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Background Aims: To investigate the feasibility and safety of haploidentical natural killer (NK) cell infusions as consolidation immunotherapy after autologous stem cell transplant (ASCT) in patients with plasma cell myeloma., Methods: Ten patients (median age, 59 years) received induction treatment followed by high-dose melphalan (200 mg/m 2 ) at day -1, ASCT at day 0 and increasing NK cell doses (1.5 × 10 6 , 1.5 × 10 7 and multiple doses of 1.0 × 10 8 cells/kg body weight) from day +1 to day +30 after ASCT. NK cells were harvested and purified from peripheral blood of haploidentical donors and expanded for 19 days with interleukin (IL)-2 and IL-15 under Good Manufacturing Practice conditions., Results: NK cell numbers increased 56.0-fold (37.4- to 75.5-fold). Patients received a median of 3.8 × 10 8 (0.9-5.7 × 10 8 ) NK cells/kg body weight in six (three to eight) infusions. Multiparametric mass cytometry analysis demonstrated an altered surface receptor repertoire of expanded NK cells with increased degranulation and cytokine production activities but diminished expression of perforin. Donor NK cells were detectable in the peripheral blood, peaking 1 h after each dose (up to 90% donor NK cells). The treatment was safe and well tolerated, without evidence of graft-versus-host disease. Comparison with a control patient population receiving ASCT without NK cell infusions showed no significant difference in relapse, progression-free survival and overall survival., Conclusions: This study demonstrates reliable manufacturing of high numbers of activated NK cells for multiple-dose infusions and safe administration of these cellular products. The trial was registered at ClinicalTrials.gov (identifier no. NCT01040026)., (Copyright © 2020 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

Systemic amyloidosis is a heterogeneous group of diseases associated with protein misfolding into insoluble beta-sheet rich structures that deposit extracellularly in different organs, eventually compromising their function. There are more than 30 different proteins, known to be amyloidogenic with “light chain” (AL)-amyloidosis being the most common type, followed by transthyretin (ATTR)-, and amyloid protein A (AA)-amyloidosis. Systemic amyloidosis is a rare disease with an incidence of around 10 patients in 1 million inhabitants. Recently several new therapeutic options have been developed for subgroups of amyloidosis patients, and the introduction of novel therapies for plasma cell myeloma has led to an increase in the therapeutic armamentarium for plasma cell disorders, including AL amyloidosis. Among them, proteasome inhibitors, immunomodulatory agents (-imids), and monoclonal antibodies have been successfully introduced into clinical practice. Still, high-quality data from randomised controlled trials regarding the benefit of these cost-intensive drugs in AL amyloidosis are widely lacking, and due to the rarity of the disease many physicians will not gain routine experience in the management of these frail patients. The diagnosis of AL amyloidosis relies on a close collaboration between clinicians, pathologists, imaging experts, and sometimes geneticists. Diagnosis and treatment options in this complex disorder should be discussed in dedicated multidisciplinary boards. In January 2020, the first meeting of the Swiss Amyloidosis Network took place in Zurich, Switzerland. One aim of this meeting was to establish a consensus guideline regarding the diagnostic work-up and the treatment recommendations for systemic amyloidosis tailored to the Swiss health care system. Forty-five participants from different fields in medicine discussed many aspects of amyloidosis. These are the Swiss Amyloidosis Network recommendations which focus on diagnostic work-up and treatment of AL-amyloidosis.

Background/aim: Novel agents such as thalidomide, lenalidomide and bortezomib have in part anti-angiogenic properties. In this study, we examined gene expression of angiogenic molecules in patients with plasma cell myeloma (PCM)., Materials and Methods: We included 93 patients with PCM treated with novel agents (immunomodulatory drugs (IMiDs), bortezomib or a combination of both). The mRNA levels of angiogenic molecules were measured using the Human Angiogenesis RT2 Profiler PCR Array. The response evaluation was performed after three cycles., Results: Regarding all 93 patients, gene expression of 15 out of 84 genes tested (pre- and post-treatment and changes in levels pre-treatment/post-treatment) were significantly different in responders compared to non-responders. Responders had a lower expression of pro-angiogenic factors and increased expression of antiangiogenic factors., Conclusion: In the IMiD-treated groups we found significant changes of expression of angiogenic genes in responders compared to non-responders, whereas in the bortezomib-based group the difference in expression of angiogenic genes was not significant., (Copyright© 2016, International Institute of Anticancer Research (Dr. John G. Delinasios), All rights reserved.)

