ALBERT

Beschreibung: Background Renal impairment is a life threatening complication of myeloma with up to 20-25% of patients presenting with renal dysfunction. Outcome is poor as a result of a high early mortality. Around 28% of newly diagnosed myeloma patients with renal failure do not survive beyond 100 days compared with 10% overall. Studies have shown that within weeks of diagnosing myeloma with renal failure, treatment with dexamethasone alone or combined with bortezomib lowers serum free light chain (sFLC) levels by more than 50% in half of patients; achieving lower sFLC levels in this early period is associated with a greater chance of being alive and dialysis free at 100 days. Methods OPTIMAL is a randomised, multi-centre phase II trial of newly diagnosed myeloma patients with renal impairment. Renal impairment defined as 18 years old, chronic kidney disease (CKD) stage 4 or 5, not pregnant or risk of pregnancy for child bearing women, or partner of male participants, free of malignancies for 〉2 years, able to comply with all trial requirements and give fully informed consent. Patients were randomised to receive 4 cycles of either Bortezomib, Bendamustine and Dexamethasone (BBD) or Thalidomide, Bendamustine and Dexamethasone (BTD); all participants received bendamustine and dexamethasone in three week cycles. Treatment period for participants receiving 4 cycles of therapy was 12 weeks. Participants not considered suitable for autologous stem cell transplant (ASCT) could be given a further two cycles of treatment (up to 6 cycles in total) in their respective arms. The trial was powered to detect 23% differences in the percentage of patients achieving 〉50% reduction in sFLC between treatment arms, e.g. from 60% to 83%, with 80% power and a 5% 2-sided significance level, recruiting 60 patients in each arm. At the pre-planned interim analysis, the data and safety monitoring committee endorsed the closure of the trial as a 60% difference in sFLC was detected and there was no obvious benefit for the BTD arm. This was also endorsed by the trial steering committee and trial management group. Co-primary endpoints were sFLC response from baseline to week 6 (after receiving two cycles of trial treatment) and renal response according to the modified International Myeloma Working Group (IMWG) criteria after receiving four cycles of trial treatment. Secondary endpoints included haematological responses, toxicity and overall survival. Results OPTIMAL recruited 31 patients between March 2015 and March 2019 from seven centres within the UK; 16 on BBD and 15 on BTD. Fifty two per cent of patients were ≤70 years old, 55% male, 35% were CKD stage 4 and 65% were CKD stage 5, 48% had planned autologous-stem cell transplantation, 75% had ECOG performance status 0 or 1, 29% were on dialysis and 90% were ISS stage III. Serum free light chain response was assessed in 29 patients where samples were available at screening and at the end of two cycles of treatment. 81% of patients on BBD achieved vGPR compared to 23% on BTD, Fisher's p=0.006, table 1. Nine patients were on dialysis at the time of screening (6 on BBD and 3 on BTD). Complete or partial renal response was achieved by 2 (50%) of patients on BBD compared to 1 (11%) on BTD, Fisher's p=0.05, table 2. Two patients on BBD arm reported reversibility of dialysis dependency after four cycles of treatment. Two patients not previously on dialysis required dialysis after 4 cycles of BTD. Seven deaths were reported from the total 31 patients (5 (31%) on BBD arm and 2 (13%) on BTD arm). There were 33 reported serious adverse events (SAEs) 14 on BBD and 19 on BTD. Conclusion OPTIMAL demonstrated a significant increase in the number of sFLC responders after the first 2 cycles for those patients allocated BBD compared to BTD; this trend continued when assessing renal response after 4 cycles with more patients being dialysis independent after receiving BBD. Funding: Project funded by NAPP Pharmaceuticals, JANSSEN-Cilag Ltd and Bloodwise (formerly named Leukaemia and Lymphoma Research). Disclosures Ramasamy: Oncopeptides and Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; NAPP Pharmaceuticals Ltd.: Research Funding; Janssen-Cilag Ltd.: Research Funding. Drayson:Abingdon Health: Consultancy, Equity Ownership.

