Matthew Streetly

Phase I Study of an Immunomodulatory Thalidomide Analog, CC-4047, in Relapsed or Refractory Multiple Myeloma

PURPOSE To assess the safety, efficacy, and immunomodulatory effects of CC-4047 (Actimid; Celgene, San Diego, CA) in patients with relapsed or refractory myeloma. PATIENTS AND METHODS Twenty-four relapsed or refractory patients were treated with a dose-escalating regimen of oral CC-4047. Clinical responses and adverse effects were identified, and peripheral T-cell subsets, serum cytokines, and proangiogenic factors were evaluated. RESULTS CC-4047 was tolerated with no serious nonhematologic adverse events. All patients were eligible for analysis. Toxicity criteria during the initial 4 weeks of study were used to define the maximum-tolerated dose (MTD). During this period, one patient withdrew with a deep vein thrombosis (DVT) probably caused by an undiagnosed primary melanoma with lymphadenopathy in the groin, one patient withdrew because of progressive disease (PD), and three patients discontinued with neutropenia. Nineteen of 24 patients continued on treatment beyond 4 weeks to PD or development of a serious adverse event. Three further patients developed a DVT at 4, 9, and 11 months. Treatment resulted in a greater than 25% reduction in paraprotein in 67% of patients, 13 patients (54%) experienced a greater than 50% reduction in paraprotein, and four (17%) of 24 patients entered complete remission. The MTD was 2 mg/d. All patients showed increased CD45RO expression on CD4(+) and CD8(+) cells, with a concomitant decrease in CD45RA(+) cells. CC-4047 treatment was associated with significantly increased serum interleukin (IL)-2 receptor and IL-12 levels, which is consistent with activation of T cells and monocytes and macrophages. CONCLUSION This study demonstrates the safety and efficacy of CC-4047. The MTD of CC-4047 orally was 2 mg/d. This is the first report demonstrating in vivo T-cell costimulation by this class of compound, supporting a potential role for CC-4047 as an immunostimulatory adjuvant treatment.

Peripheral Blood Hematopoietic Stem Cells for Transplantation of Hematological Diseases from Related, Haploidentical Donors after Reduced-Intensity Conditioning

In a multicenter collaboration, we carried out T cell-replete, peripheral blood stem cell (PBSC) transplantations from related, HLA-haploidentical donors with reduced-intensity conditioning (RIC) and post-transplantation cyclophosphamide (Cy) as graft-versus-host disease (GVHD) prophylaxis in 55 patients with high-risk hematologic disorders. Patients received 2 doses of Cy 50 mg/kg i.v. on days 3 and 4 after infusion of PBSC (mean, 6.4 × 10(6)/kg CD34(+) cells; mean, 2.0 × 10(8)/kg CD3(+) cells). The median times to neutrophil (500/μL) and platelet (>20,000/μL) recovery were 17 and 21 days respectively. All but 2 of the patients achieved full engraftment. The 1-year cumulative incidences of grade II and grade III acute GVHD were 53% and 8%, respectively. There were no cases of grade IV GVHD. The 2-year cumulative incidence of chronic GHVD was 18%. With a median follow-up of 509 days, overall survival and event-free survival at 2 years were 48% and 51%, respectively. The 2-year cumulative incidences of nonrelapse mortality and relapse were 23% and 28%, respectively. Our results suggest that PBSC can be substituted safely and effectively for bone marrow as the graft source for haploidentical transplantation after RIC.

GCS-100, a novel galectin-3 antagonist, modulates MCL-1, NOXA, and cell cycle to induce myeloma cell death

GCS-100 is a galectin-3 antagonist with an acceptable human safety profile that has been demonstrated to have an antimyeloma effect in the context of bortezomib resistance. In the present study, the mechanisms of action of GCS-100 are elucidated in myeloma cell lines and primary tumor cells. GCS-100 induced inhibition of proliferation, accumulation of cells in sub-G(1) and G(1) phases, and apoptosis with activation of both caspase-8 and -9 pathways. Dose- and time-dependent decreases in MCL-1 and BCL-X(L) levels also occurred, accompanied by a rapid induction of NOXA protein, whereas BCL-2, BAX, BAK, BIM, BAD, BID, and PUMA remained unchanged. The cell-cycle inhibitor p21(Cip1) was up-regulated by GCS-100, whereas the procycling proteins CYCLIN E2, CYCLIN D2, and CDK6 were all reduced. Reduction in signal transduction was associated with lower levels of activated IkappaBalpha, IkappaB kinase, and AKT as well as lack of IkappaBalpha and AKT activation after appropriate cytokine stimulation (insulin-like growth factor-1, tumor necrosis factor-alpha). Primary myeloma cells showed a direct reduction in proliferation and viability. These data demonstrate that the novel therapeutic molecule, GCS-100, is a potent modifier of myeloma cell biology targeting apoptosis, cell cycle, and intracellular signaling and has potential for myeloma therapy.

