ALBERT

Description: Background In younger and fit multiple myeloma (MM) patients (pt), autologous stem cell transplantation (ASCT) remains the gold standard treatment. Mobilization chemotherapy is usually administered in an inpatient regimen and Cyclophosphamide (CY) at different doses is the most used chemoterapy for collecting peripheral blood stem cells (PBSC) in MM. Clinical trials have demonstrated that intermediate dose CY (3 and 4 g/m2, ID-CY) combined with G-CSF, is an efficient mobilizing regimen with less toxicity compared with high dose CY (7 g/m2, HD-CY) in term of neutrophil recovery, thrombocytopenia, need of transfusions and IV antibiotics. (Fitoussi et al, BMT 2001; Goldschmidt et al, BMT 1996). Objective To evaluate the safety of mobilization therapy administered in an outpatient regimen, with the prospect to lower costs and minimize patient inconvenience, maintaining an optimal yield. Methods 92 pt with newly diagnosed MM underwent outpatient stem cell mobilization between 2002 and 2016 with CY 3 g/m2 (82%) or 4 g/m2 (18%) + G-CSF after induction therapy with bortezomib-based (79%) or VAD-like (21%) regimens. No antibiotics prophylaxis was routinely used. Day 0 was defined as the CY infusion day. CY was administered in 2-4 consecutive 1h infusions (depending on total dose). Hyper-hydration (3.5/4 l), antiemetics and the uroprotectant Uromitexan were began IV 1 hour before CY infusion. Subsequently, Uromitexan was continued at home orally in the next 12h. Furthermore, the patient was advised to drink 2.5/3 l of water in the next 24h. G-CSF 10 mcg/Kg was started by day +5 and continued until completion of apheresis. Blood count was monitored at day + 4 and daily from day +7. CD34+ cells were counted on peripheral blood by day 7; apheresis was started at leukocyte rise and with a value of at least 20 CD34+/μl. Number of apheresis depended on the number of CD34+ cells collected to obtain al least 4x106 CD34+/Kg. Results Median age at diagnosis of was 56y (range 34-68). MM isotype was IgA, IgG and micromolecular respectively in 18%, 58% and 24%. Prior MGUS was present in 37 cases (43%). LDH was elevated in 7 pt (11%), whereas ISS was 1/2/3 in 47%/30%/23%. Bone disease was detectable in 74% of pt, with 56% having 3 or more osteolysis. Median bone marrow plasma cell at diagnosis was 60% (range 10-95%). Pt received induction with bortezomib-based regimens (79%) or chemoterapy, mostly VAD (21%). 8 pt (9%) required second line therapy before mobilization. Response prior of mobilization was CR/sCR in 15%, VGPR in 59%, PR in 24%, and SD in 2%. Stem cell collection was successful in 98% of pt, with a median CD34+ harvest of 9.8x106/Kg. Chemotherapy was very well tolerated. Most frequently observed adverse events (AEs) were nausea and vomiting of grade 1-2. 2 pt experienced cystitis (one grade 1, one grade 2), 2 pt infections, 2 pt hyperthermia regressed rapidly without therapy, 1 patient diarrhea. 3 pt had neurological symptoms: in 2 cases they were aspecific (headache, instability); the other case presented a sudden appearance of 7th cranial nerve deficit at the end of mobilization chemotherapy infusion with negative imaging and successively regressed in few hours, interpreted as transient ischemic attack not correlated with Cy. Only 2 patient required hospitalization for AEs: 1 patient for fever grade 3 without microbiological findings, rapidly regressed with IV antibiotics; the second one for 7th cranial nerve deficit. These were the only grade 3 AEs, no grade 4 AEs verified. There were no other significant AEs related to chemotherapy. All pt except 2 proceeded to stem cell harvest and reached CD34+ target, but 5 pt required administration of Plerixafor on demand. The 2 pt not reaching CD34+ target successfully mobilized afterwards, 1 with different chemoterapy and the other with G-CSF and Plerixafor. After mobilization, 88 pt proceeded to single (45%) or double (55%) ASCT. Conclusion In conclusion, outpatient mobilization with ID-CY appears to be an efficient and safe procedure, with minimal and manageable side effects and low rate of hospitalization. Outpatient mobilization could ameliorate the quality of life of pt and reduce costs, avoiding or minimizing the hospitalization rate, without compromising the safety profile and the success of PBSC collect. Disclosures No relevant conflicts of interest to declare.

