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The authors report on the subset of AL amyloidosis patients with nonlymphoplasmacytic lymphoma, emphasizing a predominance of marginal zone lymphoma, frequent delay in diagnosis, and a generally poor prognosis.

Background: Lenalidomide (R) plus dexamethasone (d) triplet combinations have been indicated by ESMO guidelines as standard of care in first relapse for lenalidomide sensitive multiple myeloma (MM) patients (pts) (Dimopoulos et al, 2021). Meta-analysis of randomized clinical trials (RCT) shows better outcome with the combination of Daratumumab + Rd (DaraRd) over other Rd-based combinations (carfilzomib+Rd (KRd), elotuzumab+Rd (EloRd), Ixazomib+Rd (IxaRd). There are few real-life studies focusing on the pattern of utilization and outcome of different Rd triplets in first relapse MM. Aims: To explore performances of market-approved Rd-based triplets in unselected MM pts in first relapse. Patients and methods: After ethics committee approval, we review data of 366 MM pts in first relapse consecutively addressed to Rd-based triplets according to market-approved schedule after 2017. Rd-based therapies was distributed as follows: DaraRd 51.6% (189 pts), KRd 36.1% (132 pts), EloRd 8.7% (32 pts), IxaRd 3.6% (13 pts). Given the limited number of pts treated with IRd and EloRd, the analysis is focused only on DaraRd and KRd group after further excluding 51 pts (13%) addressed to salvage autologous stem cell transplant (ASCT) after daraRd (n=9)/KRd(n=42) fixed induction. Few pts in both groups were previously exposed to R/K/Dara (respectively 12 pts (3%), 8 (2%), 0). Treatment choice was influenced by market approval, with KRD regimen used more commonly in the IQR 2017- 2019, while DaraRd more commonly in the IQR 2018-2020. To limit the bias of a retrospective observation, we calculated a propensity score and we used it (after trimming of 5% of observations) to re-weight the data, according to the Inverse Probability of Treatment method (IPTW analysis). For the estimation of the propensity score, we used: age at Rd-triplet starting, ISS stage, presence of high-risk FISH, previous exposure to Bortezomib, previous ASCT, good response at first-line therapy (≥VGPR), time between diagnosis and relapse, myeloma defining events at diagnosis, type of relapse (symptomatic/biochemical), center. Details of these characteristics are reported in table1. Of note, pts addressed to DaraRd were slightly older (68,7 vs 63,4 years in KRd, p Conclusions: Our real-life study shows that DaraRd represents the most commonly received regimen at first relapse followed by KRd triplet. After propensity score matching, DaraRd and KRd combinations proved to be both effective with similar outcomes when used early in the treatment history, after one line of therapy. This study, in addition, points out the possible gap of outcome between RCT and clinical practice. Figure 1 Figure 1. Disclosures Mangiacavalli: BMS: Honoraria; Janssen: Honoraria; Takeda: Honoraria; GSK: Honoraria. Galli: BMS, Celgene, Janssen, Sanofi, Takeda: Honoraria. Belotti: Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; GSK: Membership on an entity's Board of Directors or advisory committees. Fazio: Janseen: Honoraria. Petrucci: Celgene: Honoraria, Other: Advisory Board; Janssen-Cilag: Honoraria, Other: Advisory Board; BMS: Honoraria, Other: Advisory Board; Takeda: Honoraria, Other: Advisory Board; Amgen: Honoraria, Other: Advisory Board; GSK: Honoraria, Other: Advisory Board; Karyopharm: Honoraria, Other: Advisory Board.

