Search

Background: On the basis of the DREAMM‐2 study (ClinicalTrials.gov identifier NCT03525678), single‐agent belantamab mafodotin (belamaf) was approved for patients with relapsed or refractory multiple myeloma (RRMM) who received ≥4 prior therapies, including anti‐CD38 therapy. The authors investigated longer term efficacy and safety outcomes in DREAMM‐2 after 13 months of follow‐up among patients who received belamaf 2.5 mg/kg. Methods: DREAMM‐2 is an ongoing, phase 2, open‐label, 2‐arm study investigating belamaf (2.5 or 3.4 mg/kg) in patients with RRMM who had disease progression after ≥3 lines of therapy and were refractory to immunomodulatory drugs and proteasome inhibitors and refractory and/or intolerant to an anti‐CD38 therapy. The primary outcome was the proportion of patients that achieved an overall response, assessed by an independent review committee. Results: As of January 31, 2020, 10% of patients still received belamaf 2.5 mg/kg. Thirty‐one of 97 patients (32%; 97.5% confidence interval [CI], 21.7%‐43.6%) achieved an overall response, and 18 responders achieved a very good partial response or better. Median estimated duration of response, overall survival, and progression‐free survival were 11.0 months (95% CI, 4.2 months to not reached), 13.7 months (95% CI, 9.9 months to not reached), and 2.8 months (95% CI, 1.6‐3.6 months), respectively. Response and survival outcomes in patients who had high‐risk cytogenetics or renal impairment were consistent with outcomes in the overall population. Outcomes were poorer in patients with extramedullary disease. In patients who had a clinical response and prolonged dose delays (>63 days; mainly because of corneal events), 88% maintained or deepened responses during their first prolonged dose delay. Overall, there were no new safety signals during this follow‐up. Conclusions: Extended follow‐up confirms sustained clinical activity without new safety signals with belamaf in this heavily pretreated patient population with RRMM. Extended follow‐up of patients enrolled in the ongoing phase 2 DREAMM‐2 study confirms sustained clinical activity without new safety signals in patients with relapsed or refractory multiple myeloma who receive belantamab mafodotin 2.5 mg/kg every 3 weeks. These data show that belantamab mafodotin has the potential to shift the treatment paradigm in this heavily pretreated, anti‐CD38 monoclonal antibody–exposed patient population, which has a poor prognosis and few alternative treatment options. [ABSTRACT FROM AUTHOR]

Background: Belantamab mafodotin (GSK2857916), an immunoconjugate targeting B-cell maturation antigen, showed single-agent activity in the phase 1 DREAMM-1 study in heavily pre-treated patients with relapsed or refractory multiple myeloma. We further investigated the safety and activity of belantamab mafodotin in the DREAMM-2 study.Methods: DREAMM-2 is an open-label, two-arm, phase 2 study done at 58 multiple myeloma specialty centres in eight countries. Patients (aged ≥18 years) with relapsed or refractory multiple myeloma with disease progression after three or more lines of therapy and who were refractory to immunomodulatory drugs and proteasome inhibitors, and refractory or intolerant (or both) to an anti-CD38 monoclonal antibody with an Eastern Cooperative Oncology Group performance status of 0-2 were recruited, centrally randomly assigned (1:1) with permuted blocks (block size 4), and stratified by previous lines of therapy (≤4 vs >4) and cytogenetic features to receive 2·5 mg/kg or 3·4 mg/kg belantamab mafodotin via intravenous infusion every 3 weeks on day 1 of each cycle until disease progression or unacceptable toxicity. The intention-to-treat population comprised all randomised patients, regardless of treatment administration. The safety population comprised all patients who received at least one dose of belantamab mafodotin. The primary outcome was the proportion of randomly assigned patients in the intention-to-treat population who achieved an overall response, as assessed by an independent review committee. This study is registered with ClinicalTrials.gov, NCT03525678, and is ongoing.Findings: Between June 18, 2018, and Jan 2, 2019, 293 patients were screened and 196 were included in the intention-to-treat population (97 in the 2·5 mg/kg cohort and 99 in the 3·4 mg/kg cohort). As of June 21, 2019 (the primary analysis data cutoff date), 30 (31%; 97·5% CI 20·8-42·6) of 97 patients in the 2·5 mg/kg cohort and 34 (34%; 23·9-46·0) of 99 patients in the 3·4 mg/kg cohort achieved an overall response. The most common grade 3-4 adverse events in the safety population were keratopathy (in 26 [27%] of 95 patients in the 2·5 mg/kg cohort and 21 [21%] of 99 patients in the 3·4 mg/kg cohort), thrombocytopenia (19 [20%] and 33 [33%]), and anaemia (19 [20%] and 25 [25%]); 38 (40%) of 95 patients in the 2·5 mg/kg cohort and 47 (47%) of 99 in the 3·4 mg/kg cohort reported serious adverse events. Two deaths were potentially treatment related (one case of sepsis in the 2·5 mg/kg cohort and one case of haemophagocytic lymphohistiocytosis in the 3·4 mg/kg cohort).Interpretation: Single-agent belantamab mafodotin shows anti-myeloma activity with a manageable safety profile in patients with relapsed or refractory multiple myeloma.Funding: GlaxoSmithKline. [ABSTRACT FROM AUTHOR]

High‐dose chemotherapy and autologous stem cell transplantation (ASCT) are a standard of care for transplant‐eligible patients with newly diagnosed multiple myeloma (MM). The introduction of novel agents, which range from immunomodulatory drugs and proteasome inhibitors to monoclonal antibodies and have now been integrated into both induction and salvage regimens, has dramatically revolutionized the treatment landscape of MM and challenged the role of high‐dose chemotherapy and ASCT in treating MM. These advances have led to a number of provocative questions. First, what is the current role of stem cell transplantation (SCT) in comparison with standard‐dose therapy incorporating novel agents? Second, should ASCT be performed upfront ("early") or later ("delayed") in the course of the disease? Third, should single or double ASCT be performed? Fourth, is allogeneic SCT still an option for patients with MM? This article provides an overview of available data and evidence‐based responses regarding the role of SCT in MM. High‐dose melphalan and autologous stem cell transplantation are the current standard approach for young patients with newly diagnosed myeloma as part of the first‐line treatment. At relapse, salvage autologous stem cell transplantation is a feasible and effective treatment option, whereas allogeneic stem cell transplantation may be an option for young patients with high‐risk myeloma. [ABSTRACT FROM AUTHOR]

Background: Daratumumab is a human CD38-directed monoclonal antibody indicated for the treatment of relapsed and refractory multiple myeloma (MM).Methods: A multicenter, open-label treatment protocol provided early access to daratumumab for patients who had progressive MM after they received ≥3 prior lines of therapy that included a proteasome inhibitor and an immunomodulatory agent or if they were refractory to both a proteasome inhibitor and an immunomodulatory agent. Patients received daratumumab 16 mg/kg weekly for 8 weeks, every other week for 16 weeks, and monthly until they developed disease progression, unacceptable toxicity, or 60 days after the drug gained US approval. Treatment-emergent grade ≥3 adverse events (AEs), serious AEs, and AEs of special interest were collected.Results: Three hundred forty-eight patients were enrolled at 39 US sites between June and December 2015. Patients received study therapy for a median of 1.9 months (range, 0.03-6.0 months). Fifty-two percent of patients transitioned to commercially-available daratumumab and 37% discontinued because of progressive disease. Grade ≥3 AEs occurred in 50% of patients, including thrombocytopenia (15%) and anemia (14%). Serious AEs occurred in 35% of patients (12% were drug-related), including infections (11%). Infusion reactions occurred in 56%, 2%, and 2% of patients during the first, second, and all subsequent infusions, respectively; respiratory symptoms (cough, dyspnea, throat irritation, nasal congestion) were common. The infusion reaction rate for the first infusion was 38% in 50 patients at 2 sites who received montelukast as premedication for their first infusion and 59% in patients who did not receive montelukast.Conclusions: The current findings are consistent with previously reported trials and confirm the safety profile of daratumumab in heavily pretreated US patients who have relapsed or refractory MM. Cancer 2018;124:000-000. [ABSTRACT FROM AUTHOR]

Background: The randomized phase 3 ELOQUENT-2 study (NCT01239797) evaluated the efficacy and safety of elotuzumab plus lenalidomide and dexamethasone (ELd) versus lenalidomide and dexamethasone (Ld) in relapsed/refractory multiple myeloma (RRMM), and to date, has the longest follow-up of any monoclonal antibody in patients with RRMM.Methods: In this extended 4-year follow-up of the ELOQUENT-2 trial, the coprimary endpoints of progression-free survival (PFS) and overall response rate as well as the secondary endpoint of overall survival were assessed. In the absence of head-to-head trials comparing Ld-based triplet regimens to guide treatment selection, 4 randomized controlled trials-ELOQUENT-2, ASPIRE, TOURMALINE-MM1, and POLLUX-were indirectly compared to provide insight into the relative efficacy of these regimens in RRMM.Results: Data at 4 years were consistent with 2- and 3-year follow-up data: ELd reduced the risk of disease progression/death by 29% versus Ld (hazard ratio, 0.71) while maintaining safety. The greatest PFS benefit among the assessed subgroups was observed in patients at the median time or further from diagnosis (≥3.5 years) with 1 prior line of therapy, who had a 44% reduction in the risk of progression/death, and in patients in the high-risk category, who had a 36% reduction in favor of ELd. This regimen also showed a relative PFS benefit that was maintained beyond 50 months.Conclusions: The sustained PFS benefit and long-term safety of ELd at 4 years, similar to those observed at 2 and 3 years, support ELd as a valuable therapeutic option for the long-term treatment of patients with RRMM. [ABSTRACT FROM AUTHOR]

The randomized phase III ELOQUENT-2 study ( NCT01239797) evaluated the efficacy and safety of elotuzumab + lenalidomide/dexamethasone ( ELd) versus lenalidomide/dexamethasone (Ld) in relapsed/refractory multiple myeloma. ELd reduced the risk of disease progression/death by 30% versus Ld (hazard ratio [ HR] 0·70). Median time from diagnosis was 3·5 years. We present extended 3-year follow-up data. Endpoints included progression-free survival ( PFS), overall response rate ( ORR) and interim overall survival ( OS). Exploratory post-hoc analyses included impact of time from diagnosis and prior lines of therapy on PFS, and serum M-protein dynamic modelling. ORR was 79% ( ELd) and 66% (Ld) ( P = 0·0002). ELd reduced the risk of disease progression/death by 27% versus Ld ( HR 0·73; P = 0·0014). Interim OS demonstrated a trend in favour of ELd ( P = 0·0257); 1-, 2- and 3-year rates with ELd versus Ld were: 91% versus 83%, 73% versus 69% and 60% versus 53%. In patients with ≥ median time from diagnosis and one prior therapy, ELd resulted in a 53% reduction in the risk of progression/death versus Ld ( HR 0·47). Serum M-protein dynamic modelling showed slower tumour regrowth with ELd. Adverse events were comparable between arms. ELd provided a durable and clinically relevant improvement in efficacy, with minimal incremental toxicity. [ABSTRACT FROM AUTHOR]

ATLAS (ClinicalTrials.gov Identifier: NCT02659293) is a randomized phase III clinical trial comparing intensified carfilzomib, lenalidomide and dexamethasone (KRd) maintenance to standard-of-care, single-agent lenalidomide. The recently reported primary analysis showed a progression-free survival benefit for KRd. Whilst the study met its primary endpoint, closer analysis of its design and results is necessary before this intensified maintenance strategy can be adopted in clinical practice. [ABSTRACT FROM AUTHOR]

Combining cytotoxic agents with novel agents is an inferior treatment option for patients with relapsed/refractory myeloma. Not all combination therapies have the same efficacy, and the agents in the combinations do matter. See also pages 2050‐6. [ABSTRACT FROM AUTHOR]

Background: New treatment options are needed for patients with multiple myeloma that is refractory to proteasome inhibitors and immunomodulatory drugs. We assessed daratumumab, a novel CD38-targeted monoclonal antibody, in patients with refractory multiple myeloma.Methods: In this open-label, multicentre, phase 2 trial done in Canada, Spain, and the USA, patients (age ≥18 years) with multiple myeloma who were previously treated with at least three lines of therapy (including proteasome inhibitors and immunomodulatory drugs), or were refractory to both proteasome inhibitors and immunomodulatory drugs, were randomly allocated in a 1:1 ratio to receive intravenous daratumumab 8 mg/kg or 16 mg/kg in part 1 stage 1 of the study, to decide the dose for further assessment in part 2. Patients received 8 mg/kg every 4 weeks, or 16 mg/kg per week for 8 weeks (cycles 1 and 2), then every 2 weeks for 16 weeks (cycles 3-6), and then every 4 weeks thereafter (cycle 7 and higher). The allocation schedule was computer-generated and randomisation, with permuted blocks, was done centrally with an interactive web response system. In part 1 stage 2 and part 2, patients received 16 mg/kg dosed as in part 1 stage 1. The primary endpoint was overall response rate (partial response [PR] + very good PR + complete response [CR] + stringent CR). All patients who received at least one dose of daratumumab were included in the analysis. The trial is registered with ClinicalTrials.gov, number NCT01985126.Findings: The study is ongoing. In part 1 stage 1 of the study, 18 patients were randomly allocated to the 8 mg/kg group and 16 to the 16 mg/kg group. Findings are reported for the 106 patients who received daratumumab 16 mg/kg in parts 1 and 2. Patients received a median of five previous lines of therapy (range 2-14). 85 (80%) patients had previously received autologous stem cell transplantation, 101 (95%) were refractory to the most recent proteasome inhibitors and immunomodulatory drugs used, and 103 (97%) were refractory to the last line of therapy. Overall responses were noted in 31 patients (29.2%, 95% CI 20.8-38.9)-three (2.8%, 0.6-8.0) had a stringent CR, ten (9.4%, 4.6-16.7) had a very good PR, and 18 (17.0%, 10.4-25.5) had a PR. The median time to first response was 1.0 month (range 0.9-5.6). Median duration of response was 7.4 months (95% CI 5.5-not estimable) and progression-free survival was 3.7 months (95% CI 2.8-4.6). The 12-month overall survival was 64.8% (95% CI 51.2-75.5) and, at a subsequent cutoff, median overall survival was 17.5 months (95% CI 13.7-not estimable). Daratumumab was well tolerated; fatigue (42 [40%] patients) and anaemia (35 [33%]) of any grade were the most common adverse events. No drug-related adverse events led to treatment discontinuation.Interpretation: Daratumumab monotherapy showed encouraging efficacy in heavily pretreated and refractory patients with multiple myeloma, with a favourable safety profile in this population of patients.Funding: Janssen Research & Development. [ABSTRACT FROM AUTHOR]

Treatment of plasma cell disorders has dramatically improved during the past decade as a result of the availability of new biology-based drugs, such as proteasome inhibitors and immunomodulatory agents. With increased attention to disease biology, however, it has become clear that there are many different subsets of patients with myeloma with different biologic drivers as well as different patient-based characteristics that can influence treatment. Obtaining initial genetics or genomics information can provide some of the information needed to define therapy after initial induction, and careful performance status assessment can help to define patient-specific characteristics that are important when determining the intensity of therapy. Careful assessment of both can help to optimize therapy type and duration for all patients and to improve long-term outcomes. [ABSTRACT FROM AUTHOR]

The treatment of patients with myeloma has dramatically changed over the past decade due in part to the development of new agents and myeloma-specific targets. Despite these advancements, a group for whom the long-term benefit remains less clear are patients with genetically or clinically defined high-risk myeloma. In order to successfully treat these patients, it is important to first identify these patients, treat them with aggressive combination therapy, and employ the use of aggressive long-term maintenance therapy. Future directions include the use of new immunebased treatments (antibodies or cellular-based therapies) as well as target-driven approaches. Until these treatment approaches are better defined, this review will provide a potential treatment approach for standard- and high-risk myeloma that can be followed using agents and strategies that are currently available with the goal of improving progression-free and overall survival for these patients today. [ABSTRACT FROM AUTHOR]

The article discusses research about the effectiveness of elotuzumab therapy in the management of patients with relapsed or refractory multiple myeloma. Topics mentioned include the interim analysis of progression-free survival, the role of elotuzumab in activating natural killer cells and mediating antibody-dependent cell-mediate cytotoxicity, and safety assessment of the therapy.

Abstract: Granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) both mobilize CD34+ stem cells into the blood when administered before apheresis but have distinct effects on dendritic cell (DC) differentiation. We previously demonstrated that the combination of GM+G-CSF results in fewer plasmacytoid DCs (pDCs) when used to mobilize peripheral blood stem cells for autologous transplantation. To test the hypothesis that the content of pDCs in an allograft can be modulated with the cytokines used for mobilization, we randomized the human leukocyte antigen–matched sibling donors of 50 patients with hematological malignancies to a mobilization regimen of either GM+G-CSF (n = 25) or G-CSF alone (n = 25). Primary and secondary endpoints included the cellular constituents of the mobilized grafts, the kinetics of posttransplantation immune reconstitution, and clinical outcomes of the transplantation recipients. Grafts from donors receiving GM+G-CSF contained equivalent numbers of CD34+ cells with fewer pDCs and T cells, with a higher fraction of Th1-polarized donor T cells than G-CSF mobilized grafts. Immune recovery was enhanced among recipients of GM+G-CSF. Survival was not significantly different between transplantation recipients in the two arms. The use of GM+G-CSF modulates immune function and recovery after allogeneic transplantation and should be explored in larger studies powered to evaluate clinical outcomes. [Copyright &y& Elsevier]

Summary Despite recent advances in treatment that have significantly improved overall survival, multiple myeloma (MM) remains incurable. Although rituximab, the first monoclonal antibody (MAb) evaluated in MM treatment, provided only very limited benefit, research is ongoing into a number of other MAbs directed against a variety of MM-related target antigens. Given the inherent immune dysfunction associated with MM, newer strategies that may enhance immune function in conjunction with antibodies may also provide a more fruitful clinical approach. Potential MAb targets in MM include growth factors and their receptors, other signalling molecules, and antigens expressed exclusively or predominantly on MM cells. MAb therapy involves a range of mechanisms, including antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, interference with receptor-ligand interactions, and MAb conjugation to radioisotopes or toxins. The antigens currently targeted in MM therapy are discussed, along with the development status of the corresponding MAb therapeutics. Elotuzumab, an anti-CS1 MAb, has recently achieved clinically meaningful responses when combined with lenalidomide or bortezomib in patients with relapsed and relapsed/refractory MM. Other MAbs are also showing early promise. More ongoing clinical research is required to identify optimal combination regimens and biomarkers that may help predict response to specific MAb-based combinations. [ABSTRACT FROM AUTHOR]

Treatment strategies for multiple myeloma have changed substantially over the past 10 years following the introduction of bortezomib and the immunomodulatory drugs thalidomide and lenalidomide. In the front-line setting, combination regimens incorporating these novel agents are demonstrating substantial activity, which is translating into improved outcomes compared with previous standards of care. Response rates and depth of response that were previously only seen with high-dose therapy plus stem-cell transplantation (HDT–SCT) can now be achieved with new induction regimens utilizing these novel agents. This has raised the need for trials that will determine the clinical benefit of early SCT in patients that have already achieved a high quality of response. Here, we review the improvements in response and outcome that are seen with these novel-agent regimens, both as induction therapy prior to HDT–SCT and in non-transplant patients, and highlight the latest data from key studies of various novel combinations, including regimens featuring bortezomib plus thalidomide or lenalidomide. We also review data on response and outcomes in patients with poor prognostic characteristics that indicate that the adverse impact typically seen with these factors may be overcome using novel-agent therapy. [ABSTRACT FROM AUTHOR]

Haematological toxicities and thromboembolic (TE) events are common complications of myeloma therapy. TE risk may be elevated with combination regimens, notably thalidomide/lenalidomide plus high-dose dexamethasone; concomitant erythropoietin appears to further increase the risk with lenalidomide–dexamethasone. We characterised thrombocytopenia and neutropenia in the phase 3 APEX (Assessment of Proteasome Inhibition for Extending Remissions) study of bortezomib versus high-dose dexamethasone in relapsed myeloma, and calculated the incidences of deep-vein thrombosis (DVT)/pulmonary embolism (PE) with: bortezomib or dexamethasone ± erythropoietin in APEX; bortezomib ± dexamethasone ± erythropoietin in two phase 2 studies of relapsed/refractory myeloma. Bortezomib-associated thrombocytopenia and neutropenia were transient, predictable and manageable; mean platelet and neutrophil counts followed a cyclical pattern, and improved over the treatment course. Grade 3/4 thrombocytopenia incidence was higher with bortezomib versus dexamethasone (26%/4% vs. 5%/1%), but significant bleeding events were comparable (4% vs. 5%). DVT/PE incidence was low (≤3·1%) in all analyses; addition of dexamethasone/erythropoietin did not affect TE risk. In APEX, TE risk appeared lower with bortezomib versus dexamethasone. Bortezomib caused transient and cyclical thrombocytopenia and was not associated with elevated TE risk, alone or with dexamethasone ± erythropoietin. Preliminary data suggest bortezomib may reduce the thrombogenic potential of combination regimens via inhibition of platelet function or other mechanism-specific effects on coagulation. [ABSTRACT FROM AUTHOR]

Objective: Dendritic cells (DCs) are powerful mediators of immune responses. We have demonstrated that the content of plasmacytoid (type 2) dendritic cells (DC2) within allogeneic bone marrow grafts impacts survival and graft-vs-host disease following transplantation. In order to better understand the effect of DC subsets on regulation of immunity, we tested the effect of DC subsets on T cells in a model of indirect antigen presentation to mimic presentation of host-type alloantigen by donor-type DC. Materials and Methods: Volunteers underwent apheresis without cytokine priming, and DC1, DC2, naïve, and memory T cells were purified by immunomagnetic bead and fluorescein-activated cell sorting. Purified DC1 and DC2 cells were cultured with third-party irradiated blood mononuclear cells and either naïve or memory homologous T cells in mixed lymphocyte reactions. Results: Myeloid (type 1) dendritic cells (DC1) induced significant proliferation of homologous T cells and were more effective in priming naïve T-cell responses than memory T cells responding to alloantigen. DC2 cells induced minimal T-cell proliferation regardless of the T-cell subset used as the responding fraction. Secondary mixed lymphocyte reaction studies demonstrated that DC2 primed T cells remained hyporesponsive even when challenged with a third-party alloantigen. The immunostimulatory effect of DC1 required DC-to-T–cell contact, and induced interleukin-12 secretion, while DC2 cells induced interferon-γ secretion. Polymerase chain reaction analysis of DC2-primed T cells demonstrated a significant increase in Foxp3 expression, supporting induction of a regulatory T-cell population. Conclusion: DC1 and DC2 cells induced divergent T-cell responses using homologous cells. Better understanding of DC2-mediated T-cell suppression may yield strategies that overcome tumor-specific immune tolerance and regulate graft-vs-host disease. [Copyright &y& Elsevier]

BACKGROUND: Postchemotherapy mobilization results were reviewed in patients undergoing apheresis before planned autologous hematopoietic progenitor cell (HPC) transplantation to improve the timing of collection procedures. STUDY DESIGN AND METHODS: A total of 135 attempts to collect autologous HPC were studied in 132 unique patients with lymphoid malignancies (non-Hodgkin's lymphoma, multiple myeloma, and Hodgkin's disease). Chemotherapy mobilization regimens included cyclophosphamide (n = 59), ICE (n = 46), or other regimens (n = 30). Granulocyte–colony-stimulating factor (CSF) was administered once daily at a dose of 5 μg per kg starting 2 days after the last dose of chemotherapy; granulocyte-macrophage–CSF was added at a daily dose of 5 μg per kg 6 days later. Apheresis was initiated when the blood CD34+ content was more than 20 per μL. RESULTS: In an initial cohort of 37 patients, 27 percent required apheresis during the weekend. An optimized timing for chemotherapy mobilization was developed based on retrospective data; prospective implementation of the new algorithm reduced the incidence of weekend apheresis to 13 percent in the subsequent 98 consecutive patients (p < 0.05). A median of 9 × 106 (range, 0.4 × 106-96 × 106) CD34+ cells per kg was collected from the entire cohort of 135 patients after a mean of 1.8 days of apheresis. Apheresis was initiated following a median (±SD) of 10 ± 2.7 days of cytokines. CONCLUSION: In the majority of patients, the first day of apheresis occurred 11 to 13 days after the last dose of chemotherapy with a variety of different chemotherapy regimens. Administering the last dose of chemotherapy on Thursday or Friday versus Monday, Tuesday, or Wednesday was associated with a 77 percent lower incidence in the frequency of weekend apheresis collections (p < 0.001). [ABSTRACT FROM AUTHOR]

Management of relapsed lymphoma depends upon the variables of chemosensitive disease and successful stem cell mobilization. The microtubule specific agents, paclitaxel and vinorelbine, have efficacy in relapsed lymphoma and can enhance stem cell mobilization. We performed a phase I dose-escalation study of cytarabine combined with fixed doses of vinorelbine, paclitaxel, etoposide and cisplatin (VTEPA) for patients with relapsed/refractory lymphoma. The regimen consisted of paclitaxel 175 mg/m2 and vinorelbine 30 mg/m2 on day 1; cisplatin 20 mg/m2 and etoposide 100 mg/m2 over 4 h on days 2 – 5. Cytarabine 2 g m/m2 over 4 h, in successive cohorts on 1, 2, or 3 consecutive days: cohort A day 5; cohort B days 4 – 5; and cohort C days 3 – 5. Sixteen patients (Hodgkin's disease, n = 6; non-Hodgkin's lymphoma, n = 10) were enrolled. Fourteen of 16 patients (88%) had refractory and seven patients (44%) had primary refractory disease. Major toxicities included hematologic toxicity, mucositis and infectious complications. Infectious complications (10/16 patients) included neutropenic fever, sepsis and fungal pneumonia. Dose-limiting toxicity was achieved in cohort C, which received three doses of cytarabine. There were 33% partial responses, 27% stable disease and 40% progressive disease following a single cycle of VTEPA. Two of 16 patients suffered treatment-related mortality. Five patients went on to receive autologous (n = 4) or allogeneic transplant (n = 1), and five out of seven patients in this heavily pretreated group who received VTEPA for mobilization of an autologous graft were successfully collected. The recommended dose of cytarabine for further evaluation in a phase II study is 2 g m/m2 for 2 consecutive days in combination with VTEPA. Treatment of subjects with relapsed/refractory lymphoma using VTEPA as second- or third-line salvage therapy produced remissions in some patients and permitted collection of grafts and subsequent autologous transplantation, supporting a planned phase II trial. [ABSTRACT FROM AUTHOR]

Abstract: The ability of granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) administration to increase the content of blood leucocytes and hematopoietic progenitor cells (HPCs) is well established, yet the effect of these cytokines on immune function is less well described. Recent data indicate that plasmacytoid dendritic cells (DC2) may inhibit cellular immune response. We hypothesized that administration of the combination of G-CSF and GM-CSF after chemotherapy would reduce the type 2, or plasmacytoid, DC2 content of the autologous blood HPC grafts compared with treatment with G-CSF alone. To test this hypothesis, 35 patients with lymphoma and myeloma were randomized to receive either G-CSF or the combination of G-CSF plus GM-CSF after chemotherapy, and blood HPC grafts were collected by apheresis. Cytokine-related adverse events between the 2 groups were similar. More than 2 × 106 CD34+ cells per kilogram were collected by apheresis in 14 of 18 subjects treated with G-CSF and in 16 of 17 subjects treated with GM-CSF plus G-CSF (p = not significant). There were minor differences between the 2 groups with respect to the content of T cells and CD34+ cells in the apheresis products. However, grafts collected from recipients of the combination of GM-CSF plus G-CSF had significantly fewer DC2 cells and similar numbers of DC1 cells compared with recipients treated with G-CSF alone. A third cohort of patients received chemotherapy followed by the sequential administration of G-CSF and the addition of GM-CSF 6 days later. Grafts from these patients had a markedly reduced DC2 content compared with those from patients treated either with G-CSF alone or with the concomitant administration of both cytokines. These data, and recent data that cross-presentation of antigen by DC2 cells may induce antigen-specific tolerance among T cells, suggest that GM-CSF during mobilization of blood HPC grafts may be a clinically applicable strategy to enhance innate and acquired immunity after autologous and allogeneic HPC transplantation. [Copyright &y& Elsevier]

Although multiple myeloma remains a terminal illness, the past four decades have seen a dramatic change in the outlook for a newly diagnosed patient in terms of therapies available, supportive care and insight into the pathogenesis of this disease. Among the newer agents available for treatment, thalidomide has been resurrected and discovered to be a valuable therapy for myeloma. Thalidomide appears to work, at least in part, through its anti-angiogenic properties, but much remains to be learned about its mechanism of action as well as optimal administration regimens. With the development of increasingly more potent bisphosphonates it has become possible to diminish the painful skeletal complications of myeloma, one of the most devastating problems of this disease. The most recent generation of bisphosphonates, pamidronic acid and zoledronic acid, have provided a statistically significant decrease in the skeletal complications of myeloma when used in a prophylactic manner. These agents appear to work by inhibiting osteoclast function. Progressive improvement in cytogenetic techniques has now demonstrated that almost all patients with myeloma have chromosomal abnormalities, some of which appear to confer varying degrees of prognostic significance. In particular, the changes in chromosome 13 are associated with an unusually poor outcome. These findings are serving as a guide toward learning more about the pathogenesis of myeloma as well as in identifying potential targets for therapy. Stem cell transplantation has emerged as the standard treatment for the large majority of patients with myeloma following the demonstration of superior complete remission and survival, both disease-free and overall, in a French randomised trial. Unfortunately, virtually all patients will eventually relapse following autologous stem cell transplantation, prompting continuing efforts such as tandem transplants, CD34+ selection, as well as modifications in the conditioning regimen to improve outcomes. Allogeneic bone marrow transplants appear to offer a better chance for a possible cure of myeloma but have been associated with an unusually high mortality. However, this approach is being revived with the advent of the less toxic non-myeloablative transplant that has provided an 81% short-term survival in a trial combining this approach with an initial conventional autologous bone marrow transplant. Immunotherapy with dendritic cells appears now to be a feasible way to enhance innate or acquired immunity to help eliminate minimal residual disease following autologous bone marrow transplant. Unfortunately, a cure for myeloma remains elusive but the continuing advances in management may significantly prolong survival in affected patients. [ABSTRACT FROM AUTHOR]

Thirty healthy volunteers were randomly assigned to receive either a single subcutaneous injection of GM-CSF or placebo at the time of vaccination with tetanus and diptheria toxoid (Td), influenza and hepatitis A vaccines. Humoral response was measured by weekly serum samples assayed for antibodies to tetanus toxoid (TT), influenza and hepatitis A; while cellular response to TT was determined by measuring IL-2 expression in T-cells following in vitro exposure to TT antigen using a flow cytometric assay. It was hypothesized that (1) GM-CSF would augment immune response and (2) that the frequencies of TT responsive T-cells in the blood would predict humoral responses. The administration of subcutaneous GM-CSF as an adjuvant at the time of vaccination did not augment the antibody responses to influenza or hepatitis A in normal volunteers when compared to placebo. Subjects who received GM-CSF had statistically significant lower increases in anti-tetanus antibodies than placebo recipients. Immunization with TT resulted in an increase in the frequency of antigen responsive T-cells in the blood over time. The frequencies of TT responsive T-cells in baseline blood samples were correlated with baseline anti-tetanus antibody titers, but humoral and cellular responses were not correlated following vaccination. Recipients of GM-CSF did not develop significantly higher numbers of TT responsive T-cells after vaccination compared to recipients who received placebo. [Copyright &y& Elsevier]

Summary. Neutrophil, monocyte, natural killer- and B-cell number and function are rapidly restored after bone marrow transplant (BMT), whereas T-cell reconstitution is often quite delayed. Our hypothesis was that V beta T-cell receptor (TCR) repertoire diversity among recipients of allogeneic BMT is influenced by the expression of major and minor HLA antigens in the host. The study population comprised unmanipulated and CD34[sup +]-selected allogeneic bone marrow grafts, autologous peripheral blood stem cell transplants and recipients of volunteer unrelated donor (VUD) bone marrow transplants. Using flow cytometry, the relative frequencies of 18 V beta TCR families were determined and ranked for each time point studied. Comparisons and correlations were made between paired blood samples obtained within a single patient over time, and between donors and their recipients. The pattern of the V beta TCR repertoire from allogeneic recipients and their HLA-matched donors was very similar, with a correlation coefficient (CC) of 0.59. This similarity was not as marked in VUD pairs (CC = 0.32). By 3 months after transplant, the pattern of the V beta TCR repertoire in recipients of HLA-matched sibling transplants was more similar to the pattern seen in pretransplant recipients than to the donor pattern (CC = 0.40 vs. 0.31). Our data suggest that both major and minor HLA antigens influence V beta TCR repertoire diversity and reconstitution after BMT. [ABSTRACT FROM AUTHOR]

The author reflects on the study investigating the treatments for patients with myeloma. He tries to point that despite the reseachers' recommended therapies that were believed to treat the disease, the eligibility of patients for high-dose therapy and autologous transplatation remains a question. A clear and accurate study will provide a clear and accurate information that are more beneficial to patients, the author believes.

Lay Summary: Elderly patients with myeloma derive benefits from transplantation similar to those for younger patients. Age should not be the sole criterion for determining transplant eligibility. Performance status assessment and other tools for assessing comorbidities such as the Charlson comorbidity score may potentially help in determining transplant eligibility and will allow us to move away from our heavy reliance on numerical age. [ABSTRACT FROM AUTHOR]

High-dose chemotherapy and autologous stem cell transplantation (ASCT) are a standard of care for transplant-eligible patients with newly diagnosed multiple myeloma (MM). The introduction of novel agents, which range from immunomodulatory drugs and proteasome inhibitors to monoclonal antibodies and have now been integrated into both induction and salvage regimens, has dramatically revolutionized the treatment landscape of MM and challenged the role of high-dose chemotherapy and ASCT in treating MM. These advances have led to a number of provocative questions. First, what is the current role of stem cell transplantation (SCT) in comparison with standard-dose therapy incorporating novel agents? Second, should ASCT be performed upfront ("early") or later ("delayed") in the course of the disease? Third, should single or double ASCT be performed? Fourth, is allogeneic SCT still an option for patients with MM? This article provides an overview of available data and evidence-based responses regarding the role of SCT in MM. [ABSTRACT FROM AUTHOR]

The authors discuss a study which was conducted by P. Martinez-Sanchez and colleagues regarding the use of minimal residual disease (MRD) testing through sequencing for myeloma treatment. Topics include the MRD negativity by multiparameter flow cytometry (MFC) as a predictor of long-term outcome after autologous transplant, conventional complete response (CR) in patients with high-risk myeloma, and signs of residual disease.

The author discusses a study by A. Larocca on using combined cyclophosphamide, prednisone, and pomalidomide for the treatment of relapsed myeloma. He mentions the improvement of the overall response rate among the patients using the combined regimes. He says that the study reveal the benefits of combination therapy, thus showing the higher activity of the regimen than pomalidomide/dexamethasone. He also raises the question as to whom the therapy is suited for.

In this article the authors discuss the study of C. P. Venner and colleagues regarding the efficacy of new drugs in treating myeloma. They mention that the study was conducted among transplanted patients in a province in Canada in two treatment eras, before and after 2004 depending on the use of lenalidomide and bortezomib as treatment options. They say that the significance of treatments in the natural history of myeloma must be proven before declaring a new era of treatment for the disease.

The article focuses on the collaboration among academics, foundations, and medical industry in the U.S. in the search for new therapies or to better understand biologic systems. It discusses issues concerning bridging the gap between promising laboratory observations and the development of effective therapies as well as diseases including cystic fibrosis, multiple myeloma, and type 1 diabetes mellitus.

Background: Phase 1 clinical trials introduce new therapies to humans with the goal of establishing their safety. A prior Children's Oncology Group (COG) study analyzed the proportional enrollment of patients by race, ethnicity, sex, and age for all trial phases. The current study evaluated the representation of patients by race, ethnicity, sex, and age in phase 1 clinical trials.Methods: This study evaluated 1348 children with 128 diagnoses enrolled in COG and Pediatric Brain Tumor Consortium phase 1 clinical trials in the United States from February 28, 2000 to December 29, 2008. Observed and expected proportions were calculated according to an established methodology with a representative population from Surveillance, Epidemiology, and End Results data, which included 27,766 children with the same International Classification of Diseases for Oncology (third edition) diagnostic codes.Results: Underrepresentation in phase 1 trials was seen for lymphohematopoietic (LH) tumors (9.3% observed vs 37% expected) versus solid tumors (90.6% observed vs 63% expected). Although representation was fairly proportional, Hispanics (12.6% observed vs 27% expected), particularly Hispanic females (6% observed vs 18% expected), were significantly underrepresented. The 0- to 4-year age group was underrepresented (11.7% observed vs 36.5% expected). By tumor type, the most significantly underrepresented groups were 0- to 4-year-old children and Hispanics for both solid cancers (11% observed vs 34.4% expected for 0- to 4-year-old children and 12% observed vs 24% expected for Hispanics) and LH cancers (16% observed vs 40% expected for 0- to 4-year-old children and 19.4% observed vs 33% expected for Hispanics).Conclusions: Although sex and racial/ethnic groups are mostly proportionally represented in phase 1 trials, some specific subgroups such as Hispanic children are underrepresented and may benefit from focused accrual. Cancer 2016;122:3207-14. © 2016 American Cancer Society. [ABSTRACT FROM AUTHOR]

The article reports the connections between metabolic state and therapy resistance in multiple myeloma (MM). It shows that electron transport chain (ETC) suppression promotes resistance to proteasome inhibitors (PIs). It demonstrates that mitochondrial stress promotes PI resistance and explains the need for implementing combinatorial regimens in the mitochondrial metabolic state.

The International Myeloma Working Group consensus updates the definition for high-risk (HR) multiple myeloma based on cytogenetics Several cytogenetic abnormalities such as t(4;14), del(17/17p), t(14;16), t(14;20), nonhyperdiploidy, and gain(1q) were identified that confer poor prognosis. The prognosis of patients showing these abnormalities may vary with the choice of therapy. Treatment strategies have shown promise for HR cytogenetic diseases, such as proteasome inhibition in combination with lenalidomide/pomalidomide, double autologous stem cell transplant plus bortezomib, or combination of immunotherapy with lenalidomide or pomalidomide. Careful analysis of cytogenetic subgroups in trials comparing different treatments remains an important goal. Cross-trial comparisons may provide insight into the effect of new drugs in patients with cytogenetic abnormalities. However, to achieve this, consensus on definitions of analytical techniques, proportion of abnormal cells, and treatment regimens is needed. Based on data available today, bortezomib and carfilzomib treatment appear to improve complete response, progression-free survival, and overall survival in t(4;14) and del(17/17p), whereas lenalidomide may be associated with improved progression-free survival in t(4;14) and del(17/17p). Patients with multiple adverse cytogenetic abnormalities do not benefit from these agents. FISH data are implemented in the revised International Staging System for risk stratification. [ABSTRACT FROM AUTHOR]

Background: Melphalan is an alkylating agent used in both autologous (ASCT) and allogeneic stem cell transplantation. It is a substrate of L‐type amino acid transporter‐1 (LAT‐1) and LAT‐2, which are involved in its tissue penetration and elimination. Gabapentin and pregabalin, common concomitant medications in patients with multiple myeloma undergoing ASCT, are also substrates of LAT transporters, raising concern for potential competitive inhibition of melphalan transport. We evaluated whether concurrent use of gabapentin or pregabalin in patients receiving high‐dose melphalan (≥140 mg/m2) prior to ASCT impacted frequency and severity of melphalan‐related adverse events. Objective: We aimed to determine if concurrent administration of gabapentin or pregabalin and melphalan increased melphalan toxicity. Methods: This was a single‐center, retrospective evaluation including patients ≥18 years of age who received high‐dose melphalan as part of a conditioning regimen at the Winship Cancer Institute of Emory University between August 1, 2010 and April 1, 2020 and were followed through their transplant admission. After identification and inclusion of patients who received melphalan in combination with gabapentin or pregabalin, patient matching based on age (±5 years), sex, and melphalan dose (140 mg/m2 or 200 mg/m2) was utilized to generate a comparable cohort of patients who received melphalan alone. The primary outcome was hospital length of stay (LOS); secondary outcomes included supportive care requirements between days +4 and day +14 and time to neutrophil and platelet‐20 engraftment. Results: Among 176 patients evaluated in each group, median hospital LOS was 16 days, median time to neutrophil engraftment was 14 days, and median time to platelet‐20 engraftment was 16 days in both groups. In addition, there were no significant differences in supportive care requirements between groups. Conclusion: In this study, use of gabapentin or pregabalin in combination with melphalan did not impact safety of the conditioning regimen in patients undergoing ASCT. [ABSTRACT FROM AUTHOR]

Summary: Background: We aimed to assess efficacy and tolerability of vorinostat in combination with bortezomib for treatment of patients with relapsed or refractory multiple myeloma. Methods: In our randomised, double-blind, placebo-controlled, phase 3 trial, we enrolled adults (≥18 years) at 174 university hospitals in 31 countries worldwide. Eligible patients had to have non-refractory multiple myeloma that previously responded to treatment (one to three regimens) but were currently progressing, ECOG performance statuses of 2 or less, and no continuing toxic effects from previous treatment. We excluded patients with known resistance to bortezomib. We randomly allocated patients (1:1) using an interactive voice response system to receive 21 day cycles of bortezomib (1·3 mg/m2 intravenously on days 1, 4, 8, and 11) in combination with oral vorinostat (400 mg) or matching placebo once-daily on days 1–14. We stratified patients by baseline tumour stage (International Staging System stage 1 or stage ≥2), previous bone-marrow transplantation (yes or no), and number of previous regimens (1 or ≥2). The primary endpoint was progression-free survival (PFS) in the intention-to-treat population. We assessed adverse events in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number 00773747. Findings: Between Dec 24, 2008, and Sept 8, 2011, we randomly allocated 317 eligible patients to the vorinostat group (315 of whom received at least one dose) and 320 to the placebo group (all of whom received at least one dose). Median PFS was 7·63 months (95% CI 6·87–8·40) in the vorinostat group and 6·83 months (5·67–7·73) in the placebo group (hazard ratio [HR] 0·77, 95% CI 0·64–0·94; p=0·0100). 312 (99%) of 315 patients in the vorinostat group and 315 (98%) of 320 patients in the placebo group had adverse events (300 [95%] adverse events in the vorinostat group and 282 [88%] in the control group were regarded as related to treatment). The most common grade 3–4 adverse events were thrombocytopenia (143 [45%] patients in the vorinostat group vs 77 [24%] patients in the placebo group), neutropenia (89 [28%] vs 80 [25%]), and anaemia (53 [17%] vs 40 [13%]). Interpretation: Although the combination of vorinostat and bortezomib prolonged PFS relative to bortezomib and placebo, the clinical relevance of the difference in PFS between the two groups is not clear. Different treatment schedules of bortezomib and vorinostat might improve tolerability and enhance activity. Funding: Merck. [ABSTRACT FROM AUTHOR]

This open-label, dose escalation, multicentre phase 1/2 trial was undertaken to determine the safety and tolerability of the heat shock protein 90 (HSP90) inhibitor tanespimycin (100-340 mg/m) + bortezomib (0·7-1·3 mg/m) given on days 1, 4, 8 and 11 in each 21-d cycle. Phase 2 expansion occurred at the highest tested dose of tanespimycin at 340 mg/m and bortezomib at 1·3 mg/m. Seventy-two patients (median age, 60 years) with relapsed or relapsed and refractory multiple myeloma (MM) were enrolled; 63 patients (89%) completed the study. Tanespimycin in combination with bortezomib was well tolerated; few patients experienced significant neutropenia, constipation and anorexia (<10%), and no patients developed severe peripheral neuropathy. Among 67 efficacy-evaluable patients, there were 2 (3%) complete responses and 8 (12%) partial responses, for an objective response rate (ORR) of 27%, including 8 (12%) minimal responses. Response rates were highest among bortezomib-naive patients and proved durable in all patient subgroups, including those with bortezomib-refractory disease. Pharmacodynamic analyses indicated that tanespimycin plus bortezomib effectively inhibited the proteasome, as evidenced by decreased 20S proteasome activity, and inhibited HSP90, as reflected by increased HSP70 expression. The results of this study support additional studies of this combination approach in MM. [ABSTRACT FROM AUTHOR]

Purpose: Characterize bortezomib pharmacokinetics/pharmacodynamics in relapsed myeloma patients after single and repeat intravenous administration at two doses. Methods: Forty-two patients were randomized to receive bortezomib 1.0 or 1.3 mg/m, days 1, 4, 8, 11, for up to eight 21-day treatment cycles ( n = 21, each dose group). Serial blood samples for pharmacokinetic/pharmacodynamic analysis were taken on days 1 and 11, cycles 1 and 3. Observational efficacy and safety data were collected. Results: Twelve patients in each dose group were evaluable for pharmacokinetics/pharmacodynamics. Plasma clearance decreased with repeat dosing (102-112 L/h for first dose; 15-32 L/h following repeat dosing), with associated increases in systemic exposure and terminal half-life. Systemic exposures of bortezomib were similar between dose groups considering the relatively narrow dose range and the observed pharmacokinetic variability, although there was no readily apparent deviation from dose-proportionality. Blood 20S proteasome inhibition profiles were similar between groups with mean maximum inhibition ranging from 70 to 84% and decreasing toward baseline over the dosing interval. Response rate (all 42 patients) was 50%, including 7% complete responses. The safety profile was consistent with the predictable and manageable profile previously established; data suggested milder toxicity in the 1.0 mg/m group. Conclusions: Bortezomib pharmacokinetics change with repeat dose administration, characterized by a reduction in plasma clearance and associated increase in systemic exposure. Bortezomib is pharmacodynamically active and tolerable at 1.0 and 1.3 mg/m doses, with recovery toward baseline blood proteasome activity over the dosing interval following repeat dose administration, supporting the current clinical dosing regimen. [ABSTRACT FROM AUTHOR]

Abstract: Multiple myeloma (MM) is an incurable disease characterized by the accumulation of malignant plasma cells in the bone marrow. Recently, an improved understanding of the biology of the disease has led to the development of targeted agents such as the proteasome inhibitor bortezomib and the immunomodulatory agents thalidomide and lenalidomide; however, MM remains incurable. The combination of bortezomib and an HDAC inhibitor synergistically induces MM cell apoptosis and may be of value in the treatment of patients with relapsed/refractory MM. This review examines the potential of combined proteasome and HDAC inhibition in the treatment of relapsed/refractory MM. [ABSTRACT FROM AUTHOR]

Polyclonal anti-thymocyte globulin (ATG) administered before allogeneic blood hematopoietic progenitor cell transplantation reduces the risks of graft rejection and graft-versus-host disease, but may delay posttransplant immune reconstitution caused by delayed clearance of ATG from the blood. We studied graft-versus-host disease, infections, and the kinetics of immune reconstitution in 28 patients with very poor-risk hematologic malignancies who received lymphocyte-depleted, CD34+ cell-enriched hematopoietic progenitor cell grafts from partially HLA-matched related donors (PMRD). The incidence of these clinical events was correlated with blood ATG levels in 19 transplant recipients who received rabbit ATG (r-ATG, thymoglobulin) during conditioning. Total r-ATG and the fraction of ATG antibodies that bind human cells (active ATG) were measured for up to 45 days posttransplantation using enzyme-linked immunosorbent assay and flow cytometry assays. Three patients received equine ATG (e-ATG; total dose of 60 mg/kg/day), 3 patients received 10 mg/kg r-ATG, and 22 patients received 6 mg/kg r-ATG during conditioning. All evaluable patients engrafted. Median numbers of blood CD4+ and CD8+ T cells at 100 days posttransplantation were 15 and 8 cells/μL, respectively. Acute graft-versus-host disease developed in 3 of 3 recipients of e-ATG and 1 of 25 recipients of r-ATG. Rapid T-cell reconstitution was seen only in younger patients. Overall mortality was 93% (26/28 patients) with poor immune reconstitution contributing to death in 21 of 28 patients. Recipients of 6 mg/kg r-ATG had peak levels of total and active r-ATG of 64±20 μg/mL and 9.2±5.8 μg/mL, respectively, with clearance of active r-ATG (t1/26 days) to sub-therapeutic levels (<1 μg/mL) by a median of 15 days posttransplantation (range, 8-38 days). Delayed immune reconstitution is likely a consequence of ex vivo and in vivo purging of donor T cells in the graft coupled with inadequate thymic function rather than persistence of active r-ATG in the blood for months posttransplantation. [Copyright &y& Elsevier]

