Kristian Thidemann Andersen

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.

Central nervous system involvement by multiple myeloma: A multi-institutional retrospective study of 172 patients in daily clinical practice

The multicenter retrospective study conducted in 38 centers from 20 countries including 172 adult patients with CNS MM aimed to describe the clinical and pathological characteristics and outcomes of patients with multiple myeloma (MM) involving the central nervous system (CNS). Univariate and multivariate analyses were performed to identify prognostic factors for survival. The median time from MM diagnosis to CNS MM diagnosis was 3 years. Thirty‐eight patients (22%) were diagnosed with CNS involvement at the time of initial MM diagnosis and 134 (78%) at relapse/progression. Upon diagnosis of CNS MM, 97% patients received initial therapy for CNS disease, of which 76% received systemic therapy, 36% radiotherapy and 32% intrathecal therapy. After a median follow‐up of 3.5 years, the median overall survival (OS) from the onset of CNS involvement for the entire group was 7 months. Untreated and treated patients had median OS of 2 and 8 months, respectively (P < 0.001). At least one previous line of therapy for MM before the diagnosis of CNS disease and >1 cytogenetic abnormality detected by FISH were independently associated with worse OS. The median OS for patients with 0, 1 and 2 of these risk factors were 25 months, 5.5 months and 2 months, respectively (P < 0.001). Neurological manifestations, not considered chemotherapy‐related, observed at any time after initial diagnosis of MM should raise a suspicion of CNS involvement. Although prognosis is generally poor, the survival of previously untreated patients and patients with favorable cytogenetic profile might be prolonged due to systemic treatment and/or radiotherapy. Am. J. Hematol. 91:575–580, 2016.

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.

Influence of adalimumab treatment on anastomotic strength, degree of inflammation, and collagen formation: an experimental study on the small intestine of rabbits.

Background:Adalimumab is a TNF-&agr; inhibitor, which has gained wide use in the treatment of inflammatory bowel diseases. The potential detrimental effect of TNF-&agr; inhibitors on postoperative complications such as anastomotic leakage is unknown. The aim of this study was to investigate the effect of a single therapeutic dose of adalimumab on anastomotic strength inflammation and collagen formation. Methods:Twenty-eight female rabbits (1.8-2.2 kg) were allocated to subcutaneous injection with either adalimumab (1.5 mg/kg) (n=14) or placebo (n=14). One week after medication two separate end-to-end anastomoses were performed in the jejunum. The rabbits were killed on the third postoperative day. The anastomosis were subjected to tensile strength analysis and histopathological examination. Results:No statistically significant differences were found between the two groups regarding maximum tensile strength, inflammation parameters and collagen formation in the anastomosis area. Multiple regression analysis showed no association between maximum tensile strength histological changes, time under anaesthesia, duration of surgery, weight gain, weight loss and number of sutures in either group. Conclusion:We found no statistically significant effect of a single therapeutic dose of adalimumab on anastomotic strength, histological parameters or collagen formation in rabbits.

Recognition and management of common, rare, and novel serum protein electrophoresis and immunofixation interferences

Protein electrophoresis and immunofixation are subject to a variety of analytical interferences that may affect monoclonal protein diagnostics performed in the context of monoclonal gammopathies. Interferences include endogenous substances, such as hemoglobin and fibrinogen, and exogenous compounds, such as radiocontrast dyes, antibiotics, and monoclonal antibody therapies. General approaches to managing interferences begin with recognition of the problem. Provided herein are examples of common, rare, and novel interferences with the goal of providing a comprehensive overview. With each example, specific methods and strategies are provided to manage analytical interferences to ensure that interpretative reports are accurate. Longstanding and newer technologies are also described to contextualize where interferences may be identified and avoided.

Bone healing in multiple myeloma: A prospective evaluation of the impact of first-line anti-myeloma treatment.

Myeloma cells disturb a normally balanced bone remodeling process. This imbalance of bone metabolism may cause osteopenic bones, focal osteolytic lesions and clinical symptoms. The excess bone resorption resulting in osteolytic lesions has traditionally been perceived as irreversible. We

Immunoparesis in newly diagnosed Multiple Myeloma patients: Effects on overall survival and progression free survival in the Danish population

