.86; 95% CI 0.38-1.98; p=0.730) were not significantly different between the 2 groups. No significant differences in TTP, PFS and OS were reported when MPR patients were compared with the subgroup of patients treated with low-dose dexamethasone plus lenalidomide. Similar results were found when the analysis was restricted to MPR patients and len/dex pair mates receiving lenalidomide plus low/dose dexamethasone, matched according to age and sex, and who did not received transplant. The toxicity profile was different in the two groups. Hematologic grade 3-4 toxicities were more common with MPR compared with len/dex, in particular neutropenia (66.7% vs 21.1%, p 〈 0.001) and thrombocytopenia (31.4% vs 2.6%, p 〈 0.001), respectively. Grade 3-4 gastrointestinal events (13.2% vs 2.0%, p= 0.080), thrombotic events (13.2 vs 5.9, p= 0.279) and fatigue (10.5% vs 3.9%, p= 0.395) were more common with len/dex compared with MPR. Conclusion: Results of this case-control study show that both MPR and Rd are efficacious regimens for elderly MM patients. Data need however to be carefully evaluated and randomized control trials are needed to confirm these results. Disclosures: Off Label Use: research drug in combination to standard of care. Kumar:celgene: Research Funding; millenium: Research Funding; bayer: Research Funding; novartis: Research Funding; genzyme: Research Funding. Dispenzieri:celgene: Research Funding. Gertz:celgene: Honoraria; genzyme: Honoraria; millenium: Honoraria; amgen: Honoraria. Lacy:celgene: Research Funding. Musto:celgene: Honoraria. Fonseca:medtronic: Consultancy; genzyme: Consultancy; celgene: Consultancy; amgen: Consultancy; BMS: Consultancy; otsuka: Consultancy. Petrucci:celgene: Honoraria; Janssen Cilag: Honoraria. Greipp:celgene: Research Funding. Boccadoro:jansen Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; pharmion: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Palumbo:Janssen-Cilag: Honoraria; Celgene: Honoraria.

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

Description: Abstract 446 Background: The outcome of myeloma (MM) patients who are no longer responding to thalidomide, lenalidomide or bortezomib is poor, with a median event-free survival of 5 months and median overall survival (OS) of 9 months (Kumar SK et al, Leukemia 2012). The newer immunomodulatory drug pomalidomide, has shown significant activity in these clinical conditions. Aims: We assessed dosing, efficacy and safety of pomalidomide-cyclophosphamide-prednisone (PCP) in MM patients relapsed/refractory to lenalidomide. Methods: Pomalidomide was administered in doses ranging from 1 to 2.5 mg/day on days 1–28, cyclophosphamide at 50 mg every other day on days 1–28 and prednisone at 50 mg every other day on days 1–28 for 6 cycles, followed by maintenance therapy with pomalidomide-prednisone. Thromboprophylaxis with aspirin 100 mg/day or low-molecular weight heparin was recommended at physician's discretion. Results: The maximum tolerated dose (MTD) of pomalidomide was defined as 2.5 mg/day. Fifty-two patients were enrolled at the MTD and evaluated after completing at least 1 PCP cycle. Median age was 69 years (range 41–83). The median time from diagnosis to enrolment was 55 months (range 15–203). Best responses to PCP included 6% of complete response (CR), 19% of at least very good partial response (VGPR), 54% of at least partial response (PR) and 75% of at least minimal response (MR). Time to PR was rapid (median 1.8 months). After a median follow-up of 11 months (range 1–18), 1-year progression-free survival (PFS) and OS rates were 52% and 78%, respectively. PFS was not significantly different in patients with high-risk cytogenetic compared with patients with standard-risk disease and in patients younger or older than 75 years. Toxicities were primarily hematologic and included grade 4 neutropenia (13%) and thrombocytopenia (4%). At least grade 3 non-hematologic toxicities included infections (8%), rash (6%) and neurologic (6%). Thromboembolism occurred in 1 patient. Four patients discontinued treatment for toxicity (2 infections, 1 neurologic and 1 hepatic toxicity). Conclusions: PCP induced high response rates and prolonged PFS after prior exposure to lenalidomide and bortezomib (Table), without adding significant toxicity. PCP could be considered a valuable salvage option for pre-treated MM patients. Disclosures: Palumbo: Celgene: Consultancy, Honoraria. Larocca:Celgene: Honoraria. Sciacca:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Guglielmelli:Celgene: Honoraria. Giuliani:Celgene: Research Funding. Boccadoro:Celgene: Consultancy, Honoraria.