Background: Treatment of multiple myeloma (MM) commonly encompasses combination of drugs within the three drug classes including proteasome inhibitors (PIs), immunomodulators and (IMiDs), and monoclonal antibodies, both for newly diagnosed and relapsed disease. With increasing appreciation of disease heterogeneity based on underlying genetic abnormality, and demonstration of efficacy of venetoclax in patients with t(11;14) MM, the outcomes with commonly used MM regimens among the different cytogenetic subgroups are of great interest. Venetoclax, a BCL-2 inhibitor, is being studied in t(11;14) positive MM patients who have received at least two prior lines of treatment (NCT03539744; CANOVA). However, outcomes in previously treated t(11;14) MM patients using standard of care approaches in the real-world setting is limited. Patients and methods: This non-interventional, retrospective observational cohort study included patients with t(11;14) MM from the International Myeloma Working Group (IMWG) retrospective study of t(11;14) MM. From the overall cohort, patients with t(11;14) MM receiving pomalidomide + dexamethasone (PomDex) in ≥3 rd line were selected, similar to those being enrolled in the ongoing CANOVA trial. Patients were also required to have prior exposure to lenalidomide and a PI without a history of transplant within 16 weeks prior to PomDex initiation. Patients enrolled in a clinical trial were excluded. Overall best response, time to next therapy (TTNT) as a surrogate measure for progression-free survival (PFS) and overall survival (OS) were assessed after initiation of PomDex. All analyses were descriptive in nature and were conducted using SAS 9.4 (SAS Institute Inc., Cary, NC, USA). Results: Fifty-two patients who met the inclusion criteria were analyzed. Median age was 63 years, 60% were male. Patients had a median of 3 prior lines at start of PomDex, at a median of 4.3 years from diagnosis; 52% had a prior transplant. A PR or better was observed in 34% of patients with PomDex. The median TTNT for this cohort was 6.1 months and median OS was 19.2 months. Conclusion: This retrospective study of non-trial patients with t(11;14) MM provides a benchmark for newer therapies in this patient population for comparison with both venetoclax dexamethasone in the ongoing CANOVA study as well as combinations using the pomalidomide backbone. Disclosures Karve: AbbVie: Current Employment, Current equity holder in publicly-traded company. Kumar: Roche-Genentech: Consultancy, Research Funding; Bluebird Bio: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; Novartis: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Carsgen: Research Funding; Antengene: Consultancy, Honoraria; Oncopeptides: Consultancy; Beigene: Consultancy; Tenebio: Research Funding; BMS: Consultancy, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding. Gonzalez De La Calle: Celgene-BMS, Janssen, Amgen: Honoraria. Mangiacavalli: GSK: Honoraria; Takeda: Honoraria; Janssen: Honoraria; BMS: Honoraria. Kastritis: Janssen: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Genesis Pharma: Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Esteves: AbbVie: Consultancy; BMS: Consultancy; Amgen: Consultancy; Janssen: Consultancy. Delforge: 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. Yee: Karyopharm: Consultancy; Bristol Myers Squibb: Consultancy; Oncopeptides: Consultancy; Adaptive: Consultancy; GSK: Consultancy; Takeda: Consultancy; Amgen: Consultancy; Janssen: Consultancy; Sanofi: Consultancy. Arriola: AbbVie: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Ross: AbbVie: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company. Manthena: AbbVie: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Durie: Amgen, Celgene/Bristol-Myers Squibb, Janssen, and Takeda: Consultancy; Amgen: Other: fees from non-CME/CE services .

