ALBERT

Description: Background Light-chain (AL) amyloidosis is a multi-organ amyloid deposition disease caused by misfolded protein aggregation. Current treatments have improved overall (OS) and progression-free survival (PFS) but challenges remain in improving therapy with newer agents and targeting amyloid protein deposits with novel immunotherapy. We review the literature regarding efficacy of existing chemotherapy in AL amyloidosis and summarize non-FDA approved novel drugs and monoclonal antibodies (mAbs) in early phase clinical development. Methods We searched databases including Cochrane library, PubMed and ClinicalTrials.gov for all prospective and retrospective studies (As of 4/15/2018) with measured hematologic response rate (HR) in patients with AL amyloidosis since 2000. Inclusion criteria included all prospective and retrospective studies with melphalan-based treatments, bortezomib combinations including bortezomib, cyclophosphamide and dexamethasone (VCD), bortezomib and dexamethasone (VD) and immunotherapies. We included all studies with at least 5 or more patients and reported HR. Results From 918 studies, we selected 57 studies (2640 patients) evaluating HR with melphalan-based stem cell transplant (SCT) treatments and non-stem cell transplant treatments including melphalan and bortezomib combinations. Other agents included daratumumab (anti-CD38 mAb), and ixazomib (proteasome inhibitor). Mean aggregate HR reported from studies with melphalan-based SCT treatment (17 studies, n=587) was 67%. Mean aggregate HR from all non-transplant treatments (40 studies, n=2053) was 64%. Of the non-transplant treatments, HR for melphalan-based treatments (21 studies, n=1148) was 59% and varied as follows: melphalan + lenalidomide + dexamethasone (57%) and melphalan + dexamethasone (52%). Mean aggregated HR for non-transplant bortezomib-based treatment (17 studies, n=859) was 72% consisting of VD (69%) and VCD (76%). HR with Ixazomib (1 study) and Daratumumab (1 study) was 52% and 76% respectively. Other novel drugs currently being studied include 11-1F4 (chimeric fibril-reactive mAb), GSK2398852 and GSK2315698 (anti-serum amyloid protein mAbs), and NEOD001 (anti-circulating soluble and deposited aggregated amyloid mAb). Conclusion For AL amyloidosis, melphalan-based SCT has shown effectiveness while VD and VCD demonstrate effectiveness in non-transplant patients. Further studies are warranted to evaluate novel proteasome inhibitors (Ixazomib) and emerging immunotherapy with daratumumab. Current trials including amyloid protein and fibril targeting (circulating and tissue-fixed) with novel immunotherapy are innovative and may have higher clinical efficacy, but need further testing. Disclosures No relevant conflicts of interest to declare.

Description: Introduction Myelofibrosis (MF), a BCR-ABL negative myeloproliferative neoplasm (MPN), has an annual incidence of 1 in 100000 for the primary MF and 0.3-0.7 in 100000 for secondary MF in the USA. MF patients have a median survival of 6.5 years. The primary mutation, JAK2V617F, occurs in 40-60% of MF cases. Ruxolotinib, a JAK inhibitor, has been the mainstay in treating high risk, debilitating MF but largely clinical needs are unmet. 