ALBERT

Description: Autologous stem cell transplant (ASCT) remains the standard of care for Multiple Myeloma (MM) patients younger than 70 years old. The role of induction therapy is crucial within a program of high-dose therapy since deeper is the response before, higher is the outcome of transplant. In this study, we analyzed a real life setting of patients treated with three different induction approaches: VAD (Vincristine-Adriamycin-Dexamethasone), VD (Bortezomib - Dexamethasone), and VTD (Bortezomib-Thalidomide-Dexamethasone) in terms of depth of response, 2 years therapy-free rate and toxicity. One hundred and sixty-three MM patients (pts) were included in the analysis: 62 pts treated with VAD (38%), 44 with VD (27%) and 57 with VTD (35%). In VTD group 49 pts (86%) received Bortezomib subcutaneously. As shown in Table 1, patients of the three groups were similar for D&S stage (p 0.59), a higher rate of ISS stage 3 was observed in VAD group (p=0.019), patients in VTD group were significantly older (p=0.024), median follow-up was significantly lower in VTD pts (p

Description: Abstract 3037 Fotemustine (Muphoran), a nitrosourea alkylating agent approved for use in the treatment of metastatic melanoma, has proven to be effective as single agent in relapsed/refractory multiple mieloma (MM). We report preliminary data of a phase II single centre study exploring the feasibility and the efficacy of the combination bortezomib (B) + fotemustine (Mu) + dexamethasone (D) (B-MuD) in relapsed/refractory MM patients. This study has been approved by local ethical committee; all patients (pts) signed written informed consent before the enrolment. MM pts relapsed or refractory after at least one therapy were eligible for the study. Pts who received prior bortezomib-containing regimen were included only if not considered bortezomib-refractory. Fotemustine at the escalating doses of 80 and 100 mg/m2 i.v. on day 1 was associated to Bortezomib 1,3 mg/m2 i.v. on days 1,4,8,11 + Dexamethasone 20 mg orally on days 1–2, 4–5, 8–9, 11–12 of 21-day cycle for a total of 6 cycles. Protocol was amended after the enrolment of the first five pts due to a considerable toxicity. We observed 3 grade 3–4 peripheral neuropathy, 1 grade 3 pneumonia, 4 grade 4 thrombocytopenia and two pts dropped-out (one for grade 3 pneumonia at 2° cycle, and one for grade 4 peripheral neuropathy at 3° cycles). Thus the schedule was modified as following: Fotemustine at escalating doses of 80 and 100 mg/m2 i.v. on day 1, Bortezomib 1,3 mg/m2 i.v. once weekly on days 1, 8, 15, 22, Dexamethasone 20 mg i.v. on days 1, 8, 15, 22 for six 35-day cycles. An interim analysis of feasibility and efficacy was planned after the inclusion of the first two cohort of 6 pts each, treated with escalating dose of Fotemustine according to the amended schedule. Up to now, 18 pts have been enrolled (5 pts before and 13 after the amendment): M/F 10/8, median age 69 years (44-82), median number of previous therapies 2 (1-5). Previous treatments included autologous transplant in 10 pts (59%), bortezomib in 8 pts (44%), oral melphalan in 7 pts (41%) and thalidomide in 12 (71%). After the inclusion of 12 pts the MTD for Fotemustine was established to be 100 mg/m2. No drop-outs were registered after the amendment. Preliminary data on response are available in 10 pts. Nine pts (90%) obtained at least a PR, 8 pts (80%) registered ≥VGPR (CR 10%). At time of this analysis 79 cycles were delivered: 14 before, 65 after the amendment. Eighty-nine AE of any grade were observed, 43 hematological and 46 non-hematological. Thrombocytopenia was the most common AE either before and after the amendment. Need for dose reduction was significantly lower after the amendment. In detail fotemustine was reduced in 14% of cycles before and never after the amendment (p=0.0001), bortezomib dose reduction were performed in 36% of cycles before and 15% after the amendment (p=0.08), dexamethasone dose reduction occurred in 64% of cycles before and 13% after the amendment (p=0.0001). In conclusion, this interim analysis shows that fotemustine in combination with bortezomib and dexamethasone is safe and gives encouraging results in relapsed/refractory myeloma patients with 80% of ≥VGPR. Updated results will be presented at the meeting. Disclosures: No relevant conflicts of interest to declare.