Background: Diffusion-weighted whole body MRI (WB-DWI) is a new functional imaging technique comprising anatomical and functional sequences with an emerging role in the management of multiple myeloma (MM) patients (pts) since it allows highly sensitive detection of diffuse bone marrow (BM) infiltration pattern and focal lesions, avoiding intravenous injections and radiation exposure. The aims of our study were 1) to test the correlation between plasma cells infiltration (BMPC) rate at BM biopsy and the presence of diffuse infiltration pattern at WB-DWI. 2) to compare response according to IMWG criteria and WB-DWI response and to establish the rate of discordancy (WB-DWI progression with increased focal lesions and at least a partial response according to IMWG criteria) Methods: We reviewed data regarding 45 MM patients (pts) observed in our Centre between September 2018 and July 2019 for whom quantification of serum and urine monoclonal component (MC), free light chains value (FLC), BM biopsy, whole body CT scan and WB-DWI data were available at the same time point. Sequential assessment of WB-DWI and laboratory data was available in 20 pts. Patients performed a WB-DWI (Magnetom Area, 1.5T, Siemens Enlarged Germany) for head to knee. The protocol included anatomical sequences T1 and T2 weighted with fat suppression on the sagittal plane specifically for the spine. Coronal T2 weighted fat suppression sequences are performed for the study of femural bone. Axial Dixon T1 weighted sequences of the whole scan region, in breath-old. The functional part is formed by diffusion weighted sequences in the axial plane. MM diagnosis and response were assessed by IMWG criteria. Response were categorized as follows: responsive patients if ≥PR, progressive disease if Results: Table 1 summarizes the clinical and radiological data of the population on study. Median age was 64 years (range 38-86), median number of previous lines of therapy at time of evaluation was 0 (range 0-)2; 47% pts were at the onset, 31% were in follow-up after treatment completion, 22% had progressive disease. WB-DWI showed a diffuse pattern in 22 pts (49%); in 23 patients without a diffuse pattern, 7 (30%) had PBMC >10%; BMPC infiltration rate was significantly higher in pts with presence of diffuse pattern at WB-DWI (p Conclusions: Our study findsa significant correlation between presence of WB-DWI diffuse infiltration patter and BMPC rate, highlighting the possible future use of this radiological technique for monitoring BM residual disease. In addition, this study shows the possible not negligible emergence of discordant pattern of progression, probably deriving from the spatial heterogeneity of MM clones and their different sensitivity to therapy. Disclosures Mangiacavalli: celgene: Consultancy; Janssen cilag: Consultancy; Amgen: Consultancy. Varettoni:Gilead: Other: travel expenses; ABBVIE: Other: travel expenses; Roche: Consultancy; Janssen: Consultancy. Arcaini:Celgene: Speakers Bureau; Celgene, Roche, Janssen-Cilag, Gilead: Other: Travel expenses; Gilead Sciences: Research Funding; Bayer, Celgene, Gilead Sciences, Roche, Sandoz, Janssen-Cilag, VERASTEM: Consultancy.

A study has shown that MYD88 (L265P) is a recurring somatic mutation in Waldenstrom's macroglobulinemia (WM). We developed an allele-specific polymerase chain reaction (PCR) for this mutation, and analyzed bone marrow or peripheral blood samples from 58 patients with WM, 77 with IgM monoclonal gammopathy of undetermined significance (IgM-MGUS), 84 with splenic marginal zone lymphoma (SMZL), and 52 with B-cell chronic lymphoproliferative disorders (B-CLPD). MYD88 (L265P) was detected in 58/58 (100%) patients with WM, 36/77 (47%) with IgM-MGUS, 5/84 (6%) with SMZL, and 3/52 (4%) with B-CLPD. Compared to IgM-MGUS patients with wild-type MYD88, those carrying MYD88 (L265P) showed significantly higher levels of IgM (P < .0001) and presented Bence-Jones proteinuria more frequently at diagnosis (P = .002). During follow-up, 9 patients with IgM-MGUS progressed to WM or to marginal zone lymphoma. Using a case-control approach, the risk of evolution of patients carrying MYD88 (L265P) was significantly higher than that of patients with wild-type MYD88 (odds ratio 4.7, 95% confidence interval 0.8 to 48.7, P = .047). These findings indicate that the allele-specific PCR we developed is a useful diagnostic tool for patients with WM or IgM-MGUS. In this latter condition, MYD88 (L265P) is associated with greater disease burden and higher risk of disease progression, and the mutation may therefore also represent a useful prognostic marker.

Systemic light chain (AL) amyloidosis is caused by the clonal production of an unstable immunoglobulin light chain (LC), which affects organ function systemically. Although pathogenic LCs have been characterized biochemically, little is known about the biology of amyloidogenic plasma cells (PCs). Intrigued by the unique response rates of AL amyloidosis patients to the first-in-class proteasome inhibitor (PI) bortezomib, we purified and investigated patient-derived AL PCs, in comparison with primary multiple myeloma (MM) PCs, the prototypical PI-responsive cells. Functional, biochemical, and morphological characterization revealed an unprecedented intrinsic sensitivity of AL PCs to PIs, even higher than that of MM PCs, associated with distinctive organellar features and expression patterns indicative of cellular stress. These consisted of expanded endoplasmic reticulum (ER), perinuclear mitochondria, and a higher abundance of stress-related transcripts, and were consistent with reduced autophagic control of organelle homeostasis. To test whether PI sensitivity stems from AL LC production, we engineered PC lines that can be induced to express amyloidogenic and nonamyloidogenic LCs, and found that AL LC expression alters cell growth and proteostasis and confers PI sensitivity. Our study discloses amyloidogenic LC production as an intrinsic PC stressor, and identifies stress-responsive pathways as novel potential therapeutic targets. Moreover, we contribute a cellular disease model to dissect the biology of AL PCs.