Markers of endothelial and haemostatic function in the treatment of relapsed myeloma with the immunomodulatory agent ActimidTM (CC-4047) and their relationship with venous thrombosis

Abstract:  We evaluated the serum/plasma levels of cytokines [interleukin (IL)‐6, vascular endothelial growth factor (VEGF), transforming growth factor (TGF)‐β2] and markers of coagulation, fibrinolysis, endothelial and platelet activation during the first 4 wk of treatment with the thalidomide analogue ActimidTM (CC‐4047) in 15 patients with relapsed/refractory myeloma. There was evidence of activation of endothelium (soluble vascular cell adhesion molecule, sVCAM), coagulation (prothrombin fragment 1 + 2, PF1 + 2) and fibrinolysis (D‐dimers) but no evidence of platelet activation or endothelial cell damage in myeloma patients. These parameters were not affected by the use of CC‐4047. Three of four patients with baseline D‐dimers levels >500 μg/L subsequently developed deep vein thrombosis (DVT). The hypothesis that D‐dimer level >500 μg/L may predict for those patients most at risk of thromboembolism with multiple myeloma undergoing treatment is worthy of further study.

A parainfluenza-3 outbreak in a SCT unit: sepsis with multi-organ failure and multiple co-pathogens are associated with increased mortality

The estimated frequency of parainfluenza virus 3 (PIV-3) infections following haematopoietic SCT (HSCT) is 2–7%, whereas reported mortality ranges from 18 to 33%. We report a retrospective outcome analysis following an outbreak of PIV-3 infection in our transplant unit. A total of 16 HSCT patients developed PIV-3 infection. All patients had upper respiratory tract infection, whereas lower respiratory tract infection occurred in 8 patients. Overall, 13 patients were treated with aerosolised Ribavirin (2 g t.d.s. for 5 days) and i.v. Ig (0.5 g/kg) as per standard protocol. One patient refused treatment, whereas two patients with full immune reconstitution were not treated. Overall mortality was 62.5%. Sepsis with multi-organ failure and the presence of pulmonary co-pathogens were both significantly associated with PIV-3-related mortality. Our series confirms that high mortality is associated with PIV-3 infection in HSCT recipients. In patients who develop PIV-3 infection, despite strict enforcement of infection control policies, the best strategy might be careful risk assessment, with effective broad-spectrum anti-microbials in those who are at risk of secondary infection.

Guidelines for the use of imaging in the management of patients with myeloma

The role of imaging in myeloma has gained increasing importance over the past few years. The recently revised definition of myeloma from the International Myeloma Working Group (IMWG) includes cross sectional imaging as a method to define bone disease and also incorporates its use in the disease definition for patients with suspected smouldering myeloma. The National Institute for Health and Care Excellence myeloma guidelines also recommend cross sectional imaging for patients with suspected myeloma. There is also increasing use of imaging in disease assessments and the International Myeloma Working Group has recently incorporated imaging in defining new response categories of minimal residual disease negativity, with or without imaging‐based evidence of disease. Plain X‐rays have previously been the standard imaging modality included in a myeloma work up at presentation but evidence is mounting for use of cross‐sectional modalities such as computed tomography (CT), magnetic resonance imaging (MRI) and 18fluoro‐deoxyglucose (18F‐FDG) positron emission tomography (PET)/CT. Funding and therefore availability of newer imaging techniques remains a barrier. Here, we propose an evidence‐based approach to the use and technical application of the latest imaging modalities at diagnosis and in the follow‐up of patients with myeloma and plasmacytoma.

Bortezomib, thalidomide, dexamethasone, and panobinostat for patients with relapsed multiple myeloma (MUK-six): a multicentre, open-label, phase 1/2 trial