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 ( Jan 2007 till Dec 2017) were screened for relevant studies. After screening by 2 independent reviewers, 212 articles were finalized for our final analyses. We have reviewed the mechanism of action, safety and efficacy of 2nd generation JAK inhibitors in this review. Results JAK1 inhibitor: Itacitinib reduced total symptom score (TSS) ≥ 50% in 15/42 (36%) patients. Mild gastrointestinal (GI) disturbances and some grade 3-4 myelosuppression (anemia: 33%, thrombocytopenia: 29%) were reported. JAK2 inhibitors: In PERSIST-1, pacritinib when compared to best available therapy (BAT) showed SVR ≥ 35% in 19.1% vs. 4.7% patients, with lower rates of myelosuppression (thrombocytopenia: 17%, anemia: 11%). In PERSIST-2, a phase III trial of pacritinb vs. BAT in patients with baseline cytopenias, similar efficacy was demonstrated (SVR ≥ 35%: 18% vs. 3%). Increasing rates of heart failure and intracranial hemorrhages led to a temporary hold which was lifted in August 2017. Lestaurtinib showed CI in 7 (44%) patients in a phase I trial (n=16) and 6 (27%) patients in a phase II trial (n=22). Most notable toxicities were G 1/2 GI disturbances, anemia occurred in 14% and thrombocytopenia in 23% of patients. In a phase III trial (n=193), fedratinib showed a SVR ≥ 35% and a TSS ≥ 50% in 40% and 36% patients, respectively. However, incidence of significant neurotoxicity and Wernicke's encephalopathy led to its suspension. Similarly, a trial of XL019 was terminated due to emergence of central and peripheral neurotoxicity. In a phase I trial (n=48), NS-018 exhibited a spleen length reduction (SLR) ≥ 50% in 20 (56%) patients along with prompt improvement in bone marrow fibrosis (37%). Anemia and thrombocytopenia were reported in 15% and 27% of patients, respectively. Dizziness (23%) and nausea (19%) were also reported. Gandotinib demonstrated SLR ≥50% in 62% patients, in a phase I trial (n=38). G1 diarrhea (55.3%) and nausea (42.1%) were the most common toxicities. JAK 1/2 inhibitors: SIMPLIFY-1 (S1), a phase III clinical trial (n=432) of momelotinib vs. ruxolotinib in JAK inhibitor-naïve patients, demonstrated non-inferiority for momelotinib, in spleen volume reduction (SVR) ≥ 35% (26.5% vs. 29%; p=0.01). However, SIMPLIFY-2 trial (S2), that compared these two drugs in JAK inhibitor exposed patients did not achieve similar responses with momelotinib (6.7% vs. 5.8%; p=0.90). Interestingly, momelotinib excelled at achieving transfusion independency in both trials (S1: 66.5% vs. 49.3%; p=0.001, S2: 43.3% vs 21.2%; p=0.001). Grade ≥ 3 infections and peripheral neuropathy were the major toxicities noted. These trials were suspended after 89% of patients failed to achieve the primary endpoint of SVR. AZD1480 demonstrated clinical improvement (CI) in four (11%) patients in a phase I trial (n=35). Most common adverse events included grade (G) 1-2 dizziness and anemia. Conclusion Novel JAK pathway inhibitors have shown promising efficacy in MF but safety concerns regarding the hematological (cytopenias) and non-hematological adverse effects needs to be addressed until their use in clinical practice is established. Momelotinib success in achieving anemia related endpoints is note-worthy and should be further explored in this regard. A phase II study [NCT03165734] evaluating pacritinib monotherapy as a second line treatment in patients with baseline thrombocytopenia is ongoing. Disclosures No relevant conflicts of interest to declare.

Description: Introduction: Multiple myeloma (MM) is an incurable malignancy of B-cell lineage. Introduction of immunomodulatory drugs such as lenalidomide has significantly improved overall survival of patients with MM. Lenalidomide maintenance is currently the standard of care for maintaining remission in MM. However, second primary malignancies are known to arise in patients on lenalidomide though their pathogenesis is not known. We report a patient who developed B-lymphoblastic leukemia (B-ALL) while on lenalidomide, which went into spontaneous remission after stopping lenalidomide. Whole exome sequencing (WES) was performed to examine the mutational landscape and clonal evolution of the different malignant clones. We also aimed to postulate a mechanism for lenalidomide-induced ALL. Case history and methods: A 59-year-old