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Background: Selinexor combined with dexamethasone has shown activity in patients with heavily pre-treated multiple myeloma. In a phase 1b/2 study, the combination of oral selinexor with bortezomib (a proteasome inhibitor) and dexamethasone induced high response rates with low rates of peripheral neuropathy, the main dose-limiting toxicity of bortezomib. We aimed to evaluate the clinical benefit of weekly selinexor, bortezomib, and dexamethasone versus standard bortezomib and dexamethasone in patients with previously treated multiple myeloma., Methods: This phase 3, randomised, open-label trial was done at 123 sites in 21 countries. Patients aged 18 years or older, who had multiple myeloma, and who had previously been treated with one to three lines of therapy, including proteasome inhibitors, were randomly allocated (1:1) to receive selinexor (100 mg once per week), bortezomib (1·3 mg/m 2 once per week), and dexamethasone (20 mg twice per week), or bortezomib (1·3 mg/m 2 twice per week for the first 24 weeks and once per week thereafter) and dexamethasone (20 mg four times per week for the first 24 weeks and twice per week thereafter). Randomisation was done using interactive response technology and stratified by previous proteasome inhibitor therapy, lines of treatment, and multiple myeloma stage. The primary endpoint was progression-free survival in the intention-to-treat population. Patients who received at least one dose of study treatment were included in the safety population. This trial is registered at ClinicalTrials.gov, NCT03110562. The trial is ongoing, with 55 patients remaining on randomised therapy as of Feb 20, 2020., Findings: Of 457 patients screened for eligibility, 402 were randomly allocated-195 (49%) to the selinexor, bortezomib, and dexamethasone group and 207 (51%) to the bortezomib and dexamethasone group-and the first dose of study medication was given between June 6, 2017, and Feb 5, 2019. Median follow-up durations were 13·2 months [IQR 6·2-19·8] for the selinexor, bortezomib, and dexamethasone group and 16·5 months [9·4-19·8] for the bortezomib and dexamethasone group. Median progression-free survival was 13·93 months (95% CI 11·73-not evaluable) with selinexor, bortezomib, and dexamethasone and 9·46 months (8·11-10·78) with bortezomib and dexamethasone (hazard ratio 0·70 [95% CI 0·53-0·93], p=0·0075). The most frequent grade 3-4 adverse events were thrombocytopenia (77 [39%] of 195 patients in the selinexor, bortezomib, and dexamethasone group vs 35 [17%] of 204 in the bortezomib and dexamethasone group), fatigue (26 [13%] vs two [1%]), anaemia (31 [16%] vs 20 [10%]), and pneumonia (22 [11%] vs 22 [11%]). Peripheral neuropathy of grade 2 or above was less frequent with selinexor, bortezomib, and dexamethasone (41 [21%] patients) than with bortezomib and dexamethasone (70 [34%] patients; odds ratio 0·50 [95% CI 0·32-0·79], p=0·0013). 47 (24%) patients in the selinexor, bortezomib, and dexamethasone group and 62 (30%) in the bortezomib and dexamethasone group died., Interpretation: A once-per-week regimen of selinexor, bortezomib, and dexamethasone is a novel, effective, and convenient treatment option for patients with multiple myeloma who have received one to three previous lines of therapy., Funding: Karyopharm Therapeutics., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Bortezomib is a dipeptidyl boronic acid that selectively inhibits the ubiquitin proteasome pathway, which plays a role in the degradation of many intracellular proteins. It is the first-in-class selective and reversible inhibitor of the 26S proteasome, with antiproliferative and antitumor activity. It exerts its anti-neoplastic action mainly via the inhibition of the nuclear factor-κB pathway components associated with cell proliferation, apoptosis, and angiogenesis. The drug has revolutionized the treatment of multiple myeloma and, more recently, mantle cell lymphoma. In 2003, bortezomib received accelerated approval from the US Food and Drug Administration for the treatment of relapsed/refractory multiple myeloma and in 2008 for patients with previously untreated multiple myeloma. In 2006, bortezomib was approved for the treatment of refractory/relapsed mantle cell lymphoma and, in 2014, for previously untreated mantle cell lymphoma. Bortezomib has also demonstrated clinical efficacy both as a single drug and in combination with other agents in light chain amyloidosis, lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia, and peripheral T-cell lymphomas. Furthermore, continued clinical studies are required to confirm its value for patients with indolent and aggressive B-cell non-Hodgkin lymphomas and acute leukemias.

