Per Trøllund Pedersen

First‐line treatment with bortezomib rapidly stimulates both osteoblast activity and bone matrix deposition in patients with multiple myeloma, and stimulates osteoblast proliferation and differentiation in vitro

Objectives:  The aim of the study was to investigate the effect of bortezomib on osteoblast proliferation and differentiation, as well as on bone matrix deposition for the first time in bisphosphonate‐naïve, previously untreated patients with myeloma.

Thalidomide and dexamethasone vs. bortezomib and dexamethasone for melphalan refractory myeloma: a randomized study

Objectives:  Thalidomide and bortezomib have been frequently used for second‐line therapy in patients with myeloma relapsing after or refractory to initial melphalan‐based treatment, but no randomized trials have been published comparing these two treatment alternatives.

Thalidomide and dexamethasone vs. bortezomib and dexamethasone for melphalan refractory myeloma

Objectives:  Thalidomide and bortezomib have been frequently used for second‐line therapy in patients with myeloma relapsing after or refractory to initial melphalan‐based treatment, but no randomized trials have been published comparing these two treatment alternatives.

Smoldering multiple myeloma risk factors for progression: a Danish population‐based cohort study

Several risk scores for disease progression in patients with smoldering multiple myeloma (SMM) have been proposed; however, all have been developed using single‐center registries. To examine risk factors for time to progression (TTP) to multiple myeloma (MM) for SMM, we analyzed a nationwide population‐based cohort of 321 patients with newly diagnosed SMM registered within the Danish Multiple Myeloma Registry between 2005 and 2014. Significant univariable risk factors for TTP were selected for multivariable Cox regression analyses. We found that both an M‐protein ≥30 g/L and immunoparesis significantly influenced TTP (HR 2.7, 95%CI (1.5;4.7), P = 0.001, and HR 3.3, 95%CI (1.4;7.8), P = 0.002, respectively). High free light chain (FLC) ratio did not significantly influence TTP in our cohort. Therefore, our data do not support recent IMWG proposal of identifying patients with FLC ratio above 100 as having ultra high‐risk of transformation to MM. Using only immunoparesis and M‐protein ≥30 g/L, we created a scoring system to identify low‐, intermediate‐, and high‐risk SMM. This first population‐based study of patients with SMM confirms that an M‐protein ≥30 g/L and immunoparesis remain important risk factors for progression to MM.

Causes of early death in multiple myeloma patients who are ineligible for high-dose therapy with hematopoietic stem cell support: A study based on the nationwide Danish Myeloma Database