female with history of rheumatoid arthritis was diagnosed with IgG-κ MM and treated with 8 cycles of bortezomib, Lenalidomide and dexamethasone followed by lenalidomide-maintenance (10 mg/day). At 36 months after initiation of treatment for MM, she developed lymphopenia and her bone marrow (BM) biopsy showed 38% leukemic B lymphoblasts. Lenalidomide was discontinued and a follow-up BM biopsy done 2 months later showed spontaneous complete remission of ALL, which was confirmed at 8 months. She remains in complete remission of ALL and MM without any specific treatment at 12 months after the diagnosis of ALL. BM aspirate samples at diagnosis of MM, on lenalidomide-maintenance with MM in remission, at diagnosis of ALL, and after stopping lenalidomide with MM and ALL in remission were used to perform WES with 2x150 bp reads and 100x coverage utilizing the Illumina Hiseq. The raw reads were mapped to reference genome (hg19) and compared with peripheral blood T-lymphocytes as germ line control. Variants were annotated using dbSNP, CLINVAR and COSMIC through Mutect. Clonal evolution was analyzed by SciClone. The study was approved by Institutional Review Board. Results: The burden of somatic mutations was significantly higher at diagnosis of MM when compared to the three other time points. Analysis of clonal architecture revealed the distinct clustering of mutations at specific time points (Figure). Most mutations detected at diagnosis of MM (e.g. NOTCH2, BTG1, BCLAF1) disappeared after treatment for MM. Similarly, most mutations detected only at diagnosis of ALL (e.g.PIK3CD, CDK16) became undetectable at spontaneous remission. Interestingly, clones with mutations of IGSF3 (immunoglobulin superfamily) and CXXC4 (Wnt signaling pathway) were detectable while the patient was on lenalidomide and at diagnosis of ALL but disappeared after stopping lenalidomide, which suggests that these clones gained pro-survival advantage from lenalidomide. Only a few mutations (GSDMC, NBPF20, ANAPC1) persisted in both MM and ALL stages. GSDMC is a gasdermin family member which may modulate function of MYC. NBPF20 has been described in relapsed pediatric ALL. ANAPC1 is a cell cycle gene whose transcription is regulated by Ikaros. Loss of repressor function of Ikaros was recently reported to deregulate ANAPC1 expression and cause mitotic progression of ALL in vitro. As lenalidomide is known to induce degradation of Ikaros, we hypothesize that lenalidomide may create a favorable selection pressure for B-cell clones harboring mutations in Ikaros-dependent genes. Conclusions: Clonal evolution analysis suggests that MM and ALL arose from different B-cell sub-clones, which was consistent with previous observation. However, there are a few shared mutations between MM and pre-B ALL, which may be responsible for leukemogenesis in our case. Lenalidomide may affect intracellular protein interactions to induce selection of rare B-cell clones evolving into secondary ALL. Also, our case demonstrated that simply stopping lenalidomide may lead to spontaneous and durable regression of ALL. Transcriptomic and proteomic analysis including Ikaros expression is required to further understand the mechanism of appearance of ALL and its regression after stopping lenalidomide. Figure Disclosures Shlomchik: BlueSphere Bio: Other: Founder and Equity Interest.

