Krystal Bergin

A phase 1 clinical trial evaluating marizomib, pomalidomide and low‐dose dexamethasone in relapsed and refractory multiple myeloma (NPI‐0052‐107): final study results

Marizomib (MRZ) is an irreversible, pan‐subunit proteasome inhibitor (PI) in clinical development for relapsed/refractory multiple myeloma (RRMM) and glioma. This study analysed MRZ, pomalidomide (POM) and low‐dose dexamethasone (Lo‐DEX) [PMD] in RRMM to evaluate safety and determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D). Intravenous MRZ (0·3–0·5 mg/m2) was administered over 2 h on days 1, 4, 8, 11; POM (3–4 mg) on days 1–21; and Lo‐DEX (5 or 10 mg) on days 1, 2, 4, 5, 8, 9, 11, 12, 15, 16, 22 and 23 of every 28‐day cycle. Thirty‐eight patients were enrolled that had received a median of 4 (range 1–10) prior lines of therapy; all patients received prior lenalidomide and bortezomib. No dose‐limiting toxicities (DLTs) were observed and 0·5 mg/m2 MRZ was determined to be the RP2D. The most common treatment‐related ≥Grade 3 adverse events were: neutropenia (11/38 patients: 29%), pneumonia (4/38 patients 11%), anaemia (4/38 patients; 11%) and thrombocytopenia (4/38 patients; 11%). The overall response rate and clinical benefit rate was 53% (19/36) and 64% (23/36), respectively. In conclusion, PMD was well tolerated and demonstrated promising activity in heavily pre‐treated, high‐risk RRMM patients.

Identifying Cytomegalovirus Complications Using the Quantiferon-CMV Assay After Allogeneic Hematopoietic Stem Cell Transplantation

Background A simple test to identify recovery of CMV-specific T-cell immunity following hematopoietic stem cell transplantation (HSCT) could assist clinicians in managing CMV-related complications. Methods In an observational, multicenter, prospective study of 94 HSCT recipients we evaluated CMV-specific T-cell immunity at baseline, 3, 6, 9, and 12 months after transplant using the Quantiferon-CMV, an enzyme-linked immunosorbent spot assay (ELISpot), and intracellular cytokine staining. Results At 3 months after HSCT, participants who developed CMV disease (n = 8) compared with CMV reactivation (n = 26) or spontaneous viral control (n = 25) had significantly lower CD8+ T-cell production of interferon-γ (IFN-γ) in response to CMV antigens measured by Quantiferon-CMV (P = .0008). An indeterminate Quantiferon-CMV result had a positive predictive value of 83% and a negative predictive value of 98% for identifying participants at risk of further CMV reactivation. Participants experiencing CMV reactivation compared with patients without CMV reactivation had a reduced proportion of polyfunctional (IFN-γ+/tumor necrosis factor α-positive) CD4+ and CD8+ T cells and a higher proportion of interleukin 2-secreting cells (P = .01 and P = .002, respectively). Conclusions Quantifying CMV-specific T-cell immunity after HSCT can identify participants at increased risk of clinically relevant CMV-related outcomes.

Myeloma in the Real World: What Is Really Happening?

Abstract Multiple myeloma (MM) is the second most common hematologic malignancy and is predominantly a disease of the elderly. In the past 2 decades, a range of new therapeutic options have become available, leading to improvements in patient outcomes, including both attainment of remission and overall survival. These improved outcomes have heralded a paradigm shift from a palliative approach toward more active management, including the use of sequential therapies, with the goal of prolonging progression‐free and overall survival and preserving organ function to enable delivery of further therapy at relapse. Until now, most outcome data for MM have come from clinical trials, with few reports available on patients treated outside the clinical trial setting—in the “real world.” Clinical trials are routinely undertaken in specialist centers, and extrapolation of these trial data to broader clinical practice might not accurately reflect “real‐world” patient outcomes. Optimal management of MM is of key importance for positive patient outcomes, and further scrutiny of the efficacy and safety of the various reported therapies and how clinical trial findings are being translated or applied in the real‐world management of MM is required. In the present review, we have described the minimal published evidence available through a comprehensive published data search of MEDLINE using the OvidSP interface on the management and outcomes of MM outside the setting of clinical trials, including evidence on the uptake of new therapies and their efficacy and tolerability in standard practice. Clinical registries might be able to help provide these data in the future.