To the Editor: Hodgkin lymphoma (HL) is a B-cell derived lymphoid malignancy that accounts for about 10% of all lymphomas. Despite most of patients being cured by modern regimens of chemotherapy and radiotherapy (RT), nearly 20% show primary refractoriness or relapse after initial remission. In these cases second-line chemotherapy followed by autologous stem cell transplantation (ASCT) consolidation leads in nearly 50% of patients to a long lasting remission. For patients with HL relapsed/refractory (R/R) to more than two lines of therapy, there is no standard approach and prognosis is generally dismal. Therapeutic options include palliative chemotherapy, radiotherapy, and transplant procedures. More recently, Brentuximab Vedotin (BV), an anti-CD30 monoclonal antibody conjugated with Auristatin, showed therapeutic activity in 75% of patients with HL R/R to ASCT, with 35% complete response (CR) and median progression-free survival (PFS) of nearly 6 months [1]. Limited data are available regarding the combination of BV with chemotherapeutic agents while, the combination of BV with RT has not been reported so far. A 45-year-old male, with no significant comorbidities, was referred at our Centre on August 2013 for onset of multiple lympho-adenopaties (size varying from 2 to 7 cm and involving bilateral the cervical area and the right axillary) associated with fever, night sweats, fatigue, mild cough, and mild skin itching. Total white blood cell count was 39 3 10/L (90% neutrophils, 4% lymphocytes), while hemoglobin and platelet count were 98 g/L and 635 3 10/L, respectively; erythrocyte sedimentation rate was 91 mm/hr. After lateral cervical lymphonode biopsy and standard staging, the patient was diagnosed to have a sclero-nodular, classic HL, stage IIIs (spleen) B. The patient was started on standard ABVD chemotherapy program (Dacarbazine, Bleomycin, Vinblastine, and Doxorubicin) with rapid resolution of systemic symptoms and lymphonodes disappearance. A CT-PET evaluation after two cycles showed a picture of response with FDG uptake lower than liver (Deauville Score 3). After the fourth planned ABVD course, the patient had evidence of supradiaphragmatic progression with recurrence of right supraclavicular, axilla, and mediastinal involvement. A lymphonode biopsy confirmed the initial diagnosis of scleronodular classic HL. The patient was treated in December 2013 and January 2014 with one course of IGEV (Vinorelbine, Ifosfamide, Metilprednisolone and Gemcitabine) and one course of DHAP chemotherapy (Dexamethasone, Cisplatin, Cytosine Arabinoside) each, with no response and further clinical and radiological evidence of rapid progression with reappearance of fever, itching, and lymphoadenopaties in all supradiaphragmatic areas with bulky right axillary involvement (12 cm 3 10 cm). Based on the disease’s status of chemoresistance, a haploidentical stem cell transplant (SCT) with the patient’s sister was considered. To induce a pre-transplant condition of response, and because of the high level of aggressiveness of the disease with rapid lymphnodes enlargement, a combination treatment with BV and extended field (EF) RT was started. From February to April 2014 the patient received four administrations of BV (1.8 mg/kg) every 21 days with concomitant classical mantle field RT at a dose of 36 Gy in 20 fractions. Hematological toxicity experienced during the therapy was mild, with Grade 2 anemia only after course 1 and 2, and no neutropenia or thrombocytopenia. There were no infective complication or any other major adverse effects to BV or RT, and, in particular, no clinical or functional signs of pulmonary toxicity. The patient showed rapid resolution of the clinical symptoms and progressive and gradual decrease of the size of’ the right axillary lymphoadenopathy. Pretransplant restaging documented a partial response status (according to Cheson 2007) due to the persistence of a residual single right axillary lymphoadenopathy of 3 cm in size. This status of improvement allowed, in May 2014, to proceed with haplo-identical SCT with no major complications. At present, 6 months after the end of BV plus EF-RT and 5 months after SCT, the patient is in good clinical conditions and in a complete response status. Patients with R/R HL have a poor prognosis and no standard treatment has been established so far. Allogeneic SCT seems to be a suitable treatment option for patients with a pre-SCT response condition, with nearly 30–40% PFS. Due to the good safety profile, BV is frequently associated with other systemic therapies. In our patient, the association of BV with EF RT allowed the patient to receive subsequent consolidation treatment with haplo-identical SCT. Further studies investigating the combination of RT with BV in HL are warranted.

Clinical and preclinical validation of the serum free light chain assay: identification of the critical difference for optimized clinical use

The use of the assay for the measurements of free light chains in serum (sFLCs) is increasing. However, there are technical limitations that potentially affect the use in serial measurements. We need further knowledge on the standards of analytical precision, the utility of conventional population‐based reference values and the critical difference (CD) between serial results required for significance. To answer these questions, the biological variation must be known.

