Response adaptive salvage with KTd and ASCT for functional high-risk multiple myeloma-The Australasian Leukemia and Lymphoma Group (ALLG) MM17 Trial.

We evaluated re-induction incorporating carfilzomib-thalidomide-dexamethasone (KTd) and autologous stem cell transplantation (ASCT) for newly diagnosed multiple myeloma (NDMM) refractory, or demonstrating a suboptimal response, to non-IMID bortezomib-based induction. KTd salvage consisted of thalidomide 100 mg daily and dexamethasone 20 mg orally combined with carfilzomib 56 mg/m2 days 1, 2, 8, 9, 15 and 16, of each 28-day cycle. Following four cycles, patients achieving a stringent complete response proceeded to ASCT whereas those who did not received a further two cycles then ASCT. Consolidation consisted of two cycles of KTd then Td to a total of 12 months post-ASCT therapy. Primary end-point was the overall response rate (ORR) with KTd prior to ASCT. Fifty patients were recruited. The ORR was 78% with EuroFlow MRD negativity of 34% in the intention-to-treat population and 65% in the evaluable population at 12 months post-ASCT. With follow-up >38 months median PFS and OS have not been reached with PFS and OS at 36 months of 64% and 80%, respectively. KTd was well tolerated with grade 3 and grade ≥4 adverse events rates of 32% and 10%, respectively. Response adaptive utilisation of KTd with ASCT is associated with both high-quality responses and durable disease control in functional high-risk NDMM.

Treatment of patients with multiple myeloma who are eligible for stem cell transplantation: position statement of the Myeloma Foundation of Australia Medical and Scientific Advisory Group.

The survival of patients with multiple myeloma (MM) has improved substantially since the introduction in the late 1980s of high-dose chemotherapy (HDT) supported by autologous stem cell transplantation (ASCT). Further improvements have been observed following the availability of immunomodulatory drugs (IMiD) such as thalidomide and lenalidomide, and the proteasome inhibitor, bortezomib. Here, we summarise the recommendations of the Medical Scientific Advisory Group to the Myeloma Foundation of Australia for patients considered suitable for HDT + ASCT as part of initial therapy. These recommendations incorporate the various phases of treatment: induction, HDT conditioning and maintenance therapy.

Treatment of patients with multiple myeloma who are not eligible for stem cell transplantation: position statement of the myeloma foundation of Australia Medical and Scientific Advisory Group.

Options for treatment of elderly patients with multiple myeloma have expanded substantially following the development of immunomodulatory drugs (IMiD), proteasome inhibitors and with enhancement in safety of high-dose therapy and autologous stem cell transplant (HDT + ASCT). The recognition of biological heterogeneity among elderly patients has made delivery of therapy more challenging. An individualised approach to treatment selection is recommended in an era in which highly efficacious treatment options are available for transplant-ineligible patients. Here, we summarise recommendations for patients who are considered unsuitable for HDT + ASCT, including pretreatment considerations, and induction, maintenance and supportive care therapies.

Management of systemic AL amyloidosis: recommendations of the Myeloma Foundation of Australia Medical and Scientific Advisory Group.

Systemic AL amyloidosis is a plasma cell dyscrasia with a characteristic clinical phenotype caused by multi-organ deposition of an amyloidogenic monoclonal protein. This condition poses a unique management challenge due to the complexity of the clinical presentation and the narrow therapeutic window of available therapies. Improved appreciation of the need for risk stratification, standardised use of sensitive laboratory testing for monitoring disease response, vigilant supportive care and the availability of newer agents with more favourable toxicity profiles have contributed to the improvement in treatment-related mortality and overall survival seen over the past decade. Nonetheless, with respect to the optimal management approach, there is a paucity of high-level clinical evidence due to the rarity of the disease, and enrollment in clinical trials is still the preferred approach where available. This review will summarise the Clinical Practice Guidelines on the Management of Systemic Light Chain (AL) Amyloidosis recently prepared by the Medical Scientific Advisory Group of the Myeloma Foundation of Australia. It is hoped that these guidelines will assist clinicians in better understanding and optimising the management of this difficult disease.

Relapsed multiple myeloma: who benefits from salvage autografts?

