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Renal monoclonal immunoglobulin deposition disease (MIDD) is a rare disease defined by deposition of monoclonal light chains and/or heavy chains on basement membranes and vascular walls of the kidney. We describe a case of a 71-year-old woman with kidney failure secondary to monoclonal immunoglobulin deposition disease lambda in association with plasma cell dyscrasia. Her initial serum protein electrophoresis did not demonstrate a monoclonal protein, and classic cast nephropathy was absent on renal biopsy. However, lambda light chain deposits and associated changes confirmed MIDD. She achieved a very good partial response (VGRP) after 8 cycles of CyBorD (cyclophosphamide, bortezomib, dexamethasone) and her kidney function improved. This case highlights the importance of an early diagnostic with renal biopsy to prevent end-stage renal disease. A review of the existing literature and a discussion on the management of the disease is presented.

Systemic immunoglobulin light-chain (AL) amyloidosis is characterized by deposition of amyloid fibrils of light chains produced by clonal CD38+ plasma cells. Daratumumab, a human CD38-targeting antibody, may improve outcomes for this disease.We randomly assigned patients with newly diagnosed AL amyloidosis to receive six cycles of bortezomib, cyclophosphamide, and dexamethasone either alone (control group) or with subcutaneous daratumumab followed by single-agent daratumumab every 4 weeks for up to 24 cycles (daratumumab group). The primary end point was a hematologic complete response.A total of 388 patients underwent randomization. The median follow-up was 11.4 months. The percentage of patients who had a hematologic complete response was significantly higher in the daratumumab group than in the control group (53.3% vs. 18.1%) (relative risk ratio, 2.9; 95% confidence interval [CI], 2.1 to 4.1; P0.001). Survival free from major organ deterioration or hematologic progression favored the daratumumab group (hazard ratio for major organ deterioration, hematologic progression, or death, 0.58; 95% CI, 0.36 to 0.93; P = 0.02). At 6 months, more cardiac and renal responses occurred in the daratumumab group than in the control group (41.5% vs. 22.2% and 53.0% vs. 23.9%, respectively). The four most common grade 3 or 4 adverse events were lymphopenia (13.0% in the daratumumab group and 10.1% in the control group), pneumonia (7.8% and 4.3%, respectively), cardiac failure (6.2% and 4.8%), and diarrhea (5.7% and 3.7%). Systemic administration-related reactions to daratumumab occurred in 7.3% of the patients. A total of 56 patients died (27 in the daratumumab group and 29 in the control group), most due to amyloidosis-related cardiomyopathy.Among patients with newly diagnosed AL amyloidosis, the addition of daratumumab to bortezomib, cyclophosphamide, and dexamethasone was associated with higher frequencies of hematologic complete response and survival free from major organ deterioration or hematologic progression. (Funded by Janssen Research and Development; ANDROMEDA ClinicalTrials.gov number, NCT03201965.).

BACKGROUND In glioblastomas (GBM) patients the first post-radiation MRI is usually difficult to interpret given the post-radiotherapy enhancement and possible pseudo-progression which is present in almost 50% of the patients. METHODS We retrospectively analyzed all patients with GBM treated between 2006 and 2017 at the CHUM (SARDO database). If the first brain MRI done within 3 months after the systemic treatment showed progression of contrast, these patients were considered pseudoprogressors (PsP) while the patients who had stable or response to treatment were the non-progressors (nP). If progression persisted in subsequent MRI with a change of treatment within 6 months, they were considered early progressors (eP). If subsequent MRI improved or was stable, they were classified as nP (or true pseudo-progression). RESULTS In our cohort of 470 patients with GBM, 57.7% were nP and 42.3% were PsP after the first post-treatment imagery. The median follow-up was 10 months. The nP had a longer mOS 15.3m vs 11.3m, p < 0.001, regardless of subsequent evolution. After the second assessment, 67.8% of PsP patients were then considered as eP and 36.4% of nP patients also progressed within 6 months. The nP either after the first or second evaluation had the same mOS (19.9m vs 18.3m), just like the eP (9.3m vs 8.6m), independently of the subsequent treatment. No demographic, molecular or clinical factor predicted PsP, except for tumor size (> 5cm, p=0.024). PsP incidence was similar between 2006–2011 (PsP 57.8%) and 2012–2017 (42.2%). The 1y OS with pseudo progression at the first MRI was 39.7% vs 54.8% with no progression (p=0.001) which has a meaningful impact for the patient. CONCLUSION Pseudo-progression is frequent (42%) in glioblastoma and predicts a poorer prognosis with 1y OS of 39,7%. In fact, PsP patients have more than two-thirds chance to progress precociously.

