Selinexor for the treatment of multiple myeloma.

Introduction: Despite unprecedented advances in the treatment of multiple myeloma (MM), almost all patients develop a disease that is resistant to the five most commonly used and active anti-MM agents. The prognosis for this patient population is particularly poor resulting in an unmet need for additional therapeutic options. Exportin-1 (XPO-1) is a major nuclear export protein of macromolecular cargo frequently overexpressed in MM. Selinexor is a first-in-class, oral Selective-Inhibitor-of-Nuclear-Export (SINE) compound that impedes XPO-1. Based on results of the STORM-trial, selinexor in combination with dexamethasone was granted accelerated FDA approval for patients with penta-refractory MM in July 2019.Areas covered: This article summarizes our up-to-date knowledge on the pathophysiologic role of XPO-1 in MM. Furthermore, it reviews the most recent clinical data on selinexor in combination with dexamethasone and other anti-MM agents; and discusses its safety profile, management strategies; and potential future developments.Expert opinion: Selinexor represents a next-generation-novel agent with an innovative mechanism of action that marks a significant advance in the treatment of heavily pretreated MM patients. Ongoing studies investigate its therapeutic potential also in earlier lines of therapy. Additional data is needed to confirm that selinexor and other SINE compounds are a valuable addition to our current therapeutic armamentarium.

Ixazomib maintenance therapy in newly diagnosed multiple myeloma: An integrated analysis of four phase I/II studies.

OBJECTIVES: To evaluate the safety and efficacy of maintenance therapy with the oral proteasome inhibitor ixazomib in patients with newly diagnosed multiple myeloma (NDMM) not undergoing transplantation. METHODS: Data were pooled from four NDMM phase I/II studies; patients received induction therapy with once- or twice-weekly ixazomib plus lenalidomide-dexamethasone (IRd), melphalan-prednisone (IMP), or cyclophosphamide-dexamethasone (ICd), followed by single-agent ixazomib maintenance, given at the last tolerated dose during induction, until disease progression, death, or unacceptable toxicity. RESULTS: A total of 121 patients achieved stable disease or better after induction (weekly IRd, n = 25; twice-weekly IRd, n = 18; weekly or twice-weekly IMP, n = 35; weekly ICd, n = 43) and received ≥ 1 dose of ixazomib maintenance. Grade ≥ 3 drug-related adverse events occurred in 24% of patients during maintenance; each event was reported in ≤2% of patients. Rates of complete response were 22% after induction and 35% after maintenance. A total of 28 patients (23%) improved their response during maintenance. CONCLUSIONS: Ixazomib maintenance following ixazomib-based induction is associated with deepening of responses and a positive safety profile with no cumulative toxicity in patients with NDMM not undergoing transplantation, suggesting that ixazomib is feasible for long-term administration. Phase III investigation of ixazomib maintenance is ongoing.

Maintenance and continuous therapy for multiple myeloma.

INTRODUCTION: In multiple myeloma (MM), maintenance therapy is a longer, less intensive treatment course than initial therapy that is administered postinduction to delay disease progression. Maintenance and continuous therapy have been shown to suppress minimal residual disease and deepen and prolong responses, with the goal of improving progression-free survival and overall survival. Areas covered: In this review, we have summarized current clinical trial data on maintenance and continuous therapy in newly diagnosed MM and relapsed/refractory MM (RRMM), focusing on lenalidomide and bortezomib. We have also analyzed the potential uses of newer agents, including carfilzomib, daratumumab, elotuzumab, pomalidomide, and ixazomib. Expert commentary: Although lenalidomide- and bortezomib-containing regimens have demonstrated safety and efficacy, only lenalidomide is approved for maintenance; it is the preferred agent in the National Comprehensive Cancer Network and European Society for Medical Oncology guidelines. Furthermore, results from the FIRST trial support lenalidomide plus low-dose dexamethasone (Rd) as a standard of care for continuous therapy. In RRMM, newer agents have been successfully added to Rd and data from additional trials are awaited. The vital roles of maintenance and continuous therapy and their benefits are now more clearly understood, but important questions remain regarding optimal duration of therapy and regimens.

The investigational proteasome inhibitor ixazomib for the treatment of multiple myeloma.