Description: Background: New agents have been introduced as induction prior to autologous stem cell transplant (ASCT) and as consolidation/maintenance thereafter to improve complete response (CR) rates. In this trial we evaluate Bortezomib plus Pegylated-lyposomal-doxorubicin and Dexamethasone (PAD) as induction therapy prior to reduced intensity ASCT, followed by consolidation with Lenalidomide and Prednisone (LP) and maintenance with Lenalidomide alone (L). Methods: Newly diagnosed multiple myeloma (MM) patients aged 65–75 years were eligible. Induction regimen consisted of 4 21-day PAD cycles (Bortezomib 1.3 mg/m2 days 1, 4, 8, 11, Pegylated-lyposomal-doxorubicin 30 mg/m2 day 4 and Dexamethasone 40 mg days 1–4, 8–11, 15–18). Two cycles of Cyclophosphamide 3 g/m2 plus Granulocyte-Colony Stimulating Factor were used to harvest stem cells. Patients were conditioned with tandem Melphalan 100 mg/m2 (MEL100) followed by stem cell support. After ASCT patients received consolidation with 4 28-day LP cycles (Lenalidomide 25 mg days 1–21 plus, Prednisone 50 mg every other day) followed by Lenalidomide alone maintenance (10 mg days 1–21 every 28 day). Primary objectives were safety (grade 3 non-hematologic toxicity 〈 30%) and efficacy (near CR rate 〉 35%). Results: One-hundred and two patients have been enrolled. After PAD cycles at least partial response (PR) rate was 94%, at least very good partial response (VGPR) was 59% including 13% CR. After tandem MEL100, 88% of patients achieved at least VGPR and 41% CR. After LP consolidation all patients obtained PR, 88% at least VGPR and 53% immunofixation negative CR. After a median follow-up of 14 months, 1-year progression free survival (PFS) was 92%, 1 year time to progression was 97% and 1 year overall survival was 92%. PFS was not significantly affected β2-microglobulin levels (p=0.10), presence of chromosome 13 deletion (p=0.5) or t(4;14) (p=0.61). During PAD, grade 3–4 adverse events included thrombocitopenia (13%), neutropenia (11%), infections (18%), gastrointestinal toxicities (12%), peripheral neuropathy (11%) and deep vein thrombosis (6%). During LP consolidation, grade 3–4 toxicities included neutropenia (18%), thrombocytopenia (6%), infections (6%) and deep vein thrombosis (6%). The other grade 3–4 toxicities occurred in less than 5% of patients. Conclusions: Bortezomib as induction regimen prior to reduced intensity ASCT, followed by Lenalidomide as consolidation maintenance is a highly effective regimen in elderly patients. Updated results will be presented at the meeting.

Description: Abstract 492 Background. The risk of venous thromboembolism (VTE) is high in newly diagnosed myeloma (MM) patients who receive thalidomide-based regimens. Anticoagulant prophylaxis is recommended. Controversies exist on the best thromboprophylactic regimen to adopt. Aims. In this prospective, multicenter phase III trial we evaluated the safety and the efficacy of low-molecular weight heparin (LMWH) or low-dose aspirin (ASA) or low-fixed dose warfarin (WAR) as anticoagulant prophylaxis. End-points were incidence of VTE, acute cardiovascular events, sudden death, major and minor bleeding. Methods. In a GIMEMA study, 991 newly diagnosed MM patients were randomized to VTD (Velcade 1.3 mg/m2 d 1,4,8,11; Thalidomide 200 mg/d; Dexamethasone 320 mg/21 d) or TD (Thalidomide 200 mg/d; Dexamethasone 320 mg/21 d) or VMPT (Velcade 1.3 mg/m2 d 1,8,15,22; Melphalan 9 mg/m2 d 1-4; Prednisone 60 mg/m2 d 1-4; Talidomide 50 mg/d) or VMP (Velcade 1.3 mg/m2 d 1,8,15,22; Melphalan 9 mg/m2 d 1-4; Prednisone 60 mg/m2 d 1-4). In a sub-study, patients treated with VTD or TD or VMPT were randomly assigned to receive LMWH (Enoxaparin 40 mg/d, N=223) or ASA (Aspirin 100 mg/d, N=227) or WAR (Warfarin 1.25 mg/d, N=223) for the duration of the induction therapy; 61 patients were excluded from sub-study because of indication for anticoagulant/antiplatelet therapy or high-risk of bleeding. Patients treated with VMP (N=257) did not receive any prophylaxis and were used as controls. Results. Patient characteristics and distribution of major risk factors were similar in all groups. The incidence of VTE was 5% in the LMWH group, 6% in the ASA group and 8% in the WAR group (p not significant). VTEs were 2% in the VMP group. Median time to onset of VTE for