This Policy Review presents the International Myeloma Working Group's clinical practice recommendations for the treatment of relapsed and refractory multiple myeloma. Based on the results of phase 2 and phase 3 trials, these recommendations are proposed for the treatment of patients with relapsed and refractory disease who have received one previous line of therapy, and for patients with relapsed and refractory multiple myeloma who have received two or more previous lines of therapy. These recommendations integrate the issue of drug access in both low-income and middle-income countries and in high-income countries to help guide real-world practice and thus improve patient outcomes. [ABSTRACT FROM AUTHOR]

BACKGROUND Idecabtagene vicleucel (ide-cel, also called bb2121), a B-cell maturation antigen directed chimeric antigen receptor (CAR) T-cell therapy, has shown clinical activity with expected CAR T-cell toxic effects in patients with relapsed and refractory multiple myeloma. METHODS In this phase 2 study, we sought to confirm the efficacy and safety of ide-cel in patients with relapsed and refractory myeloma. Patients with disease after at least three previous regimens including a proteasome inhibitor, an immunomodulating agent, and an anti-CD38 antibody were enrolled. Patients received ide-cel target doses of 150 x 106 to 450 x 106 CAR-positive (CAR+) T cells. The primary end point was an overall response (partial response or better); a key secondary end point was a complete response or better (comprising complete and stringent complete responses). RESULTS Of 140 patients enrolled, 128 received ide-cel. At a median follow-up of 13.3 months, 94 of 128 patients (7396) had a response, and 42 of 128 (33%) had a complete response or better. Minimal residual disease (MRD)-negative status (<10-5 nucleated cells) was confirmed in 33 patients, representing 26% of all 128 patients who were treated and 79% of the 42 patients who had a complete response or better. The median progression-free survival was 8.8 months (95% confidence interval, 5.6 to 11.6). Common toxic effects among the 128 treated patients included neutropenia in 117 patients (91%), anemia in 89 (70%), and thrombocytopenia in 81 (63%). Cytokine release syndrome was reported in 107 patients (84%), including 7 (5%) who had events of grade 3 or higher. Neurotoxic effects developed in 23 patients (18%) and were of grade 3 in 4 patients (3%); no neurotoxic effects higher than grade 3 occurred. Cellular kinetic analysis confirmed CAR+ T cells in 29 of49 patients (59%) at 6 months and 4 of 11 patients (36%) at 12 months after infusion. CONCLUSIONS Ide-cel induced responses in a majority of heavily pretreated patients with refractory and relapsed myeloma; MRD-negative status was achieved in 26% of treated patients. Almost all patients had grade 3 or 4 toxic effects, most commonly hematologic toxic effects and cytokine release syndrome. (Funded by bluebird bio and Celgene, a Bristol-Myers Squibb company; KarMMa ClinicalTrials.gov number, NCT03361748.) [ABSTRACT FROM AUTHOR]

Introduction: Patients with relapsed or refractory multiple myeloma (RRMM) represent an unmet clinical need. Belantamab mafodotin (belamaf; GSK2857916) is a first-in-class antibody–drug conjugate (ADC; or immunoconjugate) that delivers a cytotoxic payload, monomethyl auristatin F (MMAF), to myeloma cells. In the phase II DREAMM-2 study (NCT03525678), single-agent belamaf (2.5 mg/kg) demonstrated clinically meaningful anti-myeloma activity (overall response rate 32%) in patients with heavily pretreated disease. Microcyst-like epithelial changes (MECs) were common, consistent with reports from other MMAF-containing ADCs. Methods: Corneal examination findings from patients in DREAMM-2 were reviewed, and the clinical descriptions and accompanying images (slit lamp microscopy and in vivo confocal microscopy [IVCM]) of representative events were selected. A literature review on corneal events reported with other ADCs was performed. Results: In most patients receiving single-agent belamaf (72%; 68/95), MECs were observed by slit lamp microscopy early in treatment (69% had their first event by dose 4). However, IVCM revealed hyperreflective material. Blurred vision (25%) and dry eye (15%) were commonly reported symptoms. Management of MECs included dose delays (47%)/reductions (25%), with few patients discontinuing due to MECs (1%). The first event resolved in most patients (grade ≥2 MECs and visual acuity [each 77%], blurred vision [67%], and dry eye [86%]), with no reports of permanent vision loss to date. A literature review confirmed that similar MECs were reported with other ADCs; however, event management strategies varied. The pathophysiology of MECs is unclear, though the ADC cytotoxic payload may contribute to on- or off-target effects on corneal epithelial cells. Conclusion: Single-agent belamaf represents a new treatment option for patients with RRMM. As with other ADCs, MECs were observed and additional research is warranted to determine their pathophysiology. A multidisciplinary approach, involving close collaboration between eye care professionals and hematologist/oncologists, is needed to determine appropriate diagnosis and management of these patients. Trial Registration: ClinicalTrials.gov Identifier, NCT03525678. [ABSTRACT FROM AUTHOR]

Background: Purpose: The combination of a mammalian target of rapamycin inhibitor and lenalidomide showed enhanced preclinical cytotoxicity. We conducted a phase 1 study in advanced solid tumour patients to assess safety, efficacy and pharmacodynamic (PD) outcomes.Methods: We employed a 3+3 dose escalation design to establish the safety and recommended phase 2 doses (RP2D) of daily everolimus and lenalidomide in patients with advanced solid tumours. The starting doses were 5 and 10 mg, respectively, with planned escalation to maximum single-agent doses of 10 and 25 mg in the absence of dose-limiting toxicity. PD endpoints of lymphocyte subsets and immune cytokines were assessed in peripheral blood using multiparameter flow cytometry and LUMINEX assay. Efficacy was evaluated by cross-sectional imaging after every two cycles of treatment.Results: The study enrolled 44 patients, median age of 58 years and 28 males (63.6%). The RP2D was established as 10 and 25 mg daily continuously for everolimus and lenalidomide. Common (>5%) grade ≥3 adverse events included rash (19%), neutropenia (19%), hypokalaemia (11%) and fatigue (9%). Best efficacy outcomes in 36 evaluable patients were partial response in 5 (13.8%), stable disease in 24 (55.8%) and progressive disease in 7 (19.4%) patients. PD assessment revealed significant association of cytokine levels (interleukin-2 (IL2), IL21 and IL17), baseline activated and total CD8+ lymphocytes and change in B cell lymphocytes and activated NK cells with clinical benefit.Conclusions: The study demonstrated the safety of everolimus and lenalidomide with promising efficacy signal in thyroid and adenoid cystic cancers.Clinical Trial Registration: NCT01218555. [ABSTRACT FROM AUTHOR]