Background: Angiogenesis plays an important role in pathogenesis and progression of plasma cell myeloma (PCM). Novel agents such as thalidomide, lenalidomide and bortezomib, have in part antiangiogenic mechanisms of action. In this study, we examined angiogenic markers in patients with PCM and correlated these markers to treatment response to novel agents., Patients and Methods: We included 93 patients newly diagnosed with PCM treated with novel agents thalidomide or lenalidomide (immunomodulatory drugs; IMiDs), bortezomib, or a combination of IMiD and bortezomib. A panel of serum angiogenic markers was assessed by a quantitative sandwich enzyme-linked immunosorbent assay (ELISA) before and in the course of the therapy. The response evaluation was performed after three cycles of therapy. The patients were divided into responders [(stringent complete remission (sCR), complete remission (CR), very good partial response (VGPR)] and non-responders [(partial response (PR) stable disease (SD), progressive disease (PD)]., Results: The CR-plus-VGPR rate was 45% in the IMiD-based group (13/29), 52% in the bortezomib-based group (16/30) and 58% in the combination group (20/34). Baseline levels of vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), tumor necrosis factor-α (TNFα), and angiopoietin-2 (ANG2) correlated positively with advanced disease stage (p<0.005 in each case). Regarding all 93 patients, levels of VEGF, soluble VEGF receptor-2 (sVEGFR-2), basic fibroblast growth factor (bFGF), placental-derived growth factor (PGF), ANG2, HGF and neuropilin-1 (NRP1) were significantly different in responders compared to non-responders. The levels of these angiogenic factors were significantly different in the IMiD-based group and the combination group after therapy but not in the bortezomib group., Conclusion: The mode of action of IMiDs possibly leads them to have a greater antiangiogenic effect than bortezomib and thus the levels of angiogenic markers was more influenced by IMiD-based therapies in PCM. This study contributes in the understanding of the mode of action of novel agents in the treatment of PCM., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Despite the introduction of novel drugs, cure of multiple myeloma remains rare. Allo-SCT can induce long-term remission, but randomized studies in advanced disease are lacking and the influence of novel drugs remains unclear. In our retrospective analysis of all patients with myeloma allografted in Switzerland, 95 patients were transplanted between 1988 and 2011. Most patients were heavily pre-treated, and 53% received novel drugs before transplant. In all, 51% were allografted after relapse or progression. Transplant trends changed over time with an increase in reduced intensity conditioning and unrelated donors. At the time of analysis 47 patients remained alive, with a median follow-up of survivors of 53 months. Acute GVHD II-IV and chronic GVHD (cGVHD) occurred in 49% and 53%, respectively; TRM at 5 years was 18%. Five-year OS and PFS were 51% and 29%, respectively. Patients who received transplant upfront vs after relapse had a significantly better outcome, as well as those who had a related donor and achieved CR post transplant. We found no impact of pre-treatment with novel drugs or cGVHD. Although long-term remission following allo-SCT can be achieved, GVHD and TRM remain major limitations. Our series suggests that benefit is highest when allo-SCT is used early in the disease.

Conventional treatment or autologous transplantation has not been able to achieve long-term remission in patients with multiple myeloma (MM). Nonmyeloablative allogeneic transplantation might offer an option for cure without the high mortality associated with conventional conditioning. Here we present a retrospective analysis of patients with high-risk MM treated with nonmyeloablative allogeneic transplantation. In all, 52 patients with relapsed MM or high-risk features at diagnosis received 2 Gy TBI alone (n=3) or with fludarabine (n=49) as conditioning. Patients were heavily pretreated with a median of eight cycles of conventional chemotherapy and one or more autologous transplants for all but one patient. Regimen-related toxicity was low. Acute graft-versus-host disease II-IV occurred in 37% of patients, and 70% experienced chronic graft-versus-host disease (cGvHD). Median follow-up was 567 days, and transplant-related mortality was 17% in total. Estimated progression-free and overall survival at 18 months was 29.4 and 41.1%, respectively. Patients with cGvHD had a significantly higher progression-free survival, as did patients with up to eight cycles of pretreatment chemotherapy vs those with nine or more. In this highly pretreated patient group, disease control was unsatisfactory and our results suggest that a potential strategy might be to perform allogeneic transplant earlier in the course of the disease.

Background: Non-myeloablative allogeneic stem cell transplantation followed by immunomodulatory therapies is considered a potentially curative approach in the treatment of multiple myeloma and most effective in a minimal residual disease setting., Patients and Methods: The aim of this study was to find the most sensitive real-time PCR assay (TaqMan), based on the IGH rearrangement, to quantify the tumour load of 11 patients with multiple myeloma after non-myeloablative allogeneic transplantation. Patient-allele specific primers (ASO) and the TaqMan probe were derived from CDR2 and CDR3 hypervariable regions of IGH, while consensus primers were located within the FR3 and FR4/JH regions. Four different approaches of primer combinations were tested., Results: ASO-forward and -reverse primers together with the clone-specific TaqMan probe were the most sensitive approach compared with the JH (P=0.071) or the FR3 consensus primer (P <0.001). The detection limit amounted to 1/10(4)-1/10(5) cells. Consecutively, 120 samples from 11 patients prior and post allogeneic transplantation were analysed. Three patients reached complete clinical remission accompanied by molecular remission. Disease progression or relapse was seen in six patients. In five, molecular progressive disease was detected prior to the clinical diagnosis of progression or relapse., Conclusion: Patient-specific real-time IGH-PCR provides the opportunity for earlier treatment intervention.