BACKGROUND: Multiple myeloma is incurable despite the advance of autologous stem cell transplant (ASCT) and novel agents (thalidomide, bortezomib, lenalidomide). The role of ASCT as salvage therapy in relapsed myeloma remains unclear. AIM: To identify and refine the predictors of survival following salvage ASCT for relapsed multiple myeloma, so that they can be applied clinically for patient selection. METHODS: Retrospective review of patients treated salvage ASCT for relapsed myeloma at our centre from 1992 to 2011. RESULTS: Following an initial ASCT at diagnosis, 30 patients underwent salvage ASCT for subsequent relapse, with the median time to first relapse/progression being 30.2 months. All patients received reinduction, then melphalan-based conditioning with salvage ASCT. Non-relapse mortality at 100 days following salvage ASCT was 3%. The median overall survival and progression-free survival following salvage ASCT were 45 and 22 months respectively. The progression-free interval (PFI) after initial ASCT predicted survival outcomes in a time-dependent manner. With PFI following initial ASCT of <18, 18-36 and ≥36 months, the median progression-free survival following salvage ASCT was 4.2, 13.8 and 49.1 months respectively (P < 0.0001). The median overall survival was 10.7, 30.9 and 86.1 months respectively (P < 0.0001). CONCLUSIONS: Salvage ASCT is an effective and safe treatment option in selected patients and should be considered in patients relapsing ≥36 months after their initial ASCT. The time-dependent relationship between PFI and salvage ASCT outcome is important when stratifying patient groups who may benefit from this procedure.

Safety and efficacy results from an international expanded access programme to bortezomib for patients with relapsed and/or refractory multiple myeloma: a subset analysis of the Australian and New Zealand data of 111 patients.

BACKGROUND: Bortezomib has been shown to be a safe and efficacious for the treatment of relapsed and refractory multiple myeloma (MM). Here we report a subset analysis of Australian and New Zealand data from the International Extended Access Programme for bortezomib. METHODS: Patients with more than or equal to two prior lines of therapy were given bortezomib 1.3 mg/m(2) (i.v. bolus days 1, 4, 8, 11) for up to eight 21-day cycles (C). Dexamethasone, 20 mg/day p. o. on the day of, and day after, bortezomib was added after C2 for progressive disease or after C4 for stable disease. Efficacy was assessed using modified Southwest Oncology Group criteria in the intent-to-treat group. Results were compared between the Australian and New Zealand and international cohort. RESULTS: One hundred and eleven patients from 16 centres (55% men, median age 61.9 years) had a median of 5.2 +/- 2.8 treatment cycles of bortezomib. Among them, 82% had > or =3 prior therapies. Grade 3-4 treatment-related adverse events were reported in 57 patients (52%); the most common were thrombocytopenia (25.7%), anaemia (8.3%), peripheral neuropathy (7.3%) and diarrhoea (7.3%). Responses were evaluable in 106 patients: 22% achieved a best response of complete response/response and 20% partial response (overall response rate of 42%). Median times to first and best responses were 42 days and 69 days, respectively. Compared with the international cohort, the cohorts from Australian and New Zealand showed inferior overall response rates (54 vs 42%, P = 0.001), possibly due to heavier pretreatment (82% greater than or equal to three prior therapies vs 68%, P < 0.001). CONCLUSION: Our analysis confirms that bortezomib is safe and effective in relapsed and refractory MM in a real-life clinical setting.

Osteonecrosis of the jaw complicating bisphosphonate treatment for bone disease in multiple myeloma: an overview with recommendations for prevention and treatment.

Osteonecrosis of the Jaw (ONJ) is a recently recognised and potentially highly morbid complication of bisphosphonate therapy in the setting of metastatic malignancy, including myeloma. Members of the Medical and Scientific Advisory Group of the Myeloma Foundation of Australia formulated guidelines for the management of bisphosphonates around the issue of ONJ, based on the best available evidence in June 2008. Prior to commencement of therapy, patients should have an oral health assessment and be educated about the risks of ONJ. Dental assessment should occur 6 monthly during therapy. If tooth extraction is required, sufficient time should be allowed for complete healing to occur prior to commencement of bisphosphonate. As the risk of ONJ increases with duration of bisphosphonate therapy, we recommend annual assessment of dose with modification to 3 monthly i.v. therapy or to oral therapy with clodronate for those with all but the highest risk of skeletal-related event. Established ONJ should be managed conservatively; a bisphosphonate "drug holiday" is usually indicated and invasive surgery should generally be avoided. These recommendations will assist with clinical decision making for myeloma patients who are at risk of bisphosphonate-associated ONJ.

Outcome of patients with myelodysplastic syndromes: experience from a single institution in South Australia.