Description: Background: Bortezomib-related painful sensory peripheral neuropathy (Bor-PN) represents the main dose-limiting toxicity of Bor. Cornea is the most innervated tissue in human body, with the highest density of small sensitive fibers, which are the main target of Bor-PN. Corneal confocal microscopy is a rapid, noninvasive, clinical examination technique that quantifies small nerve fiber damage and is already used for early identification of neural damage in course of diabetic sensory PN. Aims: To evaluate the possible role of confocal microscopy for identification and monitoring of corneal sub-basal neural plexus damage in Multiple Myeloma (MM) patients (pts) treated with Bor and to correlate confocal microscopy findings with Bor-PN. Patients and Methods: Patients underwent corneal examination with corneal confocal microscope (Confoscan 4). Corneal sub-basal fibers were evaluated in terms of the following morphometric measurements used as sign of neural damage: nerve fiber length, nerve fiber number, beadings number, tortuosity (according to Oliveira scale and Nidek index). The study was approved by local ethic committee, all patients signed informed consent before confocal microscopy evaluation. Twenty-six MM pts treated with Bor entered the study and were compared with 20 healthy controls. Control group morphometric findings were similar to data on healthy population reported in the literature. At time of confocal assessment among MM group there were 20 MM pts (77%) under active bor treatment, 6 pts were off bor-therapy (23%), clinically evident PN (NCI grade ≤2) was reported in 10 pts (38.5%). Results: MM pts and healthy controls were well matched as far as median age and sex. Compared to healthy controls, MM pts showed: I) a significant reduction in terms of length and number of corneal fibers (median length 552 μm in MM vs 1223.5 μm in control p

Description: Abstract 1223 Poster Board I-245 Introduction This study aimed at evaluating the impact of three different pre-transplant therapies on the outcome of patients (pts) eligible for high-dose therapy. Methods two-hundred sixty eight newly diagnosed MM pts aged £65 years, Durie-Salmon stage III, II, or I in progression, were consecutively enrolled from 2000 to 2007 in three different protocols, with three different pre-transplant therapy: Group 1: (145 pts) 3 pulse-VAD cycles; Group 2: (67 pts) 3 pulse-VAD cycles plus 3 Thal-Dex cycles (thalidomide at the dose of 100 mg/day orally at bedtime, continuously for 3 months, oral dexamethasone at the dose of 20 mg on days 1-4 and 14-17 every 28 days); Group 3: (57pts) 4 Vel-Dex courses (Bortezomib 1.3 mg/m2 i.v. on days 1, 4, 8, 11; oral Dexamethasone 40 mg on days 1-4 and 8-11 every 3 weeks). After induction all pts received two DCEP-short cycles as mobilization (oral Dexamethasone 40 mg/day on days 1-4 + Cyclophosphamide 700 mg/m2/day i.v., Etoposide 100 mg/ m2/day i.v., cisPlatin 25 mg/m2/day for 2 days) with peripheral blood stem-cell (PBSC) collection prompted by G-CSF followed by one or two transplants (Tx) with melphalan 200 mg/m2 as conditioning regimen. Response was defined according to IMWG uniform criteria. Pts were considered responsive when obtaining at least a PR. Results pts in the three group were similar for age, gender, Ig type, ISS stage. A significant higher percentage of Durie and Salmon stages III was found in group 3 (83% vs 68% in group 1 and 67% in group 2, p=0.0002). The median follow-up was 46 (1-150) months for group 1, 43 (1-68) months for group 2, and 29.7 (1-79) months for group 3. At the time of this analysis in the three groups 51%, 65%, 90% of transplanted pts respectively were still alive, and progression after transplant was registered in 84%, 80%, 50% respectively. Patient flow before Tx was similar (p=0.45): 19% in group 1, 27% in group 2, 23% in group 3. In group 1, 2% of pts went off-study after VAD, and 17% after mobilization phase. In group 2, patient flow was equally distributed: 7% after pulse VAD, 10% after thal-dex, 9% after DCEP. In group 3, 12% of the pts went off-study after Vel-Dex, 11% after DCEP. Table 1 summarized responses. In group 3 (Vel-Dex) response was better along all protocol phases with respect to group 1 or 2 (p