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

Background: Several trials and analysis have explored the efficacy of bortezomib re-use in relapsed patients with multiple myeloma (MM), notably in those who have experienced good response and late relapse after the end of frontline treatments including the same drug. However, very few specific evidences on bortezomib re-challenge at first relapse are available. Patients and methods: This observational, retrospective study enrolled 135 MM patients treated from January 2002 to May 2015 in 12 Italian centres with bortezomib-based regimens as first line therapy (both in daily practice or clinical trials) and who had received again a salvage treatment containing bortezomib at first relapse, according to current clinical practice and/or guidelines recommendations. Results: Median age was 61 years (range 28-95) and 60% of patients were males. At diagnosis, ISS was 30% stage I, 30% stage II and 40% stage III; r-ISS (available in 45 cases) was 25% stage I, 44% stage II and 31% stage III. Two patients presented as primary plasma cell leukemia (PCL). First line induction treatments included VD (27%), VTD (25%), VMP (23%), PAD (10%), and further combinations of bortezomib with cyclophosphamide (11%) or other drugs (4%). Eighty-two percent of patients received a twice-week schedule and 18% once-a-week administration of bortezomib, which was initially given i.v. in 71% and s.c. in 29% of patients, respectively. Seventy-five patients (56%) underwent single (72%) or double (28%) autologous stem cell transplantation (AuSCT) as part of their frontline therapy. Consolidation or maintenance with borteomib were performed in 17 and 4 patients, respectively. As per inclusion criteria, all patients achieved PR or better response (according to IMWG criteria), including at least VGPR in 36%, CR in 20% and sCR in 1% of cases. Median duration of PFS1 was 33 months (95% CI 28-36), while median treatment free-interval (TFI) was 23 months (95% CI 22-28). Median PFS1 was 35 months (95% CI 31-43) and 27 months (95% CI 20-33) for patients undergoing or not AuSCT, respectively (p n.s.). At first relapse (clinical 65%, only biochemical 35%), anemia, neutropenia and thrombocytopenia were present in 42%, 5% and 9% of patients, respectively. Median bone marrow plasma cell infiltration was 40% (range 2-99). Bone lesions were present in 74%, hypercalcemia in 7%, high LDH values in 15% of patients. Serum beta2-microglobulin levels were increased in 48%, while albumin was decreased in 17%. Renal failure was observed in 14%, with a median value of serum creatinine of 2.2 mg/dl (range 1.4-7). PCL occurred in 3 patients. Second line regimens included VD (44%), VCD (11%), PAD (9%), VTD (7%), BVD (7%), VMP (7%), VRD (4%), VRCD (2%), or other combinations (9%). Six patients had maintenance therapy with bortezomib. Twenty-one patients (16%) received AuSCT as part of their salvage therapy, while 4 patients (3%) underwent allogeneic transplantation (AlloSCT) and 5 (4%) a tandem sequence of AuSCT followed by AlloSCT. Seventy-four percent of patients received bortezomib once-a-week, 26% twice-weekly, 35% i.v. and 65% s.c. A total of 782 cycles (median 6, range 1-13) were given. Grade 3-4 hematological and non-hematological toxicities occurred in 27% and 10% of patients, respectively. No patient reported grade 3-4 neuropathy. Bortezomib dose reductions were needed in 12%. SPM occurred in 1 patient. Overall response rate was 70%, with 24% at least VGPR and 7% CR (sCR/nCR 1.5%). Improvement of renal failure (13 cases) was complete in 4 and partial in 6 patients. Bone disease improved in 31% of patients with osteolytic lesions. Median duration of second PFS was 19 months (95% CI 13-23), while that of second TFI was 14 months (95% CI 8-17). Median PFS2 was 56 months (95% CI 50-70); it was 60 months (95% CI 54-78) for patients who underwent AuSCT and 50 months (95% CI 45-68) for those who did not (p n.s.). Median OS was 94 months (95% CI 80-121) for the entire cohort, 94 months (95% CI 75-107) for patients undergoing AuSCT, and 86 months (95% CI 76-92) for those who did not receive AuSCT. After a median follow up of 56 months, 85 patients (63%) are alive, with 41 of them in response after second line therapies containing bortezomib. Conclusions: This real-life survey indicates that re-treatments including bortezomib as first salvage therapy should be considered for selected MM patients achieving prolonged response after initial exposure to first line, bortezomib-based regimens. Disclosures Musto: Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Cascavilla:Janssen-Cilag: Honoraria. Falcone:Janssen-Cilag: Honoraria. Petrucci:Janssen-Cilag: Honoraria. Di Raimondo:Janssen-Cilag: Honoraria. Ria:Binding Site: Speakers Bureau; BMS: Speakers Bureau; BMS: Speakers Bureau; Italfarmaco: Consultancy, Speakers Bureau; Janssen-Cilag: Other: Advisory Board, Speakers Bureau; CSL Behring: Consultancy, Research Funding, Speakers Bureau. Mastrullo:Janssen-Cilag: Honoraria. D'Arena:Janssen-Cilag: Honoraria. Bringhen:Janssen-Cilag: Honoraria; Celgene: Honoraria; BMS: Honoraria; Amgen: Other: ADVISORY BOARD; Mundipharma: Other: ADVISORY BOARD; Karyopharm: Other: ADVISORY BOARD. Di Renzo:Janssen-Cilag: Honoraria. Caravita:Janssen-Cilag: Honoraria. Palumbo:Janssen Cilag: Honoraria; Takeda: Employment, Honoraria. Corso:Janssen-Cilag: Honoraria.