AIMS: To study disease characteristics of adult patients with myelodysplastic syndromes (MDS) in South Australia and to analyse their outcome and survival. METHODS: One hundred and eight adult patients with confirmed MDS from marrow biopsies in the 76-month period before April 2006 were retrospectively included in an MDS database. RESULTS: The median age at diagnosis of this cohort was 70 years, with skewing of refractory anaemia with excess blasts and refractory cytopenia with multilineage dysplasia in the younger patients. Clonal cytogenetic abnormalities were present in 42% of patients. Median survival was 48 months, and secondary transformation to acute myeloid leukaemia was seen in 27%. Survival, according to the World Health Organization subtypes in ascending order, was refractory anaemia with excess blasts, refractory anaemia, refractory anaemia with ringed sideroblast, refractory cytopenia with multilineage dysplasia and del(5q). The International Prognostic Scoring System score stratified MDS patients into different risk groups and effectively discriminated significantly different survivals, ranging from a median 4 months for high-risk patients to 72 months for low-risk patients. CONCLUSION: An MDS database provides useful information regarding the disease characteristics and survival of MDS patients in South Australia and confirms the prognostic usefulness of the International Prognostic Scoring System. The future prospective collection of results will be invaluable in evaluating the effect of novel therapies on patient prognosis.

Phase I/II study of combined granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor administration for the mobilization of hematopoietic progenitor cells.

PURPOSE: To study the toxicity and efficacy of combined granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) administration for mobilization of hematopoietic progenitor cells (HPCs). MATERIALS AND METHODS: Cohorts of a minimum of five patients each were treated subcutaneously as follows: G-CSF 5 micrograms/kg on days 1 to 12 and GM-CSF at .5, 1, or 5 micrograms/kg on days 7 to 12 (cohorts 1, 2, and 3); GM-CSF 5 micrograms/kg on days 1 to 12 and G-CSF 5 micrograms/kg on days 7 to 12 (cohort 4); and G-CSF and GM-CSF 5 micrograms/kg each on days 1 to 12 (cohort 5). Ten-liter aphereses were performed on days 1 (baseline, pre-CSF), 5, 7, 11, and 13. Colony assays for granulocyte-macrophage colony-forming units (CFU-GM) and erythroid burst-forming units (BFU-E) were performed on each harvest. RESULTS: The principal toxicities were myalgias, bone pain, fever, nausea, and mild thrombocytopenia, but none was dose-limiting. Four days of treatment with either G-CSF or GM-CSF resulted in dramatic and sustained increases in the numbers of CFU-GM per kilogram collected per harvest that represented 35.6 +/- 8.9- and 33.7 +/- 13.0-fold increases over baseline, respectively. This increment was attributable both to increased numbers of mononuclear cells collected per 10-L apheresis and to increased concentrations of progenitors within each collection. The administration of G-CSF to patients already receiving GM-CSF (cohort 4) caused the HPC content to surge to nearly 80-fold the baseline (P = .024); the reverse sequence, ie, the addition of GM-CSF to G-CSF, was less effective. The CFU-GM content of the baseline aphereses correlated with the maximal mobilization achieved (r = .74, P = .001). CONCLUSION: Combined G-CSF and GM-CSF administration effectively and predictably mobilizes HPCs and facilitates apheresis.

Prospective randomised trial of amifostine cytoprotection in myeloma patients undergoing high-dose melphalan conditioned autologous stem cell transplantation.

In this prospective multicentre trial, 90 patients undergoing autologous stem cell transplantation (ASCT) were randomised to receive (n=43) or not receive (n=47) amifostine 910 mg/m(2) prior to melphalan 200 mg/m(2). Patients were monitored for regimen-related toxicity, engraftment, supportive care, response and survival. Both groups underwent ASCT at a median of 8 months from diagnosis and were matched for disease characteristics, prior therapy and pre-ASCT disease responsiveness. Amifostine infusional side-effects were frequent, occurring in 65% of patients, but of mild severity. Amifostine use was associated with a reduction in the median grade of oral mucositis (1 vs 2, P=0.01) and the frequency of severe (WHO grades 3 or 4) mucositis (12 vs 33%, P=0.02), but no reduction in the requirement for parenteral nutrition or analgesic use. Conversion to complete remission post-ASCT occurred in 30 and 14% of the amifostine and control groups, respectively (P=0.09). With a median follow-up of 35 months, there was no statistically significant difference between the median progression-free or overall survival times for the two groups. We conclude that amifostine can be safely administered prior to high-dose melphalan and significantly reduces the frequency and severity of therapy-induced oral mucositis.