Description: Abstract 2957 Fotemustine (Muphoran), a nitrosourea alkylating agent approved for metastatic melanoma, and recently used in alternative autotransplant condition regimen (FEAM) for lymphoma patients, has proven to be active as single agent in Multiple Myeloma (MM) refractory-relapsed patients. Given the importance of reaching high-quality response even beyond frontline setting, and the proven activity of the proteasome inhibitor bortezomib + dexamethasone therapy, we explored by means of a phase I-II dose escalation study the feasibility and the efficacy of the three drug combination bortezomib (B) + fotemustine (Mu) + dexamethasone (D) (B-MuD) in MM patients (pts) relapsed after at least one therapy. The study has been approved by our local ethical committee; all pts signed written informed consent. Fotemustine was administered at two dose levels (80–100 mg/m2 i.v.) on day 1. The original 21-day schedule was early amended due to extra-hematological toxicity and a 35-day schedule was adopted (Bortezomib 1,3 mg/ m2 i.v. on days 1, 8, 15, 22, Dexamethasone 20 mg i.v. on days 1, 8, 15, 22) for a total of six courses. Twenty-four pts have been enrolled: M/F 13 (54%)/11(46%), median age 69 years (44–83), median number of previous therapies 2 (1–5). Previous treatments included autologous transplant in 13 pts (54%), bortezomib in 8 pts (33%), oral melphalan in 11 pts (46%) and thalidomide in 15 (63%). The MTD of Fotemustine was tested to be 100 mg/m2. Six pts dropped-out: 4 pts for extra-hematological toxicity, 2 for progression. The overall response rate was of 62% (CR 8%, VGPR 33%, PR 21%). Median time to first response was 36 days (range 21–83) with a median DOR of 19.4 months (95% CI 11.6–23.7 months). After a median follow-up of 24.3 months (range 1.6–32.8 months), the median OS was 28.5 months (95% CI 22.1-NR). The median TTP and the median PFS were 20.5 (95% CI 11.9–22.2 months) and 19.1 (95% CI 11.9–22.2) months respectively. Median time to next therapy (TNT) was 16.2 months (4–25.2). There was a correlation between response and PFS (p=0.0002). B-MuD resulted effective in patients previous exposed to bortezomib without difference in terms of response (p=0.25) and PFS (p=0.87) when compared to bortezomib-naive patients. As far as toxicity was concern, one-hundred and thirty-three AE of any grade were observed, 65 hematological (49%) and 68 (51%) non-hematological; Thrombocytopenia was the most common AE (32%) overall. Extra-hematological toxicity included neuropathy (23%), infections (14%), gastrointestinal symptoms (7%). Half of the events occurred during the first two cycles (49%), most were manageable, with 69% resolved or improved, 15% unchanged, 15% worsened. In conclusion B-MuD is effective and well tolerated in relapsed MM even in patients in advanced phase and previously exposed to several lines of therapies, including bortezomib. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 4003 Skeletal related events (SREs) are a significant cause of morbidity and mortality in multiple myeloma (MM). Markers of bone turn-over, in particular serum C-terminal telopeptide of type I collagen (CTX), can be used for monitoring early signs of bone damage either in osteoporosis or in neoplasm such as Multiple Myeloma. Since serum CTX levels are significantly decreased during bisphosphonate treatments (Dennis, N Engl J Med 2008), it is not clear whether serum CTX monitoring still retain a role in predicting SREs once bisphosphonate treatments was started. Aim of this study was to test whether serum CTX monitoring significantly correlates with active bone disease in a population of MM patients irrespective of concomitant bisphosphonate treatment. An unselected cohort of 87 patients with multiple myeloma diagnosed at our Hematology Division with the following characteristics entered this study: the availability of a baseline determination of serum CTX prior to start bisphosphonate therapy, multiple sequential serum CTX determinations (≥2 performed with an interval of at least 4 weeks), a radiologic evaluation available at the time of any SREs. The study was approved by our local ethical committee and conducted according to Helsinki Declaration guidelines. Patients baseline characteristics were the following: M/F 59%/41%, median age 60 (range 37–86), Durie and Salmon stage I/II/III (11%/14%/75%). During the study period (median follow-up 2.8 year, range 0.4–21 years), 73 patients (83%) experienced at least one SRE. Development of SRE was evaluated by standard skeletal x-ray, CT or MRI scan. Serum CTX was measured by an enzyme chemiluminescence method. A total of 260 serum CTX determinations were available for statistical analysis (median number of determinations for each patient 3, range 2–9). Univariate analysis found a statistically significant association between serum CTX and bone disease status with higher values in patients with active lytic lesions when compared to patients without radiological evidence of bone disease (median value 0.411 vs 0.356, p