Beschreibung: Background: The optimal therapy for patients with relapsed/refractory multiple myeloma remains controversial. Lenalidomide, an oral immunomodulatory drug, has been shown to be an effective treatment in this setting, with in-vitro laboratory data suggesting that its effect is synergistic with a number of established chemotherapeutic agents. The primary objective of this study was to determine the maximum tolerated dose and toxicity of cyclophosphamide when used in combination with lenalidomide and dexamethasone for patients with relapsed/refractory myeloma. The secondary objective was to determine clinical response rates. Methods: Cyclophosphamide was given at increasing doses from 300 mg po in cohort 1, up to the maximum planned dose of 700 mg po in cohort 5 on days 1 and 8 of a 28 day cycle, in combination with dexamethasone (20mg po, daily on days 1–4 and 8–11) and Lenalidomide (25mg po, daily on days 1–21). Maximum tolerated dose (MTD) was established as one dose level below that at which 2 or more patients suffered dose limiting toxicity (DLT). DLT was defined as Grade 4 haematological toxicity or febrile neutropenia occurring during cycle 1 of treatment, or Grade 3/4 non-haematological toxicity during cycle 1, or a failure to start cycle 2 within 7 days of scheduled day due to toxicity. Once the MTD had been established, a further ten patients were enrolled at that dose. Safety assessments were performed weekly during cycle 1, and at the end of every cycle thereafter. Response data was collected on day 28 of each cycle. Results: Toxicity The most commonly observed adverse events were; neutropenia (grade 1–3), cramps (grade 1–2), somnolence (grade 1–2), constipation/diarrhoea (grade 1–2), minor infections (grade 1–2), and musculoskeletal aches and pains (grade 1). The most common reason for dosing delays and dose reductions was grade 3 neutropenia. Maximum tolerated dose No patients receiving doses of 300 to 600mg cyclophosphamide have experienced dose limiting toxicity during the first month of treatment. 2 patients receiving 700mg qualified as having dose limiting toxicity (One patient with febrile neutropenia, pneumonia and syncope (all grade 3)), and another with grade 4 pancytopenia). The maximum tolerated dose of cyclophosphamide in combination with lenalidomide and dexamethasone has therefore been established at 600mg daily on days 1 and 8 of a 28 day cycle. Response: A total of 31 patients were enrolled into the study. Median age at enrolment was 57 years (range 42–79). Median ISS at trial entry was 1 (range 1–3). Median time since last therapy was 7 months (range 1–84). To date, 36% of patients have achieved CR or VGPR, and 81% PR or better. Responses were assessed at the end of each cycle. 25 of the 31 patients have so far achieved PR or better. Of these 25 patients, 76% had achieved their maximum response by cycle 3 day 28. Patients had received 1–6 prior lines of therapy (median 3). 28/31 patients had previously received thalidomide, 20 had received autologous stem cell transplant, and 8 received velcade. 7 patients had received all 3 and, of these, 1 achieved SD, 3 PR, and 3 CR. This suggests that lenalidomide in combination with cyclophosphamide and dexamethasone is an effective therapy for heavily pre-treated patients. Conclusion: 600mg cyclophosphamide on days 1 and 8 of a 28 day cycle is well tolerated in combination with Lenalidomide and dexamethasone. The combination is a highly effective therapy for relapsed/refractory myeloma. The majority of patients achieved a maximal response during the first 4 courses of treatment. CRD is also an effective treatment for patients who have received extensive prior chemotherapy. Whether patients need to continue treatment to nine cycles remains to be tested. Figure Figure

Beschreibung: Background: MGRS is a heterogeneous group of pathologic renal conditions attributed to a clonal plasma cell disorder, without classical features of myeloma. However, there is a need to distinguish MGRS from MGUS and unrelated renal abnormality as the clonal protein in MGRS plays a direct role in kidney damage and requires treatment of the underlying clone. Outcomes in patients with diagnosis of cast nephropathy and renal amyloidosis have been previously reported. But long-term outcomes of MGRS patients with other renal histologies remain unclear. Also data on whether the level of tumour burden in the marrow and type of treatment for MGRS influence long-term outcomes is lacking. This analysis was conducted to study long term outcomes in renal biopsy proven (non cast nephropathy & AL Amyloid) MGRS patients. Aims: This multi-centre retrospective study was set up to analyse clinical outcomes in renal biopsy proven MGRS patients. Long-term haematological and renal outcomes were analysed. Correlation between tumour burden, type of treatment