Description: Introduction Advancement in multiple myeloma (MM) has led to the development of adoptive cell transfer (ACT), an immunotherapeutic modality that utilizes body's own effector cells (T cells or Natural killer cells) to kill cancer cells. These include chimeric antigen receptor T cells (CAR-T cells), genetically modified T cell receptors (TCRs), activated Natural Killer (NK) cells and native T cells armed with bispecific antibodies. Potential antigen targets for TCRs in MM include B cell maturation antigen (BCMA), CD19, CD138, NKG2D, Ig kappa, LeY and SLMF7/CS-1, MAGE A3 and NY-ESO-1. The purpose of this review is to summarize various types of cellular therapies which are being tested in early phase clinical trials for treatment of MM. Methods We performed a comprehensive literature search (PubMed, EMBASE, AdisInsight and Clinicaltrials.gov) between January 2008 to December 2017, to identify early phase (I and I/II) trials of cellular therapy for the treatment of MM. We included studies involving cellular therapy, irrespective of the geo-location, age, sex or specific eligibility criteria. Results With initial search yielded 2537 phase I and phase I/II studies. After initial screening by two reviewers and categorization by mechanism of action, 37 clinical trials (CTs) that involved ACT were included. Out of the 37 trials, 18 are active or completed (Table 1) and 19 are recruiting subjects (Table 2). Most explored mechanism of action (21 CTs) in these trials is CAR T-cell therapy directed against B cell maturation antigen (BCMA). Anti-BCMA CART has shown promising efficacy of up to 100% objective response (OR) in a phase I trial (NCT03090659, n=22). In a phase I/II trial by Fan et al. (n=19), 6 (32%) patients showed complete response (CR), 12 (63%) developed near complete response (nCR), 1 (5%) achieved partial response (PR). In phase I trial by Ali et al. (2016, n=12), anti-BCMA CART cells led to stringent complete response (sCR) in 1 (8%) patient, very good partial response (VGPR) in 2 (16%), PR in 1 (8%) and stable disease (SD) in 8 (66%). Grade 3-4 cytokine release syndrome (CRS) was reported in 3 (25%) patients receiving high dose of CAR T cells (9 x 106 / kg in 2 patients and 3 x 106 /kg in 1 patient). Cohen et al., 2017 (n= 24) reported the objective response rate (ORR) defined as ≥PR in 11 (47%) patients. In 75% of patients with grade 3-4 CRS, tocilizumab/siltuximab was used to manage CRS. According to Garfall et al. (2018, n=10), administration of anti-CD19 CART after autologus stem cell transplant (auto-SCT) improved progression free survival (PFS) in 2 (20%) patients compared to PFS due to auto-SCT done earlier in same patients (from 181 to 479 days and 127 to 249 days). Leivas et al. (2016, n=5) showed that infusion of expanded and activated natural killer cells (NKAE) with lenalidomide have shown better response (PR=1, SD=1, SD to PD=1) than NKAE with bortezomib (SD=1, PD=1). In 10 (83%) patients, VGPR or better response was achieved after infusion of allogenic cord blood derived NK cells along with auto-SCT (Shah et al., 2017). Rapoport et al. (2017, n=25) infused CAR T-cells against cancer testes antigens (NY-ESO-1, LAGE-1a) and demonstrated the OR in 19 (76%) patients (1 sCR, 12 VGPR, 6PR) at day 100. Al-Kadhimi et al. (2011, n=9) administered activated autologous T cells armed with bispecific antibodies against CD3 and CD20 (aATC) prior to auto-SCT. Two patients achieved VGPR, two patients achieved CR while five patients developed PR. Fowler et al. (2016, n=20) used type 1 polarized, rapamycin resistant T (T1-Rapa) cells after auto-SCT in high risk myeloma patients. Out of 19 evaluable patients, 5 had ongoing CR (at 733, 787, 847, 926, 1186 days) while 14 patients had disease progression (from 64 to 917 days). No adverse effects or dose limiting toxicity was observed in any of the patients. Conclusion Adoptive cellular therapy has shown excellent clinical activity against myeloma cells in relapsed refractory patients. The adverse events like CRS and infusion reactions are concerning but manageable. The results of trials involving T cells targeting BCMA are very encouraging. Disclosures No relevant conflicts of interest to declare.