Inappropriate antidiuretic hormone secretion, abdominal pain and disseminated varicella-zoster virus infection: an unusual triad in a patient 6 months post mini-allogeneic peripheral stem cell transplant for chronic myeloid leukemia.

Severe abdominal pain followed by inappropriate antidiuretic hormone secretion (SIADH) preceding by several days the skin manifestation of varicella-zoster virus (VZV) infection in an immunocompromised patient is described. This is a rare presentation of a severe infection described previously only once in a chronic myeloid leukemia (CML) patient 5 months post allo-BMT during immunosuppressive treatment with cyclosporin A. This is the first case described in the setting of non-myeloablative preparation with fludarabine and melphalan and followed by donor leukocyte infusion (DLI) 2 and 4 months post allo-BMT. The influence of these factors on development of VZV virus infection is discussed. We also highlight the high incidence and high mortality in VZV infection in immunocompromised patients as well as the frequent atypical presentation.

An incremental response to high-dose therapy in multiple myeloma.

Results of conventional chemotherapy for multiple myeloma are disappointing. High-dose chemoradiotherapy with auto-transplantation is increasingly reported and some results are encouraging. We report the results of peripheral blood stem cell transplantation (PBSCT) for multiple myeloma at a single institution over a 6-year period. Forty patients, including 18 de novo patients, received debulking chemotherapy consisting of vincristine, adriamycin, and dexamethasone or methyl-prednisolone followed by stem cell mobilization with high-dose cyclophosphamide. Twenty-nine patients received PBSCT following high-dose chemoradiotherapy. Following PBSCT 92% of evaluable patients obtained at least a partial remission and 29% reached complete remission. Objective treatment responses, defined as at least a 50% reduction in serum paraprotein or marrow plasma cells, were observed following each treatment step of debulking chemotherapy, mobilization and PBSCT in 50, 42 and 71% of patients, respectively. The median overall survival from diagnosis in patients transplanted was 50 months and the median overall and progression-free survivals following transplant were 26 and 18 months, respectively. Median follow-up was 28 months. Overall treatment-related mortality was 20% but was significantly lower in de novo vs previously treated patients at 6 and 33% respectively (P = 0.027). De novo patients were more likely to obtain complete remission and had a longer overall survival following transplant but overall survival from diagnosis was similar to previously treated patients. A low serum B2M before mobilization predicted a longer progression-free survival. PBSCT needs to be considered early following diagnosis to maximise treatment response and reduce the high treatment-related mortality seen in heavily pretreated patients. In this treatment program a dose response effect in multiple myeloma was observed possibly suggesting that more intensive therapy than a single transplant may effect greater disease response.

CD34+ selection of autologous peripheral blood stem cells for transplantation following sequential cycles of high-dose therapy and mobilization in multiple myeloma.

A potential problem of autologous transplantation in the treatment of multiple myeloma (MM) is the infusion of tumor cells. CD34+ selection has been used to purge autografts in MM and it is also possible to reduce tumour cell contamination of autografts by cytotoxic drug therapy prior to peripheral blood stem cell (PBSC) collection. To evaluate the effectiveness of a protocol combining multiple cycles of high-dose therapy and CD34+ selection to reduce tumour contamination of PBSC autografts, 34 MM patients were entered on a treatment schedule comprising two sequential cycles of mobilisation, CD34+ selection, and transplantation following high-dose therapy. In the second cycle of mobilisation there was a five-fold reduction in tumour contamination of the stem cell harvest (0.5 x 106/kg) compared with the first cycle (2.5 x 106/kg). In the 97 CD34+ selection procedures performed a median of 185 x 108 mononuclear cells (MNC) were processed yielding a median of 0.98 x 108 CD34+-enriched cells. CD34+ cells were enriched 68-fold from 1. 3% to 88.6%. The median yield of CD34+ cells was 42.2%. Following CD34+ selection the tumour cell contamination of the leukapheresis product was reduced by a median of 2.7 logs. This study demonstrates that in multiple myeloma a significant reduction in the malignant contamination of stem cell autografts can be achieved by combining the in vivo purging effect of cytotoxic therapy with in vitro purging by CD34+ selection.

Comparison of haematological recovery times and supportive care requirements of autologous recovery phase peripheral blood stem cell transplants, autologous bone marrow transplants and allogeneic bone marrow transplants.