Immunoparesis (hypogammaglobulinemia) is associated to an unfavorable prognosis in newly diagnosed Multiple myeloma (MM) patients. However, this finding has not been validated in an unselected population-based cohort. We analyzed 2558 newly diagnosed MM patients in the Danish Multiple Myeloma Registry representing the entire MM population in Denmark from 2005–2013. Two-thousand two hundred and fifty three patients (90%) presented with reduction below lower normal levels of at least one uninvolved immunoglobulin. Using multivariable Cox regression we found that high age, high ISS score, high LDH and IgA MM were associated to both shorter overall survival and progression free survival. Furthermore, bone marrow plasma cell % was associated to short progression free survival. Immunoparesis had no independent significant effect on OS (HR 0.9 (95%CI: 0.7;1.0; p = 0.12)). Likewise, the number of suppressed immunoglobulins or the relative degree of suppressed uninvolved immunoglobulins from lower normal level (quantitative immunoparesis) was not associated to OS in the multivariable analysis. However, quantitative immunoparesis with at least 25% reduction (from lower normal level) of uninvolved immunoglobulins was associated to shorter PFS for the entire population. The impact of quantitative immunoparesis on PFS was present irrespective of calendar periods 2005–2008 and 2009–2013. Our population-based study does not confirm that immunoparesis at diagnosis is an independent prognostic factor regarding OS. However, quantitative immunoparesis is associated to a shorter PFS.

Baseline bone involvement in multiple myeloma - a prospective comparison of conventional X-ray, low-dose computed tomography, and 18flourodeoxyglucose positron emission tomography in previously untreated patients

Examination of bone lesions is a compulsory part of baseline assessments in patients with multiple myeloma (MM). Low-dose computed tomography (CT) scan has recently been recommended as a replacement of conventional X-ray for the diagnosis of osteolytic lesions by the European Myeloma Network.[1][1]

Characteristics and outcomes of patients with multiple myeloma aged 21–40 years versus 41–60 years: a multi‐institutional case‐control study

We compared the outcomes of multiple myeloma (MM) patients aged 21–40 and 41–60 years in the novel agent era. This case‐control study included 1089 patients between 2000 and 2015. Cases and controls were matched for sex, International Staging System (ISS) stage and institution. There were 173 patients in the younger group and 916 patients in the older group. Younger patients presented with a higher incidence of lytic lesions (82% vs. 72%; P = 0·04) and high‐risk cytogenetic abnormalities (83% vs. 68%; P = 0·007), but lower rate of elevated lactate dehydrogenase (21% vs. 44%; P < 0·001). Five‐ and 10‐year overall survival (OS) in younger versus older patients was 83% vs. 67% and 56% vs. 39%, respectively (P < 0·001). Similar results were seen when studying the subset of 780 patients who underwent autologous transplantation. Younger patients with ISS stage 1 had a better OS than older patients (P < 0·001). There was no survival difference between younger and older patients with ISS stage 2 or 3. Younger MM patients, aged 21–40 years, treated in the era of novel agents have a better OS than their counterparts aged 41–60 years, but the survival advantage observed in younger patients was lost in more advanced stages of MM.

Causes of early death in multiple myeloma patients treated with high-dose therapy followed by autologous stem cell transplantation: A study based on the nationwide Danish Multiple Myeloma Registry

other day for 6 doses. This was followed by a maintenance dose of 120 mg/kg IV weekly for seven weeks in responding patients. Four patients received AAT as the first therapy option after demonstrating steroid-refractory GVHD, while three patients received it as a subsequent line of treatment. The median interval between initial acute GVHD diagnosis and administration of AAT was 36 days (range 5–124 days). No adverse events related to AAT were seen. Among the seven treated patients, three had a PR at day 28; however, there were no CRs (Table 1). Six patients were evaluable for 3-month GVHD-F/A-IST-free endpoint, and none had a sustained response to AAT. One (non-evaluable) patient with PR is currently 6 weeks post therapy initiation. Four patients died due to GVHD-related complications with a median time to death post GVHD diagnosis of 138 days (Range 83–217). Over the last 2 years, several novel agents have demonstrated promise for steroid-refractory GI GVHD, however no agent has been shown to be efficacious in a randomized controlled trial. Patients with steroid-refractory GVHD often do not respond to second-line therapies, and even when they do respond, they frequently experience a flare in their disease requiring subsequent therapy as was seen in our experience with AAT. To assess durability of responses, we utilized an alternative endpoint, GVHD-F/A-IST-free, at 3 months to assess the number of patients who were still responding and free from additional therapies targeting GVHD. In the study by Mercondes et al. 33% of patients had a CR to AAT, and all patients received the drug as second line. In contrast, three out of the 7 patients in our study received AAT beyond second line and none of our patients achieved a CR with this agent alone. Additionally, all patients in our series had overall grade IIIIV disease at presentation compared to 16% (n52) in the previous study, which could be a possible reason for discrepant suboptimal activity seen in our series. It is possible the up-front application of AAT in GVHD management before steroid-refractory disease is establishment might be more beneficial. A multi-center trial evaluating AAT’s use prior to development of steroid-refractory disease is currently underway (NCT02956122), and hopefully will clarify role of this agent as frontline therapy of acute GI GVHD.