Description: Introduction Immunotherapy using monoclonal antibodies (mAbs) have been gaining significance in the treatment of multiple myeloma (MM). These include naked antibodies, checkpoint inhibitors (CPIs), novel bispecific mAbs targeting two epitopes and antibody-drug conjugates (ADCs) having a mAb conjugated to a cytotoxic drug. This review aims to summarize phase I and I/II clinical trials using mABs for the treatment of MM. Methods A comprehensive literature search using data from PubMed, Embase, AdisInsight and Clinicaltrials.gov was performed for identification of early phase (I and I/II) trials of mAbs in MM treatment (January 2008 to December 2017). Studies involving mAbs including targeting antibodies, ADCs, CPIs and bispecific mAbs were included, without considering the geo-location, age, sex or specific eligibility criteria. Drugs already approved by FDA were excluded. Results Total of 2537 phase I and phase I/II studies were identified. After screening by two reviewers and categorization by their mechanism of action, 74 clinical trials (CTs) that involved mAbs as monotherapy or in combination with other chemotherapeutic drugs for the treatment of newly diagnosed MM (NDMM) and relapsed/refractory MM (RRMM). 41 CTs are active, completed or discontinued (Table 1) and 33 CTs are recruiting, approved for recruitment or planned. Most explored mechanism of action in these trials was mAb therapy directed against CD38, IL-6, huCD40, PD-L1 and PD-1. Isatuximab (Anti-CD38) has shown objective response rate (ORR) of 〉50% in combination with lenalidomide (R) or pomalidomide (P) plus dexamethasone (d) in ongoing phase I trials NCT01749969 (n=57) and NCT02283775 (n=89) respectively. According to Vij et al. (2016) and Mikhael et al. (2018), 54% ORR (n=31) and 62% ORR (n=28) was shown by combination of isatuximab with Rd and Pd in 57 and 45 evaluable RRMM patients, respectively. In Vij et al. (2016) study, stringent complete response (sCR) in 2 (3%) patients, very good partial response (VGPR) in 13 (23%) and partial response (PR) in 16 (28%) patients was observed. In Mikhael et al. (2018) study, sCR in 1 (2%) patient, CR in 1 (2%), VGPR in 10 (21%) and PR in 16 (34%) patients was observed. In comparison, Martin et al. (2014) mentioned ORR of only 24% with isatuximab monotherapy in 34 RRMM patients. Grade (G) ≥3 pneumonia (n=4) was the most common high-grade adverse events (AEs) being reported (Table 2). Siltuximab (Anti-IL-6) has shown clinical efficacy in combination with bortezomib (V) + d and RVd in phase I and I/II CTs. Shah et al. (2016) and Suzuki et al. (2015) found ORR to be 90.9% and 67% in 11 (NDMM) and 9 (RRMM) patients when siltuximab was given combined with RVd and Vd, respectively. Clinical benefit response (CBR) i.e. ≥ minimal response (MR) was 100% with siltuximab + RVd in NDMM patients. In comparison, siltuximab monotherapy in 13 RRMM patients yielded an ORR of 15% (2 CR) as reported by Kurzrock et al. (2012). G≥3 neutropenia (n=9), G≥3 thrombocytopenia (n=6) and G≥3 lymphopenia (n=8) were most common reported high-grade AEs. Checkpoint inhibitors including pembrolizumab (anti-PD-1) and pidilizumab (anti-PD-L1) are being investigated in RRMM treatment. According to Otero et al. (2017) and Ribrag et al. (2017), 50% ORR was obtained with pembrolizumab combined with Rd compared to 0% with monotherapy, respectively. However, combination therapy was associated with G≥3 neutropenia (n=17), thrombocytopenia (n=9) and anemia (n=6) while no high-grade AEs were observed with monotherapy. Antibody-Drug conjugates including lorvotuzumab mertansine and indatuximab ravtansine have been investigated in CTs for MM treatment. Lorvotuzumab mertansine has shown clinical efficacy in combination with Rd in a phase I trial (NCT00991562). Berdeja et al. (2012) reported an ORR of 59% (1 sCR, 1 CR, 8 VGPR, 9 PR) in 32 RRMM patients. In a phase I/II trial (NCT01638936) of indatuximab ravtansine combined with either Rd or Pd, Kelly et al. (2016) showed ORR of 77% with Rd (n=43) including at least 1 CR and 4 VGPR and 79% with Pd (n=14) including 4 VGPR in total 57 RRMM patients. Conclusion Combination regimens including monoclonal antibodies, CPIs and ADCs have shown clinically significant response in RRMM and NDMM patients. The mAbs caused hematological and nonhematological AEs like cytopenias and infections which needs to be monitored closely. Disclosures No relevant conflicts of interest to declare.

