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Background: Hairy cell leukemia (HCL) responds well to purine analogs with an overall median relapse free survival of 11-16 years. Most patients can be retreated with the same or a different purine analog however a subset of patients will become resistant or develop cumulative toxicities. Novel agents such as Vemurafenib (BRAF kinase inhibitor), Bendamustine/Rituximab (BR), Moxetumomab pasudotox (anti CD-22 recombinant immunotoxin) and Ibrutinib have emerging roles in patients with relapsed HCL. Methods: Five databases (PubMed, Embase, Cochrane Library, Web of Science and ClinicalTrials.gov) were searched using the following search terms: “hairy cell leukemia” or “leukemia, hairy cell” AND “relapse” or “recurrence”. We included only prospective clinical trials with outcome data. Results: Vemurafenib monotherapy was evaluated in two separate arms of a phase 2 trial. In the US arm (n=24), the ORR was 100% (CR 42%; PR 58%). In the Italian arm (n=26), the ORR was 96% (CR 35%; PR 62%). In a phase 2 study (n=25), the combination of vemurafenib and rituximab showed CR of 100%. The combination of BR achieved an ORR of 100% whereas CR was 50% and 67% at a bendamustine dose of 70mg/m2 (n=6) and 90 mg/m2 (n=6) respectively. In a phase 3 trial, moxetumomab pasudotox (n=80) had an ORR of 75% (CR 41%). Single agent Ibrutinib (n=37) had an ORR of 54%. Therapies were generally well tolerated. Conclusion: Novel agents have good efficacy in HCL in patients with multiple relapses.

Multiple myeloma (MM) is a hematological malignancy characterized by an abnormal clone of plasma cells in the bone marrow. MM and its therapy increase the risk of complications like anemia, osteolytic lesions, pain, infections, and renal abnormalities in MM patients. Supportive care for MM patients improves the quality of life. Treatment with bisphosphonates decreases skeletal-related events. Vertebroplasty and kyphoplasty are done in cases of vertebral compression fractures. Prophylactic antibiotics and antivirals can decrease infections related to morbidity. Plasmapheresis in patients with renal dysfunctions decreases dialysis dependency and improve quality of life.

Blinatumomab and donor lymphocyte infusion (DLI) combination is a promising cancer therapy, whereby blinatumomab might achieve an initial reduction in leukemic-cell burden using T cells, and after tumor clearance, DLI can potentially stimulate the donor immune system to achieve longer lasting remission. Here, we present a 51-year-old female with mixed phenotype acute leukemia who had a hematologic relapse 3 months after she received total body irradiation-based myeloablative allogeneic hematopoietic stem cell transplantation from an unrelated human leukocyte antigen matched (10/10) donor and achieved complete remission with minimal residual disease negativity by multi-parameter flow cytometry using the combination of blinatumomab and DLI. To the best of our knowledge, this is the first report to describe the use of blinatumomab and DLI combination therapy in the treatment of B/myeloid mixed phenotype acute leukemia.

Introduction Elotuzumab is monoclonal antibody (mAb) that specifically targets signaling lymphocytic activation molecule family member 7 (SLAMF7) that is present on myeloma cells. It fights myeloma cells by stimulating phagocytic action of NK cells and via ADCC (antibody‐dependent cell‐mediated cytotoxicity) pathway. Daratumumab is an anti-CD38 mAb with dual mechanisms of action i.e. tumoricidal and immunomodulation. The aim of this study is to review the efficacy and toxicity of elotuzumab and daratumumab based 3-drug combinations in patients (pts) with multiple myeloma (MM). Methods A systematic search of PubMed, Embase, Clinicaltrials.gov, Cochrane and Web of Science was performed for elotuzumab and daratumumab based regimen in MM patients from inception to June 12, 2019. Out of 604 studies, 08 phase II and III clinical trials based on 3-drug regimen were finalized. Results Total 2809 patients (pts) were evaluated out of 2879 enrolled pts. 856 were newly diagnosed (ND) and 1953 were relapsed/refractory (R/R). Elotuzumab (E) based 3-drug regimen were evaluated in 560 whereas daratumumab (D) based 3-drug regimen were analyzed in 889 pts. ELOQUENT-3 trial (n=117) in phase II used E + pomalidomide (P) and dexamethasone (d) (EPd) for R/R pts with ≥2 prior therapies. Median (m) progression free survival (PFS) was 10.2 months (mo) in EPd versus (vs) 4.6 mo in Pd arm [Hazard ratio (HR) 0.54 (95% CI: 0.34-0.86; p=0.008)], i.e. 46% lower risk of progression or death in EPd vs Pd arm. ORR (overall response rate) was 53% (complete response [CR] 5% + stringent CR [sCR] 3% + partial response [PR] 33% + very good partial response [VGPR] 12%) in EPd vs 26% in Pd arm (odds ratio [OR]: 3.25 (1.49-7.11). Grade (G) ≥3 adverse events (AEs) were anemia (10%), neutropenia and infections (13% each). (Dimopoulos et al. 2018). Phase II trial by Jakubowiak et al. (2016) observed 1 year (y) PFS of 39% in E-Bortezomib(B)-d vs 33% in Bd arm in 152 R/R pts (HR: 0.72; p = .09) with 28% decrease in progression or death with EBd vs Bd. ORR was 66% (4% CR+ 33% VGPR + 30% PR) vs 63%. OS (overall survival) at 1 y was 85% (EBd) and 74% (Bd) (HR:0.6). G≥3 AEs were infections (21%), thrombocytopenia and peripheral neuropathy (9% each). In phase II trial, ELd (E-Lenalidomide-d) arm yielded ORR of 88% (CR 3% + sCR 5% + PR 43% + VGPR 38%) vs 74% in Ld arm in 82 ND pts. PFS at 1 yr was 93% vs 91%. G≥3 AEs included neutropenia (18%) and leukopenia (15%). (Takezako et al. 2017). Berenson et al. (2017) in phase II trial (n=70) studied G≥3 infusion reactions (IRs) using ELd in ND and R/R pts. ORR was 70% (CR 6% + VGPR 27% + PR 37%). G3 AEs included anemia in 10% pts (no G3 IRs). ELOQUENT-2 trial randomized 646 R/R pts in phase III. PFS at 4 y is 21% vs 14% (HR: 0.71, 0.59-0.86; p= .0004), favoring ELd with 29% reduction in myeloma progression or death. With VGPR of 30%, ORR was 79% vs 66 % (ELd vs Ld) with HR: 0.77; 0.62-0.95; p = 0.0176. OS at 4 y was 50% vs 43% (HR: 0.78; 0.63-0.96). G≥3 AEs included lymphocytopenia (79%), neutropenia (36%), anemia (20%) and thrombocytopenia (21%). (Dimopoulos et al, 2018). POLLUX trial used daratumumab (D)-Ld regimen in 569 R/R patients in phase III. PFS at 3 y was 55% vs 27% (DLd vs Ld) in pts with 1-3 prior therapies. With 56% CR and 80% VGPR; ORR was 93% vs 76%. DLd arm achieved 30% minimal residual disease (MRD)-negative status compared to 5% in Ld arm (p CASTOR trial in phase III (n=498) showed 18-mo PFS of 48% vs 7.9% in DBd vs Bd arm in R/R pts (HR: 0.31 (0.24-0.39); p A Phase III trial (n=737) observed 30 mo PFS of (66 vs 52) % in ≥75 y old pts [HR 0.63 (0.44-0.92)] with DLd vs Ld arms in ND transplant ineligible pts with ORR of (90 vs 81) % (≥CR 41% + ≥VGPR 77%). MRD- negative rate was (19 vs 8) % in DLd vs Ld arms respectively. G≥3 AEs were neutropenia (60%), lymphopenia (19%), anemia (16%), pneumonia (15%) and leukopenia (12%). Conclusion: Elotuzumab and daratumumab based 3-drug combinations showing great improvements in ORR, PFS and OS of ND and RR MM patients with favorable toxicity profile. Disclosures Anwer: In-Cyte: Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.