Description: 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 (

Description: Introduction Lenalidomide (Len) and low-dose Dexamethasone (dex) (Rd) in continuous is a new standard of care for elderly newly-diagnosed multiple myeloma (NDMM) patients (pts), as established by FIRST trial (Facon et al, Blood 2018). Methods and results This is a retrospective, multicentric study conducted in Italy with the aim of evaluating efficacy and tolerability of Rd in a real-life population. Thirty-seven centers were involved and data of 429 pts are available. Pts were considered eligible for the study when completing at least 2 cycles of Rd regimen. Table 1 summarizes the characteristics of pts at time of MM diagnosis. Median age was 78 years (range 57-92), 36.6% had an ECOG PS≥2, creatinine clearance (ClCr) was ULN (P=0.01) and ClCr2 still impact on OS (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: Introduction Hematologic neoplasms are associated with an increased incidence of autoimmune events, particularly evident in non‐Hodgkin lymphomas (NHL) and especially chronic lymphocytic leukemia (CLL); until now only few cases have been described in patients affected by multiple myeloma (MM) and other plasma cell disorders. The introduction of new drugs, in particular immunomodulatory drugs (IMiDs), could increase the risk of these complications. Herein we describe four cases of immune thrombocytopenia (ITP) occurred during Lenalidomide (LEN) therapy in 3 patients affected by MM and 1 with light‐chain amyloidosis. Case reports Case 1. A 66‐year old woman with relapsed IgGk MM started 2th line treatment with LEN/DEX 25 mg/d-20 mg/w. During the first 5 cycles she presented moderate hematologic toxicity which resolved after dose reduction (LEN 15 mg/d). A severe and isolated thrombocytopenia appeared after 5th cycle with patient in good partial remission (PR) for MM. A bone marrow evaluation showed absence of plasma cells and abundant megakaryocytes leading to a diagnosis of ITP. LEN was interrupted and steroid therapy (prednisone 1 mg/Kg) and IV Ig infusion administered, obtaining a transient good response (from 17 to 114 x 109/l). LEN was then restarted at lower dosage but a month after, while myeloma still was in good response, ITP relapsed complicated by intracranial hemorrhage and was successfully treated with IV Ig; Len was definitely interrupted. At the third relapse Rituximab (750 mg/w x 4 weeks) was administered with only minimal increase of platelet count (Fig 1). Afterwards, the patient died due to rapid MM progression. Case 2. A 76‐year old woman with relapsed IgGλ MM started 2th line treatment with LEN 15 mg. After the 3rd cycle, having obtained a very good partial remission (VGPR), she presented with grade 3 thrombocytopenia which did not ameliorate with LEN suspension and resolved only after introduction of steroid, thus supporting ITP diagnosis. She underwent a 4th cycle of LEN/DEX maintaining a normal platelet count but then LEN was interrupted due to rapid MM progression. (Fig 2). Case 3. A 78‐year old woman with renal amyloidosis in IgAλ gammopathy started a 2nd line treatment with LEN/DEX 15 mg/d-20 mg/w with a significant reduction in proteinuria. During the 6th cycle she presented with diffuse purpura and a platelet count of 18x109/L. She received platelet transfusion and bone marrow evaluation showed abundant megakaryocytes supporting the diagnosis of ITP. Furthermore anti‐platelet antibodies search resulted positive. Steroid therapy was started with partial response on platelet count but the patient remained steroid‐therapy dependent. Case 4. A 66‐year‐old woman affected by MM started a 2th‐line treatment with LEN‐DEX 25 mg/d-20 mg/w. After the third cycle, being the patient in PR, a isolated grade 3 thrombocytopenia developed, persisting despite discontinuation of LEN. Viral infections were excluded and antiplatelet antibodies search resulted positive. Therefore she started steroid therapy (prednisone 1 mg/Kg) with an progressive increase of platelet count from 44 to 80x109/L after a month of therapy, that is ongoing. Lenalidomide has not yet been restarted. Discussion We report four cases of ITP developing during LEN therapy with the characteristics of ITP. None of these patients had a history of previous autoimmune events, the decline of platelet count was rapid and other causes of thrombocytopenia were excluded or unlikely in all the cases. Furthermore diagnosis was supported by consistent bone marrow evaluation in two cases. Considering the temporal association in these four cases, the ITP mechanism may be related to the immunomodulation and T‐cell activation caused by LEN. Even if further other studies are needed, it seems reasonable to consider a possible association between LEN and autoimmune phenomena, in particular ITP. 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: 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: 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)

Description: Lenalidomide-dexamethasone (Rd) is a standard treatment for elderly multiple myeloma (MM) patients. In this randomized, phase III study, we investigated the efficacy and feasibility of a dose/schedule-adjusted Rd followed by maintenance 10 mg/day without dexamethasone (Rd-R) vs continuous Rd in elderly, intermediate-fit newly diagnosed MM patients. The primary endpoint was event-free survival (EFS), defined as progression/death for any cause, lenalidomide discontinuation, any hematologic grade 4 or non-hematologic grade 3-4 adverse events (AEs). Of the 199 evaluable patients, 101 received Rd-R and 98 continuous Rd. Median follow-up was 37 months. Best response rates were comparable: ≥ partial response rates were 78% vs 68% (p=0.15) in Rd-R vs continuous Rd groups. EFS was 10.4 with Rd-R vs 6.9 months with continuous Rd (HR 0.70, 95% CI 0.51-0.95, p=0.02). Median progression-free survival was 20.2 vs 18.3 months (HR 0.78, 95% CI 0.55-1.10, p=0.16), 3-year overall survival was 74% vs 63% (HR 0.62, 95% CI 0.37-1.03, p=0.06). At least 1 non-hematologic grade ≥3 AE rate was 33% vs 43% (p=0.14); the most frequent grade ≥3 AEs were neutropenia (21% vs 18%), infections (10% vs 12%) skin disorders (7% vs 3%) in Rd-R vs Rd; constitutional and central nervous system AEs mainly related to dexamethasone were more frequent with continuous Rd. Lenalidomide was discontinued for AEs in 24% vs 30% and was reduced in 45% vs 62% of patients, in Rd-R vs Rd, respectively. In intermediate-fit patients, switching to reduced-dose lenalidomide maintenance without dexamethasone after 9 cycles of Rd was feasible, with similar outcome to standard continuous Rd.