Background: Bortezomib, lenalidomide, and dexamethasone (VRd) is a standard therapy for newly diagnosed multiple myeloma. Carfilzomib, a next-generation proteasome inhibitor, in combination with lenalidomide and dexamethasone (KRd), has shown promising efficacy in phase 2 trials and might improve outcomes compared with VRd. We aimed to assess whether the KRd regimen is superior to the VRd regimen in the treatment of newly diagnosed multiple myeloma in patients who were not being considered for immediate autologous stem-cell transplantation (ASCT).Methods: In this multicentre, open-label, phase 3, randomised controlled trial (the ENDURANCE trial; E1A11), we recruited patients aged 18 years or older with newly diagnosed multiple myeloma who were ineligible for, or did not intend to have, immediate ASCT. Participants were recruited from 272 community oncology practices or academic medical centres in the USA. Key inclusion criteria were the absence of high-risk multiple myeloma and an Eastern Cooperative Oncology Group performance status of 0-2. Enrolled patients were randomly assigned (1:1) centrally by use of permuted blocks to receive induction therapy with either the VRd regimen or the KRd regimen for 36 weeks. Patients who completed induction therapy were then randomly assigned (1:1) a second time to either indefinite maintenance or 2 years of maintenance with lenalidomide. Randomisation was stratified by intent for ASCT at disease progression for the first randomisation and by the induction therapy received for the second randomisation. Allocation was not masked to investigators or patients. For 12 cycles of 3 weeks, patients in the VRd group received 1·3 mg/m2 of bortezomib subcutaneously or intravenously on days 1, 4, 8, and 11 of cycles 1-8, and day 1 and day 8 of cycles nine to twelve, 25 mg of oral lenalidomide on days 1-14, and 20 mg of oral dexamethasone on days 1, 2, 4, 5, 8, 9, 11, and 12. For nine cycles of 4 weeks, patients in the KRd group received 36 mg/m2 of intravenous carfilzomib on days 1, 2, 8, 9, 15, and 16, 25 mg of oral lenalidomide on days 1-21, and 40 mg of oral dexamethasone on days 1, 8, 15, and 22. The coprimary endpoints were progression-free survival in the induction phase, and overall survival in the maintenance phase. The primary analysis was done in the intention-to-treat population and safety was assessed in patients who received at least one dose of their assigned treatment. The trial is registered with ClinicalTrials.gov, NCT01863550. Study recruitment is complete, and follow-up of the maintenance phase is ongoing.Findings: Between Dec 6, 2013, and Feb 6, 2019, 1087 patients were enrolled and randomly assigned to either the VRd regimen (n=542) or the KRd regimen (n=545). At a median follow-up of 9 months (IQR 5-23), at a second planned interim analysis, the median progression-free survival was 34·6 months (95% CI 28·8-37·8) in the KRd group and 34·4 months (30·1-not estimable) in the VRd group (hazard ratio [HR] 1·04, 95% CI 0·83-1·31; p=0·74). Median overall survival has not been reached in either group. The most common grade 3-4 treatment-related non-haematological adverse events included fatigue (34 [6%] of 527 patients in the VRd group vs 29 [6%] of 526 in the KRd group), hyperglycaemia (23 [4%] vs 34 [6%]), diarrhoea (23 [5%] vs 16 [3%]), peripheral neuropathy (44 [8%] vs four [<1%]), dyspnoea (nine [2%] vs 38 [7%]), and thromboembolic events (11 [2%] vs 26 [5%]). Treatment-related deaths occurred in two patients (<1%) in the VRd group (one cardiotoxicity and one secondary cancer) and 11 (2%) in the KRd group (four cardiotoxicity, two acute kidney failure, one liver toxicity, two respiratory failure, one thromboembolic event, and one sudden death).Interpretation: The KRd regimen did not improve progression-free survival compared with the VRd regimen in patients with newly diagnosed multiple myeloma, and had more toxicity. The VRd triplet regimen remains the standard of care for induction therapy for patients with standard-risk and intermediate-risk newly diagnosed multiple myeloma, and is a suitable treatment backbone for the development of combinations of four drugs.Funding: US National Institutes of Health, National Cancer Institute, and Amgen. [ABSTRACT FROM AUTHOR]

Microtubule-associated serine/threonine kinase 1 (MAST1) is a central driver of cisplatin resistance in human cancers. However, the molecular mechanism regulating MAST1 levels in cisplatin-resistant tumors is unknown. Through a proteomics screen, we identified the heat shock protein 90 B (hsp90B) chaperone as a direct MAST1 binding partner essential for its stabilization. Targeting hsp90B sensitized cancer cells to cisplatin predominantly through MAST1 destabilization. Mechanistically, interaction of hsp90B with MAST1 blocked ubiquitination of MAST1 at lysines 317 and 545 by the E3 ubiquitin ligase CHIP and prevented proteasomal degradation. The hsp90B-MAST1-CHIP signaling axis and its relationship with cisplatin response were clinically validated in cancer patients. Furthermore, combined treatment with a hsp90 inhibitor and the MAST1 inhibitor lestaurtinib further abrogated MAST1 activity and consequently enhanced cisplatin-induced tumor growth arrest in a patient-derived xenograft model. Our study not only uncovers the regulatory mechanism of MAST1 in tumors but also suggests a promising combinatorial therapy to overcome cisplatin resistance in human cancers. [ABSTRACT FROM AUTHOR]

Background: The efficacy of daratumumab (DARA) both as a monotherapy and in combination with standard‐of‐care regimens in multiple myeloma (MM) has been established in clinical trials. This article presents a retrospective analysis of the safety and efficacy of DARA in combination with pomalidomide (POM) and dexamethasone (ie, daratumumab, pomalidomide, and dexamethasone [DARA‐POM‐D]) and, more importantly, the long‐term follow‐up of a cohort that was naive to DARA and POM as well as a cohort in which the utility of re‐treatment was evaluated among patients who were DARA‐ and/or POM‐refractory. Methods: Thirty‐four consecutive patients with relapsed and/or refractory MM treated with DARA‐POM‐D at the Winship Cancer Institute of Emory University from January 2015 through July 2016 were included in the analysis. The study was approved by Emory University's institutional review board. All received prior proteasome inhibitors and immunomodulatory drugs (IMiDs) and were refractory to their last line of therapy. Results: All patients were lenalidomide‐refractory, and 91% were bortezomib‐refractory. Two cohorts were identified on the basis of prior exposure to DARA and/or POM. Cohort 1 (12 patients) was DARA‐ and POM‐naive, and cohort 2 (22 patients) was DARA‐ and/or POM‐refractory. A subgroup of 12 patients in cohort 2 (cohort 3) was DARA‐ and POM‐refractory. The combination's tolerability was consistent with the results of the published phase 1b study (EQUULES) that evaluated the combination and no new safety signals were observed. The overall response rates (ORRs) were 91.7%, 40.9%, and 33.3% in cohorts 1, 2, and 3, respectively. Deep responses, including 4 stringent complete responses, were observed in cohort 1. In cohort 2, the ORR comprised 8 partial responses (PRs) and 1 very good PR. The median progression‐free survival (PFS) was not reached in cohort 1 at a median follow‐up of 41 months, and it was 3.2 months in cohort 2. DARA‐POM‐D not only was effective in DARA‐ and POM‐naive patients but also produced clinical responses in a third of patients re‐treated with these drugs. Conclusions: A better than quadrupled PFS benefit observed in cohort 1 in comparison with the previously reported benefit in the EQUULEUS trial (which led to US Food and Drug Administration approval of the DARA‐POM‐D combination) highlights the fact that the introduction of monoclonal antibody combination strategies and IMiDs as earlier lines of therapeutic options potentially could deliver better clinical outcomes. One‐third of patients refractory to separate lines of DARA and/or POM responded when they were re‐treated with a combination, and this resulted in survival benefits equivalent to those of other antimyeloma agents/combinations available for DARA‐refractory patients. There are deep responses and no additional safety signals with daratumumab, pomalidomide, and dexamethasone in naive patients refractory to their last treatment. One third of patients who are refractory to separate lines of daratumumab and/or pomalidomide respond when they are re‐treated with a combination. [ABSTRACT FROM AUTHOR]

The development of effective monoclonal antibodies for the treatment of myeloma has been a long journey of clinical and drug development. Identification of the right target antigen was a critical part of the process. CD38 as a target has been considered for some time, but clinically, daratumumab, a CD38 monoclonal antibody, was the first to be tested, and it has delivered the best clinical responses as a single agent to date. Its proven safety and efficacy in combination with other antimyeloma agents have led to several US Food and Drug Administration approvals for treating myeloma. Furthermore, the results of early trials in the induction therapy setting have demonstrated a beneficial role when it is added to the existing induction regimens. This review summarizes the importance of CD38 as a target and examines the clinical development of the CD38 monoclonal antibody daratumumab and its clinical significance in combination regimens in both patients with relapsed/refractory myeloma and patients with newly diagnosed myeloma. [ABSTRACT FROM AUTHOR]