Background: Carfilzomib (Car), a second-generation proteasome inhibitor (PI), has been approved by the US Food and Drug Administration (FDA) as therapy for relapsed and /or refractory multiple myeloma (RRMM), either as a single agent or in combination with other agents. It has proven to be superior in many ways compared to the the first generation PI, bortezomib, both in terms of superior efficacy and neuropathy related adverse effect profile. Carfilzomib has lower rate of peripheral neuropathy. In this review, we gathered data from trials which studied Carfilzomib for newly diagnosed MM (NDMM). Carfilzomib based two and three drug combination as induction regimens for the management of NDMM is an emerging approach. Through this systematic review, we explore efficacy, adverse effect profile of Car based regimens for NDMM. Methods: Per PRISMA guidelines, a thorough database search was conducted on 06/24/2019 using the following search engines; PubMed, EMBASE, Cochrane library, Scopus, Web of Science, CINAHL, and Clinicaltrials.gov. We included all published trials that used carfilzomib as an induction agent in NDMM patients and had at least response rates after induction. Results: The total number of articles identified with initial search were 1131, out of which 19 articles met our selection / eligibility criteria (n=2286). The overall response rates (ORR) after induction therapy with carfilzomib based regimens was very impressive (range: 84.3% - 100%). Two drug combination using carfilzomib and dexamethasone (n=72) had an ORR of 90% and a greater than very good partial response rate (>VGPR) of 84%. Three drug combinations used for induction therapy included carfilzomib/dexamethasone with immunomodulators (n=391) and alkylating agents (n=308). The combination of carfilzomib/dexamethasone with lenalidomide (n=189, ORR: 97% - 98%, >VGPR: 69% - 98%) and thalidomide (n=202, ORR: 90% - 94%, >VGPR: 66% - 68%) showed the best response. Alkylating agents used in combination with carfilzomib were melphalan (n=98, ORR: 90% - 93%, >VGPR: 58% - 70%), cyclophosphamide (n=192, ORR: 87% - 95%, >VGPR: 39% - 71%) and bendamustine (n=18, ORR; 100%, >VGPR: 89%). Four drug combinations with carfilzomib used were daratumumab/lenalidomide/dexamethasone (n=22, ORR: 100%, >VGPR: 90%, 12m PFS: 95%) and cyclophosphamide / thalidomide / dexamethasone (n=64, ORR; 91%, >VGPR: 69%, 24m PFS: 76%). One trial directly compared carfilzomib/melphalan/dexamethasone (n=478, ORR: 84%, >VGPR: 61%, PFS: 22.3m) with bortezomib/melphalan/dexamethasone (n=477, ORR: 79%, >VGPR: 49%, PFS: 22.1m). Another trial compared the combination of carfilzomib / dexamethasone with lenalidomide (n=315) or cyclophosphamide (n=159) that showed similar ORR (97% vs 91%) though >VGPR rate was better with lenalidomide (75% vs 60%). Efficacy data including progression free survival (PFS) for carfilzomib based regimens is reported in table 1. Most common >grade 3 hematological adverse effects reported were anemia (2% - 35%), lymphopenia (5% - 76%), thrombocytopenia (4% - 28%) and neutropenia (1% - 38%). Most Common >grade 3 non-hematological adverse events included cardiac events (5% - 10%), respiratory disorders (8% - 16%), infections (2% - 9%), hypertension (6% - 17%), renal events (9% - 10%) and hyperglycemia (6% - 23%). (Table 1) Conclusion: The overall efficacy and favorable adverse effect profile of Carfilzomib-based induction regimens seem very promising for the treatment of NDMM. Car is now approved for weekly dosing which is convenient. Due to cardiovascular toxicity seen in upto 10% cases, Car should be used very judiciously in patients with cardiovascular risk factors and heart failure. Several ongoing phase 3 clinical trials are studying Carfilzomib in various combinations will help to establish foundation for future standard therapy as well as next phase of drug development through clinical trials. Disclosures Anwer: In-Cyte: Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.

Introduction: Intracellular molecular inhibitors act by inducing apoptosis due to inhibition of intracellular proteins like 20S proteasome subunit, histone deacetylases (HDAC's), exportin 1 (XPO1), cyclin-dependent kinases (CDKs) and kinesin spindle protein (KSP). These proteins are involved in the regulation of cell cycle. The aim of our analysis is to report published literature on the clinical efficacy of intracellular molecular inhibitors in relapsed and refractory multiple myeloma (RRMM) patients. Methods: Following Prisma guidelines, we performed a comprehensive literature search on articles published after 2011. Four hundred eighty-nine articles were identified using the following five databases (Pubmed, Embase Cochrane, Web of Science and Clinical Trials.gov). After a detailed screening, we finalized 13 studies involving 902 RRMM patients. We included phase I/II, II and III studies. The studies involving drugs approved by the US Food and Drug Administration were excluded. Results:Selective inhibitor of nuclear export (SINE) compounds: Selinexor A total of 112 RRMM patients were included. Thirty-three patients were in phase I/II while 79 patients were in phase II. All patients received selinexor (60-100 mg) in different combination regimens. Forty-eight patients were quad-refractory (refractory to bortezomib, carfilzomib, lenalidomide, and pomalidomide) while 31 patients were penta-refractory (including isatuximab/daratumumab). In 110 evaluable patients, the pooled overall response rate (ORR) was 35.45%. The ORR in the subset of quad-refractory and penta-refractory patients was 21% and 20% respectively. The best response was seen when selinexor was used in combination with bortezomib (V) and dexamethasone (d) i.e. 77%.HDAC inhibitors: Vorinostat and Ricolinostat A total of 562 RRMM patients were included. Seventy-seven patients were in phase I/II, 168 patients in phase II, and 317 patients were in phase III. Five hundred and eighteen patients received vorinostat (100-400 mg) in different combination regimens while 44 patients received ricolinostat (160-240mg) in combination with Vd. The median follow-up period was 13.2-30.8 months. In 560 evaluable patients, the pooled ORR was 42.83% and 31.81% in patients who received vorinostat and ricolinostat, respectively. The best response was seen when vorinostat was used in combination with V, doxorubicin (DX) and d i.e. 67%.Proteasome inhibitors: Oprozomib and Marizomib A total of 117 RRMM patients were included. Hundred and two patients were in phase I/II while 15 patients were in phase II. Twenty-seven, 34 and 41 patients received single-agent oprozomib in the dose of 240 mg, 150-180 mg, and 240-300 mg respectively while 15 patients received single-agent marizomib (0.5 mg/m2). Out of 107 evaluable patients, the pooled ORR was 27.65% in patients who received oprozomib while no response was seen in patients who received marizomib however stable disease was seen in 31% of patients.KSP inhibitor: Filanesib A total of 50 RRMM patients were included. All patients were in phase II. Thirty-two patients received single-agent filanesib (1.5mg/m2) while 18 patients received filanesib (1.5mg/m2) in combination with d. The pooled ORR was 22%. The ORR was 19% when filanesib was used as a single agent while it was 28% when filanesib was used in combination with d.CDK inhibitors: Dinaciclib and Palbociclib A total of 61 RRMM patients were included. All patients were in phase I/II. Twenty-nine patients received single-agent dinaciclib (30-50 mg/m2) while 32 patients received palbociclib (100mg) in combination with Vd. In 52 evaluable patients, the ORR in patients who received dinaciclib was 11% while the ORR in patients who received palbociclib was 20%. Conclusion: In RRMM patients, vorinostat and selinexor when used in combination regimens demonstrated a weak efficacy with a pooled ORR of 43% and 36% respectively. The best response was seen in combination with Vd i.e. 67% and 77% respectively. The data on other intracellular molecular inhibitors (ricolinostat, oprozomib, marizomib, filanesib, dinaciclib, and palbociclib) when used either as single agents or in combination regimens, suggested a poor efficacy with an ORR of < 35%. However, future randomized well designed prospective clinical trials involving a larger population are required to further explore the efficacy of these agents in RRMM patients. Disclosures No relevant conflicts of interest to declare.