Low T-Cell Responses to Mitogen Stimulation Predicts Poor Survival in Recipients of Allogeneic Hematopoietic Stem Cell Transplantation

Background Successful engraftment and reconstitution of the innate and adaptive immune system are associated with improved outcomes in recipients of allogeneic hematopoietic stem cell transplantation (HSCT). A clinically meaningful and simple biomarker of immunosuppression could potentially assist clinicians in their decision-making. We aimed to determine the relationship between T-cell production of interferon gamma (IFN-γ) in response to phytohemagglutinin (PHA) to clinical outcomes in HSCT recipients. Methods A prospective observational multicenter study of 73 adult allogeneic HSCT recipients was conducted in Melbourne, Australia. Eligible participants were >18 years and at risk of cytomegalovirus disease. T-cell responses to PHA were assessed at 3, 6, 9, and 12 months post-HSCT using the commercial quantiferon-cytomegalovirus assay, which quantifies IFN-γ production by ELISA following stimulation with PHA. A low response was defined as IFN-γ <0.5 IU/ml following stimulation with PHA. Results At 3 months post-HSCT, high responses to PHA (median IFN-γ 7.68 IU/ml) were seen in 63% of participants and low responses to PHA (median IFN-γ 0.06 IU/ml) in 37%. IFN-γ responses to PHA were significantly associated with the severity of acute graft versus host disease (AGVHD) (spearman r = −0.53, p < 0.001) and correlated with blood lymphocyte count (spearman r = 0.52, p < 0.001). Twelve month overall survival was greater in individuals with high compared to low IFN-γ response to PHA at 3 months [92 vs. 62%, respectively, Cox proportional hazard ratio (HR): 4.12 95% CI: 1.2–13.7, p = 0.02]. Non-relapse mortality (NRM) was higher in individuals with low IFN-γ response to PHA (competing risk regression HR 11.6 p = 0.02). In individuals with no AGVHD compared to AGVHD and high IFN-γ response to PHA compared to AGVHD and low IFN-γ response to PHA, 12-month survival was 100 vs. 80 vs. 52%, respectively (log rank test p < 0.0001). Conclusion Low IFN-γ response to PHA at the 3-month time-point following allogeneic HSCT was predictive of reduced 12-month overall survival, increased NRM, and reduced survival in recipients with AGVHD. Assessing IFN-γ response to PHA post-HSCT may be a clinically useful immune biomarker.

Adverse impact of high donor CD3+ cell dose on outcome following tandem auto-NMA allogeneic transplantation for high-risk myeloma

High-risk (HR) multiple myeloma (MM) has poor outcomes with conventional therapy. Tandem autologous-non-myeloablative (NMA) allogeneic stem cell transplantation (autologous stem cell transplantation (ASCT)-NMA allogeneic SCT) is potentially curative secondary to graft-versus-myeloma effect. We retrospectively analysed ASCT-NMA allogeneic SCT outcomes of 59 HR and relapsed MM patients. At a median follow-up of 35.8 months, the outcomes for HR-MM upfront tandem ASCT-NMA allogeneic SCT and standard-risk (SR) MM upfront ASCT alone were comparable (median PFS 1166 days versus 1465 days, P=0.36; median overall survival (OS) not reached in both cohorts, P=0.31). The 5-year PFS and OS of patients who had ASCT-NMA allogeneic SCT after relapsing from previous ASCT were 30% and 48% respectively. High CD3+ cell dose (>3 × 108/kg) infusion was associated with more acute GvHD (grade 2–4) (47% vs 17.5%; P=0.03), extensive chronic GvHD (80% vs 50%; P=0.04), increased transplant-related mortality (26.3% vs 5%; P=0.009) and inferior OS (median OS 752 days vs not reached; P=0.002). On multivariate analysis, response achieved with tandem transplant (<CR vs CR vs stringent CR; hazard ratio=5.54, confidence interval=2.67–11.5; P<0.0001) and CD3+ cell dose infused (hazard ratio=1.42; confidence interval=1.21–1.67; P<0.0001) emerged as factors influencing OS. We conclude that tandem ASCT-NMA allogeneic SCT is an effective therapy for HR or relapsed MM and that higher CD3+ doses have an adverse impact on transplant outcome.