applied and level of response obtained was also analysed. Methods: Thirty-seven MGRS patients were retrospectively audited across 3 centres in the United Kingdom and 1 centre in the Republic of Ireland between 2004 and 2016. Patients were eligible for inclusion if they had a confirmed diagnosis of MGRS by renal biopsy. Patients with cast nephropathy and renal AL Amyloidosis were excluded. Renal survival was defined as the time until renal replacement therapy was required or failure to come off the renal replacement therapy commenced at diagnosis. Overall survival (OS) was calculated from the time of MGRS diagnosis until death from any cause. Results: Median age at diagnosis was 68 years and median follow-up was 33.5 months (range, 0.7-141.7 months). There were 29 male patients and 8 female patients. 20/25 patients had hypertension at the time of diagnosis (records unavailable for 12 patients). Majority of patients were kappa light chain restricted 85% vs 15% lambda LC restricted. Renal histology showed: 65% Light Chain Deposition Disease, 8% Mixed Heavy and Light Chain Deposition Disease, 1 % Proliferative Glomerulonephritis with monoclonal IgG, 11% Light Chain Tubulopathy, 6% Cryoglobulunemia, 3% Immunotactoid Glomerulonephritis. Renal survival for the whole cohort was 74% and overall survival was 84%. At the time of renal biopsy, 43% of patients had 〉10% plasma cells versus 46% of patients with 10% plasma cells versus 70 % in

Beschreibung: Allogeneic transplantation is the only potentially curative treatment option for myeloma (MM). While reduced intensity conditioning (RIC) regimens are associated with lower transplant related morbidity and mortality (TRM), this approach is offset by an increase in relapse rates in myeloma. Method & Materials: We conducted a prospective study on the use of pDLI in myeloma patients with declining donor T cell chimerism following alemtuzumab based RIC allogeneic transplants. 19 consecutive patients were recruited. Patients received 100mg of Alemtuzumab 1H in total over 5 days in vivo as part of the pre-transplant conditioning regimen. There were 8 females and 11 males with a median age of 54 years (range: 41–63). Median lines of prior therapy was 2 (1–4), and 17(84%) had at least one prior autograft. 15 patients were transplanted with related donors and 4 unrelated. The median followed up of the cohort was 25.5 months (4–82). Fractionated peripheral blood (PB) and unfractionated bone marrow (BM) chimerism was performed on day 30, 60, 100 and 3–6 monthly thereafter using promega powerplex 16 genetic identity system. The samples were electrophoresed on an ABI 3130 XL capillary sequencer and analysed using Genemapper 4.0 software. Metaphase cytogenetics of unfractionated BM overnight cultures and Y-FISH for sex mismatch transplants was performed at various time points. Escalating doses of pDLI was given to patients with falling donor T cell chimerism (

Beschreibung: Abstract 2813 Poster Board II-789 Osteoclast, in addition to eroding the bone resulting in lytic lesions, enhances plasma cell proliferation and survival via direct cell to cell contact. Src family protein tyrosine kinases (SFKs) and c-Abl kinase play important role downstream of integrin adhesion receptors, and regulate the cytoskeletal organisation, cell motility and gene expression in response to cell adhesion. We hypothesised targeting SFKs and Abl kinase with the small molecule tyrosine kinase inhibitor Dasatinib has potential to reduce adhesion of plasma cells to ECM proteins in the bone marrow and modify the microenvironment by inhibiting osteoclast function, specifically bone resorption. As a result, myeloma cells could be sensitised to drugs with cytotoxic properties such as dexamethasone. Osteoclasts were generated from primary bone marrow mononuclear cells of myeloma and MGUS patients (n=10). Using Immunofluorescence, we found that Dasatinib 100nM but not dexamethasone inhibited osteoclastogenesis and disrupted the actin cytoskeletal organisation with actin clusters formed in the periphery of the cell. There was absence of actin ring formation at sealing zones which is essential for bone resorption. This effect consistently led to impaired osteoclast function, evidenced by fewer resorption pits formed on rabbit dentine slices on toluidine blue staining. Experiments were repeated ≥ 3 times. In plasma cells, the combination of dexamethasone and Dasatinib synergistically (Calcusyn software) inhibited cell proliferation at clinically relevant concentrations and induced apoptosis of human and murine myeloma cell lines alone and in cocultures with human stromal cells ( p