Ixazomib is an investigational, reversible 20S proteasome inhibitor. It is the first oral proteasome inhibitor under clinical investigation in multiple myeloma (MM). Under physiological conditions, the stable citrate ester drug substance, ixazomib citrate (MLN9708), rapidly hydrolyzes to the biologically active boronic acid, ixazomib (MLN2238). Preclinical studies have demonstrated antitumor activity in MM cell lines and xenograft models. In Phase I/II clinical studies ixazomib has had generally manageable toxicities, with limited peripheral neuropathy observed to date. Preliminary data from these studies indicate ixazomib is active as a single agent in relapsed/refractory MM and as part of combination regimens in newly diagnosed patients. Phase III studies in combination with lenalidomide-dexamethasone are ongoing.

Preclinical data and early clinical experience supporting the use of histone deacetylase inhibitors in multiple myeloma.

Histone deacetylases (HDACs) mediate protein acetylation states, which in turn regulate normal cellular processes often dysregulated in cancer. These observations led to the development of HDAC inhibitors that target tumors through multiple effects on protein acetylation. Clinical evidence demonstrates that treatment with HDAC inhibitors (such as vorinostat, panobinostat, and romidepsin) in combination with other antimyeloma agents (such as proteasome inhibitors and immunomodulatory drugs) has promising antitumor activity in relapsed/refractory multiple myeloma patients. This mini-review highlights the role of protein acetylation in the development of cancers and the rationale for the use of HDAC inhibitors in this patient population.

New proteasome inhibitors in myeloma.

Proteasome inhibition has a validated role in cancer therapy since the successful introduction of bortezomib for the treatment of multiple myeloma (MM) and mantle cell lymphoma, leading to the development of second-generation proteasome inhibitors (PI) for MM patients in whom currently approved therapies have failed. Five PIs have reached clinical evaluation, with the goals of improving efficacy and limiting toxicity, including peripheral neuropathy (PN). Carfilzomib, an epoxyketone with specific chymothrypsin-like activity, acts as an irreversible inhibitor and was recently FDA approved for the response benefit seen in relapsed and refractory MM patients previously treated with bortezomib, thalidomide and lenalidomide. ONX-0912 is now under evaluation as an oral form with similar activity. The boronate peptides MLN9708 and CEP-18770 are orally bioactive bortezomib analogs with prolonged activity and greater tissue penetration. NPI-0052 (marizomib) is a unique, beta-lactone non-selective PI that has been shown to potently overcome bortezomib resistance in vitro. All of these second-generation PIs demonstrate encouraging anti-MM activity and appear to reduce the incidence of PN, with clinical trials ongoing.

Perifosine , an oral, anti-cancer agent and inhibitor of the Akt pathway: mechanistic actions, pharmacodynamics, pharmacokinetics, and clinical activity.

INTRODUCTION: Perifosine is a novel targeted oral Akt inhibitor currently in Phase III clinical development for treatment of colorectal cancer (CRC, in combination with capecitabine) and multiple myeloma (MM, in combination with bortezomib and dexamethasone). AREAS COVERED: The mechanism, preclinical testing, and clinical activity of perifosine in CRC and MM are discussed, with supportive pharmacokinetic information presented. Appropriate literature searches were carried out for background and discussion purposes. EXPERT OPINION: In preclinical models, perifosine has been shown to target phosphatidylinositol 3-kinase-Akt signaling. In CRC cell lines, preclinical studies indicate that perifosine may enhance the cytotoxic effects of fluorouracil, likely primarily through the nuclear transcription factor-kappa B pathway. A placebo-controlled Phase II randomized trial of capecitabine ± perifosine in previously treated patients with metastatic CRC showed the combination to be superior. In MM, Phase I/II clinical trials have established the optimal dosing schedule for perifosine and bortezomib in combination, and demonstrated that perifosine can sensitize to, or overcome resistance to, bortezomib, associated with prolonged responses and a favorable side effect profile. Ultimately, the favorable tolerability of perifosine will allow for its testing in combination with multiple targeted therapies to improve PFS and OS, which represent an important unmet need in these populations.

Tailoring treatment for multiple myeloma patients with relapsed and refractory disease.