Multiple myeloma (MM, plasma cell myeloma) is a malignant hematologic disease characterized by the clonal proliferation of malignant plasma cells. The treatment of MM has changed dramatically in recent years, with the introduction of new drugs into therapeutic strategies, both in the front line setting and in relapsed refractory disease. However, most patients eventually relapse and often demonstrate multiple drug resistance. Therefore there is still an urgent and unmet need to define the molecular mechanisms of resistance for available drugs in order to enhance the use of existing treatments and design more effective therapies. Genetic abnormalities are well known to play a central role in MM resistance to available drugs, and epigenetic aberrations mainly affecting the patterns of DNA methylation and histone modifications of genes, especially tumor suppressors, can be involved in the resistance mechanism. Moreover, defects in the mechanisms of apoptosis, senescence and DNA repair could also contribute to drug resistance. In addition, mutations or alterations in the expression of the drug target can influence response to therapy. Achieving a better understanding of the pathways and protein expression involved in MM drug resistance and the development of novel therapeutic strategies are important goals for further progress in the treatment of MM. This review gives a critical overview of the role of cellular, microenvironmental and molecular mechanisms of drug resistance in MM., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Introduction: Over the last few years, several new synthetic drugs, particularly Bruton's tyrosine kinase (BTK), phosphatidylinositol 3-kinase (PI3K) and BCL-2 inhibitors have been developed and investigated in chronic lymphocytic leukemia (CLL). Areas covered: This review highlights key aspects of BTK, PI3K and BCL-2 inhibitors that are currently at various stages of preclinical and clinical development in CLL. A literature review of the MEDLINE database for articles in English concerning CLL, B-cell receptor, BCL-2 antagonists, BTK inhibitors and PI3K inhibitors, was conducted via PubMed. Publications from 2000 through July 2017 were scrutinized. The search terms used were acalabrutinib, ACP-196, BGB-3111, ONO-4059, GS-4059, duvelisib, IPI-145, TGR-1202, copanlisib, Bay 80-6946, buparlisib, BKM-120, BCL-2 inhibitors, venetoclax, ABT-263, navitoclax, CDK inhibitors, alvocidib, flavopiridol, dinaciclib, SCH 727,965, palbociclib, PD-0332991, in conjunction with CLL. Conference proceedings from the previous five years of the ASH and EHA Annual Scientific Meetings were searched manually. Additional relevant publications were obtained by reviewing the references from the chosen articles. Expert opinion: The use of new synthetic drugs is a promising strategy for the treatment of CLL. Data from ongoing and future clinical trials will aid in better defining the status of new drugs in the treatment of CLL.

The antibody-drug conjugate (ADC) is a combination of a cytotoxic agent and monoclonal antibodies (mAbs) through a stable specialized chemical linker. After ADC binds to the target antigen, the conjugate is internalized and toxin is released, leading to the death of a target cell. Lorvotuzumab mertansine, indatuximab ravtansine, and milatuzumab-doxorubicin are currently under clinical development for use in multiple myeloma (MM). Preliminary data from recent studies indicate that these agents induce responses in patients with relapsed and/or refractory MM and have an acceptable safety profile.