Beschreibung: Background: RI occurs in ≈ 20%-30% of newly diagnosed MM pts and is associated with poor prognosis (Knudsen et al. Eur J Haematol. 2000; Kyle et al. Mayo Clin Proc. 2003). Data from 2 pivotal trials (MM-002, MM-003) suggested comparable efficacy and tolerability of POM + LoDEX in pts with or without moderate RI (Siegel ASH 2012; Weisel ASCO 2013). However, these trials excluded pts with severe RI. MM-013 (NCT02045017) is a European multicenter, open-label phase 2 study designed to assess the efficacy, safety, and pharmacokinetics of POM + LoDEX in RRMM pts with moderate or severe RI, including those on dialysis. Methods: The trial is enrolling RRMM pts (N = 80) across 3 cohorts: cohort A (moderate RI, estimated glomerular filtration rate [eGFR] ≥ 30 to 〈 45 mL/min/1.73 m2, n = 33), cohort B (severe RI without dialysis, eGFR 〈 30 mL/min/1.73 m2, n = 33), and cohort C (severe RI requiring dialysis, n = 14). Pts must have MM-related RI and have received ≥ 1 prior Tx (including lenalidomide). POM 4 mg is administered on days 1-21 of a 28-day cycle and LoDEX 40 mg/day (20 mg for pts aged 〉 75 yrs) on days 1, 8, 15, and 22 until progressive disease (PD) or unacceptable toxicity. At the time of submission of this abstract, 17 pts terminated Tx; this abstract focuses on tolerability in these pts. Results: This trial is still recruiting; at the time of data cutoff for this abstract, 39 pts were enrolled. Data are included for 17 pts who discontinued Tx. Of all 39 pts, 12 were assigned to cohort A, 18 to cohort B, and 9 to cohort C. The median age of the total population was 72 yrs (range, 52-86 yrs), with 67.7% being male. The median number of prior lines of therapy was 4.0 (3.5 in cohort A, 5.0 in cohort B, and 3.0 in cohort C). This distribution was similar in the 17 pts who discontinued Tx so far (4, 7, and 6 in cohorts A, B, and C, respectively), with a median age of 72 yrs and 58.8% being male. Reasons for discontinuation of Tx were PD (7 pts), adverse events (AEs; 3 pts), death (5 pts: 2 pts due to PD, 2 pts due to infections, 1 pt due to hyperkalemia), and other reasons (2 pts: 1 pt aged 86 yrs with general health problems, 1 pt with increasing RI). Median Tx duration in these pts was 6.9 weeks in cohort A, 12.6 weeks in cohort B, and 12.9 weeks in cohort C. The dosage of POM was reduced to 3 mg in 3 pts (1 patient in each cohort), in all cases due to an AE (thrombocytopenia in 2 pts, pneumonia in 1 pt). However, no further Tx reductions occurred. The most frequent toxicity of any grade in the pts who discontinued was hematologic (82.4% [14 pts]), notably neutropenia in 58.8% (50% in cohort A, 42.9% in cohort B, 83.3% in cohort C), anemia in 52.9% (50% in cohort A, 28.6% in cohort B, 83.3% in cohort C), and thrombocytopenia in 52.9% (75% in cohort A, 14.3% in cohort B, 83.3% in cohort C). Grade 3/4 neutropenia occurred in 47.1%; grade 3/4 thrombocytopenia occurred in 35.3%. Notably, febrile neutropenia was reported in only 1 pt in cohort A. Granulocyte colony-stimulating factor was used in 52.9% of pts. Non-hematologic AEs were less frequent. Infections occurred in 7 pts (41.2%), all of which were pulmonary infections, with the exception of 1 case of nasopharyngitis. Asthenia (23.5%) and fatigue (23.5%) occurred predominantly in cohort C. No thromboembolic events or secondary primary malignancies have been reported to date. Conclusions: These data suggest that the combination of POM and LoDEX can be safely administered in pts with RI. A starting dose of POM 4 mg can be used throughout all stages of RI, and the side effects seen in this population have been previously reported with POM use (ie, mainly hematologic events and infections). Rates of neutropenia and thrombocytopenia are similar to reports in a non-RI population. Dose modifications should be considered in pts who develop neutropenia and thrombocytopenia; in pts showing signs of infections, dose interruptions may be considered. Disclosures Off Label Use: Pomalidomide in MM patients with renal insufficiency.. Dimopoulos:Janssen: Honoraria; Celgene: Honoraria; Janssen-Cilag: Honoraria; Genesis: Honoraria; Onyx: Honoraria; Novartis: Honoraria; Amgen: Honoraria. van de Donk:Janssen Pharmaceuticals: Research Funding; Amgen: Research Funding; Celgene: Research Funding. Gamberi:Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Kueenburg:Celgene Corporation: Consultancy, Honoraria. Rosettani:Celgene Corporation: Employment. Collins:Celgene Corporation: Employment. Lersch:Celgene Corporation: Employment. Bacon:Celgene Corporation: Employment, Equity Ownership. Weisel:Noxxon: Consultancy; Celgene: Consultancy, Honoraria, Other: Travel Support, Research Funding; BMS: Consultancy, Honoraria, Other: Travel Support; Novartis: Other: Travel Support; Janssen Pharmaceuticals: Consultancy, Honoraria, Other: Travel Support, Research Funding; Onyx: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other: Travel Support. Sonneveld:Amgen: Honoraria, Research Funding; Karyopharm: Research Funding; SkylineDx: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding.