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Disulfiram (DSF), a familiar FDA-approved drug used for alcohol withdrawal, has recently been verified with potent antitumor therapeutic effect by generating Cu(DTC)2, which is the complex of its metabolite diethyldithiocarbamate (DTC) and copper. However, its poor tumor selectivity and insufficient endogenous Cu2+ concentration within tumor site largely hinders the application of DSF-based antitumor therapy. Therefore, a GSH-responsive coordination nanoparticles (Cu-IXZ@DSF) was established as a copper carrier to achieve synchronous but separate delivery of Cu2+ and DSF without antitumor ability, further to realize selectively triggered tumor in situ Cu(DTC)2 generation for antitumor therapy. A widely-used proteasome inhibitor ixazomib (IXZ) was chosen as ligands and Cu2+ was used as coordination nodes to form nanosized Cu-IXZ@DSF. The DSF encapsulated in Cu-IXZ@DSF could be reduced to DTC by intracellular GSH, which could contend for Cu2+ and realize in situ high toxic Cu(DTC)2 generation. Meanwhile, the chelation could lead to the disassembly of Cu-IXZ@DSF and release of IXZ to eventually achieve tumor specific “transformation from low toxicity to high toxicity” chemotherapy. The results of in vitro and in vivo experiments demonstrated that the as-prepared nanoplatform Cu-IXZ@DSF showed good biosafety and excellent antitumor effect via endoplasmic reticulum stress (ERS) as well as reactive oxygen species (ROS) generation pathway. Therefore, this nanocarrier provides an inspiring strategy with specific-triggered antitumor Cu(DTC)2 generation for DSF-based chemotherapy with high therapeutic effect and biosafety and showing great potential of treating cancer.

PURPOSE Proteasome inhibitors are effective in Waldenström's macroglobulinemia (WM) but require parenteral administration and are associated with polyneuropathy. We investigated efficacy and toxicity of the less neurotoxic oral proteasome inhibitor ixazomib combined with rituximab, in patients with relapsed WM. METHODS We conducted a multicenter phase I/II trial with ixazomib, rituximab, and dexamethasone (IRD). Induction consisted of eight cycles IRD wherein rituximab was started in cycle 3, followed by rituximab maintenance. Phase I showed feasibility of 4 mg ixazomib. Primary end point for phase II was overall response rate (ORR [≥ minimal response]) after induction. RESULTS A total of 59 patients were enrolled (median age, 69 years; range, 46-91 years). Median number of prior treatments was 2 (range, 1-7); 70% had an intermediate or high WM-IPSS (International Prognostic Scoring System for WM) score. After eight cycles, ORR was 71% (42 out of 59) (14% very good partial response [PR], 37% PR, and 20% minor response). Depth of response improved until month 12 (best ORR 85% [50 out of 59]: 15% very good PR, 46% PR, and 24% minor response). Median duration of response was 36 months. The average hematocrit level increased significantly (0.33-0.38 L/L) after induction ( P < .001). After two cycles of ixazomib and dexamethasone, immunoglobulin M levels decreased significantly (median 3,700-2,700 mg/dL, P < .0001). Median time to first response was 4 months. Median progression-free survival and overall survival were not reached. After median follow-up of 24 months (range, 7.4-54.3 months), progression-free survival and overall survival were 56% and 88%, respectively. Toxicity included mostly grade 2 or 3 cytopenias, grade 1 or 2 neurotoxicity, and grade 2 or 3 infections. No infusion-related reactions or immunoglobulin M flare occurred with use of subcutaneous rituximab. Quality of life improved significantly after induction. In total, 48 patients (81%) completed at least six cycles of IRD. CONCLUSION Combination of IRD shows promising efficacy with manageable toxicity in patients with relapsed or refractory WM.

Pan-proteasome inhibitors (pPIs) significantly improve outcomes in patients with multiple myeloma; however, their indiscriminate inhibition of multiple proteasome and immunoproteasome subunits causes diverse toxicities, including thrombocytopenia. We investigated the mechanisms underlying the platelet depletion induced by the pPIs bortezomib, carfilzomib, and ixazomib. An established thrombocytopenia model was adapted for each compound (bortezomib, ixazomib, and carfilzomib) to compare the following two pharmacodynamic mechanisms: a reversible inhibition of new progenitor cell formation (the myelosuppression model) and a reversible effect on the function of megakaryocytes to bud new platelets (platelet formation model). Bortezomib, ixazomib, and carfilzomib plasma concentration profiles and platelet counts were extracted from the literature. Pharmacokinetic (PK) and thrombocytopenia models were developed to predict the PK of these drugs and to describe their effects on proliferating cells and platelet budding. The PK models reproduced the exposure of the three compounds at steady state well compared with those reported in the literature. Both the platelet formation and myelosuppression models seemed able to describe the platelet depletion caused by bortezomib, ixazomib, and carfilzomib. Estimated structural parameters in the myelosuppression model were in the range of the values reported in the literature, whereas the mean transit time estimated with the platelet formation model was 3-fold to 10-fold higher than the highest reported value. The model of drug-induced myelosuppression yielded estimates of structural parameters in the range of those previously reported. The platelet formation model captured the temporal variation reported in clinical studies.

BACKGROUND Maintenance therapy with proteasome inhibitors (PIs) can improve outcomes of multiple myeloma (MM) patients, however, the neurotoxicity and parenteral route of bortezomib limit its long-term use. An efficacious, tolerable, and convenient PI option is needed. METHODS In this single-center, real-world study, we retrospectively analyzed the outcome and safety profile of ixazomib-based maintenance therapy in patients who plateaued with the responses of steady disease or better after bortezomib-based induction therapy in MM patients not undergoing transplantation. RESULTS Of all the 71 patients, 37 cases (52.1%) were newly diagnosed MM (NDMM) and 34 cases (47.9%) were relapsed and/or refractory MM (RRMM). The overall response rate (ORR) was 81.7%, including 34 patients (47.9%) with a very good response rate or better (≥VGPR) after a median of nine cycles (6-14) of bortezomib-based induction therapy. Then the ORR was transformed to 74.6% including 39 patients of ≥VGPR (54.9%) after a median of six courses (2-25) of ixazomib-based maintenance therapy. Of these, 18 patients (25.4%) exhibited responses deepened. With 26.5 months median follow-up, median progression-free survival (PFS) was 28.4 and 16.5 months from the start of bortezomib and 16.2 and 10.0 months from the initiation of ixazomib in NDMM and RRMM group, respectively. Moreover, responses deepened during the maintenance phase (hazard ratio: 0.270, p = 0.007), and responses of ≥VGPR during the induction phase (hazard ratio: 0.218, p

Background TOURMALINE-MM1 was a global study that demonstrated a significant improvement in progression-free survival with ixazomib plus lenalidomide and dexamethasone compared with placebo plus lenalidomide and dexamethasone, in patients with relapsed and/or refractory multiple myeloma. The current study was conducted to evaluate further the efficacy and safety of ixazomib plus lenalidomide and dexamethasone in Japanese patients. Methods This phase 2, open-label, single-arm, multicenter study enrolled patients aged ≥ 20 years with relapsed and/or refractory multiple myeloma at 16 sites in Japan. Patients refractory to lenalidomide or proteasome inhibitor-based therapy at any line were excluded. The primary endpoint was the rate of very good partial response or better in the response-evaluable analysis set. Secondary endpoints were progression-free survival, overall response rate, duration of response, time to progression, overall survival and safety. Results In total, 34 patients were enrolled. The rate of very good partial response or better was 50.0% (95% confidence interval 31.9–68.1) and the overall response rate was 84.4% (95% confidence interval 67.2–94.7). Median progression-free survival was 22.0 months (95% confidence interval 17.3–not evaluable) and median overall survival was not estimable. The safety profile of ixazomib plus lenalidomide and dexamethasone in this study was similar to that in the TOURMALINE-MM1 study. Conclusions The efficacy and safety of ixazomib plus lenalidomide and dexamethasone in Japanese patients with relapsed and/or refractory multiple myeloma are comparable with reported TOURMALINE-MM1 study results. Clinicaltrials.gov identifier NCT02917941; date of registration September 28, 2016.

In this study, we aimed to modify the immune response in the long term after allogeneic bone marrow transplantation (allo-BMT) by using the proteasome inhibitor ixazomib (IXZ) at the late stages of the post-transplant period. This approach facilitated the immune reconstitution after transplantation. IXZ significantly prolonged survival and decreased the risk of chronic graft-versus-host disease (cGvHD) in two different murine models without hampering the graft-versus-leukemia (GvL) effect, as confirmed by bioluminescence assays. Remarkably, the use of IXZ was related to an increase of regulatory T cells both in peripheral blood and in the GvHD target organs and a decrease of effector donor T cells. Regarding B cells, IXZ treated mice had faster recovery of B cells in PB and of pre-pro-B cells in the bone marrow. Mice receiving ixazomib had a lower number of neutrophils in the GvHD target organs as compared to the vehicle group. In summary, delayed administration of IXZ ameliorated cGvHD while preserving GvL and promoted a pro-tolerogenic immune response after allo-BMT., Takeda company (PCRS-2016-101751) partially supported the study; This work has been partially supported by the CIBERONC (CB16/12/00480), and TerCel 16/0011/0035. Spanish Association Against Cancer (AECC-POSTD18023LOPE) fellowship (TLR).

BACKGROUND AND PURPOSE Aberrant lipid metabolism is recognized as a key feature of cancer cells. Our initial research on MS-based analysis of lipids in a multiple myeloma (MM) cell line showed a significant accumulation of lipids in multiple myeloma cells after proteasome inhibition. This finding prompted us to hypothesize that multiple myeloma cell survival depends on the maximal utilization of abnormally accumulated lipids. Therefore, we explored whether lipid metabolism-modulating agents would synergize with proteasome inhibitors. EXPERIMENTAL APPROACH Lipid accumulation in multiple myeloma cells was measured by MS. Synergism between lipid regulators and proteasome inhibitors was assessed by cell viability and apoptosis. A novel stable derivative of fenofibrate (FCE) was synthesized and used to treat multiple myeloma cells in vitro and in vivo along with the proteasome inhibitor ixazomib. ChIP-seq, western blotting and RT-qPCR were performed to explore the potential mechanism(s) underlying the increase in lipid levels in multiple myeloma cells after proteasome inhibition. KEY RESULTS Accumulation of lipids in multiple myeloma cells was induced by proteasome inhibition. Lipid-lowering drugs and MG-132 exerted a synergistic effect to kill multiple myeloma cells. FCE showed significant synergistic activity in vitro and in vivo with ixazomib. The abnormal lipid accumulation in multiple myeloma cells that was enhanced by proteasome inhibitors might be due to the elevated SREBP1/2 expression induced by ATF4. CONCLUSIONS AND IMPLICATIONS Our results provide a proof of principle and support for the further clinical evaluation of the combination of lipid-modulating drugs with proteasome inhibitors in the treatment of multiple myeloma.

Összefoglaló. Bevezetés: A myeloma multiplex mindmáig alapvetően gyógyíthatatlan betegség, ezért nagy klinikai jelentőségük van az eredményes mentő kezeléseknek. A szájon át adható első proteaszómagátlóval, az ixazomibbal kiegészített lenalidomid-dexametazon terápia jól tolerálható, csak orális szerekből álló kombináció, mely hazánkban 2015 áprilisától kezdődően a „Named Patient Program” keretén belül vált elérhetővé relabált, refrakter myeloma multiplexes betegek kezelésére. Célkitűzés: Kutatásunk célja az ixazomib-lenalidomid-dexametazon kezelés mellett a hosszú távon progressziómentes túlélők célzott vizsgálata. Módszer: A program keretében összesen 7 centrumban 80 visszaeső beteg részesült e triplet kezelésben, adataikat retrospektíven elemeztük. Leíró statisztikai és Kaplan–Meier-analízist végeztünk. Eredmények: A betegek nagyobb hányada reagált: 63,75%-os válaszarány mellett 14 (17,5%) betegnél nem volt terápiás válasz/stabil betegség alakult ki, és 15-nél (18,75%) a betegség a kezelés mellett is progrediált. A progressziómentes túlélés a teljes betegcsoportban 10,6 hónapnak adódott, ugyanakkor 16 beteg (18,75%) két éven túl progressziómentesnek bizonyult, sőt közülük 11-nél a betegség még 3 év után sem progrediált. Tanulmányunkban a fenti, hosszú távú túlélő betegcsoport tulajdonságait tárjuk fel. Megbeszélés: A folyamatos terápia a myeloma multiplex kezelésében meghatározóvá vált. Ezért fontos ismernünk, hogy kik lehetnek azok a betegek, akik különösen sokat profitálnak egy bizonyos terápiából. A hosszú távon progressziómentes túlélők között az immunglobulin-nehézláncot érintő transzlokációk vagy triszómiák közül (trend szintjén) az utóbbiak kedvezőbb progressziómentes túléléssel bírtak, de progressziómentes platót mindkét betegcsoportban észleltünk. A betegség tumortömegét mérő nemzetközi stádiumbeosztás (ISS) nem jelezte előre a hosszú túlélést. Gyógyszerelhagyáshoz vezető mellékhatást a hosszú távú túlélő csoportban egyet sem regisztráltunk; az észlelt mellékhatások nagy része enyhe volt. Következtetések: Munkánk során az ixazomib-lenalidomid-dexametazon kombinációt effektívnek és biztonságosnak találtuk relabált, refrakter myeloma multiplex kezelésére, mely a betegek mintegy hatodánál több éven át eredményesen alkalmazható. Cikkünkkel a hazai beteganyagon szerzett tapasztalatainkat szeretnénk megosztani a COVID–19-világjárvány alatt különösen aktuálissá vált, tisztán orális terápiás lehetőségről. Orv Hetil. 2021; 162(36): 1451–1458. Summary. Introduction: Despite great advances in therapy, multiple myeloma is still a largely incurable disease, therefore the importance of salvage therapies is paramount. The first oral proteasome inhibitor ixazomib in combination with lenalidomide-dexamethasone is a tolerable, orally administered regime, which has become available for Hungarian relapsed, refractory multiple myeloma patients from April 2015 in the Named Patient Program. Objective: Our goal was to investigate the long-time progression-free surviving patient population treated with the ixazomib-lenalidomide-dexamethasone triplet. Method: We retrospectively studied a total of 80 patients from 7 centers who received the triplet combination. Survival analyses were performed. Results: Two-third of the patients responded: the overall response rate was 63.75%. 14 patients (17.5%) did not respond/had stable disease and 15 patients (18.75%) outright progressed upon therapy. Although progression-free survival was only 10.6 months for the entire patient cohort, the disease in a subgroup of 16 patients did not progress within two years. In fact, 11 of them were still in sustained remission after 3 years of therapy. Our goal was to analyze the characteristics of this subgroup. Discussion: The idea of long-term therapy of multiple myeloma is gaining widespread acceptance. Therefore it is important to know which patients may benefit the most from certain therapies. Among these 16 long-term responder patients, reciprocal translocation of the immunoglobulin heavy chain seemed to lack an adverse impact on progression-free survival; comparable to trisomies, both curves had a progression-free plateau. The International Staging System (ISS) score at the start of therapy did not predict long-term survivorship. Most of the side effects in this subgroup were mild, manageable, none led to therapy discontinuation. Conclusion: Ixazomib-lenalidomide-dexamethasone was confirmed to be an effective and safe combination for relapsed, refractory multiple myeloma, and one-sixth of the treated patients were able to receive it for several years, effectively. This fully oral therapeutic option is at its best during the present COVID–19 pandemic. Orv Hetil. 2021; 162(36): 1451–1458.

Background. Preclinical studies have shown that the combined inhibition of EGFR and NF-kB pathways to target the RalB/TBK1 pathway led to synergistic antitumor activity. Based on this rationale, we conducted a Phase I dose-escalation study combining the EGFR inhibitor erlotinib with the NF-kB inhibitor ixazomib in advanced solid tumors. Patients and methods. Patients with advanced solid tumors were eligible. The bayesian optimal interval phase I dose escalation design was used to establish the maximum tolerated dose and recommended phase 2 dose (RP2D). Results. Nineteen patients with a range of solid tumors were enrolled. The most common treatment-related adverse events of any grade were diarrhea (42.1%, 8/19), followed by rash (36.8%, 7/19) and nausea (21.1%, 4/19). The combination RP2D for oral ixazomib was 4.0 mg on days 1, 8, and 15 of a 28-day cycle, with oral erlotinib 150 mg daily. While no patient achieved RECIST v1.1 objective responses, 3 patients with advanced sarcoma experienced durable RECIST v1.1 stable disease ≥ 6 months (8.4, 10.6, and 15.7 months) and the best response was -13% decrease in clear cell sarcoma. Conclusions. The combination of erlotinib and ixazomib was safe and well tolerated among patients with advanced cancer, with preliminary signals of antitumor activity in patients with advanced sarcoma.

In the first phase 3 study in relapsed/refractory AL amyloidosis (TOURMALINE-AL1 NCT01659658), 168 patients with relapsed/refractory AL amyloidosis after 1–2 prior lines were randomized to ixazomib (4 mg, days 1, 8, 15) plus dexamethasone (20 mg, days 1, 8, 15, 22; n = 85) or physician’s choice (dexamethasone ± melphalan, cyclophosphamide, thalidomide, or lenalidomide; n = 83) in 28-day cycles until progression or toxicity. Primary endpoints were hematologic response rate and 2-year vital organ deterioration or mortality rate. Only the first primary endpoint was formally tested at this interim analysis. Best hematologic response rate was 53% with ixazomib–dexamethasone vs 51% with physician’s choice (p = 0.76). Complete response rate was 26 vs 18% (p = 0.22). Median time to vital organ deterioration or mortality was 34.8 vs 26.1 months (hazard ratio 0.53; 95% CI, 0.32–0.87; p = 0.01). Median treatment duration was 11.7 vs 5.0 months. Adverse events of clinical importance included diarrhea (34 vs 30%), rash (33 vs 20%), cardiac arrhythmias (26 vs 15%), nausea (24 vs 14%). Despite not meeting the first primary endpoint, all time-to-event data favored ixazomib–dexamethasone. These results are clinically relevant to this relapsed/refractory patient population with no approved treatment options.

We evaluated the efficacy and tolerability of continuous ixazomib-thalidomide-dexamethasone (ITd: 4 mg, day 1, 8, 15; 100 mg daily; and 40 mg weekly). A total of 39 patients with relapsed/refractory multiple myeloma (RRMM) aged ≥18 years with one to three prior lines of therapy were enrolled from two tertiary centres in Victoria and South Australia, Australia. The overall response rate (ORR) was 56·4% with a clinical benefit rate of 71·8%. The median progression-free survival was 13·8 months [95% confidence interval (CI) 8·2–22·2] and median overall survival was not reached. The median time to best response and duration of response was 3·7 months (95% CI 2·8–10·5) and 18·4 months (95% CI 10·2–31·0) respectively. Prior immunomodulatory drug (IMID) exposure was associated with a lower ORR (40% vs. 73·7%, P = 0·03). Survival outcomes in patients with prior proteasome inhibitor (PI) and/or IMID exposure were similar. Patients received a median (range) of 11 (1–31) cycles of therapy and six patients (15%) remained on therapy at the time of final analysis. Grade 3/4 haematological and non-haematological adverse events were reported in 7·7% and 20·6% of patients respectively. ITd dose reductions were required in 15·4%, 48·7% and 35·9% of patients respectively. The present study demonstrates promising effectiveness and tolerability of ITd as an affordable all-oral PI-IMID approach for RRMM. Refereed/Peer-reviewed

Multiple available combinations of proteasome inhibitors, immunomodulators (IMIDs), and monoclonal antibodies are shifting the relapsed/refractory multiple myeloma (RRMM) treatment landscape. Lack of head-to-head trials of triplet regimens highlights the need for real-world (RW) evidence. We conducted an RW comparative effectiveness analysis of bortezomib (V), carfilzomib (K), ixazomib (I), and daratumumab (D) combined with either lenalidomide or pomalidomide plus dexamethasone (Rd or Pd) in RRMM. A retrospective cohort of patients initiating triplet regimens in line of therapy (LOT) ≥ 2 on/after 1/1/2014 was followed between 1/2007 and 3/2018 in Optum’s deidentified US electronic health records database. Time to next treatment (TTNT) was estimated using Kaplan-Meier methods; regimens were compared using covariate-adjusted Cox proportional hazard models. Seven hundred forty-one patients (820 patient LOTs) with an Rd backbone (VRd, n = 349; KRd, n = 218; DRd, n = 99; IRd, n = 154) and 348 patients (392 patient LOTs) with a Pd backbone (VPd, n = 52; KPd, n = 146; DPd, n = 149; IPd, n = 45) in LOTs ≥2 were identified. More patients ≥75 years received IRd (39.6%), IPd (37.8%), and VRd (36.7%) than other triplets. More patients receiving VRd/VPd were in LOT2 vs other triplets. Unadjusted median TTNT in LOT ≥ 2: VRd, 13.9; KRd, 8.7; IRd, 11.4; DRd, not estimable (NE); and VPd, 12.0; KPd, 6.7; IPd, 9.5 months; DPd, NE. In covariate-adjusted analysis, only KRd vs DRd was associated with a significantly higher risk of next LOT initiation/death (HR 1.72; P = 0.0142); no Pd triplet was significantly different vs DPd in LOT ≥ 2. Our data highlight important efficacy/effectiveness gaps between results observed in phase 3 clinical trials and those realized in the RW.

Proteasome inhibitor drugs have provided a major breakthrough in the treatment of multiple myeloma and other hematological malignancies. Currently, there are three clinically used proteasome inhibitor drugs, namely bortezomib, carfilzomib, and ixazomib. Fueled by the remarkable successes of these drugs, additional drug candidates are actively pursued by targeting the proteasome and other components in the ubiquitin–proteasome pathways. Efforts are ongoing to overcome the drawbacks of the existing proteasome inhibitor drugs, optimize their pharmacokinetic aspects, and expand their clinical utility beyond the current indications, in particular for solid cancer therapy. Over the several decades, a variety of nanoparticulate delivery systems have been designed and applied to cancer therapy with a goal of improving the efficacy and safety. This review summarizes the pharmacokinetic aspects of the clinically used proteasome inhibitor drugs and the notable findings from the recent reports on the novel nanoparticulate delivery systems of bortezomib and carfilzomib. With the help of novel nanoparticulate delivery systems, the therapeutic utility of the proteasome inhibitor drugs is likely to expand to various types of cancer and other pathological conditions including neurodegenerative and inflammatory diseases.

Multiple myeloma (MM) survival rates have been substantially increased thanks to novel agents that have improved survival outcomes and shown better tolerability than treatments of earlier years. These new agents include immunomodulating imide drugs (IMiD) thalidomide and lenalidomide, the proteasome inhibitor bortezomib (PI), recently followed by new generation IMID pomalidomide, monoclonal antibodies daratumumab and elotuzumab, and next generation PI carfilzomib and ixazomib. However, even in this more promising scenario, febrile neutropenia remains a severe side effect of antineoplastic therapies and can lead to a delay and/or dose reduction in subsequent cycles. Supportive care has thus become key in helping patients to obtain the maximum benefit from novel agents. Filgrastim is a human recombinant subcutaneous preparation of G-CSF, largely adopted in hematological supportive care as “on demand” (or secondary) prophylaxis to recovery from neutropenia and its infectious consequences during anti-myeloma treatment. On the contrary, pegfilgrastim is a pegylated long-acting recombinant form of granulocyte colony-stimulating factor (G-CSF) that, given its extended half-life, can be particularly useful when adopted as “primary prophylaxis,” therefore before the onset of neutropenia, along chemotherapy treatment in multiple myeloma patients. There is no direct comparison between the two G-CSF delivery modalities. In this review, we compare data on the two administrations’ modality, highlighting the efficacy of the secondary prophylaxis over multiple myeloma treatment. Advantage of pegfilgrastim could be as follows: the fixed administration rather than multiple injections, reduction in neutropenia and febrile neutropenia rates, and, finally, a cost-effectiveness advantage.

Purpose Ixazomib is a selective, effective, and reversible inhibitor of 20S proteasome and is approved for the treatment of multiple myeloma. Ubiquitin-conjugating enzyme E2 (UBE2K) is involved in the synthesis of K48-linked ubiquitin chains and is the target of certain drugs used for the treatment of tumors. The purpose of this study was to investigate the relationship between ixazomib and UBE2K in myeloma cells. Methods We used CCK-8 and Annexin V-FITC/propidium iodide kit to detect the effects of ixazomib on survival and apoptosis of RPMI-8226 and U-266 myeloma cell lines. Quantitative polymerase chain reaction and western blot were used to detect the change in gene and protein expression levels of myeloma cells treated with ixazomib. Furthermore, the regulatory effects of ixazomib on UBE2K and its downstream targets were investigated following the overexpression of UBE2K. Results In myeloma cells, ixazomib decreased cell survival and increased apoptosis in a dose-dependent manner. Ixazomib significantly increased the expression of HIST1H2BD, MNAT1, NEK3, and TARS2, while decreasing the expression of HSPA1B and UBE2K. In addition, ixazomib inhibited the proliferation of myeloma cells, blocked cell cycle, induced cell apoptosis, and increased the production of reactive oxygen species by inhibiting UBE2K expression. Lastly, ixazomib regulates mitosis- and apoptosis-related genes by lowering UBE2K expression. Conclusion In summary, ixazomib leads to impaired proliferation of myeloma cells by targeting UBE2K.

Proteasome inhibitor (PI) therapy has improved the survival of multiple myeloma (MM) patients. However, inevitably, primary or acquired resistance to PIs leads to disease progression; resistance mechanisms are unclear. Obesity is a risk factor for MM mortality. Oxidized LDL (OxLDL), a central mediator of atherosclerosis that is elevated in metabolic syndrome (co-occurrence of obesity, insulin resistance, dyslipidemia and hypertension), has been linked to an increased risk of solid cancers and shown to stimulate pro-oncogenic/survival signaling. We hypothesized that OxLDL is a mediator of chemoresistance, and evaluated its effects on MM cell killing by PIs. OxLDL potently suppressed the ability of the boronic-acid based PIs bortezomib (BTZ) and ixazomib, but not the epoxyketone-based PI carfilzomib, to kill human MM cell lines and primary cells. OxLDL suppressed BTZ-induced inhibition of proteasome activity and induction of pro-apoptotic signaling. These cytoprotective effects were abrogated when lipid hydroperoxides (LOOHs) associated with OxLDL were enzymatically reduced. We also demonstrated the presence of OxLDL in the MM bone marrow microenvironment as well as numerous granulocytes and monocytes capable of cell-mediated LDL oxidation through myeloperoxidase. Our findings suggest that OxLDL may be a potent mediator of boronic acid-based PI resistance, particularly for MM patients with metabolic syndrome, given their elevated systemic levels of OxLDL. LDL cholesterol-lowering therapy to reduce circulating OxLDL, and pharmacologic targeting of LOOH levels or resistance pathways induced by the modified lipoprotein, could deepen the response to these important agents and offer clinical benefit to MM patients with metabolic syndrome. This article is protected by copyright. All rights reserved.

Purpose: In ALK-rearranged non–small cell lung cancer (NSCLC), impacts of concomitant genetic alterations on targeted therapies with ALK-tyrosine kinase inhibitors (ALK-TKI) are not yet well understood. Here, we investigated genetic alterations related to ALK-TKI resistance using clinico-genomic data and explored effective therapies to overcome the resistance in preclinical models through the identification of underlying molecular mechanisms. Experimental Design: We used integrated clinical and next-generation sequencing data generated in a nationwide lung cancer genome screening project (LC-SCRUM-Japan). ALK-rearranged NSCLC cell lines expressing wild-type or mutant TP53 were used to evaluate cellular apoptosis induced by ALK-TKIs. Results: In 90 patients with ALK-rearranged NSCLC who were treated with a selective ALK-TKI, alectinib, TP53 comutated patients showed significantly worse progression-free survival (PFS) than TP53 wild-type patients [median PFS, 11.7 months (95% confidence interval, CI, 6.3–not reached, NR) vs. NR (23.6–NR); P = 0.0008; HR, 0.33 (95% CI, 0.17–0.65)]. ALK-rearranged NSCLC cell lines that lost p53 function were resistant to alectinib-induced apoptosis, but a proteasome inhibitior, ixazomib, markedly induced apoptosis in the alectinib-treated cells by increasing the expression of a proapoptotic protein, Noxa, which bound to an antiapoptotic protein, Mcl-1. In subcutaneous tumor models, combination of ixazomib and alectinib prominently induced tumor regression and apoptosis even though the tumors were generated from ALK-rearranged NSCLC cells with nonfunctional p53. Conclusions: These clinical and preclinical results indicate concomitant TP53 mutations reduce the efficacy of alectinib for ALK-rearranged NSCLC and the combined use of a proteasome inhibitor with alectinib is a promising therapy for ALK-rearranged/TP53-mutated NSCLC.

Maintenance therapy post autologous stem cell transplant (ASCT) is commonly employed in myeloma patients to prolong remission, as relapse invariably occurs after ASCT. After initial diagnosis and risk stratification, patients receive initial therapy with a combination of drugs, typically a proteasome inhibitor and an immunomodulatory imide drug (IMiD), and in those considered eligible, high-dose chemotherapy followed by autologous stem cell transplant. The aim of our study was to review the literature and consolidate evidence regarding different maintenance therapies post stem cell transplant in myeloma patients. We reviewed major databases including PubMed, Cochrane Library and Evidence-Based Medicine Reviews (EBMR), along with American Society of Hematology/American Society of Clinical Oncology (ASH/ASCO) conference abstracts to include relevant literature. Ongoing clinical trials were also reviewed. Consolidation therapy is often employed to enhance the response to induction therapy and SCT and also to delay progression. Melphalan and thalidomide with or without steroids were initially used as maintenance therapy. More recently, lenalidomide-, bortezomib-, ixazomib-, or carfilzomib-based regimens have been employed as maintenance. Lenalidomide and bortezomib are the most commonly used drugs, with the latter being preferred in high-risk populations. Newer trials are utilizing tumor-specific antigen based vaccines along with adoptive T-cell therapies, and monoclonal antibodies as maintenance therapy. We conclude that maintenance therapy post SCT, with lenalidomide or bortezomib is the standard of care in myeloma patients. Patient tolerability, disease risk stratification and prior therapy received are major determinants of the choice of maintenance. Significant toxicity associated with maintenance therapies is a hindrance to long-term maintenance post stem cell transplant.

Relevance. Among the groups at high risk of developing invasive pneumococcal infections, patients with multiple myeloma (MM) stand out among the highest rates of morbidity and mortality due to the presence of profound immunosuppression. Aims: to outline the current state of the problem of vaccine prevention of pneumococcal infection in patients receiving treatment for multiple myeloma, to present the evidence base for vaccination with conjugated pneumococcal vaccine. A continuous data review method was used to evaluate the studies on vaccination approaches against pneumococcal infection in patients with multiple myeloma. Conclusions. The article presents modern epidemiological data, as well as the results of original studies of clinical and immunological aspects of pneumococcal vaccination in patients with MM receiving new targeted agents and immunotherapy. The effectiveness of the use of the conjugated pneumococcal vaccine in patients treated with MM with bortezomib, lenalidomide, and ixazomib was indicated. An independent protective effect of pneumococcal vaccination has been shown as a preventive measure in a cohort of patients with MM, against the background of treatment with new targeted drugs.

Primary plasma cell leukemia (pPCL) is an aggressive variant of multiple myeloma (MM). Immunoglobulin heavy chain (IgH) translocations are found in a majority of pPCL cases, supporting a central relation to pathogenesis of pPCL. However, two independent IgH translocations are barely detected at the onset of pPCL, and their significance is yet to be elucidated. Here, we report a case of an aggressive pPCL with simultaneous IGH/MYC and IGH/CCND1 translocations. A 73-year-old man was referred to our hospital with back pain and diagnosed as having pPCL with more than 50% circulating plasma cells. Cytogenetic analysis revealed 47, Y, t (X; 8;14) (q24; q24; q32), t (11; 14) (q13; q32), and +18. IGH/MYC and IGH/CCND1 translocations were confirmed by fluorescence in situ hybridization analysis. Bortezomib and dexamethasone treatment achieved rapid elimination of peripheral malignant plasma cells, and the patient maintained a partial response for 18 months. After biological relapse, he received salvage therapy with ixazomib, lenalidomide, and dexamethasone, followed by pomalidomide and dexamethasone, and exhibited stable disease for an additional 14 months. Although IGH/MYC translocation in association with dysregulation of antiapoptotic pathway leads to worse prognosis in lymphomas, the novel agent-based regimen showed good efficacy, suggesting that IGH/MYC plays a different role in the pathogenesis of MM. IGH/CCND1 and IGH/MYC translocations may have contributed to abrupt onset of pPCL in this case.

Dystrophin deficiency makes the sarcolemma fragile and susceptible to degeneration in Duchenne muscular dystrophy. The proteasome is a multimeric protease complex and is central to the regulation of cellular proteins. Previous studies have shown that proteasome inhibition improved pathological changes in mdx mice. Ixazomib is the first oral proteasome inhibitor used as a therapy in multiple myeloma. This study investigated the effects of ixazomib on the dystrophic muscle of mdx mice. MDX mice were treated with ixazomib (7.5 mg/kg/wk by gavage) or 0.2 mL of saline for 12 weeks. The Kondziela test was performed to measure muscle strength. The tibialis anterior (TA) and diaphragm (DIA) muscles were used for morphological analysis, and blood samples were collected for biochemical measurement. We observed maintenance of the muscle strength in the animals treated with ixazomib. Treatment with ixazomib had no toxic effect on the mdx mouse. The morphological analysis showed a reduction in the inflammatory area and fibres with central nuclei in the TA and DIA muscles and an increase in the number of fibres with a diameter of 20 µm(2) in the DIA muscle after treatment with ixazomib. There was an increase in the expression of dystrophin and utrophin in the TA and DIA muscles and a reduction in the expression of osteopontin and TGF‐β in the DIA muscle of mdx mice treated with ixazomib. Ixazomib was thus shown to increase the expression of dystrophin and utrophin associated with improved pathological and functional changes in the dystrophic muscles of mdx mice.

Objectives Emerging treatments for relapsed or refractory multiple myeloma (rrMM) have led to increasing options for many patients. This study aimed to assess changes in utilization of these options in Germany with a focus on modern triplet regimens including new agents, such as carfilzomib, ixazomib, elotuzumab and daratumumab, and to evaluate whether this had an impact on rrMM‐related outcomes over time. Methods The study population consisted of 1255 rrMM patients who were assigned to one of the following 6 treatment groups: immunomodulatory drug (IMiD)‐based doublets, proteasome inhibitor (PI)‐based doublets, daratumumab monotherapy, PI‐IMiD‐based triplets, monoclonal antibodies (mAbs)‐based triplets, or other treatment. Results Use of triplet‐based therapy regimens increased from 5.9% in 2014 to 31.4% in 2017. In parallel, use of IMiD‐based doublets decreased from 74.3% in 2014 to 37.6% in 2017. Over the same time period, the risk of death decreased by 32% and the risk of hospitalization which was reduced by 30%. The risk for serious adverse events remained unchanged. Conclusions Between 2014 and 2017, the use of triplet‐based therapy regimens for rrMM in Germany has significantly increased and this was associated with a significant decline in deaths and hospitalizations without an increased incidence of serious adverse events.

Waldenström macroglobulinaemia is an indolent B-cell lymphoma with clearly defined criteria for diagnosis, initiation of therapy, and response, which was established by consensus panels at previous International Workshops for Waldenström Macroglobulinaemia (IWWM). The treatment options for Waldenström macroglobulinaemia continued to be researched after the publication of the eighth IWWM consensus recommendations in 2016, and at the tenth IWWM in New York, USA (October, 2018) an international consensus panel was formed to update treatment recommendations. Participants were selected as members of the consensus panel based on their expertise on Waldenström macroglobulinaemia. The initial live discussion took place during the tenth IWWM meeting and two separate teleconferences were held in June, 2019, and January, 2020, to refine recommendations. No external or financial support was received for the elaboration of these recommendations. According to these updated consensus recommendations, alkylating drugs (bendamustine, cyclophosphamide) and proteasome inhibitors (bortezomib, carfilzomib, ixazomib), both in combination with rituximab, as well as BTK inhibitors (ibrutinib), alone or in combination with rituximab, are preferred first-line therapy options for symptomatic patients with Waldenström macroglobulinaemia. In previously treated patients with Waldenström macroglobulinaemia who had an initial durable response, reuse of a previous regimen or another primary therapy regimen are acceptable options. Novel BTK inhibitors (acalabrutinib, zanubrutinib, tirabrutinib) and the BCL2 antagonist venetoclax appear safe and active, and represent emerging options for the treatment of Waldenström macroglobulinaemia. The choice of therapy should be guided by the patient's clinical profile, genomic features, and drug availability.

Multiple myeloma (MM) is an incurable condition with variable clinical course. The study included a group of patients with especially poor-prognosis, individuals with relapsed/refractory multiple myeloma (RRMM) and specific cytogenetic disorders. Among the currently used therapies the ixazomib-lenalidomid-dexamethasone (IRd) is considered as a candidate to improve outcomes. The aim of the study was to evaluate the safety and efficacy of IRd regimen in the treatment of patients with RMMM.Nine patients aged 52-82 years who received ixazomib in the early access programme, were included in the study. All patients met the criteria for recurrent/relapsed MM and had high (t(4:14), t(14:16), del17p or +1q21) risk aberrations. Previous chemotherapy regimens included thalidomide and bortezomib. Median duration of exposure to ixazomib was 12 months.One patient with multiple cytogenetic aberrations and extramedullary plasmocytoma died because of progression after two months of treatment. In the remaining patients, the objective response to treatment was reached, and in four cases it was qualified as a very good partial response (VGPR). Observed adverse effects included neutropenia, infections, and oedema (in three cases Grade 3). Eight patients continue treatment, in two cases the decision was made to reduce lenalidomide doses.Preliminary results suggest potentially high efficacy and good safety profile of IRd therapy in patients with RRMM and unfavourable cytogenetics.

The induction therapy containing ixazomib, an oral proteasome inhibitor, has shown favorable efficacy and safety in clinical trials, but its experience in real-life remains limited. In routine practice, few patients received ixazomib-based induction therapy due to reasons including (1) patients’ preference on oral regimens, (2) concerns on adverse events (AEs) of other intravenous/subcutaneous regimens, (3) requirements for less center visits, and (4) fears of COVID-19 and other infectious disease exposures. With the aim of assessing the real-life effectiveness and safety of ixazomib-based induction therapy, we performed this multi-center, observational study on 85 newly diagnosed multiple myeloma (NDMM) patients from 14 medical centers. Ixazomib-based regimens included ixazomib-lenalidomide-dexamethasone (IRd) in 44.7% of patients, ixazomib-dexamethasone (Id) in 29.4%, and Id plus another agent (doxorubicin, cyclophosphamide, thalidomide, or daratumumab) in 25.9%. Different ixazomib-based therapies were applied due to (1) financial burdens or limitations on local health insurance coverage, (2) concerns on treatment tolerance, and (3) drug accessibility issue. Ten patients received ixazomib maintenance. The median age was 67 years; 43.5% had ISS stage III disease; 48.2% had an Eastern Cooperative Oncology Group performance score ≥ 2; and 17.6% with high-risk cytogenetic abnormalities. Overall response rate for all 85 patients was 95.3%, including 65.9% very good partial response or better and 29.5% complete responses. The median time to response was 30 days. The response rate was similar across different ixazomib-based regimens. Median progression-free survival was not reached. Severe AEs (≥ grade 3) were reported in 29.4% of patients. No grade 3/4 peripheral neuropathy (PN) occurred. Patients received a median of 6 (range 1–20) cycles of ixazomib treatment; 56.6% remained on treatment at data cutoff; 15.3% discontinued treatment due to intolerable AEs. These results support that the ixazomib-based frontline therapy was highly effective with acceptable toxicity in routine practice and the ixazomib oral regimens could be good alternative options for NDMM patients.

Objective To assess the short-term efficacy and safety of ixazomib in Chinese multiple myeloma (MM) patients in the real world. Methods Fifty-nine MM patients who received at least one cycle of ixazomib-based therapy between 1 June 2018 and 30 September 2019 were retrospectively analyzed in Tianjin Medical University General Hospital. Thirteen newly diagnosed MM (NDMM), 13 refractory/relapsed MM (RRMM) and 33 continuous therapy (27 bortezomib peripheral neuritis (PN) intolerant and six maintenance therapy) MM patients were included. The indicated overall response rate (ORR), time to overall response (TOR), and adverse events (AEs) were investigated. Results The ORR in NDMM was 76.9%, with one complete response (CR), five very good partial response (VGPR), four partial response (PR), median PFS, and TOR were 122 (66-272) days and 49 (22-108) days. The ORR in RRMM was 46.2%, with one CR, two VGPR, three PR, median PFS, and TOR were 79 (28-169) days and 59 (23-88) days. The ORR in continuous therapy MM patients was 100%, with nine stringent CR, 15 CR, six VGPR and three PR, median TOR was 75 (25-141) days. There were no significant differences regarding ORR between patients with cytogenetic high risk and standard risk in three subgroups (all P>0.05). The most frequent hematological AEs were anemia (13.6%) and thrombocytopenia (10.2%). The most common nonhematological AEs were PN (25.0%) and diarrhea (13.6%). Conclusion The real-world data demonstrated that ixazomib-based therapy was generally effective and safe in the short term for MM patients.

The therapeutic strategy for relapsed and refractory multiple myeloma (RRMM) integrates a holistic approach regarding patient, disease, and drug-related factors. Patient-related factors include age, frailty status, and underlying comorbidities, especially cardiovascular and renal diseases and peripheral neuropathies that affect tolerability to multiple drug combinations or transplantations. Disease-related factors encompass these multiple patient-related factors, particularly the aggressiveness of the disease and cytogenetics. Regarding drug-related factors, the approval of novel proteasome inhibitors (such as carfilzomib and ixazomib), immunomodulatory agents (such as pomalidomide), monoclonal antibodies (such as daratumumab and elotuzumab), and new classes of drugs increasingly makes the choice treatment more complex and necessitates a comprehensive summary and an update of the efficacy and toxicities of each antimyeloma drug and its combinations. Further, careful monitoring of the side effects and supportive care throughout the course of treatment are important to achieve better outcomes for patients with RRMM.

Since the introduction of an alkylator to the treatment of multiple myeloma (MM), new effective agents have been developed, such as immunomodulatory drugs including thalidomide, lenalidomide, and pomalidomide; proteasome inhibitors including bortezomib, carfilzomib, and ixazomib; monoclonal antibodies including daratumumab and elotuzumab; and deacetylase inhibitors including panobinostat. Numerous regimens with these new agents have been developed and they have contributed in improving survival outcomes in MM patients. In addition, the recommended therapies for newly diagnosed MM change every year based on the results of clinical trials. This review will discusses the appropriate induction therapies based on recent clinical trials for patients with newly diagnosed MM.

The prognosis for patients with multiple myeloma has improved substantially over the past decade with the development of new, more effective chemotherapeutic agents and regimens, and improved management of toxicities. Treatment of relapsed or refractory multiple myeloma represents a vital aspect of the overall care for patients with multiple myeloma and a critical area of ongoing biologic and clinical research. The choice of regimen at relapse is usually based on the prior response, toxicities, assessment of prognostic factors, age and comorbidities of individual patients, their somatic condition and expected effectiveness and tolerability. The new drugs, such as ixazomib, carfilzomib, pomalidomide, daratumumab and elotuzumab in combinations in doublet or triplet regimens, have greatly increased the treatment armory against myeloma. Long-term continuous therapies as a new strategy for relapsed or refractory multiple myeloma have been shown to provide an eradicating of minimal residual disease and deep prolong responses, with the goal of improving progression-free survival and overall survival. The integration of novel agents into the treatment paradigm has shifted the perception of multiple myeloma from an incurable fatal disease to a manageable chronic one. This review discusses the most recent and effective regimens for the relapsed or refractory multiple myeloma treatment, based on the results of recently published phase II and III clinical trials. Analyses the current clinical trial data discussed with a focus on lenalidomide or bortezomib as a basis of new treatment regimens.

Extensive inter-individual variation in response to chemotherapy (sensitive vs resistant tumors) is a serious cause of concern in the treatment of multiple myeloma (MM). In this study, we used human myeloma cell lines (HMCLs), and patient-derived CD138+ cells to compare kinetic changes in gene expression patterns between innate proteasome inhibitor (PI)-sensitive and PI-resistant HMCLs following test dosing with the second-generation PI Ixazomib. We found 1553 genes that changed significantly post treatment in PI-sensitive HMCLs compared with only seven in PI-resistant HMCLs (p

Although survival of multiple myeloma patients has at least doubled during recent years, most patients eventually relapse. At the time of relapse, the use of alternative drugs to those given upfront is current practice. However, many new options are currently available for the treatment of relapsed multiple myeloma, including recently approved drugs, such as the second- and third-generation proteasome inhibitors (carfilzomib and ixazomib), the second- and third-generation immunomodulatory drugs (lenalidomide and pomalidomide), the monoclonal antibodies (daratumumab and elotuzumab) and the histone deacetylase inhibitor (panobinostat). We here describe new treatment options for relapsed multiple myeloma in Poland based on drugs that can be used as part of the Ministry of Health's drug program in the context of ESMO guidelines.

Objectives Evaluating potential relationships between progression‐free survival (PFS) and tumor gene expression patterns and mutational status was an exploratory objective of the phase 3 TOURMALINE‐MM1 study (NCT01564537) of ixazomib‐lenalidomide‐dexamethasone (IRd) vs placebo‐Rd in 722 patients with relapsed/refractory multiple myeloma (MM). Methods We utilized gene expression and mutation data from screening bone marrow aspirates to identify tumors with non‐canonical nuclear factor‐κB (NF‐κB) signaling pathway activation. Results DNA/RNA sequencing data were available for 339 (47.0%)/399 (55.2%) patients; 49/339 (14.5%) patients had non‐canonical NF‐κB pathway gene mutations (tumor‐necrosis‐factor receptor‐associated factor 2, 3 [TRAF2, TRAF3], baculoviral‐inhibitor‐of‐apoptosis repeat‐containing 2/3 [BIRC2/3]), and PFS was significantly longer with IRd vs placebo‐Rd in these patients (hazard ratio [HR] 0.23). In patients with lower TRAF3 expression (median not reached vs 11 months, HR 0.47) and higher NF‐κB‐inducing kinase (NIK) expression (median not reached vs 14 months, HR 0.45), both associated with non‐canonical NF‐κB pathway activation, PFS was significantly longer with IRd vs placebo‐Rd. TRAF3 expression was decreased in patients harboring t(4;14) and 1q21 amplification, suggesting increased non‐canonical NF‐κB pathway activation. Conclusions Adding ixazomib to Rd provides clinical benefit in MM tumors with increased non‐canonical NF‐κB pathway activity. This is a potential mechanism for activity in 1q21 amplified high‐risk tumors.

In the past decade, several new therapies have been approved for use in multiple myeloma, including the novel oral agent, ixazomib. Ixazomib, like bortezomib and carfilzomib, is a proteasome inhibitor, a class of agents that are a mainstay of treating multiple myeloma in both the frontline and relapsed settings. Ixazomib is administered orally and offers many potential advantages over the subcutaneous or intravenous administration of bortezomib. In this single-center, retrospective medication use evaluation, adult patients with multiple myeloma receiving either ixazomib or bortezomib in the outpatient setting were assessed to evaluate financial implications and tolerability. A total of 28 patients were included. The total wholesale acquisition cost for one cycle of ixazomib was $9942, and $6412 for bortezomib. Average reimbursement per cycle was $9205 for ixazomib and $5664 for bortezomib. Secondarily, the incidence of interruption in therapy was evaluated. Ixazomib was associated with a slightly higher incidence of interruption compared to bortezomib, 42.9% and 35.7%, respectively. It is notable that ixazomib has similar drug reimbursement rates to bortezomib, but slightly higher rates of interruption in therapy. In conclusion, if tolerable for the patient, ixazomib may offer a financially acceptable alternative for the treatment of multiple myeloma.

The majority of gastrointestinal stromal tumors (GISTs) are driven by oncogenic KIT signaling and can therefore be effectively treated with the tyrosine kinase inhibitor (TKI) imatinib mesylate. However, most GISTs develop imatinib resistance through secondary KIT mutations. The type of resistance mutation determines sensitivity to approved second-/third-line TKIs but shows high inter- and intratumoral heterogeneity. Therefore, therapeutic strategies that target KIT independently of the mutational status are intriguing. Inhibiting the ubiquitin-proteasome machinery with bortezomib is effective in GIST cells through a dual mechanism of KIT transcriptional downregulation and upregulation of the pro-apoptotic histone H2AX but clinically problematic due to the drug’s adverse effects. We therefore tested second-generation inhibitors of the 20S proteasome (delanzomib, carfilzomib and ixazomib) with better pharmacologic profiles as well as compounds targeting regulators of ubiquitination (b-AP15, MLN4924) for their effectiveness and mechanism of action in GIST. All three 20S proteasome inhibitors were highly effective in vitro and in vivo, including in imatinib-resistant models. In contrast, b-AP15 and MLN4924 were only effective at high concentrations or had mostly cytostatic effects, respectively. Our results confirm 20S proteasome inhibitors as promising strategy to overcome TKI resistance in GIST, while highlighting the complexity of the ubiquitin-proteasome machinery as a therapeutic target.

Introducción: el mieloma múltiple refractario o recidivante es un reto para los médicos tratantes. En la actualidad existen múltiples opciones terapéuticas para estos casos, sin embargo, la evidencia científica sobre su eficacia comparativa aún se encuentra en construcción. Objetivo: comparar, a través de un metaanálisis en red, la eficacia y seguridad reportada en ensayos clínicos del daratumumab con otros tratamientos en pacientes con mieloma múltiple recidivante o refractario. Metodología: se realizó una búsqueda sistemática de la literatura a través de bases de datos para la identificación de ensayos clínicos que evaluaran los efectos terapéuticos de las tecnologías en salud utilizadas en el manejo del mieloma múltiple refractario o recidivante que tuvieran un comparador común con el daratumumab. Posteriormente, se hizo un metaanálisis en red para la comparación de la eficacia, las comparaciones indirectas fueron ajustadas. Se estimaron OR y sus intervalos de confianza. Resultados: se incluyeron siete ensayos clínicos en el metaanálisis. Cuando el comparador común fue el bortezomib/dexametasona, el daratumumab fue superior comparado con el carfilzomib (OR 0,49; IC95% 0,99, 0,7) y bortezomib/dexametasona (OR 0,26, IC95% 0,54, 0,37). Cuando el comparador común fue lenalidomida/dexametasona, el daratumumab fue superior al carfilzomib (OR 0,21, IC95% 0,13, 0,36), ixazomib (OR 0,4, IC95% 0,26, 0,83) y elotuzumab (OR 0,28, IC95% 0,18, 0,44) sobre la progresión de la enfermedad o muerte. Las reacciones adversas severas fueron similares entre los grupos. Conclusiones: el daratumumab es una herramienta terapéutica que muestra resultados superiores en términos de la progresión de la enfermedad o muerte y con una proporción de reacciones adversas severas similar en comparación con otras alternativas terapéuticas.

With improving outcomes in amyloid light-chain (AL) amyloidosis, there is a need to study novel agents in this setting. We report outcomes of 40 patients with relapsed AL amyloidosis treated with ixazomib + lenalidomide + dexamethasone (IRd). Haematological responses were assessed on an intention-to-treat basis at three months: complete response (CR) - 8 (20·5%), very good partial response (VGPR) - 8 (20·5%), partial response (PR) - 7 (17·9%) and no response (NR) - 16 (41·0%). One patient had missing data. Six patients subsequently improved response. Best responses were: CR - 10 (25·6%), VGPR - 8 (20·5%), PR - 7 (17·9%), NR - 14 (35·9%). Cardiac and renal organ responses occurred in 5·6% and 13·3% respectively. Median progession-free survival (PFS) was 17·0 months (95% CI 7·3-20·7 months), improving to 28·8 months (95% CI 20·6-37·0 months) in those achieving CR/VGPR. Median overall survival was 29·1 months (95% CI 24-33 months). Serious adverse events were seen in 14 (35·0%) patients inclusive of 15 admissions due to: infection (6/15, 40·0%), fluid overload (5/15, 33·3%), cardiac arrhythmia (2/15, 13·3%), renal dysfunction (1/15, 6·6%) and anaemia (1/15, 6·6%). In summary, IRd is an oral treatment option with a manageable toxicity profile leading to deep responses in 47% of patients with relapsed AL amyloidosis.

The vast majority of patients with light-chain (AL) amyloidosis are not eligible for stem cell transplant and are treated with conventional chemotherapy. Conventional regimens are based on various combinations of dexamethasone, alkylating agents, proteasome inhibitors, and immunomodulatory drugs. The choice of these regimens requires a careful risk stratification, based on the extent of amyloid organ involvement, comorbidities, and the characteristics of the amyloidogenic plasma cell clone. Most patients are treated upfront with bortezomib and dexamethasone combined with cyclophosphamide or melphalan. Cyclophosphamide does not compromise stem cell mobilization and harvest and is more manageable in renal failure. Melphalan can overcome the effect of t(11;14), which is associated with lower response rates and shorter survival in subjects treated with bortezomib and dexamethasone, or in combination with cyclophosphamide. Lenalidomide and pomalidomide are the mainstay of rescue treatment. They are effective in patients exposed to bortezomib, dexamethasone, and alkylators, but deep hematologic responses are rare. Ixazomib, alone or in combination with lenalidomide, increases the rate of complete responses in relapsed/refractory patients. Conventional chemotherapy regimens will represent the backbone for future combinations, particularly with anti-plasma-cell immunotherapy, that will further improve response rates and outcomes.

We provide our recommendations (not evidence based) for managing multiple myeloma patients during the pandemic of COVID-19. We do not recommend therapy for smoldering myeloma patients (standard or high risk). Screening for COVID-19 should be done in all patients before therapy. For standard-risk patients, we recommend the following: ixazomib, lenalidomide, and dexamethasone (IRd) (preferred), cyclophosphamide lenalidomide and dexamethasone (CRd), daratumumab lenalidomide and dexamethasone (DRd), lenalidomide, bortezomib, and dexamethasone (RVd), or cyclophosphamide, bortezomib, and dexamethasone (CyBorD). For high-risk patients we recommend carfilzomib, lenalidomide, and dexamethasone (KRd) (preferred) or RVd. Decreasing the dose of dexamethasone to 20 mg and giving bortezomib subcutaneously once a week is recommended. We recommend delaying autologous stem cell transplant (ASCT), unless the patient has high-risk disease that is not responding well, or if the patient has plasma cell leukemia (PCL). Testing for COVID-19 should be done before ASCT. If a patient achieves a very good partial response or better, doses and frequency of drug administration can be modified. After 10–12 cycles, lenalidomide maintenance is recommended for standard-risk patients and bortezomib or ixazomib are recommended for high-risk patients. Daratumumab-based regimens are recommended for relapsed patients. Routine ASCT is not recommended for relapse during the epidemic unless the patient has an aggressive relapse or secondary PCL. Patients on current maintenance should continue their therapy.

Lack of head-to-head trials highlights a need for comparative real-world evidence of proteasome inhibitors plus Rd. Methods: In this retrospective, US population-representative EHR study of RRMM patients initiating IRd, KRd, or VRd in line of therapy (LOT) ≥2 between 1/2014 and 9/30/2018, 664 patients were treated in LOT ≥2 with: IRd, n = 168; KRd, n = 208; VRd, n = 357. Median age was 71/65/71 years; 67%/70%/75% had a frailtymodified score of intermediate/frail; 20%/28%/13% had high cytogenetic risk in I-/K-/V-Rd groups. Risk of PI-triplet discontinuation was lower for I- vs. K-Rd (HR: 0.71) and I- vs. V-Rd (HR: 0.85); unadjusted, median TTNTs (months): 12.7/8.6/14.2 (LOT ≥2) and 16.8/9.5/14.6 (LOT 2–3) (I-/K-/V-Rd). Adjusted TTNT was comparable between I-/K-/V-Rd in LOT ≥2 with a TTNT benefit among intermediate/frail patients for I- (HR: 0.70; P=0.04) and V- (HR: 0.73; P50% of patients are excluded. Individualized treatment based on patient characteristics, such as frailty status, is especially pertinent in an elderly RRMM population.

Introduction : The ubiquitination system is the most important cascade of protein degradation independently of lysosomal function. The proteasome system is actively involved in cell cycle regulation. Therefore, proteasome inhibition can lead to inhibition of tumor cell proliferation, and therefore it constitutes a potential therapeutic anticancer approach especially in the therapeutic algorithm of patients with multiple myeloma. Areas covered Three different proteasome inhibitors are currently approved, bortezomib, carfilzomib and ixazomib, and they have been investigated in multiple myeloma and other hematological malignancies. Multiple myeloma cells are extremely sensitive to this inhibition which leads to accumulation of proteins and endoplasmic reticulum stress, leading finally to apoptosis. However, these agents lack specificity, since they target both the constitutive proteasome and the immunoproteasome. Targeting the constitutive proteasome is the main reason for side toxicity due to the effect on normal tissues. In contrary, immunoproteasome inhibition may reduce the adverse events while maintaining the therapeutic efficacy. In this review the authors present the role of the available proteasome inhibitors in myeloma therapeutics and future perspectives of both selective and non-selective proteasome inhibitors. Expert opinion The available non-selective proteasome inhibitors have changed the therapeutics of multiple myeloma the last 10 years and have significantly improved the clinical outcomes of the patients. Furthermore, selective proteasome inhibitors are now under preclinical investigation and there is hope that their optimization will come with an improved safety profile with at least comparable efficacy.

Simple Summary New treatments in multiple myeloma are embraced by patients and physicians but are also associated with substantial higher costs. To ensure the affordability and accessibility of health care, an evaluation of the outcomes in relation to the costs is increasingly requested. However, an up-to-date summary and assessment of the cost-effectiveness evidence for multiple myeloma treatments is currently lacking. We identified the cost-effectiveness studies currently available and show that novel treatments could improve survival with almost 4 years compared to standard of care. However, additional costs compared to standard of care could increase up to USD 535,530 per patient. The ratio between outcomes and costs is above currently accepted willingness to pay thresholds. Our results show cost-effectiveness ratios should be either improved or less favorable ratios should be accepted to ensure accessibility to promising treatments. Abstract Background: Novel therapies for multiple myeloma (MM) promise to improve outcomes but are also associated with substantial increasing costs. Evidence regarding cost-effectiveness of novel treatments is necessary, but a comprehensive up-to-date overview of the cost-effectiveness evidence of novel treatments is currently lacking. Methods: We searched Embase, Medline via Ovid, Web of Science and EconLIT ProQuest to identify all cost-effectiveness evaluations of novel pharmacological treatment of MM reporting cost per quality-adjusted life year (QALY) and cost per life year (LY) gained since 2005. Quality and completeness of reporting was assessed using the Consolidated Health Economic Evaluation Reporting Standards. Results: We identified 13 economic evaluations, comprising 32 comparisons. Our results show that novel agents generate additional LYs (range: 0.311–3.85) and QALYs (range: 0.1–2.85) compared to backbone regimens and 0.02 to 1.10 LYs and 0.01 to 0.91 QALYs for comparisons between regimens containing two novel agents. Lifetime healthcare costs ranged from USD 60,413 to 1,434,937 per patient. The cost-effectiveness ratios per QALY gained ranged from dominating to USD 1,369,062 for novel agents compared with backbone therapies and from dominating to USD 618,018 for comparisons between novel agents. Conclusions: Cost-effectiveness ratios of novel agents were generally above current willingness-to-pay thresholds. To ensure access, cost-effectiveness should be improved or cost-effectiveness ratios above current thresholds should be accepted.

Objective To evaluate the safety profile of ixazomib combined with lenalidomide and dexamethasone in patients with relapsed/refractory multiple myeloma (RRMM) in clinical practice in Japan through an all-case post-marketing surveillance. Methods This was a nationwide non-interventional observational study conducted in Japan. The study included all patients who received ixazomib from May 24 to September 24, 2017. Ixazomib was administered to RRMM patients according to the Japanese package insert. All enrolled patients were observed until the completion of the sixth treatment cycle or until ixazomib discontinuation. The patient treatment course, including adverse events (AEs), was reported. Results The safety analysis set included 741 patients; the median age was 71 (range 35-92) years old, and the median number of prior treatment lines was 3 (range 1-30). Adverse drug reactions (ADRs) occurred in 572 (77.2%) patients, most commonly being thrombocytopenia (49.9%), diarrhea (29.2%), and nausea (12.4%). Serious ADRs occurred in 193 (26.0%) patients, most commonly being thrombocytopenia (9.9%) and diarrhea (5.9%). Thrombocytopenia, severe gastrointestinal disorders, infections, skin disorders, and peripheral neuropathy were prespecified as ADRs of clinical importance; the frequency of these ADRs (grade ≥3) were 28.5%, 9.4%, 7.4%, 2.2%, and 1.3%, respectively. Treatment discontinuation was most common with thrombocytopenia and severe gastrointestinal disorders (49 and 43 patients, respectively). Eleven patients died due to ADRs (16 events). Conclusion These results suggest that ixazomib has a tolerable safety profile in clinical practice in Japan. However, close AE management for thrombocytopenia and gastrointestinal disorders should be considered.

The proteasome is responsible for mediating intracellular protein degradation and regulating cellular function with impact on tumor and immune effector cell biology. The proteasome is found predominantly in two forms, the constitutive proteasome and the immunoproteasome. It has been validated as a therapeutic drug target through regulatory approval with 2 distinct chemical classes of small molecular inhibitors (boronic acid derivatives and peptide epoxyketones), including 3 compounds, bortezomib (VELCADE), carfilzomib (KYPROLIS), and ixazomib (NINLARO), for use in the treatment of the plasma cell neoplasm, multiple myeloma. Additionally, a selective inhibitor of immunoproteasome (KZR-616) is being developed for the treatment of autoimmune diseases. Here, we compare and contrast the pharmacokinetics (PK), pharmacodynamics (PD), and metabolism of these 2 classes of compounds in preclinical models and clinical studies. The distinct metabolism of peptide epoxyketones, which is primarily mediated by microsomal epoxide hydrolase, is highlighted and postulated as a favorable property for the development of this class of compound in chronic conditions.

Despite the recent introduction of new therapies for multiple myeloma (MM), it remains an incurable disease. As MM progresses, patients experience cycles of relapse and remission, with remission periods becoming increasingly shorter as the disease becomes less treatment-sensitive. The treatment of relapsed refractory MM (RRMM) remains a significant clinical challenge. Patients with RRMM are a highly heterogeneous group and choosing the most appropriate treatment requires careful consideration. Furthermore, the number of treatment options for MM is continually growing with no definitive consensus to guide treating clinicians. The emergence of second-generation proteasome inhibitors (e.g., carfilzomib and ixazomib), immunomodulatory drugs (e.g., pomalidomide) and monoclonal antibodies (e.g., isatuximab) has expanded an already complex treatment landscape. This review provides a clear summary of the available treatments for MM and discusses how to tailor treatments to individual patients' needs. Novel treatments currently under clinical development, including venetoclax, melflufen and CAR T-cell therapies, are also discussed.

Nocardia brain abscess is relatively rare, accounting for about 1–2% of all brain abscesses, and its mortality rate is three times higher than of other types of bacterial brain abscesses; thus, early diagnosis and treatment are essential. Nocardia brain abscess generally occurs in immunodeficient patients. We report a case of Nocardia farcinica brain abscess in a multiple myeloma patient treated with proteasome inhibitor (bortezomib and ixazomib), cyclophosphamide, and corticosteroid. The patient was treated with ceftriaxone and trimethoprim-sulfamethoxazole, together with drainage of the brain abscess. Regular brain MRI follow-ups showed that intracranial lesions were gradually absorbed and improved.