BACKGROUND Panobinostat (a pan histone deacetylase inhibitor) is approved in combination with bortezomib and dexamethasone for patients with relapsed multiple myeloma who have received two or more previous lines of therapy. We aimed to improve the safety of this combination and investigate efficacy by incorporating low-dose thalidomide, using sub-cutaneous weekly bortezomib, and determining the maximum tolerated dose of panobinostat in this regimen. METHODS We did a phase 1/2, multicentre, open-label trial (MUK six) at four hospitals in the UK, enrolling patients with relapsed, or relapsed and refractory, multiple myeloma aged at least 18 years, with an Eastern Cooperative Oncology Group performance status of 2 or less who had previously received 1-4 lines of therapy. Exclusion criteria included any antimyeloma treatment within 28 days of study drugs (except dexamethasone 160 mg >48 h before treatment). We used a rolling six escalation design to determine the maximum tolerated dose of panobinostat, and allocated patients to receive subcutaneous bortezomib 1·3 mg/m2, and oral thalidomide 100 mg, dexamethasone 20 mg, and panobinostat 10, 15, or 20 mg (escalated to 20 mg according to the escalation schedule). Treatment was given during a 21-day cycle (bortezomib on days 1 and 8; thalidomide every day; dexamethasone on days 1, 2, 8, and 9; and panobinostat on days 1, 3, 5, 8, 10, and 12) for 16 cycles in the absence of disease progression or unacceptable toxicity. Patients were permitted to come off study for autologous stem cell transplantation. The primary objective was to determine the maximum tolerated dose and recommended dose of panobinostat, and to estimate the proportion of patients with an overall response that was equal to a partial response or greater within 16 cycles of treatment at the recommended panobinostat dose in the modified intention-to-treat population. We assessed safety in all patients who received a trial drug (ie, bortezomib, thalidomide, dexamethasone, or panobinostat). This trial is registered at ClinicalTrials.gov, number NCT02145715, and with the ISRCTN registry, number ISRCTN59395590 and is closed to recruitment. FINDINGS Between Jan 31, 2013, and Oct 30, 2014, we enrolled 57 eligible patients who received at least one dose of trial medication or any drug. One dose-limiting toxicity was reported (grade 3 hyponatremia at the 20 mg dose), therefore the maximum tolerated dose was not reached, and 20 mg was deemed to be the recommended dose. 46 patients were treated with panobinostat 20 mg (the intention-to-treat population). 42 patients (91%, 80% CI 83·4-96·2) of 46 achieved the primary endpoint of an overall response that was equal to a partial response or greater. Most adverse events were grade 1-2 with few occurrences of grade 3-4 diarrhoea or fatigue. The most common adverse events of grade 3 or worse in the safety population (n=57) were reduced neutrophil count (15 [26%]), hypophosphatemia (11 [19%]), and decreased platelet count (8 [14%]). 46 serious adverse events were reported in 27 patients; of 14 suspected to be related to the trial medication, seven (50%) were gastrointestinal disorders. INTERPRETATION Panobinostat 20 mg in combination with bortezomib, thalidomide, and dexamethasone is an efficacious and well tolerated regimen for patients with relapsed multiple myeloma. FUNDING Novartis and Myeloma UK.

Time to redefine Myeloma

In November 2014 the International Myeloma Working Group (IMWG) revised the definition of multiple myeloma, such that asymptomatic patients with newly diagnosed multiple myeloma without any of the traditional ‘CRAB’ (hypercalcaemia, renal impairment, anaemia, bone disease) end organ damage criteria but with one of three new criteria would be recommended to start treatment. Previously, the standard of care for such patients was expectant management. These three new criteria are: greater than 60% clonal plasma cells on bone marrow biopsy, a serum free light chain (sFLC) ratio of >100 (the involved sFLC must be >100 mg/l) and greater than one unequivocal focal lesion on advanced imaging (low dose whole body computerized tomography, magnetic resonance imaging, 18F fluorodeoxyglucose positron emission tomography). Although this would appear to affect a small number of patients, the impact of these changes are broad, leading to an increased use of advanced imaging, a debate around the management of patients previously diagnosed with smouldering myeloma, changed terminology and clinical trial design and an extension of the use of biomarkers. For the first time the philosophy of treatment in myeloma will change from treatment initiation only being triggered by overt end organ damage to an era where sub clinical risk factors will also be taken into account.

Weekly intravenous bortezomib is effective and well tolerated in relapsed/refractory myeloma.

Bortezomib is an effective antimyeloma therapy, but clinical benefits can be limited by neurotoxicity. In newly diagnosed, older patients, modification of the biweekly dosing schedule to weekly regimens improves tolerability whilst maintaining efficacy. There is less information on the efficacy and tolerability of weekly bortezomib regimens in the relapsed/refractory setting. Here, we report our experience of weekly intravenous bortezomib in clinical practice in relapsed/refractory patients.

Second autologous transplant with cyclosporin/interferon α -induced graft versus host disease for patients who have failed first-line consolidation

Summary:The prognosis for patients with non-Hodgkins lymphoma (NHL) and advanced Hodgkins disease (HD) who relapse following autologous transplant is poor. We report on a pilot study designed to evaluate the feasibility of using Cyclosporin A and interferon α to induce autologous GVHD following a second autologous transplant for relapsed lymphoma. In all, 10 patients entered the study with median age 46.5 years. Diagnosis was NHL (n=7) or Hodgkins lymphoma (n=3). All had relapsed from a prior autologous transplant. The second transplant was well tolerated by all patients. Histological changes consistent with cutaneous GVHD developed in 30% of patients at a median of 22.5 days from transplant and settled spontaneously in all cases. Five patients have died (four from progressive disease) at a median 7 months from second transplant. Five patients are still alive and in complete remission at a median of 20 months from transplant. Median overall survival for the group is 13.5 months and median relapse-free survival has not been reached at 42 months. This is a well-tolerated regimen for use in this poor-risk group of patients with lymphoma. The overall survival and event-free survival are encouraging, however further studies are necessary.