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

To the editor: MYD88 (L265P) is a recurrent somatic mutation in Waldenstrom macroglobulinemia (WM).[1][1][⇓][2][⇓][3]-[4][4] By means of allele-specific polymerase chain reaction (AS-PCR), the MYD88 mutation is detectable in almost all patients with WM and in roughly half the patients with IgM

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 Conclusions: Confocal microscopy can be a useful tool for detection of Bortezomib induced neural damage in MM patients. Prospective studies are needed to evaluate if it could help physicians in detecting neural damage in advance with respect to the emergence of clinically evident Bor-PN. Disclosures No relevant conflicts of interest to declare.

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 In conclusion, this analysis shows an increased occurrence of EMR in the last decade, which appears to be independent from the better survival. Sequential exposure to novel biological agents emerges as a risk factor for EMR occurrence.Table 1Characteristics at diagnosis of the 456 patients treated from 2000 to 2010CRAB Symptoms:63 (13%)· Absent393 (87%)· PresentMedian Age61 (28-86) yearsMyeloma Type:268 (59%)· IgG100 (22%)· IgA79 (17%)· Light chain5 (1%)· Non-secretory4 (1%)· Other (IgD/IgM)D&S42 (9%)• I132 (30%)• II• III267 (61%)ISS(n=347)· I93 (27%)· II6 (2%)· III248 (71%)Extramedullary disease at diagnosis391 (86%)• No65 (14%)• Yes· Adjacent to bone51 (78%)14 (22%)· Extraosseous organs Disclosures: No relevant conflicts of interest to declare.

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.

Abstract 3997 Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant plasmacell dyscrasia with a high prevalence. Diagnostic criteria include: presence of serum monoclonal component (MC) Disclosures: No relevant conflicts of interest to declare.

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 In conclusion, this study confirmed a positive association between serum CTX and presence of active bone disease. In addition serum CTX levels show a significant decrease under treatment with bisphosphonates. Taking into account these observations, patient-specific variations rather than the absolute serum CTX value should be used for detecting the onset of new SREs during a concomitant bysphosphonates treatment. Tab 1: Levels of serum CTX according to bone disease status and bisphosphonates treatment. Bisphosphonates treatment Progression in bone disease Active None Yes 0.219 (0.03–1.79) 0.533 (0.02–4.14) No 0.139 (0.03–0.69) 0.345 (0.071–1.57) Disclosures: No relevant conflicts of interest to declare.

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.

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 Conclusion In this study, only CR not VGPR impacts on the outcome. Vel-Dex producing a significant high CR rate after TX (38%), seems to improve survival of MM patients candidate to high-dose therapy with respect to conventional pre-transplant strategies. Disclosures Morra: Roche:.