Preclinical studies demonstrated activity of the oral proteasome inhibitor (PI) ixazomib (IXA) in bortezomib-resistant multiple myeloma (MM) and synergy with immunomodulatory drugs. We therefore conducted a phase I/II study to establish the safety and preliminary efficacy of IXA with pomalidomide (POM) and dexamethasone (DEX) in lenalidomide (LEN)/PI-refractory MM. Dose escalation established a 4 mg dose of POM and IXA and 20/40 mg dose of DEX as the maximum tolerated dose. The phase II portion of the trial was redesigned and started anew after 6 patients had been randomized to IXA-POM-DEX due to a rapidly changing treatment landscape. Among the 29 evaluable LEN/PI-refractory patients treated with IXA-POM-DEX in phase I / II, the overall response rate (partial response or better) was 51.7% with a median duration of response of 16.8 months (range 56 days - 4.1 years), median progression-free survival 4.4 months (95% confidence interval [CI]: 3.0 - 18.4) and median overall survival 34.3 months (95% CI: 19.2 - not reached). Hematologic, gastrointestinal, and constitutional adverse events were common and consistent with the side effect profiles of the individual agents. Our results support further evaluation of this all-oral regimen in relapsed/refractory MM. This article is protected by copyright. All rights reserved.

Introduction: Amyloidosis is a disorder where misfolded proteins get deposited in different tissues. The most common of them is immunoglobulin light chain (AL) deposition, otherwise known as AL amyloidosis. Cardiac involvement generally correlates with poor prognosis, and treatment options are limited if presented late. Novel disease-modifying agents are being studied in on-going trials to optimize treatment strategy. This review aims to summarize the updates on upcoming treatment options for AL amyloidosis, particularly involving the heart. Methodology: We performed a comprehensive literature search on PubMed, clinicaltrials.gov, and Cochrane databases (last updated on May 20, 2020). We used MeSH terms along with their keywords and combined their results. The literature search generated a total of 652 references. Two independent reviewers screened the articles and shortlisted 21 clinical trials that were included in our final review. Results: Monoclonal antibodies (daratumumab, isatuximab, elotuzumab and birtamimab) are being studied as monotherapy and combinations in relapsed/refractory (RR) AL amyloidosis. Despite good data on efficacy and safety, Daratumumab has not been approved yet in this category for advanced cardiac amyloidosis patients. Isatuximab showed the overall hematological response (HR) of 56% in phase I trial in a combination regimen and is now being evaluated as monotherapy in phase II. In a recent phase III trial of RR AL amyloidosis patients, the median progression-free survival was assessed over 24.5 months. It was increased from 14.9 months (lenalidomide and dexamethasone alone) to 19.4 months (elotuzumab, lenalidomide, and dexamethasone). Immunomodulators (lenalidomide, pomalidomide, thalidomide) are well studied for safety in other malignancies. Lenalidomide in various combinations has shown hematological response of greater than 60% in AL amyloidosis. Similarly, pomalidomide has shown an overall hematological response of 48-50% in two different early phase trials. Moreover, thalidomide was associated with significant toxicity in phase I/II trials and was discontinued. Second-generation proteasome inhibitors (ixazomib and carfilzomib) were assessed in RR cases of AL amyloidosis. Ixazomib achieved a hematological response of 52%. However, carfilzomib has been associated with cardiovascular toxicity and a higher risk of hospitalization in phase I trials, making it unsuitable. Venetoclax has shown encouraging results in multiple myeloma, particularly in t(11:14). 50% of AL amyloidosis cases have t(11:14) in whom venetoclax can be beneficial. A trial [NCT03000660] was suspended halfway citing clinical hold from regulatory authorities. Alkylating agents, mainly bendamustine, are currently under study after it showed a survival advantage in heavily pretreated cases [NCT01222260]. Underexplored venues: Small interfering RNAs (siRNAs) have a favorable response and excellent toxicity profile in AL amyloidosis. Issues regarding half-life and delivery systems have limited their use. CAEL-101, a novel chimeric fibril-reactive monoclonal antibody (gG1κ 11-1F4), tolerated well with improved organ function in AL amyloidosis in an early phase trial where it improved global longitudinal strain from baseline -9.58 to -13.39. SB203580 + rapamycin combination works in synergy with the former inhibiting the p38 MAPK pathway markedly reducing the toxicity of light chain immunoglobulins on cardiac myocytes and the latter restoring the SB203580-induced autophagic dysregulation. Epigallocatechin-3-gallate (EGCG) was well tolerated and found non-inferior to standard chemotherapy in a small phase II trial [NCT01511263]. Serum amyloid P (SAP) is a chaperone protein in amyloid fibril formation. Anti-SAP antibodies have shown promising results with safe toxicity profile in phase I trial [NCT01777243] in non-cardiac involved patients. However, another trial in cardiac involved cases was terminated due to significant toxicity. Table 1 Conclusion: Numerous drugs with novel mechanisms of actions are being studied, and results so far offer hope for improving the therapy & outcomes, especially in patients with cardiac involvement. The drug combination regimens lead to slow down the disease progression by interfering at multiple steps in the cascade of light chain synthesis, secretion, deposition, and organ clearance. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.

Introduction . In multiple myeloma (MM), the presence of translocation t(4;14) and/or 17p deletion, found in around 10 to 15% of the patients, is considered as high-risk feature associated with adverse survival. Despite recent advances in the treatment of MM, t(4;14) and del(17p) are still associated with poor outcome. The aim of this study was to analyze the trends of survival in patients with newly diagnosed MM harboring t(4;14) and or 17p deletion over the past two decades. Methods . Patients from five French centers with newly-diagnosed MM from 2001 to 2019 and displaying del(17p) and/or t(4;14) were retrospectively included. Cytogenetics abnormalities were detected by interphase fluorescence in situ hybridization (FISH) and del(17p) positivity cut-off was 30%. New agents were defined as: pomalidomide, carfilzomib, ixazomib and anti-CD38 monoclonal antibodies. Results . 246 patients carrying either t(4;14) (n=106 patients), del(17p) (n=121 patients) or both (n=19 patients) were included. Median age was 64 years (range, 35-91). ISS and R-ISS score were 3 in 88 patients (36%). Eighty-seven patients (35%) were diagnosed in 2001-2010 period, and 159 (65%) in 2011-2019 period. Front-line autologous stem-cell transplantation (ASCT) was performed in 121 (49%) patients. Among transplant eligible patients, 112 patients (n=93%) received triplet induction, 78 patients (64%) a consolidation regimen and 15 patients (12%) a maintenance therapy. Double-ASCT was decided in 21 patients (17%). Among transplant ineligible patients, 61 patients (49%) received melphalan-based regimen in first line, 36 (29%) a bortezomib-based and 15 patients (14%) a lenalidomide-based regimen. At any line, 92 patients (37%) received at least one of the new agents with only 12 patients (5%) in frontline therapy. Median follow-up was 41 months (IQR: 21-69). Median overall survival (OS) was 58.4 months (IQR: 50.1-66.5) for the entire cohort, 55.5 months (IQR: 46.6-78.3) for del(17p), 62.5 months (IQR: 54.2-76.1) for t(4;14) and 48.6 months (18.1-not reached) for patients with both (p=0.2). Median of first progression-free survival (PFS1) was 25.6 months (IQR: 22.2-29.8), with no difference between del(17p), t(4;14) or both (p=0.57). Importantly, no improvement of median OS was observed in patients diagnosed between 2001-2010 in comparison with patients diagnosed between 2011-2019 (63.7 versus 53.2 months, p=0.32). In univariate and multivariate analysis: age (continuous and cut-off 71 years-old) and ASCT significantly were associated with risk of death (HR: 1.03, 1.09 and 0.45, respectively). Median OS of patients eligible to ASCT was 76.1 months (IQR: 62.5-90.3) vs 42.5 months (IQR: 36.8-54.6) for patients not eligible (HR 0.45, 95%CI 0.28-0.0.71; p Conclusion . This large multicenter real-world study confirms that patients with newly diagnosed MM carrying del(17p) and/or t(4;14) remain a therapeutic challenge with no significant overall survival improvement in the past decades despite the use of novel agents. The definition of high-risk MM patients is evolving with incorporation of new markers (i.e chromosome 1 abnormalities, PET-imaging). Minimal-residual disease achievement will also re-defined risk stratification. Nonetheless, the need for innovative approaches such as earlier strategies using new agents or immunotherapy (CAR-T cells, bispecific T-cell engager antibodies) may significantly improve outcomes. Figure captions Table 1. Clinical, biological characteristics, treatment and survival of the 246 included patients based on period of diagnosis. IQR: interquartile range; FISH: fluorescence in situ hybridization; ISS: international score system; LDH: lactate dehydrogenase; ASCT: autologous stem cell transplantation; len: lenalidomide; Poma: pomalidomide; Carfil: carfilzomib; Ixa: ixazomib; mAb: monoclonal antibodies; OS: overall survival Figure 1. Kaplan-Meier curves for overall survival for the 246 included patients based on period of diagnosis. Figure 1 Disclosures Moreau: Amgen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Novartis: Honoraria; Takeda: Honoraria. Touzeau:Takeda: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Sanofi: Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; GlaxoSmithKline: Honoraria, Research Funding.