Because the old alkylating drug bendamustine (BDM) is currently under evaluation in patients with multiple myeloma, we compared its efficacy to that of melphalan in 29 human myeloma cell lines (HMCLs). The concentrations of BDM and melphalan that killed 50% of cells (LD50) in HMCLs were linearly correlated (p < 0.001), and reactive oxygen (ROS) scavengers similarly inhibited cell death induced by both drugs. Sensitivity of HMCLs to both drugs was correlated to p53: the BDM and melphalan median LD50 values of TP53(wild-type) HMCLs were more than two-fold lower than those of TP53(abnormal) HMCLs (p < 0.001), and p53 silencing in TP53(wt) NCI-H929 cells inhibited BDM- and melphalan-induced cell death. Both drugs induced expression of p53 targets, p21, Puma and DR5, only in TP53(wt) HMCLs. In primary cells, both drugs induced an increase in DR5 expression in cells without del(17p). Finally, we demonstrated that the combined effect of BDM and melphalan was additive, and that BDM did not overcome melphalan resistance and vice versa.

BACKGROUND Before 2012, Temozolomide (TMZ) was used for low-grade gliomas (LGG) to avoid Lomustine toxicity. After 2012 RTOG data, Procarbazine, Lomustine and Vincristine (PCV) given sequentially with radiotherapy became standard treatment with the side effects burden associated. METHODS We retrospectively reviewed our SARDO clinical database of patients with low-grade glioma LGG grades 2 and 3 between 2006 and 2017 at CHUM University Health Center. Molecular profile for these tumors is reflex and standard in our institution since 2016. RESULTS A total of 123 patients were identified with grade 2 and grade 3 LGG; 37 (30%) treated with PCV and 86 (70%) received TMZ. Median follow up was 11mo for PCV 11mo vs 22mo TMZ. Both groups were balanced in terms of median age, sex, neurologic symptoms and surgery rate. 53% patients had tumor untested for IDH1-2 and codeletion1p19q because of diagnostic before 2016. Disparities were noted with a predominance of grade 3 in the TMZ group (74% vs 27%, p< 0.01). TMZ was the preferred regimen before 2012 (100% vs 43%) and PCV became the standard of care after 2012 (0% vs 57%). Radiation use as first line treatment was 90%. The 4y OS was not significantly longer for PCV 50% compared with TMZ 47% with mOS between both groups (PCV NR vs TMZ 39.9mo, p=0.158). When controlled for tumor grade, the 2y OS was 80% for PCV vs 64% for TMZ,p=0.542. The 4y PFS was trendly longer for PCV group 78% than TMZ group 45%, p=0.148. CONCLUSION As we are still waiting for the prospective ongoing prospective trials comparing these 2 regimens, PCV and radiation are still standard of care regimens for grade 2 and 3 LGG. This retrospective data is not reassuring for a replacement for PCV with TMZ.

Introduction: Multiple myeloma (MM) remains incurable with standard therapies. Allogeneic stem cell transplantation (alloSCT) is the only curative treatment for these patients. We hypothesized that bortezomib (BTZ) consolidation after tandem autologous stem cell transplantation (ASCT) and nonmyeloablative (NMA) alloSCT could improve quality of response while decreasing relapse and cGVHD. We also sought to determine prospectively the predictive value of bone marrow minimal residual disease (MRD) evaluation using a highly sensitive flow cytometry assay. Methods: Newly diagnosed myeloma (NDMM) patients ≤65 years with high-risk (HR) features (based on cytogenetics, ISS 3 or plasma cell leukemia) or ≤50 year regardless of risk status with an 8/8 HLA matched donor are eligible to participate in this prospective trial. After a BTZ-based induction and ASCT, outpatient NMA alloSCT is performed with either fludarabine and cyclophosphamide (sibling donor) or fludarabine and TBI 2 Gy (unrelated donor) followed by peripheral blood stem cells. GVHD prophylaxis consists of tacrolimus and MMF. BTZ is initiated on day +120 post-alloSCT at 1.3 mg/m2 every 2 weeks for 1 year. Response evaluation is based on IMWG criteria. Bone marrow MRD evaluation is performed on 10x106 nucleated cells with highly sensitive (≥10-5) next-generation flow cytometry using the 8-color EuroFlow protocol (CD45, CD38, CD138, CD56, CD19, CD27, CD81, CD117, CyIgκ and CyIgλ) before alloSCT, before BTZ and every 3 months for 2 years. Immunophenotypic complete response (iCR) is defined as stringent CR in addition to 2 consecutive negative MRD results. aGVHD and cGVHD are evaluated prospectively. Results: As of June 29th 2018, 37 patients have been enrolled with a median age of 53 (range: 35-64) years. ISS 3 is found in 43% and HR cytogenetics in 54% (5% del17p, 14% t(4;14), 22% gain 1q21 and 14% >1 HR cytogenetics). Induction consisted of CyBorD (81%) or VTD (19%) for a median of 4 (range: 4-7) cycles. Median times from induction to ASCT and from ASCT to alloSCT were 5.8 and 4.4 months, respectively. Sibling and unrelated donor transplants were performed in 43% and 57%, respectively. KPS and HCT-CI were 90 (range 80-100) and 1 (range 0-3), respectively. Median follow-up is 21 (range 0-39) months after alloSCT. Of enrolled patients, 34 have started BTZ and received 92.5% of planned doses, with no dose reduction needed for toxicity. Observed grade ≥3 non-hematologic toxicities possibly/related to BTZ included diarrhea (n=1), viral hemorrhagic cystitis (2 adenovirus, 1 BK) and nocardial brain abscesses (n=1). Cumulative incidences of grade II-IV and III-IV aGVHD were 26% and 11%. Incidences of all grade, moderate/severe and severe cGVHD at 24 months were 61%, 47% and 10%, respectively, with mostly mouth, skin and liver involvement. Compared to 27 historical controls who did not receive BTZ after tandem transplant, the incidence of moderate/severe cGVHD was much lower in BTZ recipients (47 vs 78%; p=0.002). After reviewing each target organ involvement, mouth and eye cGVHD were significantly less severe with BTZ. Three patients died, one from myeloma progression and 2 from grade III aGVHD, with a 24-month non-relapse mortality of only 8%. BTZ consolidation improved depth of response, increasing ≥CR rate from 64% to 85% and iCR rate from 25% to 59%, regardless of cytogenetic abnormalities (Table 1). Probability of progression-free survival (PFS) at 24 months was 65% (CI 95%: 42-81) while overall survival (OS) was 90% (CI 95%: 70-97; Fig. 1A). The cumulative incidence of progression at 24 months was 28%. Importantly, the presence of ≤50 myeloma cells in the bone marrow 10 months post-alloSCT (after 6 months of BTZ) was associated with a significantly lower probability of progression (15% versus 80%; p=0.03; Fig. 1B). Conclusion: Tandem ASCT-NMA alloSCT followed by BTZ consolidation results in a remarkably high rate of ≥CR, including iCR. For the first time in allogeneic transplant recipients, MRD evaluation using the EuroFlow protocol demonstrates that identification of ≤50 myeloma cells in the bone marrow 10 months after alloSCT/6 months after BTZ seems predictive of a better outcome. If confirmed, this landmark could be used to design future therapeutic interventions in order to decrease the risk of relapse after tandem transplant. Finally, BTZ following alloSCT is safe and may contribute to decrease both incidence and severity of cGVHD. Disclosures Leblanc: Amgen Canada: Membership on an entity's Board of Directors or advisory committees; Janssen Inc.: Membership on an entity's Board of Directors or advisory committees; Celgene Canada: Membership on an entity's Board of Directors or advisory committees; Takeda Canada: Membership on an entity's Board of Directors or advisory committees. Sebag:Amgen Canada: Membership on an entity's Board of Directors or advisory committees; Takeda Canada: Membership on an entity's Board of Directors or advisory committees; Janssen Inc.: Membership on an entity's Board of Directors or advisory committees; Celgene Canada: Membership on an entity's Board of Directors or advisory committees. Cohen:ExCellThera: Patents & Royalties: Royalities from sales of UM171. Kiss:Alexion: Membership on an entity's Board of Directors or advisory committees, Research Funding; Otsuka: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lachance:ExCellThera: Patents & Royalties: Royalities from sales of UM171. Roy:Kiadis Pharma: Other: Travel support; University of Montreal: Patents & Royalties: Author on patent; Hopital Maisonneuve Rosemont: Patents & Royalties: Author on patent. Sauvageau:ExCellThera: Employment, Equity Ownership. Roy:Janssen Inc.: Membership on an entity's Board of Directors or advisory committees; Takeda Canada: Membership on an entity's Board of Directors or advisory committees; Celgene Canada: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding.

Background: Bortezomib, a reversible inhibitor of the 26S proteasome widely used in the treatment of multiple myeloma, is now being used in various other indications. Pharmacy directors gave the Therapeutic Drug Management Program (TDMP - www.pgtm.qc.ca) the mandate to evaluate bortezomib use in four University Hospitals in Quebec, Canada. Objectives: Describe bortezomib use for all indications in our hospitals and review its utilisation in the treatment of multiple myeloma. Methods: A review of pharmacy databases was performed to identify patients who received bortezomib between June1st 2012 and May 31st 2013. The pharmaceutical and medical records of every patient who received bortezomib were reviewed to assess the treatment, pathology and adverse events. Results: Two hundred and thirty two bortezomib regimens were administered to 227 different patients during the study period. Median age was 68. The most frequent indication (55%) was first-line treatment of multiple myeloma (n=128) followed by treatment of relapsed/refractory disease (31%) (n=73). Various other indications, including amyloidosis (n=17), lymphoplasmacytic lymphoma (n=12) and mantle cell lymphoma (n=2), represented 13% of the population. At the time of data analysis, 35% of patients were still treated with bortezomib, 25% had finished their planned treatment and 34% had discontinued treatment because of adverse events or disease progression. Fifteen patients (6%) died during the study period. Among the 45 patients eligible for autologous stem cell transplant (ASCT), the main regimen used was the association of bortezomib and dexamethasone (VelDex) (n=27), primarily using subcutaneous bortezomib (n=24) at 1.3 mg/m2 (n=30). Median treatment duration was four cycles. Twenty-eight patients have undergone ASCT and only two progressed. The association of bortezomib, melphalan and prednisone (VMP) (54.2%) followed by VelDex (29%) and the association of cyclophosphamide, bortezomib and dexamethasone (CyborD) (16.8%) were the regimens used in the population (n=83) not eligible to ASCT. Response rate using international uniform response criteria for multiple myeloma was 47.9% excluding patients still receiving treatment at the time of data collection. Seventy three patients received bortezomib for relapsed/refractory myeloma. Of these patients, thirty two (43.8%) discontinued therapy, nineteen due to disease progression, eight for the occurrence of side effects and five for other reasons. The initial dose was variable, from 1.0 to 1.6 mg/m2, and close to half of this patient population received CYBorD (49.4%), followed by VelDex (30.2%) and VMP protocols (15%). The number of cycles for patients who completed treatment (4 to 9) as well as the median exposure time (57 to 223 days) was also highly variable. Respectively 8.5% and 10.9% of the population treated with bortezomib for multiple myeloma were hospitalized (n=17) or had to discontinue treatment (n=22) because of adverse events (mostly hematologic toxicity, peripheral neuropathy or gastro-intestinal toxicity). Conclusions: Bortezomib is widely used in the treatment of multiple myeloma. Treatment algorithms should be developed and implemented to optimize the use of bortezomib, particularly in the relapsed/refractory setting. Standard regimens should also be implemented in each center. The utilisation of pre-printed orders for the prescription of chemotherapy regimens promotes uniform prescription. A review of the literature should be performed and recommendations should be made for the use of bortezomib in off-label indications like amyloidosis and lymphoplasmacytic lymphoma. Disclosures Off Label Use: bortezomib use in amyloidosis and lymphoplasmacitic lymphoma. Lemieux-Blanchard:celgene: Membership on an entity's Board of Directors or advisory committees; Amgen and Janssen: Other: preceptorship. Bérard:Janssen: Honoraria. Sebag:Janssen: Honoraria; Amgen: Honoraria; Celgene: Honoraria; Novartis: Honoraria.