Background. Monoclonal gammopathy of undetermined significance (MGUS) is defined by the presence of a serum M-protein Aims of the study. To evaluate whether the pattern of presentation of MGUS has changed over the last three decades. Patients and methods. The charts of MGUS patients (pts) diagnosed from 1975 to 2007 were reviewed. The following data were gathered: age, sex, haemoglobin (Hgb), type and size of serum M-protein, uninvolved Ig levels, serum FLC, urine M-protein, BMPC, serum albumin and β2-microglobulin. The study included 1400 pts divided into three groups according to the date of diagnosis: 1975–1987 (group I, 102); 1988–1997 (group II, 380); 1998–2007 (group III, 918). Differences among groups were evaluated using chi-square test for categorical variables and Kruskal-Wallis non-parametric Anova for numerical variables. A P-value ≤0.05 was considered statistically significant. Results., The median age of patients was 63 years (range 20–92), 740 were males and 660 females. The median time from the first detection of M-protein to diagnosis of MGUS was 3.2 months (range 1–264). Serum M-protein was 73% IgG, 13% IgM, 11% IgA, 3% biclonal; light chain was k in 63% of pts, λ in 37%. The serum M-protein was Conclusions. The pattern of presentation of MGUS has changed over time. Patients diagnosed in the last decade have more favourable presenting features as compared to those diagnosed before. This could be due to the availability of more sensitive diagnostic techniques able to detect minimal M-proteins. Another possible explanation is that pts are more frequently and promptly referred by their treating physicians to an hematologic centre, allowing an earlier diagnosis. Both circumstances could led to the identification of a subset of pts with different presentation and maybe a better outcome with respect to the MGUS diagnosed in the past decades. This could entail a different approach of physicians in the management of MGUS patients.

Extramedullary myeloma (EMM) at diagnosis or during the course of the disease is rare and often anecdotal. We reviewed the records of 965 consecutive MM pts diagnosed and followed from 1969 to July 2007 in order to evaluate: the overall incidence of EMMs and the changes over time clinical presentation, response to treatment and outcome of EMM pts divided into two subgroups according to the time of appearance, at diagnosis or during the course of the disease. We considered three periods: 1969–1989 (conventional chemotherapy, CCT); 1990–1999 (introduction of high-dose therapy, HDT); 2000–2007, (era of novel agents). The overall incidence of EMM was of 13% (129/965 pts), 87/42 M/F, median age 58 (31–80) years. A prior MGUS was present in 24 pts and a solitary plasmacytoma in 10 (8%). Characteristics at the time of EMM were: 77 pts IgG (60%), 23 IgA (18%), 2 IgM (2%), 16 light chain (12%), 11 not secretory (8%); 29 pts were in stage I, 14 in stage II, 86 in stage III; 30/129 pts (23%) were asymptomatic. More frequently involved sites were: paravertebral (40%), rib cage (32%), pelvis (10%). Multiple localizations were present in 27 pts (21%). A plasmacytic leukemia was observed during the follow-up in 9 pts (7%). The overall median follow-up was 24.4 (2.5–148) months. Seventy-three pts presented EMM at the time of diagnosis with different incidences in the 3 periods: 1969–1989 4.5%, 1990–99 4.3%, 2000–07 12.7%. These pts were treated with HDT in 43 cases (59%) and CCT in 30 (41%). Radiotherapy (RT) was associated in 38 pts (52%). A partial response (PR) was achieved in 49 pts (67%). Progression or relapse were observed in 46 pts (63%) and the median time to progression (TTP) and overall survival (OS) in this subgroup of pts were 17.3 and 21.5 months respectively. The other 56 pts showed an EMM during the course of the disease after a median time of 20 (2–144) months from diagnosis. EMM incidence varied as follows: 1969–1989 2.7%, 1990–99 7.2%, 2000–07 7.4%. Median number of previous lines of therapy was 1 (range: 1–7), including HDT in 22 pts (39%), thalidomide or lenalidomide in 18 (32%), bortezomib in 5 (9%). The median time from HDT to EMM was 17 (2–125) months. Treatment of these pts consisted of CCT in 36 cases (64%), thalidomide in 3 (5%) and bortezomib in 8 (14%). RT was given in 29 cases (52%). Response rate in this subgroup was low, only 30% of pts obtained a PR. The median TTP and OS from the time of appearance of EMM were 4.7 and 6.5 months respectively and the overall survival from the diagnosis was 29.9 months. The two groups of EMM pts were also compared for all the clinical characteristics, response to therapy and outcome. EMM pts at diagnosis showed higher levels of monoclonal component and haemoglobin, and lower bone marrow plasmacytosis with respect to the others. OS from diagnosis was similar in the two groups. In conclusion, our study shows an increased incidence of EMM over time. The more recent increase of EMM at diagnosis might be due to the wider use of more sensitive imaging techniques as CT scan and magnetic resonance, while during the course of the disease after 1990 could be related to the longer survival of pts thanks to the new therapeutic approaches. Anyway, the presence of EMM whether at diagnosis or at progression seems to negatively affect the outcome of pts since the OS is shorter than MM pts without EMM.