Description: Bendamustine (B) is an alkylating agent with unique chemical structure (purine-like benzimidazole ring) and high cytotoxic activity. In the last decade, the association of B and rituximab (BR) emerged as the worldwide most popular standard treatment of patients (pts) with indolent non-Hodgkin lymphomas (iNHL), in both relapsed/refractory (R/R) and untreated setting. Autologous stem-cell transplant (ASCT) is the standard option in young fit pts with R/R iNHL and has been recently demonstrated to improve survival of follicular lymphoma (FL) pts with early treatment failure (ETF: within 2 years [yrs] of frontline immunochemotherapy [I-CT], Casulo et al, BBMT 2018). The structure similarity with fludarabine, which is associated with a well-known peripheral blood stem cell (PBSC) mobilization impairment, may limit the use of B in younger pts with iNHL potentially candidates for ASCT. Moreover, the effectiveness of CD34+ cells collection in pts treated previously with B is essentially still unknown and based on few small series. We retrospectively analyzed rates of CD34+ cells collection in consecutive pts with iNHL undergoing PBSC mobilization attempt, who had previously received treatment with B (in the same or in a previous line of therapy) in 12 centers of the Fondazione Italiana Linfomi. The primary endpoint was the rate of pts who were able to obtain a successful harvest of PBSC (≥2 x106/Kg of body weight). Overall, we collected complete data about 45 pts with iNHL undergoing PBSC mobilization attempt after previous treatment with B (Table 1). The majority of pts had FL (n=39). Median age at diagnosis was 52 yrs (35-66). Frontline treatments comprised R-CHOP in 27 pts (60%) and BR in 11 (24%). All but 2 pts, who were mobilized during 1st line therapy, experienced disease relapse and initiated 2nd line treatment, including reinduction I-CT, PBSC mobilization and ASCT consolidation. Among pts with FL, 13 (33%) relapsed within 24 months (ETF). Median lines of therapy at PBSC mobilization were 2 (1-4). Eleven pts (24%) received B in 1st line, 29 (65%) as part of 2nd line (n=29, 65%), and 5 (11%) in 3rd or 4th line of therapy. The most frequent mobilization strategy (40 cases, 88%) was CT plus G-CSF (including R-HD-AraC in 27), with "on demand" plerixafor adjunction in 4 cases (10%). Then, two pts (4%) underwent PBSC mobilization with G-CSF only (+ plerixafor in 1) while 3 pts (7%) received G-CSF (+ plerixafor in 1) immediately after a BR course. At first mobilization attempt, 38 out of 45 pts (84%) collected ≥2 x106 CD34+/Kg (Table 2), including 2/2 (100%) in G-CSF only, 35/40 (88%) in CT + G-CSF and 1/3 (33%) in BR cohort (p=0.039), with a median of 1 (1-4) apheresis procedure. Five out of 7 pts who failed first mobilization underwent a second attempt (1 with G-CSF + plerixafor, 3 with CT + G-CSF and 1 with CT + G-CSF + plerixafor) collecting all ≥2 x106 CD34+/Kg. Considering all mobilization attempts, 43/45 pts (96%) reached successful harvest of PBSC (≥2 x106/Kg) and 38/45 (84%) obtained an optimal PBSC collection (≥5 x106/Kg). Median number of PBSC collected was 6.46 x106/kg (3-18). Pre-mobilization bone marrow involvement significantly affected PBSC mobilization (p=0.03), as well as response at mobilization (CR 92%, PR 60%, SD 50%, p=0.02) while cumulative dose of B (〉720 mg/m2, p=0.9) or timing from last B administration (≤3 months, p=0.34) did not. At multivariable analysis, mobilization type (p500/μl and PLT 〉20000/μl: 11 and 13 days). We observed 1 case of MDS (EB-2) and 1 sarcoma after ASCT. At a median follow-up of 6.3 yrs (0.7-14), only 3 pts died (2 for progression and 1 for viral encephalitis), with 8-yrs OS of 89.6% (Fig. 1) and a median PFS from ASCT of 8.1 yrs. Notably, FL pts experiencing ETF did not exhibit worse OS (85.7 vs 87.1% at 8-yrs, p=0.7). High rate of success in PBSC collection reported in this large real-world study supports the evidence that pre-treatment with B does not affect PBSC mobilization in iNHL pts, although we confirmed that B does not display per se a mobilizing capacity. Salvage strategy including ASCT resulted in overall favorable outcome in young pts with R/R iNHL and seemed able to overcome the negative prognostic impact of ETF in FL. Disclosures Luminari: Celgene: Consultancy; Roche: Consultancy; Gilead: Consultancy; Servier: Consultancy; Sandoz: Consultancy. Passamonti:Celgene: Consultancy, Speakers Bureau; Roche: Consultancy; Novartis: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Speakers Bureau.