Responses to treatment of relapsed and refractory multiple myeloma are characteristically short, and median survival is as brief as 6 months. Although prognostic factors in the context of relapsed and refractory disease require further characterization, high-risk patients include those with certain cytogenetic abnormalities, high beta2-microglobulin, and low serum albumin. The development of novel therapies targeting disease biology and tumor microenvironment has significantly improved the outlook for patients with relapsed and refractory disease, with bortezomib (Velcade), a first-in-class proteasome inhibitor, and the immunomodulatory agents thalidomide (Thalomid) and lenalidomide (Revlimid) constituting "backbone"agents in this setting. More recent approaches for treating relapsed and refractory myeloma that are recommended by the National Comprehensive Cancer Network include single-agent bortezomib, single-agent lenalidomide, bortezomib/dexamethasone, bortezomib plus pegylated liposomal doxorubicin, lenalidomide/dexamethasone, and lenalidomide/bortezomib/dexamethasone. Individualized treatment of progressive myeloma should take into account the time to progression and/or the type of prior therapy. Additional clinical challenges discussed in this article are renal dysfunction, extramedullary disease, and advanced bone disease. Finally, participation in clinical trials is especially encouraged in this patient population.

Impact of high-dose chemotherapy on the ability to deliver subsequent local-regional radiotherapy for breast cancer: analysis of Cancer and Leukemia Group B Protocol 9082.

PURPOSE: To report, from Cancer and Leukemia Group B Protocol 9082, the impact of high-dose cyclophosphamide, cisplatin, and BCNU (HD-CPB) vs. intermediate-dose CPB (ID-CPB) on the ability to start and complete the planned course of local-regional radiotherapy (RT) for women with breast cancer involving >or=10 axillary nodes. METHODS AND MATERIALS: From 1991 to 1998, 785 patients were randomized. The HD-CPB and ID-CPB arms were balanced regarding patient characteristics. The HD-CPB and ID-CPB arms were compared on the probability of RT initiation, interruption, modification, or incompleteness. The impact of clinical variables and interactions between variables were also assessed. RESULTS: Radiotherapy was initiated in 82% (325 of 394) of HD-CPB vs. 92% (360 of 391) of ID-CPB patients (p = 0.001). On multivariate analyses, RT was less likely given to patients who were randomized to HD treatment (odds ratio [OR] = 0 .38, p < 0.001), older (p = 0.005), African American (p = 0.003), postmastectomy (p = 0.02), or estrogen receptor positive (p = 0.03). High-dose treatment had a higher rate of RT interruption (21% vs. 12%, p = 0.001, OR = 2.05), modification (29% vs. 14%, p = 0.001, OR = 2.46), and early termination of RT (9% vs. 2%, p = 0.0001, OR = 5.35), compared with ID. CONCLUSION: Treatment arm significantly related to initiation, interruption, modification, and early termination of RT. Patients randomized to HD-CPB were less likely to initiate RT, and of those who did, they were more likely to have RT interrupted, modified, and terminated earlier than those randomized to ID-CPB. The observed lower incidence of RT usage in African Americans vs. non-African Americans warrants further study.

Emerging therapies for multiple myeloma.

Multiple myeloma (MM) is a clonal plasma cell malignancy clinically characterized by osteolytic lesions, immunodeficiency, and renal disease. There are an estimated 750,000 people diagnosed with MM worldwide, with a median overall survival of 3 - 5 years. Besides chromosomal aberrations, translocations, and mutations in essential growth and tumor-suppressor genes, accumulating data strongly highlight the pathophysiologic role of the bone marrow (BM) microenvironment in MM pathogenesis. Based on this knowledge, several novel agents have been identified, and treatment options in MM have fundamentally changed during the last decade. Thalidomide, bortezomib, and lenalidomide have been incorporated into conventional cytotoxic and transplantation regimens, first in relapsed and refractory and now also in newly diagnosed MM. Despite these significant advances, there remains an urgent need for more efficacious and tolerable drugs. Indeed, a plethora of preclinical agents awaits translation from the bench to the bedside. This article reviews the scientific rationale of new therapy regimens and newly identified therapeutic agents - small molecules as well as therapeutic antibodies - that hold promise to further improve outcome in MM.

Novel biological therapies for the treatment of multiple myeloma.

