Immunoglobulin (Ig) D multiple myeloma (MM) is a rare subtype of MM comprising 2% of all the cases. Malignant plasma cell invasion leads to signs and symptoms similar to other subtypes of MM. The synthesis rate of IgD is lower in IgD MM patients, making it very difficult to diagnose compared to other subtypes. As there is no available diagnostic test with 100% accuracy, the diagnosis of IgD MM is based on multiple factors. Recent advances in the treatment have resulted in a better overall survival for IgD MM patients. The aim of this systematic review was to summarize the data on presentation patterns, diagnosis modalities, management strategies, and outcomes in patients with IgD MM.

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Background: Clonal plasma cells in multiple myeloma (MM) over express b-cell lymphoma-2 protein (BCL2). Which is the target for venetoclax (VEN). VEN has a promising efficacy and a favorable safety profile in MM patients. This review highlights the efficacy of VEN for the treatment of relapsed refractory (RR) MM. Methodology: We performed a comprehensive database search on four major databases(PubMed, Embase, Cochrane, and Clinical trials.gov). Our search strategy included MeSH terms and keywords for multiple myeloma and VEN, including trade names and generic names, from the date of inception of the database to April 2020.The initial search revealed 782 articles. After excluding review articles, duplicates, and non-relevant articles,we included six studies(four clinical trials and two retrospective studies), which reported an overall response rate (ORR) in RRMM patients. Proportions along with 95% Confidence Interval (CI) were extracted to compute pooled analysis using the 'meta' package by Schwarzer et al. in the R programming language (version 4.0.2) to report the efficacy of VEN. We pooled the results of the experimental arms of included trials using the inverse variance method and logit transformation. Between studies,the variance was calculated using Der Simonian-Laird Estimator. Results: We identified 568 patients from four clinical trials [Moreau et al.2019, the BELLINI trial, (n=291, venetoclax arm= 194, placebo arm= 97)], Costa et al. 2018 (n=42), Kumar et al. 2017(n=66), and Moreau et al. 2017 (n=66)] and two retrospective studies (Kambhampati et al. 2020 (n= 47) and Sidiqi et al.2019 (n=56)). Among which 563 patients were evaluable for the treatment outcomes. One hundred and forty two patients (25%) had t(11:14)mutation. The median age of the patients ranged from 64-66 years, and the median number of prior therapies was ≥2. The median dose of venetoclax ranged from 50 mg/day to 1200 mg/day in dose-escalation cohorts of clinical trials while in the retrospective study by Kambhampati, S et al., the median dose of venetoclax was 800 mg/day. The pooled overall response rate (ORR) for all patients who received venetoclax (n=466) was 57% (95% confidence interval (CI) 0.34-0.77, p<0.01; I2=95%), with the highest rates of 84% and 79% being reported from phase III trial using VEN + bortezomib (V) + dexamethasone (d) by Moreau et al.(2019), and VEN + carfilzomib + d in phase II clinical trial by Costa et al. (2018), respectively (Figure 1A). A minimum ORR of 21% was observed in a retrospective study by Siddiqi et al. (2019). Among 142 patients with positive t(11:14) in all studies, ORR was 56% (95% CI 0.44-0.68, p<0.11; I2=44%) (Figure 1B) with the highest rate of 100% being reported from Costa et al., though the number of patients was small. Among 362 patients with no t(11:14) ,ORR was 33% (95% CI 0.16-0.55, p<0.01: I2=89%), with the highest rate of 56% being reported from Moreau et al. in a phase III trial using VEN-Vd (Figure 1C). The highest median duration of response (DOR) (23.4 months) was reported with combination therapy of VEN-Vd. Two hundred and thirty eight (42%) of the patients discontinued VEN, among whom 132 (55%) were reported to have progressive disease. The most common grade≥3 hematological adverse effects were neutropenia, thrombocytopenia, and anemia. The gastrointestinal distress was the most common non-hematological toxicity reported in all the studies. Sixty four (33%) patients died on VEN arm vs. 24 (25%) on placebo in the BELLINI trial, the trend of OS is non-significantly better in VEN arm in t(11:14) while OS is non-significantly worse in non t(11:14) group. Conclusion: VEN is an effective treatment option for relapsed and refractory multiple myeloma patients with t(11:14) translocation. The overall response rate and the duration of response are better in patients with t(11:14). The CANOVA trial is ongoing now to better answer the debatable question of VEN efficacy in t(11;14) MM patients. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau. Fazal:Jansen: Speakers Bureau; Stemline: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Gilead/Kite: Consultancy, Speakers Bureau; Glaxosmith Kline: Consultancy, Speakers Bureau; Agios: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Incyte Corporation: Consultancy, Honoraria, Speakers Bureau; Karyopham: Speakers Bureau; Celgene: Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharma: Consultancy, Speakers Bureau.

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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.