Background: Bisphosphonates (Bi) have been proven to be effective in preventing or delaying skeletal complications in multiple myeloma (MM) with a significant improvement of the quality of life. The 2002 ASCO guidelines indicate that once initiated intravenous Bi should be continued until an evident substantial decline of performance status. Recently, osteonecrosis of the jaw (ONJ) has been reported as complication of intravenous Bi treatment, with an incidence ranging between 6 and 13% and a greater occurrence in patients (pts) receiving zoledronic acid (Zol) than in those treated with pamidronate (Pam). Aim. In this retrospective study we evaluated the incidence of ONJ and of skeletal related events (SRE) in a cohort of MM pts divided in two groups according to the schedule of administration of Bi; group A: monthly administrations until tolerated (standard), group B: monthly administrations during the first year and then every 3 months (reduced). Methods: One hundred and six MM pts (M: 63, F: 43) were included in this study: 51 pts received a standard treatment (group A) and 55 a reduced schedule (group B). Pam 90 mg i.v. was administered as a three hour infusion and Zol 4 mg i.v. as a 15 minutes infusion. SRE was defined as: pathologic fracture, radiation to bone, spinal cord compression with vertebral fracture, hypercalcemia. Results: No difference was found between the two groups concerning pts characteristics at the onset: age, sex, extension of bone disease, status of the disease (progressive or responsive). Twenty pts received only Pam, 42 only Zol and 44 pts Pam followed by Zol. The distribution of the different type of Bi was not different in the two groups. ONJ occurred in 7 pts (6.6%) with a significant difference between the two groups: 6 pts in standard schedule (11.7%) and 1 in the reduced (1.8%), p=0.01, after a median time of 22.8 months in group A, and 37.8 months in the case of group B. Four of out 7 ONJ occurred during the second year of treatment (12–24 months): that period resulted significantly related (p=0.000) to the occurrence of ONJ with respect to the others (24–38 months, 40–100 months). All ONJ occurred in pts treated with Zol alone (5 pts) or with Zol after Pam (2 pts), whereas no cases were observed in Pam alone pts (p= 0.005). The median number of infusions was 20 with comparable results in the two groups (20 in group A, 19 in group B). SRE was observed in 38 pts (35.8%): 16 pts in group A and 22 pts in group B without statistical difference (p=0.6), after a median time of 9.8 months. Conclusions: These results suggest that the reduced schedule of Bi is associated with a significant lower incidence of ONJ and, although the sample size is limited, the appearance of ONJ seems delayed with respect to the standard treatment. Moreover, the incidence of SRE is similar in the two groups. In conclusion, the reduced schedule, could be applied in order to combine the antiresorptive efficacy of Bi with a higher safety and a better compliance.