patients who received LMWH or ASA or WAR were 4.7, 2.4 and 2.4 months, respectively. Patients who received higher doses of both steroids and thalidomide (VTD and TD) had a higher VTE incidence (7%) in comparison with those who received lower doses (VMPT, 3%, p=0.06). Patients treated with bortezomib (VTD and VMPT) had a lower VTE incidence (5%) in comparison with patients on TD (8%, p=0.08). The rates of cardiovascular events were 2% in the LMWH group, 1% in the ASA group and 0.5% in the WAR group. The incidence of major and minor bleeding was 2% in the LMWH group, 3% in the ASA group and 1% in the WAR group (p not significant). The incidence of combined thrombosis, bleeding and cardiovascular events was 9% in the LMWH group, 10% in the ASA group and 9% in the WAR group (p not significant). Conclusion. The overall incidence of VTE was less than 10% in all groups and was not superior to that expected during the natural course of MM. The LMWH patients had lower risk of VTE, although no statistical difference was observed. LMWH, WAR and ASA are likely to be effective thromboprophylactic regimens. The final analysis on 991 patients will be presented at the meeting. Disclosures: No relevant conflicts of interest to declare.

Description: Background and aims: Persistence of molecularly detectable minimal residual disease (MRD) is a nearly constant finding in MM following autologous transplantation (ASCT). On the other hand, molecular remission (MR) can be obtained in MM in the allogeneic setting and is a basic requisite for long-term disease control (Corradini et al, Blood 2003). In this study a consolidation treatment, including Bortezomib/Thalidomide/Dexamethasone (VTD), was employed in the post-ASCT setting in patients (pts) undergoing strict molecular monitoring by qualitative and quantitative PCR to induce further cytoreduction and to verify if a proportion of them could enter MR. Patients and methods: Inclusion criteria were: a documented complete or very good partial remission (CR or VGPR) following ASCT delivered as first line treatment; no previous treatment with thalidomide and bortezomib; presence of a molecular marker based on the IgH rearrangment. Primary endpoint of the study was to obtain MR in 〉 20% of pts. Methods: VTD had to be started within 6 months from ASCT. Each cycle consisted of: Bortezomib 1.6 mg/m2 as an IV injection once weekly (on days 1, 8, 15, 22) followed by a 13-day rest period (days 23–35); Thalidomide at the initial dose of 50 mg/day PO once daily, with increments of 50 mg every 7 days up to 200 mg; Dexamethasone 20 mg/day PO once daily, on days 1 to 4, 8 to 11 and 15 to 18 followed by a 17-day rest period (days 19–35). A total of 4 cycles were delivered. MRD was assessed on bone marrow (BM) samples at study entry, after two VTD courses, at the end of treatment and then at six months intervals. Qualitative and quantitative PCR analysis were carried out using IgH-derived patient-specific primers as already described (Voena et al, Leukemia 1997; Ladetto et al, Biol Bone Marrow Transpl 2000). Results: Forty pts were enrolled and are evaluable at study entry. As expected 94% of pts were PCR-positive following ASCT. 18% did not receive the whole planned treatment, including one toxic death. The six pts requiring treatment reduction/discontinuation were nevertheless included in the MRD analysis. 35 PCR-positive pts at study entry are evaluable after 2 VTD courses and 17% converted to PCR negativity. 27 pts are evaluable at the end of the program with a PCR-negativity rate of 22%. Subsequent follow-up samples are available in 22 pts. All PCR-negative pts assessed at 6 months (four cases) and at 6 and 12 months (two cases) persisted in MR. Seven relapses/progressions occurred and were all among PCR-positive pts. Real-time PCR has been so far performed in ten persistently PCR-positive pts with a 〉0.5 log tumor reduction in eight of them (median 1.2 log; range 0.2–2.1). Conclusions: VTD consolidation allows a proportion of CR/VGPR MM pts to enter MR and has a measurable anti-tumor effect also in persistently PCR-positive pts. This study is the first demonstration that new non chemotherapeutic agents have activity on MRD persisting following ASCT and indicate that MR is an achievable goal also outside the allogeneic transplantation setting.