The therapeutic management of multiple myeloma (MM) for the last several decades has mainly involved regimens based on use of glucocorticoids and cytotoxic chemotherapeutics. Despite progress in delineating the activity of such regimens, at either conventional or high doses, MM has remained an incurable disease, without substantial improvement in the median overall survival. This has sparked major interest in the development of novel therapies that in part capitalize on recent advances in our understanding of the biology of MM, including the molecular mechanisms by which MM cell-host bone marrow (BM) interactions regulate tumor-cell growth, survival, and drug resistance in the BM milieu. The development of in vitro and in vivo models of MM-stromal interactions has allowed not only for better characterization of these molecular phenomena but also for identification of specific therapeutic strategies to overcome these interactions and achieve an enhanced anti-MM effect, even against MM resistant to conventional therapies. Herein, we review the latest progress in the development of these novel anti-MM therapies, with major focus on therapies which have translated from preclinical evaluation to clinical application, including thalidomide and its more potent immunomodulatory (IMiD) derivatives, the first-in-class proteasome inhibitor bortezomib (formerly known as PS-341), and arsenic trioxide (As2O3).

Proteasome inhibition in the treatment of cancer.

The proteasome is the main extralysosomal system involved in intracellular proteolysis. A number of proteasome substrates, including cyclins, IkappaB, and p53, are critical to cell cycle progression and apoptosis. Interruption of the degradation of these substrates through proteasome inhibition is a novel and unique approach to the treatment of malignancies. First-generation proteasome inhibitors lacked usefulness because of broad specificity and irreversible binding to the proteasome. However, the later synthesis of the peptide boronic acid proteasome inhibitor bortezomib allowed for selective, reversible binding. Basic investigations have reported the antitumor activity of bortezomib in a variety of hematologic and solid tumor models and have demonstrated the ability of bortezomib to enhance chemosensitivity and overcome cellular mechanisms of drug resistance attributable, in part, to abrogation of NF-kappaB induction. In patients with relapsed, refractory multiple myeloma who had received a median of six prior regimens, treatment with bortezomib resulted in a 35% response rate (complete plus partial plus minimal response) using criteria of the European Group for Blood and Marrow Transplantation. Encouraging activity has been demonstrated with bortezomib in the first-line treatment of myeloma and in patients with mantle cell lymphoma. Investigations of its utility in the treatment of patients with solid tumors are ongoing.

Bortezomib: proteasome inhibition as an effective anticancer therapy.

Inhibition of the proteasome results in disruption of protein homeostasis within the cell that can lead to apoptosis, a phenomenon preferentially observed in malignant cells. Bortezomib (VELCADE) is a first-in-class proteasome inhibitor developed specifically for use as an antineoplastic agent. Its first indication, for the treatment of relapsed myeloma in patients who have received at least two prior treatments and progressed on their previous treatment, was based in part on the magnitude of activity demonstrated in Phase II trials. An interim analysis of a Phase III trial demonstrated a significant efficacy advantage of bortezomib over high-dose dexamethasone in patients with relapsed myeloma. Clinical development is ongoing to investigate its activity as monotherapy and in combination regimens for the treatment of non-Hodgkin's lymphoma, solid tumors, and early presentations of myeloma.

Immunomodulatory drug costimulates T cells via the B7-CD28 pathway.

Although thalidomide (Thal) does not directly induce T-cell activation, it increases proliferation of T cells following CD3 activation. In this study, we examined the immunomodulatory effects of a more potent analog of Thal, immunomodulatory drug (IMiD), on T cells. Although IMiD3 does not directly stimulate proliferation of normal donor CD3+ T cells, it significantly costimulates proliferation of CD3+ T cells induced by CD3 ligation (stimulation index [SI], 2.4), immature dendritic cells (DCs; SI, 2.1), and mature DCs (SI, 2.6). T-cell proliferation triggered by DCs was abrogated by cytotoxic T lymphocyte antigen 4-immunoglobulin (CTLA-4-Ig), and IMiD3 partially overcomes this inhibitory effect. IMiD3 also overcomes the inhibitory effects of CTLA-4-Ig on Epstein-Barr virus (EBV) and influenza (Flu)-specific CD4 and CD8 T-cell responses, as measured by cytokine capture and enzyme-linked immunosorbent spot (ELISPOT) assay. IMiD3 did not induce up-regulation of CD28 expression on T cells, or of CD80-CD86 expression on dendritic cells. Importantly, IMiD3 triggers tyrosine phosphorylation of CD28 on T cells, followed by activation of nuclear factor kappaB (NF-kappaB), a known downstream target of CD28 signaling. These results therefore define the costimulatory mechanism whereby IMiD3 induces T-cell activation and provide the cellular and molecular basis for use of IMiD3 as an adjuvant in immunotherapeutic treatment strategies for multiple myeloma.