Introduction Light chain multiple myeloma (LCMM) constitutes approximately 15% of patients with multiple myeloma (MM). It has an earlier average age of onset (54 years) and appears to have a poorer prognosis when compared to IgG or IgA variant. The main aim of our analysis is to study the published literature on the efficacy of bortezomib (V) based regimens and disease monitoring in patients with LCMM. Methods We performed a literature search of articles published after 2012 using following four databases (PubMed, Embase, Cochrane Library and Web of Science). We included only English language studies and summarized our data using medians, absolute values, and percentages. Results The literature search identified a total of 390 articles on LCMM. After detailed scrutiny, 6 studies involving a total of 1054 LCMM patients (pts) were included. In a study by Zhang et al. (2014) including 96 pts, 66 pts received 4 cycles of V (1 mg/m2) with dexamethasone (D) (20 mg) while 30 pts received non-V regimens. In bortezomib group, the overall response rate (ORR) was 95.5%. Complete response (CR) was seen in 56.1% pts while 39.4% pts showed partial response (PR). In non-bortezomib group, the ORR was 60%. CR was seen in 10% pts while 50% pts showed PR. The overall survival (OS) at 3 and 5 years in bortezomib group was 33% and 24% respectively while the OS in non-bortezomib group was 28% and 9% respectively (p=0.335). The progression free survival (PFS) at 1, 2 and 3 years in bortezomib group was 37%, 25% and 8% respectively while the PFS at 1 and 2 years in non-bortezomib group was 27% and 9% respectively (p=0.036) (Table 1). In two different studies by Mrachacz et al. (2015) and Tessenow et al. (2017), a total of 45 pts were treated with V (1.3 mg/m2) in combination with bendamustine (B) (60 mg/m2) and prednisone (P) (100 mg). ORR was 95.5% including 37.7% pts with CR, 22.2% pts with very good partial response (VGPR) and 35.5% pts with PR. Median OS at 24 and 30 months was 95% and 96 % respectively while PFS at 24 and 30 months was 90% and 68% respectively. In another study by Heaney et al. (2017) including 576 pts, 567 (98.4%) pts were identified by serum free light chain (sFLC) level compared to 460 (79.8%) pts which were identified by urine free light chain (uFLC) level. Hundred thirty-two pts were evaluated at maximum response to therapy with V. ORR was 98.4% including 43.1% pts with CR, 44.6% pts with VGPR, 10.6% pts with PR and 1.5 % pts had stable disease (SD). In a study by Dejoie et al. PFS (2016) including 113 pts, Urine Protein Electrophoresis (UPEP) was positive in 87 (78.3%) out of 111 evaluable pts while serum involved free light chain (iFLC) was positive in all (113) pts. Seventy eight %, 37% and 18% pts showed abnormal UPEP at baseline (diagnosis), treatment cycle 1 and treatment cycle 3 respectively while 100%, 71% and 46% of pts showed abnormal iFLC at baseline, treatment cycle 1 and treatment cycle 3 respectively, indicating sFLC as more sensitive indicator of the disease than UPEP. Abnormal iFLC level at the end of consolidation therapy showed a statistically significant shorter PFS than pts with normal iFLC level [p= 0.004; Hazard ratio (HR) = 2.7; 95% CI = 1.4-5.4]. UPEP did not reach any statistical significance in determining PFS [p = 0.178; HR= 1.6; 95% CI= 0.8-3.3]. No statistically significant data was found for abnormal iFLC and abnormal UPEP in determining OS [(p= 0.164; HR= 2.2; 95% CI= 0.7-6.6) and (p= 0.891; HR= 0.9; 95% CI= 0.2-4.0) respectively]. However, abnormal sFLC ratio at the end of consolidation therapy showed a statistically significant shorter PFS (p= 0.006; HR= 3.1; 95% CI= 1.4-6.8) as well as OS (p=0.047; HR=7.8; 95% CI= 1.0-58.5). In a similiar study by Bradwell et al. including 224 pts, 82 pts were evaluated at follow up after chemotherapy with vincristine, doxorubicin and melphalan. CR was seen in 26 (31.7%) pts as indicated by normal uFLC levels compared with only 9 (10.9%) pts by their normal sFLC levels, indicating false negative results with uFLC compared to sFLC. Conclusion There is a paucity of data on LCMM in the literature. V has shown superior efficacy in LCMM patients over non-V regimens with ORR > 95%. Moreover, V showed better PFS at 2 years when used with bendamustin compared to VD (95% vs. 25%). Similarly, V with B showed better OS i.e. 90% at 2 years. Moreover, sFLC levels were more sensitive in indicating the disease and predicting PFS and OS compared to uFLC levels, hence monitoring of LCMM patients should include serum assays. Disclosures No relevant conflicts of interest to declare.

Background: Treatment for post-transplant relapsed/refractory acute lymphoblastic leukemia (R/R-ALL) is not well defined. A majority of ALL relapses occur within two years after allogeneic stem cell transplantation (allo-SCT). Blinatumomab, an anti-CD19/CD3 bispecific antibody, exerts cytotoxic activity leading to apoptosis of CD19 positive B cells. Blinatumomab and DLI combination therapy is a promising new concept in cancer treatment, whereby blinatumomab might achieve an initial reduction in ALL tumor burden using T-cells, and after tumor clearance, DLI can potentially stimulate the donor immune system to achieve longer lasting remission. Methods: Literature search was performed using PubMed, EMBASE, Cochrane and Web of Science databases up to 3 July 2018. MeSH terms and keywords of blinatumomab, DLI and ALL were used. Results: Comprehensive search retrieved over 150 articles. After exclusion criteria were applied, three studies (n=15 patients) met our inclusion criteria. We summarized data on 15 patients (table 1). Outcomes were not reported homogeneously. Two studies (Ueda, M. et al. 2016; Paul, S. et al. 2017) reported CR in months and one study (Bondarenko, SN. et al. 2017) reported the response rate (RR). Before starting blinatumomab therapy, 12 patients had post-transplant bone marrow relapse, 1 patient had an extramedullary relapse and 2 patients had a minimal residual disease (MRD) without marrow relapse. Total cycles of blinatumomab ranged from 2 to 4. Total cycles of DLI ranged from 1 to 2 given after at least one cycle of blinatumomab. DLI was mostly given with blinatumomab during cycle 3 (ranged from cycle 2 to cycle 4). Blinatumomab doses were not uniformly reported. DLI doses varied between 1x107 and 5x107. Complete remission (CR) with MRD negative status was achieved after 2 cycles of blinatumomab in 3 patients, 2 of them remained in CR for 7 and 13 months. One patient achieved CR and negative MRD status 7 months after initiation of blinatumomab (total cycles of combination therapy=2). Ten patients who had median number of 2 cycles of blinatumomab showed RR of 70%. Grade I acute skin GVHD was reported in one patient during the cycle 3 of blinatumomab before the first combination therapy. One patient developed grade II aGVHD after the combination therapy (cycles were not reported). One patient developed GVHD involving mouth and skin during the second cycle of combination therapy (cycle 3). Grade 3 late-onset acute skin and gut GVHD were reported in one patient after the first dual therapy (cycle 3). No fatalities were observed with combination therapy. Therapy was stopped in one patient who had isolated central nervous system (CNS) relapse detected in the cerebral spinal fluid and orbit following allo-SCT; the patient was treated with intrathecal chemotherapy and radiation. One patient died of extramedullary and hematologic relapses seen at 6 and 11 months after initiating blinatumomab, respectively. This patient previously had a marrow relapse before starting therapy. One patient having an extramedullary disease progressed despite blinatumomab and DLI. Conclusion: Blinatumomab and DLI combination therapy appears to be safe and effective, specially for patients with MRD positive status after stem cell transplantation. Large prospective studies are required to completely understand the efficacy and safety of this combination therapy. Disclosures No relevant conflicts of interest to declare.

Introduction: Despite the recent advancements in the treatment of multiple myeloma (MM), there is a constant need of newer therapies in order to treat the complex issue of the disease relapse and refractory disease. Isatuximab (ISA) is a non-Food and Drug Administration (FDA) anti-CD38 monoclonal antibody that acts through immune cell engagement and direct tumor targeting. We report efficacy & toxicity of ISA in newly diagnosed MM ((NDMM) as well as relapsed, refractory MM (RRMM) patients (pts). Methods: Following Prisma guidelines, we performed a comprehensive literature search on articles published after January 2012 using PubMed, Embase, Cochrane Library, Web of Science and Clinicaltrials.gov. On initial search, 246 articles were found and after a detailed screening, 6 completed and 11 ongoing phase I/II/III studies were included. Results: A total of 249 pts were included. Two hundred thirty-four pts had RRMM while 15 pts had NDMM, overall response rate (ORR) was 37.60% and 87% respectively. In a phase I trial involving 34 pts with RRMM, single-agent ISA (1-20 mg/kg) was given. The median age of pts was 64 years (y) [range (r) = 38-85]. The overall response rate (ORR) was 24% with a partial response (PR) in 18% pts. The most common adverse events (AEs) were nausea (34%), fatigue (49%), fever (29%) and headache (26%) and upper respiratory infection (23%). In a phase II trial, 97 pts with RRMM were stratified into 4 groups. Single-agent ISA [3mg/kg, every 2 week,(Q2W); 10 mg/kg, Q2W - every 4 weeks (Q4W); 10 mg/kg (Q2W), 20 mg/kg (QW-Q2W)] was given. The median age of pts was 62.5 y (r = 38-85). The ORR was 9%, 20%, 29% and 24% respectively. The cumulative ORR was 20.6%. The median time to first response was 1.4 months (M) while the median duration of response was 6.6 M. The most common AEs were nausea (33%), fatigue (30%), diarrhea (26%) and cough (24%). In a phase Ib trial, 57 pts with RRMM were stratified into 5 groups. ISA [3 mg/kg (Q2W); 5 mg/kg (Q2W); 10 mg/kg (Q2W); 10 mg/kg (QW-Q2W); 20 mg/kg (QW-Q2W)] in combination with lenalidomide (R) (25mg), and dexamethasone (D) (40 mg) was given. The median age of pts was 61 y (r = 42-76). The median time since the initial diagnosis was 4 y. The ORR was 33%, 67%, 63%, 50%, and 50% respectively. The cumulative ORR was 56% with complete response (CR) in 3.8 % pts, very good partial response (VGPR) in 32.7 % pts and PR in 19.2 % pts. The progression-free survival (PFS) was 8.5 M (r=4.73-16.59). The most common grade 3 and 4 AEs were neutropenia (60%), lymphopenia (58%), leukopenia (53%), anemia (25%), thrombocytopenia (38%), pneumonia (9%), fatigue (7%), and dyspnea (4%). In another phase Ib trial, 36 pts with RRMM were stratified into 3 groups. ISA (5 mg/kg; 10 mg/kg, 20 mg/kg) in combination with pomalidomide (P) (4 mg), and D (40 mg) was given. The ORR was 63%, 55%, and 50% respectively. The cumulative ORR was 55.5%. The median time to first response was 4.1 weeks (W) while the median duration of response was 33.1 W. The most common grade 3 AEs were neutropenia (81%), lymphopenia (75%), and leukopenia (75%). In another phase Ib trial involving 10 pts with RRMM, ISA (10-20 mg/kg) in combination with carfilzomib (CFZ) (27 mg) was given. The median number of prior lines of therapy was 4.5 (2-8). The ORR was 80% with VGPR in 20% pts and PR in 60% pts. The most common grade 3 and 4 AEs were lymphopenia (64%), anemia (9%), and neutropenia (9%). In a phase Ib trial involving 15 pts with NDMM, ISA (10 mg) in combination with bortezomib (V) (1.3 mg/m2) and cyclophosphamide (CY) (300 mg/m2) was given. The median age of pts was 71 y (r= 68-80). The ORR was 87% with CR in 33% pts, VGPR in 27% pts, and PR in 27% pts. The median time to first response was 1.5 M while the median duration of response was 11 M. The most common grade 3 and 4 AEs were lymphopenia (50%), leucopenia (18%), neutropenia (8%), anemia (6%) and thrombocytopenia (6%). Conclusion: In RRMM pts, ISA as a single agent has shown weaker efficacy when compared to combination regimens i.e. ORR 21% vs. 58%. The best result was seen when ISA was used in combination with CFZ demonstrating an ORR of 80%. In NDMM pts, combination regimens have shown excellent efficacy with an ORR of 87%. Nausea and fatigue were the major AEs reported with the monotherapy while neutropenia, leucopenia, and lymphopenia were the major AEs reported with the combination regimens. Further studies involving a larger population are required to gather evidence in favor of the improved efficacy and to evaluate AEs. Disclosures No relevant conflicts of interest to declare.

Background Myelodysplastic Syndrome (MDS) represents a heterogeneous group of diseases with clonal proliferation, bone marrow failure and increase risk of progression to acute leukemia. Histone deacetylase inhibitors (HDACi) modulate the epigenetics of cancer cells to promote differentiation and programmed cell death. Our aim is to study the efficacy and safety of HDACi in patients with MDS/ acute myeloid leukemia (AML). HDACi can be a safer alternative in patients with high risk MDS who are not eligible for stem cell transplantation or high intensity chemotherapy. Methods A comprehensive literature search was done using following 5 databases: (Pubmed,Embase,Web of Science,Cochrane library,Clinical Trials.Gov) in accordance with the PRISMA guidelines. We included 21 trials (Phase II/III ) with a total 1654 patients,of which 1030 patients recieved HDACi and were evaluable for respone. Our primary objective was to determine efficacy of HDACi based regimen in terms of overall response rate (ORR) and composite complete response rate (CCR). A meta-analysis was done for regimen that were evaluated in more than one trials to report ORR and CRR.CMA software V.3 was used to run metaanalysis to calculate the response and the heterogenity among studies were assesed by using I2 test.A random -effect model was applied. Results: The pooled analysis (95% CI) with 1030 evaluable patients in MDS/ AML showed an overall response rate of 37.1% (32.3-42.3 : I2= 86.105 )with composite response (comp CR=CR+Cri+mCR) of 30.8%(26.8-35.1) .The median overall survival of those who received HDACi ranges from 8 -25 months.The Base line Characterstics,Outcome and Toxicity of HDACi in MDS/AML are summarized in Table 1. In the meta-analysis (n=57) of two trials (Garcia et al, 2007 & Luger et al. 2013), combination regimen of Mocetinostat- Azacytidine had an ORR of 54%(95% CI: 10.2-92.3) and composite complete response (CCR) of 18.9% (95% CI :9.3-34.7) in patients with MDS/AML. Combination of Vorinostat-Cytarabine-Idarubicin had an ORR of 50.7% (95% CI :40.7-96.5) and CCR of 30.1% (95% CI: in 111 patients with MDS/AML in a meta-analysis of trials by Prebet et al. 2013 and Manero et al. 2012. The meta-analysis of 3 trials evaluating Vorinostat-Azacitadine regimen (Craddock et al. 2017; Sekers et al. 2017 & Montalbano et al. 2016) had an ORR 38.3%( 95 % CI :18-63) CCR of 29%(95% CI: 11-58) in a total patient population of 274 patients. The regimen of Valproate- Deictibine/Cytarabine was evaluated in 3 separate trials with a total patient population of 156 which showed an ORR of 41.6% (95 % CI :20.9-65.6)and a CCR of 28.3%(95% CI 18.9-42.7) in the metanalysis. The meta-analysis of 3 trials evaluating a three-drug regimen of Valproate-Azacytadine-All trans retinoic acid(ATRA) showed an ORR of 32.2%(95% CI :24.2-41.3) and CCR of 23.7%(95 %CI 13.1-39.0) in 144 MDS/AML patients. In a trial by Manero et al (2017), the combination of Pracinostat and Azacitadine had an ORR of 67.5% (95% CI :51.7-80.01) CCR of 60%(95% CI 44.3-73.8) in 51 AML/MDS patients. A single trial evaluating regimen of Panobinostat and Azacitadine (n=40) had an ORR of 37.5% and CCR of 27.5%. Combination of Panobinostat and Decitabine in a trial by Geoffry et al in 2017 (n=52), the ORR was 21.2% and CCR of 19.2%.The Overall response rate and Composite response rate of HDACi in MDS/AML are mentioned in Table 2 and Table 3. Conclusion: Most of the HDACi like Mocetinostat,Valproic acid ,Pracinostat when used in combination with either Hypomethylating agents(Azacytidine ,decitabine) or purine analogs (cytarabine/idarubicin) produced a good response.Pracinostat in combination with azacytidine showed the best ORR among the studies but there was only single study mentioning this combination.Single agent studies with resposne were also not evaluable.Most of MDS patients get resistant to hypomethlating agent thus there is need to explore newer agents and HDACi agents is a promising group. Disclosures No relevant conflicts of interest to declare.

Introduction: Multiple myeloma (MM) is associated with end organ damage that negatively impacts the quality of life (QOL)and supportive care has a potential to improve symptoms. Methods: After detailed search on Pubmed, Cochrane, Embase and Clinical Trials.gov, we finalized total 36 articles on supportive care published after 2004. Results: Management of skeletal events: Mhaskar et al. (2017, n=3257) compared bisphosphonates (BPs) with placebo (PBO) in preventing pathological vertebral fractures, skeletal-related events (SRE), reported risk ratio (RR) of 0.74 in each; 95% CI 0.62-0.89 and 0.63-0.88 respectively. Both zoledronic acid (ZA) and clodronic acid prevent SRE, but mortality rate was better reduced with ZA (hazard ratio [HR]=0.84; p=0.0118), (Gareth et al. 2010, n=1960). In a study by Zuradelli et al. (2009, n= 240); hypocalcemia developed in 93 (38.8%) patients on ZA for a median of 2.3 months (range, 0-34.9). Vitamin D and calcium replacement is essential in patients developing hypocalcemia with BPs, (Kennel et al. 2009). Vertebral augmentation procedures improved pain after compression fracture (n=923) by 4.8, 4.6 and 4.4 points at 1 week, 1 year and beyond 1 year respectively, (Khan et al. 2014). Valerie et al. (2011, n=84) analyzed improvement in bone pain with radiotherapy (median 45 grays) in 92 % patients. Prophylaxis of infections: Leng et al. (2018, n=70,687) observed reduced risk of herpes zoster (HZ) reactivation in patients on bortezomib or carfilzomib + HZ prophylaxis (2.4%) vs 5.8% in non-prophylactic group, (attributable risk reduction: 0.42; 95% CI 0.31-0.56). Teh et al. (2016, n=199) reported reduced risk of varicella zoster virus reactivation with valacyclovir (500 mg) in patients on bortezomib based therapy and following autologous stem cell transplant (ASCT) vs no prophylaxis (HR=0.06 vs 16.9; p Role of plasmapheresis in renal impairment (RI): Alkhatib et al. (2017) showed that plasmapheresis reduced dialysis dependency by removing serum free light chains (sFLC) in patients with RI (n=147), (RR 0.45; P = 0.02). Yu-X et al. (2015, n=147), showed lower 6-month dialysis dependency ratio with plasmapheresis and chemotherapy (PP + CTH) vs CTH alone, (15.6% vs 37.2%; RR=2.02; p = 0.04). High cut-off hemodialysis lowered sFLC level in 61% (n=42) and 63% patients at day 12 and 21 respectively. Out of these, 71% and 69% patients became dialysis independent, (Hutchison et al. 2012, n=67). Peripheral neuropathy (PN): Bortezomib caused PN in 124/331 (37%) patients (Richardson et al. 2009) whereas with thalidomide, the incidence of PN was 38% and 73% at 6 and 12 months, respectively, (Mileshkin et al. 2006, n=75). PN improved in 68% patients on bortezomib with dose modifications (n=72) vs 47% patients, without dose modification (n=19). (Table 1 and 2). Significant improvement in PN was seen with duloxetine vs placebo (1.06 vs. 0.34; p= 0.003), (Smith et al. 2013, n=231). Arbaiza et al. (2007, n=36) showed improvement in neuropathic pain with tramadol (p= < 0.001). Epoetin and derivates for anemia: Castelli et al. (2017, n= 31; median creatinine 1.2 mg/dL (0.8-3.0)) reported hemoglobin (Hb) increase of ≥1g/dL and ≥2g/dL in 71% and 31.7% patients respectively with epoetin α, transfusions requirement reduced from 2.39 ± 1.05 to 1.23 ± 1.36 (p < 0.001). Begiun et al. (2013, n= 72) compared the effect of darbepoetin (D) ± iron (Fe) vs placebo on erythroid recovery after ASCT. All patients receiving D + Fe achieved Hb ≥13 g/dL (p Conclusion: Along with anti-myeloma chemotherapy therapy, management of complications (anemia, infections, renal insufficiency) and other associated symptoms is necessary to improve the quality of life. Disclosures No relevant conflicts of interest to declare.

Background: Ixazomib (Ixa) is the first FDA approved oral proteasome inhibitor to be used for relapsed and refractory multiple myeloma (MM). We conducted a comprehensive systematic review and meta-analysis of all published prospective clinical trials to analyze the efficacy and safety of ixazomib in newly diagnosed multiple myeloma (NDMM) and relapsed/refractory multiple myeloma (RRMM). Method: After review of literature (last updated June 30, 2018) using database searches (Pubmed, Embase, Cochrane Library, Web of Science and Clinical Trials.gov), from a total of 1290 studies, only fifteen clinical trials (n=1387) met the inclusion criteria for RRMM and eight clinical trials (n=537) met criteria for NDMM. CMA software v.3 was used for meta-analysis. Heterogeneity among studies was assessed using the I2 test. A random-effect model was applied. Result: Based on pooled analysis, an overall response rate (ORR) of 40.6% (95% CI:19.4-66.0) with a very good partial response or better (≥VGPR) of 15.7% (95% CI: 6.8-32.1) in RRMM and ORR (CR+VGPR+PR) of 77.5% (95% CI: 73.1-81.4, I2=48.05) in NDMM was observed. Most common grade (G) ≥ 3 adverse events (AE) based on regimen were calculated using pooled analysis in MM patients. Ixazomib Based Regimen in RRMM: Ixazomib as monotherapy: Four studies (n=192) evaluated the efficacy of ixazomib as a single agent. On subgroup pooled analysis on Ixa as monotherapy, an ORR of 22.7% (95% CI: 13.3-35.9, I2=45%) was observed with ≥VGPR of 7.8% (95% CI: 2.7-20.3). Pooled analysis for safety profile on most common G ≥ 3 adverse events (AEs) were thrombocytopenia 32.3% (95% CI: 22.4-44.2), neutropenia 21.5% (95% CI: 12.6-34.1), diarrhea 13.1% (95% CI: 6.8-23.9), fatigue 11.6% (95% CI: 7.4-17.7) and peripheral neuropathy 2.2% (95% CI: 0.7-6.6). Ixazomib in two drug regimen: In RRMM, two clinical trials (n=92) evaluated the efficacy of Ixa weekly with dexamethasone (D). In this subgroup pooled analysis, ORR of 40.7% (95% CI: 22.8-61.5, I2=41.76%) with ≥VGPR of 19.5% (95% CI: 4.6-52) was calculated. One study reported event-free survival (EFS) of 8.4 months(4.5-12.8) with a 1-year overall survival rate of 96% (95% CI: 91-100). In our analysis for safety (n=102), common G≥ 3 AEs calculated was thrombocytopenia in 20% (95% CI: 7.5-43.7), neutropenia in 14.3% (95% CI: 3.7-41.6), fatigue in 9.1% (95% CI: 5.0-16.2), diarrhea in 5.7% (1.1-25.5), nausea in 5.7% (95% CI: 1.4-20.2) and peripheral neuropathy in 5.7% (95% CI: 1.4-20.2). Ixazomib in three drug regimen: In RRMM, the efficacy of Ixa was evaluated inten clinical trials (n=646), an ORR of 56.3% (95% CI: 41.8-65.5, I2=82%) with ≥VGPR of 22.8% (95% CI: 13.2-36.4) was noted. Best response was seen when Ixa was used in combination with lenalidomide (R) and dexamethasone, with reported ORR of 78.3%. Common AEs were neutropenia 23.5% (95% CI: 16-33.1), thrombocytopenia 18.8% (95% CI: 13.4-25.6) anemia 10.5% (95% CI: 8.2-13.2), diarrhea 6.3% (95% CI: 3.4 -11.3), fatigue 4.2% (95% CI:2.7-6.4), nausea 1.8% (95% CI: 0.9-3.5) and peripheral neuropathy 2.3% (95% CI: 1.3-3.9). Ixazomib Based Regimen In NDMM: Pooled analysis of subgroup study for combination regimen of Ixa as IRD, Ixa-Thalidomide (T)-D, Ixa-Cyclophosphamide (C)-D, and with Ixa -melphalan-prednisone (IMP), their estimated ORR was 83.7% (95% CI: 75.6-89.5), 80.8% (95% CI: 72.8-86.9), 75% (95% CI: 66.6-82) and 66% (95% CI: 52.4-77.4) respectively. We also measured the efficacy of Ixa as a maintenance therapy, estimated ORR was 81.5% (95% CI: 36.6-97.1, I2=90.5%). In one phase II maintenance study (n=64), a combination of IR receiving patients (n=34), an ORR of 90.4% with VGPR of 53% was reported. Median progression-free survival (PFS) was not reached after a median follow up of 37.8 months and estimated 2-year PFS was 81%. Common G≥3 AEs in NDMM patients were neutropenia 21.6% (95% CI: 11.2-37.6), thrombocytopenia 15.9% (95% CI: 4.7- 42), infections 15.2% (95% CI: 10.3-21.9) and peripheral neuropathy 7.9% (95% CI: 4.7-13). Conclusion: In our pooled analysis (95%CI), Ixazomib has shown promising efficacy both in NDMM as well as RRMM. Especially in three drug regimen it showed an estimated ORR of 84.8% in NDMM and 56.3% RRMM.Cytopenia was a common side effect.Peripheral neuropathy was noted to be a rare side-effect (2.6%) in RRMM. Further studies are required to evaluate efficacy and safety of ixazomib in combination therapies in NDMM. Disclosures No relevant conflicts of interest to declare.

Introduction Drugs that target activating mutations of Janus Kinase 2 (JAK2) have been the backbone of myelofibrosis (MF) management. With recent advancements in our understanding of the underlying molecular mechanisms involved in myelofibrosis (MF) pathogenesis, numerous novel agents have been developed in the last decade. We have systematically reviewed the mechanisms of actions, efficacy and safety of these drugs. Methods A comprehensive literature research was performed using PubMed, Cochrane, EMBASE, Web of Science and Clinicaltrials.gov. We included all trials that were under development in phase I/II/III trials. Our search identified 1642 full-length manuscripts or abstracts with published results in the last decade were screened for relevant studies. Of these, 212 articles were finalized for our final analyses. Results Hedgehog inhibitors (saridegib, glasdegib and sonidegib) targets signaling membrane protein, smoothened. The combination of sonidegib + ruxulotinib (RUX) elicited the best response. Spleen volume reduction (SVR) ≥35% and spleen length reduction (SLR) ≥50% was reported in 15 (55.6%) and 25 (92.6%) patients. Histone deacetylase inhibitors (panobinostat, pracinostat, vorinostat, givinostat) target JAK2-H3Y41-HP1 pathway involved in hematopoiesis and leukemogenesis. The combination of pracinostat + RUX demonstrated the best response in a phase II trial (n=22), with clinical improvement (IWG-MRT) in splenomegaly, symptoms and both were reported in four (18%), two (9%), and ten (45%) patients that were durable for a median of 7.5 months. Immunomodulators: Lenalidomide has shown anemia responses in 32% of patients in combination with prednisone, in a phase II trial (n=40). Improvement in bone marrow fibrosis (10/11 patients with G4 reduced to G2 or better) was also seen. Pomalidomide with or without prednisone has shown anemia responses varying from 17-24% across different trials. However, a recent phase III trial (n=32) comparing pomalidomide vs. placebo, found no difference in transfusion independence rates (16% vs. 16%, p=1.00). Azacytidine (AZA) and decitabine (DCB) are hypomethylating agents. An objective response rate (ORR) of 69% (n=39) with AZA+RUX was noted. DCB+RUX demonstrated an ORR of 57% with a median overall survival of 10.4 months, in a phase I trial (n=21). Imetelstat is a telomerase inhibitor that has shown an ORR of 21% among 33 MF patients. Responses were characterized by BMF improvement (n=4) and transfusion independence (3/7 responders). Anti Fibrotics: PRM 151, a recombinant pentraxin-2, has shown an ORR of 35% in a phase II trial (n=27). Anemia response was noted in 6/15 (40%) patients and BMF improvement in two patients, durable up to 72 weeks. Simtuzumab, an antibody lysysl oxidase like-2 (LOXL2) enzyme, failed to show any clinical benefit in a phase II study of 54 patients. Sotatercept and luspatercept are ligand "traps" that limit the activity of TGF-B superfamily ligands, involved in erythroid differentiation. Sotatercept monotherapy achieved transfusion independence (TI) in six (35%) of 17 evaluable patients. Luspatercept has recently been under investigation in patients with MF (NCT03194542). LCL-161 is a second mitochondrial activator of caspases (Smac)-mimetic, A phase II clinical trial (n=33) found an ORR of 30% (n=9). Five (56%) of the nine responders achieved anemia responses. Buparilisib and everolimus targets the PI3K/mTOR pathway. Buparilisib, a PI3K inhibitor, demonstrated a SLR ≥ 50% in 72% patients whereas everolimus, an mTOR inhibitor, showed an ORR of 23%. Conclusion The combination of ruxolitinib with some of these novel agents such as hedgehog inhibitors and hypomethylating agents have shown promising efficacy with response rates of more than 40%. LCL-161 and sotatercept has been reassuring with respect to anemia management, achieving response rates of more than 30%. PRM-151 has shown durable responses and will be the first antifibrotic for MF, if approved. Even though initial results with some of these novel agents have been ground breaking, there is a need to further explore pathways that can be targeted to help prolong survival and modify the disease course in MF patients. Disclosures No relevant conflicts of interest to declare.

Background: Sickle cell disorder (SCD) and transfusion dependent beta-thalassemia (TDT) are inherited disorders of β-globin genes leading to ineffective erythropoiesis, hemolysis and multi-organ damage. Though allogenic hematopoietic cell transplantation (allo-HCT) in the only potentially curative therapy, lack of full HLA-matched donor, increased risk of myeloablative conditioning (MAC) regimen related toxicity, poor prognosis in older age groups (>14 years), and a high risk of infections and graft versus host disease (GVHD) culminating into a high transplant related mortality (TRM) preclude HCT as a treatment option for many patients. Gene therapy has been proposed as a relatively new treatment option for these monogenic disorders. It involves transfection of harvested CD34+ hematopoietic stem cells (HSC) with viral vector to transfer a normal beta globin gene, which are then transplanted back to the autologous donor. However, the available data on gene therapy is extremely variable. The purpose of this review is to evaluate the risks and outcomes of SCD and TDT patients undergoing gene therapy. Methods: A systematic search of databases using PubMed, Embase, Web of science, Cochrane database and Clinicaltrials.gov was performed on with no restrictions of language or time period. A total of 4312 articles were identified and after duplicates removal, 3508 articles were screened for relevance. Clinical studies reporting the most recent follow up results about the efficacy and safety of gene therapy in patients with hemoglobinopathies were considered for inclusion. Their quality assessment was done using the Cochrane tool, and bias was evaluated regarding the study selection, performance, detection, attrition and the reporting of the clinical trials. RESULTS (table-1): Only 7 articles qualified for the strict selection criteria with an N of 47: six studies were phase I trials (Cavazzana, M. et al 2010, Boulad, F. et al 2013, Marktel, S. et al 2017, Kwiatkowski, J. et al 2017, Cavazzana, M. et al 2017, Kanter, J. et al 2017) and one was a phase III trial (Walters, M. et al 2017). Thirty five patients (74.4%) had TDT while 12 patients (25.5%) had SCD. All these patients did not have a suitable HLA-matched HCT donor. The length of follow up was heterogeneous owing to the step wise enrollment of participants and ranged from 2-36 months. Except for 4 cases, the age of included population was >13 years. Lentivirus BB305 encoding the HbAT87Q globin gene was used for gene delivery in 81% patients (n=38). The normal beta globin gene was transduced in remaining 9 TDT cases and it involved transduction using TNS 9.3.55 vector in two cases and with GLOBE lentivirus in 7 cases. MAC with busulfan was used in 81% cases (n=38), while treosulfan+thiotepa was used in 7 cases. The non-myeloablative (NMA) conditioning with busulfan was used in only 2 cases (both TDT). Bone marrow harvest was the source of HSCs in all SCD cases. Except for 3 SCD cases in HGB-204 trial and 3 TDT cases in HGB-207 which measured the potential improvement in outcome by an increase in DP-VCN, the range of drug vector copy number (DP-VCN) was 0.3-1.5 copies per diploid genome. The total hemoglobin (HB) level at last follow up was reported for 62% cases (n=29) and it was >8.8 g/dl in all cases. Twenty-one (60%) thalassemia cases were in a transfusion (Tx) free state at last follow up, including the 7 cases (20%) who developed a complete independence from transfusions. No such Tx-free state was noted in SCD cases although they developed a reduction in the Tx-requirement and 75% SCD cases (n=9) had a 30-100% reduction in the frequency of VOCs. All the cases were alive at their recent follow up with manageable toxicity form conditioning. Acceptable safety until the median follow-up from the 7 trials was established in all cases, with no reported development of post-treatment leukemia or new malignancy in these trials. DISCUSSION: In this largest series of gene therapy for the treatment of hemoglobinopathies (to our knowledge), we find it to be clinically effective in terms of reduction in transfusion needs; data to suggest an improved OS and disease free survival is promising, however long term data is awaited. Gene therapy appears to bypass the limitations faced by allo-HCT especially a high early TRM. Randomized trials reporting the efficacy and safety outcomes with longer follow ups are urgently required. Disclosures No relevant conflicts of interest to declare.

Background: Multiple Myeloma (MM) remains incurable. Majority of the patients ultimately relapse with a lower median event free survival after each successive line of therapy. For newly diagnosed MM patients, the median progression free survival (PFS) has improved drastically with the advent of novel agents. Aim of our review is to discuss median PFSnwith novel agents in the 2nd 3rd and 4th line of treatment in MM. Methods: A comprehensive literature search was done in accordance with the PRISMA guidelines from Jan 1st 2010 to May 30th 2018 using the following 4 databases: PubMed/ Medline, Elsevier/Embase, Wiley/Cochrane and clinicaltrials.gov. Inclusion criteria consisted of all prospective clinical trials that a) included patients with 1-3 prior lines of therapies b) received novel therapeutic agents as an intervention c) outcome was reported as median PFS. We excluded case series, retrospective/observational studies, systematic reviews/meta-analysis. We identified 4777 records through initial database search. After removing duplicates and further screening, 59 full-text articles were assessed for eligibility. 50 articles were subsequently excluded with reason and 9 articles constituting 4937 patients were selected for data extraction and final analysis. Result In a randomized clinical trial (RCT) by Dimopolous et al (2017), 396 patients (median age: 64) in the carfilzomib, lenalidomide and dexamethasone (KRD) arm had median PFS of 26.3 m. In comparison, 396 patients in the control group (median age: 65) that received RD regimen had a median PFS of 17.6 m. Percentage of patients with prior bone marrow transplant (BMT) and high-risk (HR) cytogenetics was 54.8% and 12.1% respectively in the KRD regimen and 57.8% and 13.1% respectively in the RD regimen. The median prior number of therapies was 2 in each group. In the trial by Avet-Loiseau et al 2017, patients in the Ixazomib-RD arm (n=360; HR cytogenetics=21%) had a median PFS of 20.6m as compared to 14.7 m in the control group (RD) arm (n=362; HR cytogenetics=17%). Median prior number of therapies was 2 in each group and 59% and 57% of the patients had prior BMT respectively. Lonial et al (2015) showed that the group (n=321; median age 67) that received elotuzumab-RD regimen had median PFS of 19.4m compared to 14.5m in the control group (n=325; median age 66) that received RD regimen. Prior median therapies were 2 in each arm and BMT was done in 52% and 57% of the patients respectively. A RCT of two drug regimen by Chang et al (2017) showed that patients (n= 464) who received KD had a higher median PFS (18.7m) as compared to patients (n= 465) who received bortezomib(V)-D (9.4 m). KD arm had 37.2% patients with prior BMT as compared to 49.6% in the VD arm whereas the median prior number of therapies was 2 in each arm. HR cytogenetics were present in 21% and 24% respectively. In the trial by Orlowski et al (2015), there was no improvement in the median PFS with the addition of Siltuximab to V as compared to V alone. Similarly, no significant improvement in median PFS was noted by Dimopolus et al (2017) in the combination regimen of Vorinostat-V as compared to placebo-V. In the trial by white et al (2017), the median PFS was 6.2 with bevacizumab-V as compared to 5.1m with placebo-V. In a trial by Richardson et al (2016), Panobinostat-VD had a median PFS of 11.99 which was higher than 8.08 with placebo-VD. Conclusion: Regimen consisting of KRD has the highest median PFS in MM patients with multiple prior lines of therapy followed by IRD based regimen. Limitations of our analysis include a heterogeneous patient population and exclusion of data with daratumumab based regimen because of unavailability of median PFS specifically in the 2nd 3rd and 4th line setting in the published clinical trials. Disclosures No relevant conflicts of interest to declare.

Background: IgD multiple myeloma (MM) is a rare subtype contributing 2% of all multiple myeloma cases. Despite difficulty and delay in diagnosis, recent advances in the treatment of multiple myeloma in general also improved the outcomes for IgD myeloma subtype. The aim of this study is to summarize the data on presentation patterns, diagnosis, management approaches and outcomes for patients (pts) with IgD myeloma. Methods: A comprehensive literature search for articles published after December 2013 was performed using four databases: PubMed, Embase, Cochrane, and Clinicaltrials.gov. With initial search we identified 209 articles and after screening by two independent reviewers we included only 8 studies in the final analysis. Results: A total of 166 pts with IgD MM were included from 8 selected retrospective case series. Lambda (λ) was the predominant light chain sub-type in 136 patients (81.9%). Initial manifestations of IgD MM were Bence jones proteinuria (BJP>2 g/day-64.5%), renal dysfunction (63%), bone pain (55.9%), weakness, fatigue (34.2%) and extra medullary involvement (28.3%). Renal function was assessed by estimated glomerular filtration rate (eGFR2mg/dl) in 46.1% patients. Cytogenetic karyotype analysis in 56 pts using fluorescence in-situ hybridization (FISH) identified abnormal cytogenetics in 41 (73.2%) patients, cases were further classified as high risk (85.7%) and standard risk (14.3%). The patient characteristics and disease manifestations are mentioned in Table 1. Serum protein electrophoresis (SPEP) showed positive monoclonal spike (M) spike in 84% of the patients. The median M spike value for IgD MM was 9.42 g/l in a cohort of 17pts, (Djidjik et al.) which was lower as compared to IgG (median: 35 g/L) and IgA (median: 32 g/L) in this study. Abnormal serum free light chain ratio (sFLCR) was observed in 83% pts. Quantitative serum IgD levels were elevated only in 28% of the cases. Bone marrow (BM) plasmacytosis showing > 40% abnormal plasma cells was detected in 95.6% of the patients. N glycans are newly discovered biomarkers used for detecting abnormal protein glycosylation in MM patients. NG1(6)A2F and NG1(3)A2F were the two most significant N glycan markers for IgD MM patients with sensitivity of 95% & 95.2%, respectively and specificity of 95% & 78.6%, respectively. The prognostic significance of several other biomarkers studied in IgD MM is mentioned in Table 2. Treatment details were available for 149 patients and overall response rate (ORR) was seen in 125 (83.9%) patients while 24 (15.4%) patients had progressive or stable disease. The median overall survival (mOS) was between 9 - 62 months. Novel agents (NA) such as bortezomib, thalidomide and lenalidomide were given to 111 (74.4%) pts with the mOS between 15 - 38.6 months. Conventional agents (CA) such as melphalan, vinblastine, vincristine, epirubicin, and ifosfamide were given to 38 (25.5%) patients with mOS between 12.5 - 17 months. Data showed bortezomib based regimens resulted in a higher ORR (ORR=94%, CR=52%) compared to non bortezomib based regimens (ORR=77.8%, CR=27.7%) respectively. Stem cell transplant (SCT) was used in 37 (24.8%) patients with chemotherapy (NA=26, CA=11) which showed good response rate (ORR>90%,CR >60%). The comparison of response rate with different drugs is mentioned in the Table 3. Conclusion: N-glycan assay can overcome the limitations of SPEP and quantitative serum IgD assay in the diagnosis of IgD MM. This difficulty is posed by the lower concentrations of M spike ( SPEP) or lower-normal serum IgD value on quantitative serum assays, which can delay its diagnosis. Novel and conventional agents have good responses with ORR>90%, but mOS of conventional agents was lower when compared to novel agents. Bortezomib based regimens showed better responses when compared to non-bortezomib regimens. The best response (ORR=95%) was obtained with use of SCT in combination with novel agents. Serum free light chain levels, N glycan assay and serum IgD quantification were found to be the best prognostic markers for IgD MM. Disclosures No relevant conflicts of interest to declare.

Background: Elotuzumab (elo) is a humanized monoclonal antibody, which has been approved by the FDA for use in combination with lenalidomide (lena) and dexamethasone (dexa) in patients (pts) with relapsed and refractory multiple myeloma (RRMM). Elotuzumab is effective as a single agent, as well as in combination for multiple myeloma treatments, supporting the use of elo in pts with RRMM and newly diagnosed multiple myeloma (NDMM) pts. Method: After review of literature using database searches was done on 6/27/18 (Pubmed, Embase, Cochrane Library, Web of Science and Clinical Trials.gov), 9 prospective and 1 retrospective study with 1128 enrolled pts met the inclusion criteria to date in RRMM and 2 clinical trials including 123 pts in NDMM (Table 1). CMA software v.3 was used for meta-analysis. A random-effect model was applied. Result: Regimens used in RRMM: Based on pooled analysis (95% CI), an overall response rate (ORR) of 66% (54-76.2) was calculated in 685 evaluable pts treated with elo based regimens in RRMM (Figure 1). Most common grade (G) ≥ 3 hematological adverse events (HAE) and non-hematological adverse events (NHAE) based on regimen were calculated using pooled analysis in RRMM pts (Table 2). Anemia was noted in 12.1% ( 7.7-18.6) in 559 pts, while neutropenia in 14.5% (7.5-26.4) out of 591 pts and thrombocytopenia (tcp) in 11.9% (7.9-17.4) in 198 evaluable pts. Diarrhea 5.5% (3.6-8.3), pyrexia 2.4% (1.5-4), peripheral neuropathy (PN) 8.4% (3.8-17.8) were measured in 626, 668 and 143 pts respectively. Elotuzumab as monotherapy: 1 study (n=34) evaluated the efficacy of elo as single agent in RRMM. The median age, time from diagnosis and number of prior therapies were 64.5 years (y) (46-87), 4.4 y (0.9-12.8) and 4.5 y (2-10) respectively. It produced an ORR of 1.4% (0.1-19.1 95% CI) in 34 evaluable pts. Adverse events recorded were pyrexia and fatigue in 17.6% and 8.8% pts respectively. Elotuzumab in two drug regimen: In RRMM, 2 clinical trials (n=49) evaluated the efficacy (95% CI) of elo, ORR of 25% (4.1-72.3) was calculated. The best PFS (progression free survival) produced was in combination of elo 20 mg with bortezumib (bort) 1.3mg/m2 of 9.46 months as compared to 1.8 months when elo10mg/kg + dexamethasone (dexa) 28mg was used. In our analysis for safety, common G≥ 3 HAE calculated were, thrombocytopenia 8.7% (3.3-21.1) n=49, neutropenia 10.7 % (3.5-28.4) n=28 pts and anemia 7.1% (1.8-24.5) n=28 pts. NHAE included diarrhea 1.7% (0.1-22.3), PN 10.7% (3.5-28.4), pyrexia 1.7% (0.1-22.3) in 28 evaluable pts each. Elotuzumab in three drug regimen: In RRMM, 10 clinical trials including 602 pts evaluated the efficacy of elo as a part of triple drug regimen, producing an ORR of 72.2% (54-76.2). The best results were produced with the combination of elo 10-20mg/kg + lenalidomide (lena) 25mg + dexa 40mg producing a PFS of 32.2 mo and 28.62 mo in its phase I and II cohorts respectively. Based on pooled analysis (95% CI) common HAE calculated were neutropenia 17.5% (7.6-35.4) in n=563, thrombocytopenia 12.7% (8.2-19.4) in n=149 and anemia 13% (8-20.5) in n=531 pts. Common G ≥ 3 NHAE estimated were diarrhea 5.7% (3.7-8.6), PN 6.6% (2-19.2), pyrexia 2.5% (1.5-4.1) in 598, 115 and 640 pts respectively. Elotuzumab based regimen in NDMM: A currently ongoing clinical trial NCT02272803 has produced promising results in NDMM pts. As a part of three drug regimen with dose of elo 10mg/kg-20mg/kg, lena 25mg, dexa 20mg in 40 pts produced an ORR of 87.5% (73.2-95.8) versus control group of lena 25mg plus dexa 40mg in 42 pts with an ORR of 73.8% (58-86.1). The PFS rate recorded at 1 year was 93% (79-98%) and 91% (73-97%) respectively. The HAE G ≥ 3 included, neutropenia 18% and leukopenia 15%. In another study with 41 pts, elo was used in combination with lena, bort and dexa producing an ORR of 100% and greater than grade 3 adverse events including Tcp 15%, PN 2%. Conclusion: Results produced in our study suggest that elotuzumab is highly effective when used in pts with RRMM and NDMM. Combination regimens for elo produces an ORR ranging from 79-83% with elo + lena+ dexa, proving that the best results were produced by three drug regimens. Large prospective studies are required to evaluate efficacy and safety of elotuzumab in combination therapies. Disclosures No relevant conflicts of interest to declare.

Introduction: Central Nervous System (CNS) involvement in multiple myeloma (MM) is a rare extramedullary manifestation which occurs in less than 1% of MM cases. The median survival after the diagnosis (Dx) is 1-2 months (M). Literature review revealed us of various treatment modalities i.e. systemic chemotherapy (CT), intrathecal therapy (IT), and radiotherapy (RT). The primary aim of our analysis is to summarize published literature on presentation patterns and review effective management strategies regarding CNS involvement in MM and its outcome. Methods: We performed a systematic review of 2533 articles published from 2005 using five databases (PubMed, Embase, Cochrane Library, Web of Science and ClinicalTrials.gov). After a detailed screening, 28 studies were included. Results: A total of 550 patients (pts) data is included. Eighty-eight (16%) pts had CNS involvement at the time of their initial presentation and 462 (84%) pts had disease detected at the time of relapse / refractory (R/R) disease . The median reported follow up, from the time of initial Dx, was 18 months (M) [range (r) = 3.4-75M]. The median age of pts was 58 years (y) (r= 40-71). The clinical presentations were heterogeneous with cranial nerve palsy (21%), headache (17%), confusion (17%), visual disturbances (17%), extremity weakness (9%), cord symptoms (5%) and nausea / vomiting (5%). The CNS region involved was identified in 366 pts: 163 (44.5%) pts had leptomeningeal (LM) involvement, 98 (26.8%) pts had dural (D)/osteodural (OD) involvement, 10 (2.7%) pts had LM + D/OD involvement, 90 (24.6%) pts had intraparenchymal (IP) involvement and 5 (1.4%) pts had LM + IP involvement. Hundred twenty-nine pts had International Staging System (ISS) information availabe at the time of MM Dx, out of which 39 (30%) pts had stage I disease, 32 (25%) pts had stage II disease and 58(45%) pts had stage III disease. The median time ( reported in studies) for CNS involvement after MM Dx ranges from 2.5-122 M in pts who underwent systemic treatment and 7-96 M in patients who underwent stem cell transplant (SCT). Five hundred twelve (93%) pts underwent treatment, out of which 42 (8.2%) pts had IT therapy with methotrexate and/or cytarabine, 44 (8.5%) pts had RT, 170 (33.2%) pts had CT, 103 (20.1%) pts had IT + RT + CT, 77 (15%) pts had RT + CT, 16 (3.1%) pts had IT + RT and 60 (11.7%) pts had IT + CT. One hundred two pts had SCT along with the other therapies. Among the pts who received systemic treatment, 34 patients received therapy with conventional agents (CA), 80 patients received therapy with novel agents (NA), 347 patients were treated with combination therapy of CA and NA. Data regarding the rest 51 patients were not available. Bortezomib (V) based regimens were given in 158 pts; immune-modulators (IMiD) based regimens in 153 pts; vincristine, adriamycin, dexamethasone (VAd) regimen in 21 pts; alkylators in 85 pts; carfilzomib in 7 pts; bendamustine in 5 pts; pomalidomide in 5 pts and daratumumab was given in 2 pts. The mOS in patients who received NA therapy was 4-25 M. The mOS in patients who received CA therapy was 2.7-8 M. The mOS in patients who received both CA and NA was 2-7.4 M. Seventy-five out of 512 patients were evaluated for efficacy, out of which, 30 pts showed complete response (CR), 6 pts showed very good partial response (VGPR), 17 pts showed partial response (PR) and progressive disease (PD) was seen in 22 pts. Death was reported in 370 out of total 550 pts. Conclusion: Our analysis demonstrated that systemic CT with CA & NA, RT and IT therapy either alone or in combination are the currently available strategies employed in treating CNS myeloma. Furthermore, NA therapies have shown an increase in the overall survival i.e. up to 25 months. The IMiD have shown good CNS penetrance [thalidomide (30-40%), lenalidomide (11%) and pomalidomide (39-49%)] and effectiveness in the clearance of myeloma cells from CSF. There is no established standard of care for CNS myeloma. As prognosis remain dismal for such patients, newer innovative approaches need to be tested in clinical trials (use of drugs like thiotepa, IT Daratumomab, combination regimens for IT therapy coupled with CNS penetrating systemic therapy etc.) to improve current treatment outcomes. Disclosures No relevant conflicts of interest to declare.

BACKGROUND: Despite recent advancements in treatment for multiple myeloma (MM) there is a constant need for newer therapies to tackle the complex issue of relapse and therapy after relapse for patients with MM. Ibrutinib is an oral inhibitor of Bruton tyrosine kinase (BTK), which is overexpressed in the plasma cells. We conducted a comprehensive literature search to analyze the efficacy, dosing and toxicity profile of ibrutinib in relapsed MM. METHODS: Database search using PubMed, EMBASE, Cochrane Library, Web of Science and Clinicaltrials.gov was performed on 06/05/18 (last update) . All clinical trials that used ibrutinib either as monotherapy or in combination regimens in the setting of relapsed and refractory multiple myeloma (RRMM) were included. RESULTS: A total of 388 articles were found on the initial search and after screening, three phase I and II clinical trials qualified for inclusion. Ibrutinib based regimen data (n=155 patients) was analyzed (Table 1). Majority (68%) of the patients were refractory to their previous line of therapy. Ibrutinib Monotherapy: Monotherapy (n=31) with a dose of 420 mg/d to 840 mg/d demonstrated a 0% ORR (overall response rate). A median PFS (progression-free survival) of 0.9 to 2.8 months was noticed with ibrutinib monotherapy. Most common hematological adverse events (HAE) noted were anemia (32%), thrombocytopenia (29%) and neutropenia (13%). All-grade gastrointestinal disturbances (GI) were observed in 90% of cases, fatigue and respiratory infections (RI), each in 39% and muscle spasms in 23% of cases. Ibrutinib + Dexamethasone: The addition of 40 mg dexamethasone to 560 mg/d (n=18) and 840 mg/d (n=43) ibrutinib showed an ORR of 6% and 5% and reported median PFS of 3.7 months and 4.6 months, respectively. Side effects included anemia (26%), thrombocytopenia (23%), and neutropenia (2%). GI toxicity was noted in 82% patients, fatigue in 46%, RI in 15% and muscle spasms reported in 15% patients. Ibrutinib + Carfilzomib: At 560 mg/d dose of ibrutinib, the addition of 27 mg/m2 (n=3) and 36 mg/m2 of carfilzomib (n=5) showed a response of 67% and 40%, respectively. The best response was elicited when 20 mg of dexamethasone was added to 36 mg/m2 of carfilzomib and ibrutinib at a dose of 840 mg/d (n=18; ORR: 71%) and 560 mg/d (n=17; ORR: 71%). The median duration of responses was 12.9 months. Minimal responses were observed in an additional 4 patients giving an overall clinical benefit rate of 76%. At a dose of 36 mg/m2 of carfilzomib, median PFS was reported as 8.1 and 6.4 months at 560 mg/d and 840 mg/d doses of ibrutinib, respectively. Most common HAE were anemia (35%), thrombocytopenia (28%) and neutropenia (9%). Eighty-six percent of patients developed GI disturbances while fatigue and muscle spasms were noted in 53% and 19%, respectively. RI were observed in 51% of patients. Ibrutinib + Bortezomib: The combination of ibrutinib given at 840 mg/d dose with a twice weekly dose of bortezomib 1.3 mg/m2 elicited a response in 46% (n=20) patients, and minimal responses in 4 (21%) patients. Most common GI disturbance was diarrhea (50%). Upper respiratory infections were noted in 30% cases while, asthenia and peripheral edema seen in 20% of cases. Bortezomib/IMiD Refractory Cohort: Patients refractory to prior bortezomib (n=27) showed an encouraging ORR of 73% that was durable for a median of 9.1 months when ibrutinib+carfilzomib+dexamethasone regimen was used. Similarly, another cohort (n=25) of double refractory patients treated with a combination of ibrutinib and dexamethasone demonstrated minimal response in 4 (16%) and disease stabilization in another 5 (20%) patients. High-Risk Cohort: In a population of high-risk cytogenetics (del 17p and/or t[4;14]; n=11) treated with 560 mg/dl to 840 mg/dl of ibrutinib, 36 mg/m2 of carfilzomib and (+/-) 20 mg of dexamethasone showed an ORR of 78%, response was durable for a median of 9.1 months, and achieved a median progression free survival (PFS) of 8.1 months . CONCLUSION: Ibrutinib has demonstrated a promising efficacy (70-80% of ORR in combination regimens) along with an acceptable toxicity profile in the heavily pre-treated and dual drug refractory MM patients. Larger prospective clinical trials are needed to further evaluate its efficacy. Disclosures No relevant conflicts of interest to declare.