Description: Background: The association of Melphalan, Prednisone and Lenalidomide (MPR) has shown significant anti-myeloma activity in newly diagnosed Multiple Myeloma (MM) patients. In this phase I/II study, the more frequent adverse events were neutropenia and thrombocytopenia. Non-hematologic toxicities were unusual. Methods: We analyzed the kinetics and risk factors for neutropenia and thrombocytopenia in 21 patients (median age 69 years) who received nine four-week cycles of MPR at the maximum tolerated dose (melphalan 0.18 mg/Kg d 1–4, lenalidomide 10 mg d 1–21, prednisone 2 mg/Kg d 1–4, followed by maintenance period with lenalidomide 10 mg/day for 21 days every 4 weeks). We also up-dated efficacy end-point. At the occurrence of grade-3 neutropenia, G-CSF was administered for 5–7 days. The occurrence of grade-4 neutropenia despite G-CSF administration or any other grade-4 hematological toxicities required withholding of treatment and subsequent dose reduction at the start of the following cycle. A new cycle was allowed if the neutrophil count was 〉1×109/L and platelet count 〉50×109/L. A delay of 2 weeks was allowed, a delay beyond 2 weeks required dose reduction and a delay beyond 4 weeks required therapy discontinuation. Results: Grade-3 neutropenia occurred in 38.1% of patients, grade-4 neutropenia in 14.2% of patients, but febrile neutropenia was 9.5%. G-CSF was administered in 42.3% of patients. The mean neutrophil count at the start of each MPR cycle was 2.69 × 109/L (SD 1.4). The mean neutrophil count at nadir (day 15–21) of each cycle was 1.43 × 109/L (SD 1.0). The incidence and depth of neutropenia did not increase with the number of cycles. The mean neutrophil count during maintenance was 2.11 × 109/L (SD 1.0). Grade-3 thrombocytopenia occurred in 14.2% of patients and grade-4 thrombocytopenia in 9.5%; one patient required platelet transfusion. The mean platelet count at the start of each MPR cycle was 174 × 109/L (SD 63.9). The mean platelet count at nadir (day 15–21) of each cycle was 121 × 109/L (SD 56.3). Thrombocytopenia was more pronounced after 9 cycles of treatment. The mean platelet count after 9 cycles was 109 × 109/L (SD 53). The mean platelet count at the end of 6 months of lenalidomide maintenance therapy was 158 × 109/L (SD 79.2). One patient required lenalidomide dose reduction for severe neutropenia. Three patients discontinuated therapy for severe thrombocytopenia and neutropenia. Grade 3–4 hematologic toxicity was more frequent in patients with low baseline neutrophil count and in those with Bence-Jones myeloma. Neutropenic fever (9.5%), cutaneous reaction (9.5%), thromboembolism (4.8%) were the most frequent grade 3–4 non-hematologic adverse events. After a median follow-up of 29.5 months, the median time-to-progression was 28.5 months, the median progression-free survival was 28.5 months and the 2-years overall survival was 90.5%. No death was reported in the first 18 months of treatment. Conclusions: MPR is a promising first line regimen for elderly MM patients. Hematologic adverse events were frequent but manageable with the use of G-CSF.

Description: Bortezomib has been evaluated as induction regimen to improve cyto-reduction before autologous stem cell transplant. Combinations including bortezomib, doxorubicin and dexamethasone have shown encouraging results. Melphalan at 100 mg/m2 has been suggested as reduced-intensity conditioning regimen for elderly patients. In this prospective multicenter phase II study, bortezomib, pegylated-liposomal-doxorubicin and dexamethasone (PAD) followed by tandem melphalan 100 mg/m2 has been investigated in newly diagnosed patients aged 65–75 years. The induction regimen included four 21-day PAD cycles (bortezomib 1.3 mg/m2 days 1, 4, 8, 11, pegylated-liposomal-doxorubicin 30 mg/m2 day 4 and dexamethasone 40 mg days 1–4, 8–11, and 15–18 for cycle 1 and days 1–4 for cycles 2–4). Cyclophosphamide (3 g/m2) plus G-CSF were used to harvest stem cells. Patients were then conditioned with tandem melphalan 100 mg/m2 followed by stem cell infusion. A single interim analysis has been planned. Sixty-five patients have been enrolled in the study and 37 completed the induction cycles. Median age was 69 years; median β2-microglobulin 3 mg/L; median albumin 4.1 g/L; chromosome 13q deletion was detected by FISH in 35% of patients. After the 4 courses of PAD 97.1% of patients achieved at least a partial response (PR), 50% at least a very good partial response (VGPR), 11.8% an immunofixation negative complete remission (CR). After tandem melphalan 100 mg/m2, all patients achieved at least a PR, 80% at least a VGPR and 30% an immunofixation negative CR. After 4 cycles of PAD, grade 3–4 hematologic events were thrombocytopenia (13.5%) and neutropenia (8.1%); more frequent grade 3–4 non-hematologic toxicities were peripheral neuropathy (21.6%) and infections (10.8%). One early toxic death was reported (central nervous system bleeding) and two patients had to discontinue therapy due to pneumonia and HBV reactivation. Eighty-two percent of patients achieved successful stem cell harvest (〉4 CD34+ cells/Kg). PAD is an effective induction approach, it may improve autologous transplant results in selected elderly patients. Updated results of the interim analysis will be presented at the meeting.