Introduction Subcutaneous (SC) injection of bortezomib was reported to be safe and effective in myeloma patients. In September 2012, we standardised all bortezomib containing-protocols at our centre and changed the route of administration form intravenous (IV) to subcutaneous. This way of administration is more convenient for patients and staff and is reported to decrease the rate of peripheral neuropathies. Objectives This retrospective study aimed to describe the safety of this new administration technique, specifically regarding change in blood pressure and hematologic toxicity. Blood pressure (BP) was measured before and after each SC injection to evaluate the risk of hypotension, an adverse reaction frequently reported with IV bortezomib administration. Secondly, we wanted to analyse the rate of neutropenia and thrombocytopenia during the treatment to see if a complete blood count (CBC) is needed before every injection, versus only once weekly. Other adverse events were also collected. Methods This retrospective study included all patients who received bortezomib for multiple myeloma or amyloidosis at the Centre hospitalier de l'Université de Montréal (CHUM) between June 1, 2012 and May 31, 2013. Date was collected through medical and pharmaceutical patient records. Our local ethics board approved this study. Results A total of 45 patients received bortezomib for MM or amyloidosis with a median age of 68 years (SD ± 9.3) and 53.3 % were male. Patients received bortezomib in various protocols including Vel-Dex (42.2%), VMP (44.4%) and CyBorD (13.3%). The median starting dose of bortezomib was 1.3 mg/m2 (SD ± 0.13). Patients received SC only bortezomib injections (71.1%) or IV only (15.6%) or were switched from IV to SC (13.3%) for a total of 157 cycles (786 doses). A total of 444 BP values before and 425 BP values after SC bortezomib were analysed. No significant difference was detected between the average systolic BP (125 vs 125; p=0.76), diastolic BP (70 vs 71; p=0.77) or heart rate (79 vs 78; p=0.89) between the 2 measurements. Hypotension, defined as a drop of 20 mmHg of systolic BP, occurred 18 times (4.2%) but systolic BP was never below 90 mmHg. One patient had a severe dysautomia, possibly related to bortezomib that required the discontinuation of the treatment. At our center, CBC are performed prior to each bortezomib dose. Neutropenia occurred in 10 % of the total doses received. Risk factors influencing neutropenia were the use of oral alkylating agent (melphalan and cyclophosphamide) in the regimen and baseline neutrophil count less than 2.0 x 109. Many patients also received bortezomib for a relapsed / refractory disease and were previously exposed to many lines of therapy. Thrombocytopenia occurred in 7,2% of doses received. Cutaneous toxicity occurred mostly with the first patients treated with the SC technique. With time, nursing changed their technique and further skin reactions were less reported. Neuropathy occurred in 21 patients (13 SC, 4 IV, 4 IV to SC), caused dose reductions in 7 patients (2 SC, 2 IV, 3 IV to SC) and treatment discontinuation in 2 patients (SC). Conclusion Our results demonstrate SC bortezomib was well tolerated. The rates of hypotension was quite low. Also rates and intensity of neutropenia and thrombocytopenia varied among different bortezomib containing regimens. Because of the low rate of profound neutropenia, Vel-Dex and VMP protocols can be modified to decrease the number of CBC to once weekly during the cycle rather than before every injection. More data are needed with CyBorD protocol before drawing any conclusions. Disclosures: Adam: Jansen Ortho: Honoraria. Lemieux-Blanchard:Celgene: Honoraria. Lemieux:Jansen Ortho: Honoraria.