Radiographic skeletal survey (RSS) is the standard diagnostic tool for the screening of bone lesions in multiple myeloma (MM) at diagnosis and during the course of disease. Its major limitation is the low sensitivity in detecting minimal bone lesions and in differentiating active from inactive osteolyses. Several studies demonstrated the superiority of magnetic resonance imaging (MRI) over RSS for the detection of spinal and pelvis bone lesions. However, a significant proportion of patients develops bone lesions elsewhere, therefore MRI of spine and pelvis is inadequate for the staging and follow-up of patients. Recently, whole-body MRI (WB-MRI) has been used with promising results for the detection of secondary bone lesions in patients with non-haematological malignancies. The aims of this study were to evaluate the potential role of WB-MRI in the staging and follow-up of MM patients, using RSS as a standard of reference, and to study the correlation of MRI findings with biochemical markers of bone turnover. Characteristics of the 9 patients included in the study were the following: median age 57 years (46–67), 6 males and 3 females; 4 patients were untreated and asymptomatic, and 5 previously treated with chemotherapy. On the same day, all patients underwent RSS and WB-MRI, and blood sampling for serum osteocalcin (OC) as a marker of bone formation, and for carboxyterminal telopeptide of type I collagen (ICTP) as a marker of bone resorption. RSS and WB-MRI were read by two independent radiologists. WB-MRI was performed with a 1.5-T scanner (Magnetom Symphony Maestro Class). The skull, thorax, pelvis, femoral and lower leg bones were imaged in coronal planes, while sagittal images of the spine were acquired. T1-weighted spinecho (SE) and short-tau inversion time inversion recovery (STIR) sequences (TR 2670, TE 101, TI 150) with a maximum field of view of 450 mm and slice thickness of 5 mm were obtained. As reference standard contrast-enhanced MRI was performed in patients with discordant data at RSS and WB-MRI. RSS was negative in 5 patients, whereas in 4 revealed lytic lesions stable with respect to prior controls. In the group of RSS-negative patients, WB-MRI was positive in 3/5 cases, 2 of whom had marrow and serum progression at the time of evaluation. All 4 RSS-positive patients showed lytic lesions also at WB-MRI with an overlapping pattern of distribution. Only the lesions at humeral bones were not detected by WB-MRI, because humeri are outside the field of view. WB-MRI, however, was superior to RSS in identifying lytic lesions in the spine and pelvis. Biochemical markers of bone metabolism were evaluable in 8/9 cases. ICTP levels were high only in one patient without evidence of bone lesions both at RSS and WB-MRI. OC levels were low in 6 of 8 evaluable patients, and 5 of them had a positive WB-MRI. In conclusion, WB-MRI seems more sensitive than RSS for the detection of bone lesions in MM patients. In particular, it is more suitable for the initial staging of the disease in asymptomatic stage I MM and for the follow-up of patients with a stable picture of lytic lesions at RSS. There is no correlation between ICTP levels and the radiological findings, whereas OC levels are decreased in patients with extensive bone involvement.

The mechanisms underlying the mobilization of peripheral blood stem cells (PBSC) are still unknown, even though studies on healthy donors and on cancer patients have hypothesised a central role for CD34+ stem cells adhesion molecules and for chemokines serum levels. The type of mobilizing regimen and the pathologic condition can exert different effects on cytokine levels and adhesion molecules expression. To evaluate the modification of these parameters during mobilization we studied 10 MM patients treated with DCEP chemotherapy (Decadron, Cyclophosphamide, Etoposide, cis-Platin) followed by G-CSF (5 mg/kg/day starting 48 hours after chemotherapy until PBSC collection). The expression of four CD34+ cell adhesion molecules (Thy1, L-selectin, VLA4, CXCR4) was measured in the bone marrow before mobilization therapy and in the leukapheresis product. Serum levels of five cytokines (TGF-β, IL-8, HGF, VEGF-A, sVCAM-1) were assessed, through specific ELISA kits, before therapy, 5 days after the G-CSF stimulation and at stem cells collection. Each parameter was correlated with the number of CD34+ cells collected. Thy1 significantly decreased (p=0.007) and L-selectin significantly increased (p=0.038) in nearly all cases. By contrast, no statistically significant differences were observed for VLA4 and CXCR4 due to a consistent variability. Serum levels of IL-8 showed an increase at day 5, then a significant decrease at the time of the harvest (p=0.013); VEGF-A constantly increased (p In conclusion, this study shows that during stem cells mobilization in MM Thy-1 expression significantly decreases while L-selectin increases; the behaviour of VLA-4 and CXCR4 is extremely variable. As regards cytokines, we found a statistically significant increase of VEGF-A level, while TGF-β, which induces the stem cell homing, decreases during the mobilization allowing stem cells to migrate in the peripheral blood. High baseline levels of TGF-β and VEGF-A predict a good stem cells harvest.