Description: Introduction and aim of the study: monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) have a distinct risk of evolving towards symptomatic multiple myeloma (MM) but it is widely accepted that they should not be treated until clinical evolution. The clinical presentation of symptomatic MM includes severe complications like acute renal failure, spinal cord compression by vertebral collapse, pathologic bone fractures which cannot be completely avoided even by strict follow-up of MGUS/SMM patients. The recent availability of effective and less toxic therapies has fueled renewed interest in the identification of prognostic models able to predict the risk of impending progression of MGUS/SMM patients to symptomatic MM and criteria for MM defining events have been recently broadened to allow an earlier start of treatment even in asymptomatic patients (Rajkumar SV et al, Lancet Oncol 2014). However, from a clinical perspective it would be more important to prevent the development of severe MM related complications by treating those MGUS/SMM considered at high risk of developing them. To this end, we have analyzed known risk factors for MGUS/SMM progression and other disease biomarkers in order to identify those able to consistently predict an high risk of "severe MM" development. Methods: we retrospectively analyzed 67 patients with symptomatic MM with a known previous history of MGUS/SMM, referred to our division from 1985 to December 2014 (23 males, 44 females; median age at MGUS/MM diagnosis 60 years). Focusing on the first assessment of their asymptomatic disease, we compared patients who subsequently developed severe CRAB criteria (Bladé J et al, Hematol Oncol Clin North Am. 2007), defined as having at least one of the following: hypercalcemia 〉 11.5mg/dL, creatinine 〉 4mg/dL, Hb 〈 8 mg/dL, severe bone lesions characterized by pathological fractures or causing spinal nerve compression, and called "severe MM" with patients who lacked severe CRAB symptoms at MM diagnosis, in order to identify risk factors for "severe MM" during its asymptomatic phase. Variables analyzed for comparison were: involved/uninvolved free light chains (FLC) ratio, monoclonal component (MC) quantification, presence of evolving pattern of MC (defined as an increase in the level of MC of at least 10% in 6 months), presence of immunoparesis, LDH levels, 24h-urinary protein levels, Ig isotype and bone marrow plasma cells percentage. Frequency of follow up was also considered (every 6 months or more). Time to treatment start (TTTS) from MGUS/SMM diagnosis, progression free survival (PFS) from first line treatment and overall survival (OS) were also calculated. Results: median 24-hour urine protein levels were significantly higher in MGUS/SMM patients who subsequently developed "severe MM", compared with patients without severe CRAB symptoms at MM diagnosis (140 vs 90mg/24h, p 0.022, see Figure 1), with an increased risk of severe myeloma related complications for MGUS/SMM patients with more than 200mg/24h urine proteins (Odds Ratio 2.65, p 0.037). Risk was highest in 4 MGUS/SMM patients with 24h-urinary protein levels higher than 1500mg (Odds Ratio 8.43, p 0.030) who invariably developed "severe MM". No difference were found comparing other variables. Of note, there was no difference between the two subgroups in terms of median TTTS (5.3 vs 8.3 years for MGUS patients and 1.7 vs 1.6 years for SMM, respectively), PFS ( 24.4 vs 32.2 months, respectively) and OS (nr vs 4.36), although a higher early mortality was observed in patients with "severe MM" (2 y OS 69% vs 93%). Conclusions: increased 24h-urinary protein levels (〉 200mg) in MGUS/SMM patients are associated with a higher risk of the occurrence of severe CRAB symptoms at MM progression. Further data with larger series of patients are needed to better define the best predictive threshold for "severe MM". However, patients with more than 1500mg/24h urinary protein loss represent a small subgroup of MGUS/SMM patients who should better start treatment while still asymptomatic. Figure 1. 24h-urinary protein (mg) levels in the asymptomatic phase Figure 1. 24h-urinary protein (mg) levels in the asymptomatic phase Disclosures No relevant conflicts of interest to declare.