The development of non-chemotherapeutic agents, including monoclonal antibodies (mAbs) and other targeted drugs, makes chemotherapy-free treatment an attractive option for chronic lymphocytic leukemia (CLL). The classical mAb, rituximab, has been authorized for use in both first-line and second-line therapy for CLL. New mAbs directed against CD20, ofatumumab, and obinutuzumab (GA-101) have also been approved for the treatment of this disease. Recently, several new mAbs with potential benefits over the approved anti-CD20 antibodies have been developed for use in CLL. Anti-CD37, anti-CD19, and anti-CD40 mAbs are in early clinical trials and show promise in treating CLL. In addition, the combination of mAbs with B-cell receptor signaling pathway inhibitors and immunomodulatory drugs makes the chemotherapy-free option a reality today. Combinations of antibodies with targeted drugs like ibrutinib, idelalisib, or lenalidomide are expected to replace chemotherapy-based combinations for treating CLL in the near future. However, phase III trials should confirm the benefit of these new treatment strategies and establish their exact place in the therapeutic armamentarium for CLL., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Introduction: Over the last few years, several new immunological drugs, particularly monoclonal antibodies (mAbs), immunomodulatory drugs and B-cell receptor (BCR) pathway inhibitors have been developed and investigated in chronic lymphocytic leukemia (CLL). This article summarizes recent discoveries regarding their mechanism of action, pharmacological properties, clinical activity and toxicity, as well as the emerging role of these agents in CLL., Areas Covered: A literature review of mAbs, BCR pathway inhibitors and immunomodulating drugs was conducted of the MEDLINE database via PubMed for articles in English. Publications from 2000 through February 2015 were scrutinized. The search terms used were alemtuzumab, BI 836826, duvelisib ibrutinib, idelalisib, lenalidomide, monoclonal antibodies, MEDI-551, MOR208, obinutuzumab, ocaratuzumab, ofatumumab, ONO-4059, otlertuzumab, spebrutinib, veltuzumab and XmAb5574 in conjunction with CLL. Conference proceedings from the previous 5 years of the American Society of Hematology, European Hematology Association, American Society of Clinical Oncology, and ACR/ARHP Annual Scientific Meetings were searched manually. Additional relevant publications were obtained by reviewing the references from the chosen articles., Expert Opinion: The use of mAbs, BCR inhibitors and immunomodulating drugs is a promising new strategy for chemotherapy-free treatment of CLL. However, definitive data from ongoing and future clinical trials will aid in better defining the status of immunological drugs in the treatment of this disease.

Introduction: Hairy cell leukemia (HCL) is a rare subtype of B-cell chronic lymphoid leukemia. It is characterized by progressive pancytopenia, splenomegaly and infiltrations of the bone marrow, liver and spleen. Over the last few years, several new immunological drugs, particularly immunotoxins, BRAF inhibitors and B-cell receptor (BCR) pathway inhibitors have been developed and investigated as potential treatment options., Areas Covered: This article summarizes recent investigational therapies of HCL, looking at their: mechanism of action, pharmacological properties, clinical activity and toxicity, as well as their emerging role in its treatment. The authors conducted a literature review of the MEDLINE database for articles in English concerning immunotoxins, BRAF inhibitors and BCR pathway inhibitors via PubMed. Publications from 2000 through to June 2015 were scrutinized. The search terms used were: BRAF, vemurafenib, dabrafenib, ibrutinib, monoclonal antibodies, immunotoxins, moxetumomab pasudotox, and rituximab in conjunction with HCL. The authors also searched manually the conference proceedings from the previous 5 years of the American Society of Hematology, European Hematology Association, American Society of Clinical Oncology, and ACR/ARHP Annual Scientific Meetings were searched manually. Additional relevant publications were obtained by reviewing the references from the chosen articles., Expert Opinion: The use of vemurafenib and moxetumomab pasudotox is a promising new strategy for the treatment of HCL. Data from ongoing and future clinical trials will aid in better defining the status of new drugs in the treatment of HCL.

Purine nucleoside analogues (PNA) are the cytotoxic agents highly active in the treatment of indolent lymphoid malignancies. These drugs have chemical structure similar to adenosine or deoxyadenosine. PNAs are characterized by a similar mechanism of cytotoxicity both in proliferating and quiescent cells, such as inhibition of DNA synthesis, inhibition of DNA repair and accumulation of DNA strand breaks. In addition, PNAs induce apoptosis which is the end-point of their action. Older PNAs, pentostatin (DCF; 2'- deoxycoformycin), cladribine (2-CdA; 2-chloro-2'-deoxyadenosine) and fludarabine (2-fluoro-9-(-D-arabinosyl)-adenine) were approved by Food and Drug Administration (FDA) for the treatment of hematological malignancies. In addition three novel PNAs: clofarabine (CAFdA), nelarabine (ara-G) and forodesine (immucillin H, BCX-1777) have been synthesized and introduced into preclinical studies and clinical trials. This review summarizes current knowledge on the mechanism of action and pharmacokinetic properties of older and new PNAs. Clinical activity and toxicity of PNAs, especially in hairy cell leukemia (HCL), hairy cell leukemia variant (HCL-V), prolymphocytic leukemia (PLL) and other rarer chronic lymphoid leukemias, are also presented. 2-CdA and DCF, introduced in the 1980s, changed radically the treatment modality, inducing complete and durable responses in the majority of patients with HCL. In contrast, the results of the treatment of HCL-V with PNA are rather poor. There are also several reports indicating activity of PNAs in PLL and large granular lymphocyte leukemia. Clofarabine, nelarabine and forodesine need further investigation in rarer lymphid leukemias, to better define their status in the treatment of these disorders.

Over the last few years, several monoclonal antibodies have been investigated in patients with B-cell lymphoid malignancies. Rituximab is the most important monoclonal antibody of clinical value in these disorders. Rituximab is an IgG1 chimeric antibody containing murine light- and heavy-chain variable region sequences and human constant region sequences. Since approval in 1997, rituximab has become the standard of care in follicular B-cell lymphoma, chronic lymphocytic leukemia (CLL) and aggressive lymphoma when combined with chemotherapy. Higher clinical benefits of rituximab can be seen in patients with CLL when it is added to other chemotherapeutic agents. Several recent reports have suggested that in patients with CLL, rituximab combined with purine nucleoside analogs (PNAs) or PNAs and cyclophosphamide may improve the results with acceptable toxicity, both in previously untreated and refractory/relapsed patients. The randomized, multinational Phase III study (REACH trial) has shown that rituximab combined with fludarabine and cyclophosphamide (R-FC regimen) results in 10 months longer progression-free survival, and higher overall response and complete response rates than fludarabine and cyclophosphamide (FC regimen) in previously treated patients. The German CLL study group initiated a multicenter, multinational Phase III trial, CLL8, to evaluate the efficacy and tolerability of R-FC versus FC for the first-line treatment of patients with advanced CLL. The overall response rate was significantly higher in the R-FC arm (95%) compared with FC (88%). The complete response rate in the R-FC arm was 44% compared with 27% in the FC arm. The recently updated analysis has demonstrated longer overall survival in the R-FC group. Recent clinical observations have revealed that combinations of rituximab with pentostatin and cyclophosphamide, or cladribine and cyclophosphamide are also highly active regimens in previously untreated CLL. In addition, the results of treatment with high-dose methylprednisolone in combination with rituximab in advanced CLL resistant to fludarabine have been reported recently by several groups. However, available therapies are only partially effective in CLL, exposing an obvious need to develop new, more specific and active drugs. Recently, several new anti-CD20 monoclonal antibodies have been developed and are now being evaluated in clinical trials.

TRU-016, under development by Trubion Pharmaceuticals Inc and Facet Biotech Corp, is an intravenously administered anti-CD37 IgG fusion protein for the potential treatment of B-cell malignancies, including chronic lymphocytic leukemia (CLL) and non-Hodgkin's lymphoma (NHL), as well as for autoimmune and inflammatory diseases. TRU-016 was created by humanizing SMIP-016, a mouse/human chimeric protein that demonstrated antitumor activity against lymphoid malignancies in preclinical studies, including in human B-cell tumor mouse xenograft models. In addition, TRU-016 demonstrated synergistic or additive activity in NHL cells in combination with rituximab, rapamycin, doxorubicin and bendamustine. In a phase I/II clinical trial in refractory or relapsed patients with CLL or small lymphocytic lymphoma, TRU-016 was well tolerated, with clinical benefit and a reduced absolute lymphocyte count observed in all cohorts dosed at > 0.1 mg/kg. TRU-016 is a promising therapeutic agent for patients with B-cell lymphoid malignancies, especially patients refractory to standard treatment.