DCEP as a bridge to ongoing therapies for advanced relapsed and/or refractory multiple myeloma

Abstract There is limited data describing dexamethasone, cyclophosphamide, etoposide, and cisplatin (DCEP) in relapsed refractory multiple myeloma (RRMM). We reviewed 65 patients with RRMM receiving DCEP between 2005 and 2017 in two Melbourne Hospitals. Patients had received a mean of three prior treatment lines (range, 1–11). The mean number of cycles of DCEP was two (range, 1–4). Overall response rate (ORR) was 55% whilst 19% achieved MR and SD. Median overall survival (OS) was 9.6 months. Those bridged to autologous stem cell transplant (ASCT) had significantly improved OS compared to those who were not (median 32.8 vs. 10.7 months, p=.0004). Significant treatment-related mortality (TRM) was observed (9.7%), mostly attributable to grade 3–4 neutropenia and febrile neutropenia. Mandatory use of G-CSF is, therefore, warranted to prevent septic complications. In heavily pretreated RRMM, DCEP is an effective bridge to definitive therapy but in the absence of the latter, its value is questionable.

Peripheral blood stem cell mobilisation with G-CSF alone versus G-CSF and cyclophosphamide after bortezomib, cyclophosphamide and dexamethasone induction in multiple myeloma.

Bortezomib-based induction is often used in transplant-eligible patients with myeloma. The optimal peripheral blood stem cell (PBSC) mobilisation strategy in this context is unclear. We reviewed the efficacy of G-CSF alone (G-alone) vs. G-CSF and cyclophosphamide (G-cyclo: standard dose: 1.5–2 g/m2; high dose: 3–4 g/m2) PBSC mobilisation strategies in 288 patients who only received bortezomib, cyclophosphamide and dexamethasone (VCD) induction prior to autograft across six apheresis centres from November 2012 to June 2017. ‘Uncomplicated successful mobilisation’ was defined as achieving a PBSC yield of ≥4 × 106/kg within two aphereses, without plerixafor or mobilisation-associated toxicity (predominantly febrile neutropenia, FN). Success rates were 84% in G-cyclo standard dose (6% FN), 64% in G-cyclo high dose (18% FN) and 69% in G-alone (plerixafor successfully salvaged 8/9 patients). Median total stem cell yield was significantly higher with G-cyclo, but not different between the two cyclophosphamide doses. Age greater than the median of 61 years was associated with higher failure rates (22 vs. 11%, p = 0.01) and lower PBSC yield, especially in the G-alone group. Prior radiotherapy exposure did not impact on collection success. Our observations suggest that both G-cyclo standard dose and G-alone are reasonable mobilisation strategies. The former may be preferred if salvage plerixafor is unavailable.

Design and development of the Australian and New Zealand (ANZ) myeloma and related diseases registry.

BackgroundPlasma cell dyscrasias (PCD) are a spectrum of disorders resulting from the clonal expansion of plasma cells, ranging from the pre-malignant condition monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma (MM). MM generates a significant burden of disease on the community and it is predicted that it will increase in both incidence and prevalence owing to an ageing population and longer survival secondary to new therapeutic options. Robust and comprehensive clinical data are currently lacking but are required to define current diagnostic, investigational and management patterns in Australia and New Zealand (ANZ) for comparison to both local and international guidelines for standards of care. A clinical registry can provide this information and subsequently support development of strategies to address any differences, including providing a platform for clinical trials. The Myeloma and Related Diseases Registry (MRDR) was developed to monitor and explore variations in practices, processes and outcomes in ANZ and provide benchmark outcomes nationally and internationally for PCD. This paper describes the MRDR aims, development and implementation and discusses challenges encountered in the process.MethodsThe MRDR was established in 2012 as an online database for a multi-centre collaboration across ANZ, collecting prospective data on patients with a diagnosis of MGUS, MM, solitary plasmacytoma or plasma cell leukaemia. Development of the MRDR required multi-disciplinary team participation, IT and biostatistical support as well as financial resources.ResultsMore than 1250 patients have been enrolled at 23 sites to date. Here we describe how database development, data entry and securing ethics approval have been major challenges for participating sites and the coordinating centre, and our approaches to resolving them. Now established, the MRDR will provide clinically relevant and credible monitoring, therapy and ‘real world’ outcome data, to support the conduction of high quality studies. In addition, the Myeloma 1000 sub-study is establishing a repository of paired peripheral blood specimens from registry patients to study mechanisms underlying disease progression.ConclusionEstablishment of the MRDR has been challenging, but it is a valuable investment that will provide a platform for coordinated national and international collaboration for clinical research in PCD in ANZ.