Description: Background: Bortezomib Disclosures Corso: Janssen-Cilag: Honoraria.

Description: There is widespread concern about a possible higher prevalence of extramedullary relapse (EMR) in patients with multiple myeloma (MM) in the era of novel biological agents. Aims of this study were: i) to assess the prevalence of treatment-emergent EMR in a cohort of patients extensively exposed to biological drugs; ii) to investigate the association between previous exposure to biological drugs and subsequent EMR. Following approval by our institutional Ethics Committee, we reviewed clinical and hematologic data of 456 MM patients (pts) who were consecutively observed in our Department between 2000-2010. This time frame allowed us to study the effect of the introduction of the novel biological agents (bortezomib, thalidomide, lenalidomide) in addition to standard chemotherapy and high-dose therapy (HDT) on EMR occurrence. Extramedullary disease was categorized as follows: a) soft tissues masses adjacent to bone; b) localizations in extra-osseous organs. Survival and extramedullary disease prevalence were compared with an historical cohort of 182 patients observed in our Department between 1994-1999, when only HDT was available [Ann Oncol 2010, 21(2):325-30]. Table 1 summarizes the main characteristics of the new cohort at diagnosis. After a median follow-up of 39 months (range 0-150 months), 63 (13%) patients remained asymptomatic. In symptomatic patients (n=393, 87%), first line therapy included HDT in 199 (51%) cases, and novel agents in 137 (35%). In relapsing patients (n=271), the median number of subsequent treatments was 2 (1-8); 40 (14%) patients were treated with chemotherapy alone, the remaining 231 (86%) received various treatments including at least one biological agent The prevalence of extramedullary disease at clinical onset was 14% in the recent cohort vs 6% in the historical cohort (p=0.004). The prevalence of EMR in patients of the new cohort without extramedullary disease at diagnosis was 24% (92 patients). Sites involved included soft tissue adjacent to bone in 47%, and extraosseous organs in 53% of cases. When compared to the historical cohort, MM patients had a better outcome (median OS 6.4 vs 3.9 years, P

Description: Background Elderly multiple myeloma (MM) patients are an heterogeneous population. Aging is associated with an increased frequency of co-morbidities, frailty and disability, with negative impact on treatment tolerance and outcome. A simple and reliable scoring system, based on geriatric assessment, has been developed to predict survival and used also to predict the risk of severe toxicities or treatment discontinuation in elderly newly diagnosed MM patients treated with lenalidomide-, bortezomib- or carfilzomib-based induction regimens. Methods Patients with newly diagnosed MM, ineligible for high-dose therapy and autologous stem cell transplantation due to age (≥65 years) or coexisting co-morbidities, enrolled in 3 prospective multicenter trials, were included in the analysis. Up-front dose reductions were performed according to patients age (full doses for patients ≤75 years and reduced for patients 〉75 years). Details on treatment regimens and results of these studies have previously been reported (Gay F et al EHA 2013, Larocca A et al EHA 2013, Bringhen S et al EHA 2013). At diagnosis, a geriatric assessment had been performed, to assess co-morbidities, cognitive and physical conditions. Results 869 patients were included in the analysis: 659 enrolled in the lenalidomide-based, 152 in the bortezomib-based and 58 in the carfilzomib-based trial. Median age was 74 years, and 44% of patients were older than 75 years. Median follow-up was 18 months. In univariable analysis, the risk of death was higher in patients aged 75-80 (Hazard Ratio, HR 1.37, p=0.11), and in patients older than 80 years (HR 2.75, p