The haematological recovery time, infection rate and supportive care requirements of patients receiving recovery phase autologous peripheral blood stem cell transplants (APBSCT) (n = 38), autologous bone marrow transplants (autoBMT) (n = 13) and allogeneic bone marrow transplants (alloBMT) (n = 14) were compared with respect to the time post-transplant to reach 0.1, 0.5 and 2.0 x 10(9) neutrophils/l and 50 and 150 x 10(9) platelets/l, the length of hospitalization, fever and antibiotic use, the incidence of documented infection and the number of red cell and platelet transfusions. The APBSCT group had a significantly more rapid recovery of neutrophils and platelets and their supportive care requirements were significantly less than the autoBMT and the alloBMT groups. There was no difference between the latter two groups. The most significant variables contributing to the differences in haematological recovery times were the granulocyte-macrophage progenitor (CFU-GM) dose infused and, to a lesser extent, patient age. The APBSCT group received a higher CFU-GM dose of 87 +/- 12 x 10(4)/kg BW compared with 12 +/- 5 and 17 +/- 3 x 10(4)/kg BW in the autoBMT and the alloBMT groups, respectively (p = 0.0001). Patient age showed a negative correlation with the rate of recovery because the APBSCT group, which recovered faster was also older (48 +/- 2 years, compared with 33 +/- 3 and 31 +/- 2, respectively, p = 0.0001). On multivariate analysis, CFU-GM dose was the only variable to show a significant correlation with all the haematological recovery endpoints studied in these 65 patients.(ABSTRACT TRUNCATED AT 250 WORDS)

The optimization of collection of peripheral blood stem cells for autotransplantation in acute myeloid leukaemia.

Between November 1982 and November 1986 31 patients with acute myeloid leukaemia underwent peripheral blood stem cell apheresis during haemopoietic regeneration following induction chemotherapy. A retrospective analysis of the factors affecting the efficacy of stem cell harvest and of the clinical outcome of these patients was performed. The mean number of myeloid progenitor cells (CFU-GM) collected was significantly higher in the complete remission group (n = 22) than in the partial remission group (n = 9). Fifty x 10(4) CFU-GM/kg body weight or more, which produced rapid, complete and sustained haemopoietic reconstitution after autografting in our patients, were collected from six of nine patients who underwent three or four 7-litre aphereses over 5-7 days using a lymphocyte collection procedure on the Fenwal CS3000 [Protocol B] but only from two of 12 patients who underwent three or four 5-litre aphereses over 3-5 days using the Aminco Celltrifuge [Protocol A] (p less than 0.05). No adverse effects on the rates of neutrophil, platelet and lymphocyte recovery after induction chemotherapy or on long-term disease-free survival for patients who achieved a complete remission could be attributed to apheresis when compared with a historical control group of 39 patients who achieved complete remission following the same induction chemotherapy but did not undergo apheresis. We conclude that sufficient numbers of peripheral blood stem cells to produce safe and rapid haemopoietic reconstitution can be collected from most patients who achieve complete remission using apheresis Protocol B without impairment of haemopoietic recovery or adversely affecting the length of complete remission.

Granulocyte colony-stimulating factor (G-CSF) dose-dependent efficacy in peripheral blood stem cell mobilization in patients who had failed initial mobilization with chemotherapy and G-CSF.

For 10 consecutive patients in our unit who did not show a significant rise in blood progenitor cells within 14 days following chemotherapy and G-CSF, we increased the G-CSF dose from 5 to 10 microg/kg/day (n = 9) or from 10 to 15 microg/kg/day (n = 1). As a result, there were significant increases in total yield as well as yield per apheresis of mononuclear cells, CD34+ cells and CFU-GM (P < 0.025, <0.01 and <0.005, respectively). After G-CSF dose escalation, six of the 10 patients had sufficient CD34+ cells for performing transplantation. These results demonstrate a dose-dependent response of progenitor cell mobilization by G-CSF when used in combination with chemotherapy. Moreover, increasing the dose of G-CSF as late as the third week of mobilization may still provide sufficient cell yield even with patients who did not show a significant mobilization with conventional doses of G-CSF.

[Pyloric stenosis caused by gallstone diseases]. / Pylorusstenosen, verursacht durch Gallensteinerkrankungen

During the 15 year period between 1958 and 1973 the authors operated on 21 cases of pyloric stenosis caused by biliary calculi, occuring in 12 percent of their patients suffering from pyloric stenosis. They call attention to the fact that cholecystectomy made in good time can prevent pyloric stenosis being a complication of neglected cases.