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High-dose chemotherapy followed by autologous stem cell transplantation (HD-ASCT) as well as the introduction of novel agents (NA) significantly improved survival for patients with multiple myeloma (MM). A total of 150 unselected newly diagnosed MM patients treated at our institution from 1998 to 2017 were retrospectively analyzed. Median age at diagnosis was 69 years (range 33-93 years) with a median follow-up of 48.6 months. The median overall survival (OS) for the entire cohort was 60.7 months (range 0.3-280.1). Patients who received frontline HD-ASCT (p < 0.01) or NA-based first-line treatment (p = 0.043) had a significantly better OS. According to the revised Myeloma Comorbidity Index (R-MCI), patients were defined as fit (36.5%), intermediate-fit (44.5%), or frail (19%) with a significant difference in OS between these categories (p < 0.01). Multivariate analysis revealed R-MCI as an independent prognostic factor for OS (p < 0.01). Presence of subclinical amyloid deposits (A+) was detected in 18 out of 66 patients (27.3%) and significantly correlated with a serum free light chain (sFLC) ratio ≥ 100 (p = 0.01) and bone marrow plasma cell infiltration > 60% (p = 0.04). Furthermore, patients with A+ had significantly worse OS compared with their counterparts (p = 0.048). Our results corroborate the efficacy of both early HD-ASCT and the use of new agents as initial therapy of MM patients in "real-world" daily clinical practice. The R-MCI is an easily applicable tool to stratify MM patients and may support treatment decisions. The prognostic value of subclinical amyloid deposition should be validated within prospective studies. more...

Objective: A post hoc analysis of two phase III trials was carried out to explore the influence of age and treatment factors on the effect of bortezomib consolidation on progression-free survival (PFS) post autologous stem cell transplantation (ASCT)., Methods: Patients with newly diagnosed multiple myeloma were assigned to one of two trials (ClinicalTrials.gov IDs: NCT00416273, NCT00416208), which were conducted in parallel, based on age (18-60 or 61-75 years, respectively). Following induction and ASCT, patients were randomized 1:1 to four 35-day cycles of bortezomib consolidation (1.6 mg/m 2 IV on days 1, 8, 15, 22) or observation only., Results: Median PFS with bortezomib consolidation vs observation was 33.6 vs 29.0 months (P = 0.3599) in patients aged 18-60 years (n = 202), and 33.4 vs 26.4 months (P = 0.0073) in patients aged 61-75 years (n = 155), respectively. Bortezomib consolidation post-ASCT appeared to equalize outcomes between older and younger patients who received prior treatment of differing intensity. This suggests that the effect of consolidation may be relative and may depend on the composition and intensity of induction and high-dose therapy., Conclusion: Older patients receiving less intensive prior treatment could experience a larger PFS benefit from bortezomib consolidation., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.) more...

Unlabelled: Multiple myeloma (MM) is with an incidence of 4-6/100 000 inhabitants a fairly frequent malignancy of B cells. The incidence increases markedly with age. In this review changes in the treatment of relapsed / refractory myeloma during the last decade have been analysed. The present standard of care in the progressive or refractory myeloma was elaborated by the working group "Refractory Multiple Myeloma" using an extensive literature search for studies published between 2003 and 2013. Outside of clinical trials, high-dose therapy with stem cell transplantation is recommended in fit patients up to 75 years without significant comorbidities. Ongoing studies address the question about the least toxic and the most effective treatment. Therefore, inclusion of patients in therapeutic trials and use of novel agent combinations is highly recommended, e.g. with 3(rd) generation-IMIDs (pomalidomide), new proteasome inhibitors, such as carfilzomib, ixazomib or oprozomib, antibodies, such as elotuzumab, daratumumab or SAR650984, siltuximab, tabalumab, denosumab, romosozumab, BTK-, HSP-inhibitors and other innovative phase I/II agents., Conclusion: Based on new insights in the pathogenesis of the disease, treatment options for MM have changed significantly in recent years. There is a significantly larger treatment diversity, i.e. more MM-active agents and combinations are available today. Even with relapsed MM, patients with the disease often live longer and have fewer complications., (© Georg Thieme Verlag KG Stuttgart · New York.) more...

The individual risk of infection and requirements for medical treatment after high-dose chemotherapy have been unpredictable. In this prospective, multicenter, open-label study we investigated the potential of granulocyte colony-stimulating factor (G-CSF) responsiveness as a predictor. A total of 168 patients with multiple myeloma or lymphoma received a single dose of subcutaneous G-CSF (lenograstim, 263 μg) after high-dose chemotherapy. Highly variable leukocyte peaks were measured and grouped as low (quartile 1; leukocytes 100-10 100/μL), medium (quartile 2; leukocytes > 10 100-18 300/μL), and high (quartiles 3/4; leukocytes > 18 300-44 800/μL). G-CSF responsiveness (low vs medium vs high) was inversely correlated with febrile neutropenia (77% vs 60% vs 48%; P = .0037); the rate of infection, including fever of unknown origin (91% vs 67% vs 54%; P < .0001); days with intravenous antibiotics (9 vs 6 vs 5; P < .0001); and antifungal therapy (P = .042). In multivariate analysis, G-CSF responsiveness remained the only factor significantly associated with infection (P = .016). In addition, G-CSF responsiveness was inversely correlated with grade 3/4 oral mucositis (67% vs 33% vs 23%; P < .0001). G-CSF responsiveness appears as a signature of the myeloid marrow reserve predicting defense against neutropenic infection after intensive chemotherapy. This study is registered at http://www.clinicaltrials.gov as NCT01085058. more...

Treatment for multiple myeloma (MM) has changed beyond recognition over the past two decades. During the early 1980s, MM inevitably resulted in a slow progressive decline in quality of life until death after about 2 years, while today patients can expect a 50% chance of achieving a complete remission, median survival of 5 years, and a 20% chance of surviving longer than 10 years. An international expert opinion meeting (including members of the GIMEMA and DSMM study groups) was held in 2009. One of the outcomes of the meeting was the development of a consensus statement outlining contemporary optimal clinical practice for the treatment of MM. The international panel recommended that the state of the art therapy for MM should comprise: (a) evidence-based supportive care, (b) effective and well-tolerated chemotherapeutic regimens, (c) autologous hematopoietic stem cell transplant (ASCT) for patients suitable for intensive conditioning therapy, and (d) evidence-based incorporation of novel anti-MM agents. Maintenance strategies have also become increasingly important for the prolongation of remission after front-line therapies. In addition, improved understanding of the biology of MM has led to the development of novel biological therapeutic agents such as thalidomide, lenalidomide, bortezomib, and others. These agents specifically target intracellular mechanisms and interactions, such as those within the bone marrow microenvironment, and have been integrated into MM treatment. This report reviews recent clinical advances in the treatment strategies available for MM and provides an overview of the state of the art management of patients with MM. more...

In this study, we show that adenosine monophosphate-activated protein kinase (AMPK) is expressed and activated in multiple myeloma cells. The inhibition of AMPK induced growth arrest and reduction of cell viability in the cell viability assay using the water-soluble tetrazolium salt 4-[3-(4-iodophenyl)-2-(4-nitrophenyl)-2H-5-tetrazolio]-1,3-benzene disulfonate (WST-1 assay). Induction of apoptosis was determined by annexin-V and propidium iodide staining. The prevention of apoptosis using the pancaspase inhibitor ZVAD-fmk and caspase-3 cleavage upon incubation with the AMPK inhibitor (AMPKI) is shown. Furthermore, incubation of myeloma cells with AMPKI resulted in the downregulation of pAMPK, Mcl-1 and Bcl-xL. Coincubation of AMPKI and melphalan led to a strong additional increase of apoptosis in myeloma cells. We conclude that AMPKI has a strong antimyeloma activity in vitro and represents a new targeted strategy in the treatment of multiple myeloma. more...

An active assessment of the host capacity to prevent infection during myelosuppression should be beneficial in patients receiving high-dose chemotherapy. A single dose of granulocyte colony-stimulating factor (G-CSF) (5 microg/kg) was given to 57 patients with multiple myeloma early after the completion of 85 high-dose chemotherapy (melphalan 200 mg/m2) courses. This provoked a highly variable white blood cell (WBC) peak after 12 to 14 hours. The median WBC count was 21,000/microL (range, 6400-60,600/microL) after a first high-dose therapy (n = 50) and 13,500/microL (range, 4700-24,800/microL) after a second high-dose therapy (n = 35). The responsiveness to single G-CSF was associated with the risk of infection during subsequent cytopenia (P =.003). This association was significant after adjustment for neutropenia duration. Notably, the result of testing G-CSF responsiveness was opportunely available before the onset of leukopenia, and G-CSF responsiveness was more informative than neutropenia duration regarding the risk of infection. Furthermore, there was an association between the responsiveness to G-CSF and stem cell engraftment (P <.005), which remained significant after adjustment for the number of transplanted CD34+ cells. Our results show for the first time that G-CSF potentially could be used for an early in vivo assessment of defense to infection in recipients of high-dose chemotherapy. more...