Description: Introduction: Rationale for anticancer vaccine therapy is based on humoral and/or cellular response against unique tumor antigens (Ag). Peptide vaccines specific for Ag are under investigation for patients with multiple myeloma (MM). Among cell-based vaccines, monocyte derived dendritic cell (MDDC) fused with myeloma cells serve as Ag presenting cells to develop an immune response against a variety of targets. The purpose of this study is to report clinical response and tolerability of anti-myeloma vaccines. Methods: We included phase I and I/II trials developed between January 2008 to December 2017, where vaccines or viruses were used against MM, irrespective of the geo-location, age, and sex. We performed a comprehensive literature search (last update 3-30-2018) using the following databases: PubMed, Embase, AdisInsight, and Clinicaltrials.gov. Results: The initial search identified 2537 early phase studies. After screening by 2 reviewers and categorization by mechanism of action, 25 clinical trials (CT) that involved vaccines and/or viruses were included. We added 1 CT after the manual search. Therapy was given to 3 distinct classes of patients: patients without prior treatment (high risk smoldering MM or stage I MM, 4 CT), as an adjunct therapy for patients undergoing FDA approved treatments [high dose chemotherapy (HDT), allogeneic (allo-SCT) or autologous stem cell transplant (ASCT), 9 CT], and patients with residual or relapsed/refractory (RR) disease after FDA approved therapies (11 CT). Of the included 25 CT, 14 have published results available for analysis. For patients without prior treatments, PVX-410, a multi-peptide vaccine, resulted in at least minimal response (MR) in 50% of patients when combined with lenalidomiden and achieved stable disease (SD) for 60% of patients when used alone at 12 months follow up. Treatment with Idiotype-pulsed mature MMDC targeting idiotype proteins in MM showed MR in 30% of patients and SD in 43% of patients at 12 months. For patients receiving vaccines as an adjuvant treatment, recMAGE-A3 resulted in complete response (CR) and very good partial response (VGPR) in 46% and 54% respectively, at 3 months post ASCT follow up. By 12 months post ASCT, these responses were 38% CR and 23% VGPR. Treatment with MDDC (MAGE3 + Survivin + BCMA) resulted in SD in 42% of patients at a median of 25 months post vaccination and 55 months post ASCT. ScFv-FrC, a DNA fusion vaccine, resulted in CR in 50% and MR/SD in 21% at 52 weeks post vaccination. Ongoing CR/PR was maintained for 3+ years in 57 % patients, 4+ years in 36%, and 5+ years in 14% of patients following ASCT; OS was 64% after a median follow up of 85.6 months . Patients treated with MDDCs/tumor cells fusion vaccine had 69% SD after vaccination and 20% SD at a median of 26 months. When vaccines were given as a salvage therapy in RR MM, ImMucin vaccine showed a CR in 30% of patients during treatment, 20% maintained CR, and 13% had SD at a median of 24 months. Galinpepimut-S vaccine showed CR or very good partial response (VGPR) in 37% of patients at a median of 12 months, and 26% CR and VGPR at 18 months, with a progression free survival rate of 23.6 months. Patients receiving mHag loaded host MDDC vaccination also showed 8% CR for 〉 6 years (n=1) and 8% PR for 19 weeks (n=1); 33% had SD. Reolysin (wild-type reovirus), a virus-based vaccine, was used in 3 trials for RR MM patients. When alone, 42% of patients had SD and 58% had PD. When combined with dexamethasone and bortezomib 37% of patients had SD lasting for 3 cycles. Whereas, when combined with dexamethasone and carfilzomib, all patients had decrease in monoclonal proteins, with VGPR reported in 28%, PR in 43%, MR in 8%, and SD in 8% patients after 8 cycles. Most vaccines were well tolerated by patients, only grade (G) 1 and G2 side effects (SE), which were mostly flu-like symptoms and local skin reactions. G3 SE included pneumonia with mHag DC and Bcl2 peptide vaccine, GVHD with hTERT tumor vaccine, DVT and rash seen with scFv-FrC DNA vaccines. G4 SE were rare, but seen with reolysin, requiring 2 patients to be removed from study, and with DC/tumor cell fusion vaccine (1 pulmonary embolism). Conclusion Anti-myeloma vaccination therapy appears to be well tolerated, which makes it a promising adjuvant therapeutic agent against MM. Current data reveals positive immunologic activity in most patients and there is possibility of promising clinical responses with further drug development. Disclosures No relevant conflicts of interest to declare.