The Danish National Multiple Myeloma Registry

Aim The Danish National Multiple Myeloma Registry (DMMR) is a population-based clinical quality database established in January 2005. The primary aim of the database is to ensure that diagnosis and treatment of plasma cell dyscrasia are of uniform quality throughout the country. Another aim is to support research. Patients are registered with their unique Danish personal identification number, and the combined use of DMMR, other Danish National registries, and the Danish National Cancer Biobank offers a unique platform for population-based translational research. Study population All newly diagnosed patients with multiple myeloma (MM), smoldering MM, solitary plasmacytomas, and plasma cell leukemia in Denmark are registered annually; ~350 patients. Amyloid light-chain amyloidosis, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes syndrome), monoclonal gammopathy of undetermined significance and monoclonal gammopathy of undetermined significance with polyneuropathy have been registered since 2014. Main variables The main registered variables at diagnosis are patient demographics, baseline disease characteristics, myeloma-defining events, clinical complications, prognostics, first- and second-line treatments, treatment responses, progression free, and overall survival. Descriptive data Up to June 2015, 2,907 newly diagnosed patients with MM, 485 patients with smoldering MM, 64 patients with plasma cell leukemia, and 191 patients with solitary plasmacytomas were registered. Registration completeness of new patients is ~100%. A data validation study performed in 2013–2014 by the Danish Myeloma Study Group showed >95% data correctness. Conclusion The DMMR is a population-based data validated database eligible for clinical, epidemiological, and translational research.

Evaluation of the serum free light chain (sFLC) analysis in prediction of response in symptomatic multiple myeloma patients: rapid profound reduction in involved FLC predicts achievement of VGPR.

Observational data from clinical studies indicate that the goal of first‐line therapy in newly diagnosed patients with symptomatic multiple myeloma (MM) should be very good partial response (VGPR) or better, preferably before high‐dose treatment. We evaluated the value of early measurements of involved free light chains (iFLC) in prediction of high‐quality responses. Measuring iFLC has a potential advantage due to a short half‐life compared to the half‐life of the M‐protein.

Clinicopathological features of plasmablastic multiple myeloma: a population-based cohort

Multiple myeloma (MM) is a common malignant hematological disease displaying considerable heterogeneity. Historical data indicate a prognostic significance of plasmablastic morphology, proliferation, and adverse cytogenetics, but there is little knowledge on the degree of interdependency of these parameters. The aim of this study was to study the degree of overlap between these variables. In a consecutive population‐based cohort of 194 untreated MM patients, morphology, and proliferation index, using immunohistochemical double staining for Ki‐67 and CD138, was analyzed. In addition, cytogenetic changes were studied by karyotyping and fluorescence in situ hybridization (FISH). Plasmablastic morphology correlated with unfavorable clinical features, high proliferation index, high percentage of plasma cell infiltration in the bone marrow, abnormal karyotype, and del(13q) detected by karyotyping, which indicates that plasmablastic morphology reflects advanced and highly proliferative disease. However, plasmablastic morphology did not correlate with established adverse prognostic cytogenetics identified by FISH, for example, t(4;14), t(14;16) and del(17p).

Danish National Lymphoma Registry.

Aim of database The Danish National Lymphoma Registry (LYFO) was established in order to monitor and improve the diagnostic evaluation and the quality of treatment of all lymphoma patients in Denmark. Study population The LYFO database was established in 1982 as a seminational database including all lymphoma patients referred to the departments of hematology. The database became nationwide on January 1, 2000. Main variables The main variables include both clinical and paraclinical variables as well as details of treatment and treatment evaluation. Up to four forms are completed for each patient: a primary registration form, a treatment form, a relapse form, and a follow-up form. Variables are used to calculate six result quality indicators (mortality 30 and 180 days after diagnosis, response to first-line treatment, and survival estimates 1, 3, and 5 years after the time of diagnosis), and three process quality indicators (time from diagnosis until the start of treatment, the presence of relevant diagnostic markers, and inclusion rate in clinical protocols). Descriptive data Approximately 23,000 patients were registered in the period 1982–2014 with a median age of 65 years (range: 16–100 years) and a male/female ratio of 1.23:1. Patients can be registered with any of 42 different subtypes according to the World Health Organization classifications. Conclusion LYFO is a nationwide database for all lymphoma patients in Denmark and includes detailed information. This information is used for both epidemiological research and clinical follow-up as well as for administrative purposes.