Chronic lymphocytic leukaemia (CLL) is the most common adult leukaemia in Europe and North America. The disease is characterized by proliferation and accumulation of small CD5+ B cells in blood, lymph nodes, spleen, liver and bone marrow. The natural clinical course of CLL is highly variable, and chemotherapy is usually not indicated in early and stable disease. However, patients with progressive and more advanced CLL require treatment. For many years, chlorambucil with or without corticosteroids was used in previously untreated patients with CLL. More recently, purine nucleoside analogues (PNAs) [fludarabine, cladribine and pentostatin] have been included in treatment approaches for this disease, and chlorambucil is no longer the leading standard everywhere. Currently, this drug is rather recommended for the treatment of older, unfit patients with co-morbidities, especially in European countries. Significantly higher overall response (OR) and complete response (CR) rates in patients treated initially with PNAs than in those treated with chlorambucil or cyclophosphamide-based combination regimens have been confirmed in randomized, prospective, multicentre trials. Moreover, PNAs administered in combination with cyclophosphamide produce higher response rates, including CR and molecular CR, compared with PNA as monotherapy. Recent reports suggest that the administration of monoclonal antibodies (mAbs) can significantly improve the course of CLL. At present, two mAbs have the most important clinical value in patients with CLL. The first is rituximab, a human mouse antibody that targets CD20 antigens, and the second is alemtuzumab, a humanized form of a rat antibody active against CD52. Several recent reports suggest that in patients with CLL, rituximab combined with a PNA can increase the OR and CR rates compared with PNA or rituximab alone, with acceptable toxicity. In randomized trials, the combination of rituximab with fludarabine and cyclophosphamide (FC-R regimen) demonstrated higher rates of OR, CR and progression-free survival in patients with previously untreated and relapsed or refractory CLL than fludarabine plus cyclophosphamide (FC regimen). Several reports have confirmed significant activity with alemtuzumab in relapsed or refractory CLL, as well as in previously untreated patients. Recently, several new agents have been investigated and have shown promise in treating patients with CLL. These treatments include new mAbs, agents targeting the antiapoptotic bcl-2 family of proteins and receptors involved in mediating survival signals from the microenvironment, antisense oligonucleotides and other agents. The most promising are new mAbs directed against the CD20 molecule, lumiliximab and anti-CD40 mAbs. Oblimersen, alvocidib (flavopiridol) and lenalidomide are also being evaluated both in preclinical studies and in early clinical trials. In recent years, a significant improvement in haematopoietic stem cell transplantation (HSCT) procedures in patients with high-risk CLL has been observed. However, the exact role of HSCT, autologous or allogeneic, in the standard management of CLL patients is still undefined.

SMIP-016, a new anti-tumour agent, is a mouse/human chimeric fusion protein built on the ADAPTIR™ (modular protein therapeutic) platform targeting human CD37. In this study, for the first time, we examined pro-apoptotic activity of SMIP-016 in combination with monoclonal anti-CD20 antibody, ofatumumab (HuMax-CD20) in de novo chronic lymphocytic leukaemia (CLL) cells and in different B-cell neoplasm-derived lines. In CLL cells SMIP-016 exerted significant cytotoxicity (versus control – p = 0.01). In the in vitro models, SMIP-016 was also distinctly active against Raji line (Burkitt lymphoma; BL) (versus control – p = 0.007), Riva-1 line (diffuse large B-cell lymphoma; DLBCL) (versus control – p = 0.002) and RPMI 8226 line (multiple myeloma cells; MM) (versus control – p = 0.03). In studies combining SMIP-016 and ofatumumab, the cytotoxicity against CLL cells was significantly higher than the agents used alone ( p < 0.03). Remarkably enhanced cytotoxic activity of SMIP-016 and ofatumumab in combination was also observed in Raji and Riva-1 cell lines ( p < 0.01 and p < 0.003, respectively). Importantly, both agents induced cytotoxicity at very low concentrations which suggests that potential side-effects may be decreased in clinical practice. The mechanism responsible for cytotoxicity of SMIP-016 in all the examined models was connected with caspase-dependent apoptosis. In majority of cell types SMIP-016 induced overexpression of Bax protein, as well as downregulation of Bcl-2, cIAP1 ( p < 0.03) and Smac/DIABLO ( p < 0.003) apoptosis-regulating proteins. In conclusion, our study demonstrated high pro-apoptotic activity of SMIP-016, especially in combination with ofatumumab, against ex vivo CLL cells, and BL or DLBCL in vitro cell lines. Thus, further preclinical studies in in vivo models are warranted, as this combination may be a promising therapeutic concept for treatment of those malignancies. [ABSTRACT FROM AUTHOR]