Carsten Helleberg

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.

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.

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.

The impact of comorbidity on mortality in multiple myeloma: a Danish nationwide population-based study

To describe the prevalence of comorbidity and its impact on survival in newly diagnosed multiple myeloma patients compared with population controls. Cases of newly diagnosed symptomatic multiple myeloma during the 2005–2012 period were identified in the Danish National Multiple Myeloma Registry. For each myeloma patient, 10 members of the general population matched by age and sex were chosen from the national Civil Registration System. Data on comorbidity in the myeloma patients and the general population comparison cohort were collected by linkage to the Danish National Patient Registry (DNPR). Cox proportional hazards regression models were used to evaluate the prognostic significance of comorbidity. The study included 2190 cases of multiple myeloma and 21,900 population controls. The comorbidity was increased in multiple myeloma patients compared with population controls, odds ratio (OR) 1.4 (1.1–1.7). The registration of comorbidity was highly increased within the year preceding diagnosis of multiple myeloma (OR 3.0 [2.5–3.5]), which was attributable to an increased registration of various diseases, in particular, renal disease with OR 11.0 (8.1–14.9). The median follow‐up time from diagnosis of multiple myeloma for patients alive was 4.3 years (interquartile range 2.4–6.3). Patients with registered comorbidity had increased mortality compared with patients without comorbidity, hazard ratio 1.6 (1.5–1.8). Multiple myeloma patients have increased comorbidity compared with the background population, in particular during the year preceding the diagnosis of myeloma.

Early relapsed disease of multiple myeloma following up-front HDM-ASCT: a study based on the Danish Multiple Myeloma Registry in the period 2005 to 2014

Despite the introduction of proteasome inhibitor (PI) and immunomodulatory drugs (IMiDs) as induction treatment some patients still experience early relapse after autologous hematopoietic bone marrow transplantation (HDM-ASCT) and these patients have poor outcome [1–4]. Few studies have addressed early relapse after HDM-ASCT as a risk marker for poor overall survival (OS). Kumar et al. found an OS of 20.1 months for patients with a relapse within 1 year following VAD or thalidomide as induction treatment [5] and OS was only 23.1 months among patients who received induction treatment with IMiDs and PI [3]. In 2010, we found an OS of 28.7 months for patients with relapse within 18 months from HDM-ASCT before induction treatment with PI and IMiDs [2]. The aim of this study was to analyze outcome and prognostic markers for OS in patients with an early relapse after HDM-ASCT in a population-based cohort of multiple myeloma (MM) patients before and after IMiDs and PI was used as induction and relapse treatment. A total of 1970 patients were diagnosed with MM in the period 2005–2014 at one of the four participating Danish centers (Odense, Roskilde, Herlev, and Rigshospitalet. The centers Aarhus and Aalborg did not participate) and registered in the population-based Danish Multiple Myeloma Registry (Supplementary Figure 1) [6]. Five hundred and seventy-five patients were treated with HDM-ASCT. Elevated lactate dehydrogenase (LDH) was defined as levels >205 U/L. High LDH was defined as LDH levels >410 U/L as a clinical trial uses this criteria to select high-risk patients (EudraCT number: 2015-004831-11). High-risk myeloma was defined as the presence of t(4;14), t(14;16), or loss of 17p in myeloma cells (HR1) or as t(4;14), t(14;16), gain of 1q, loss of 17p, and elevated LDH (HR2) [7]. Patient data were divided into two calendar periods: 2005–2008, when cyclophosphamide was used as induction treatment (229 patients; 40%), and 2009–2014 where >80% of the patients received bortezomib-based induction treatment (346 patients, 60%) (Supplementary Table 1 and 4) [6]. Maintenance treatment is not approved in Denmark. Treatment options at relapse were thalidomide (since 1998), bortezomib (since 2003), and lenalidomide (since 2005) (Supplementary Table 2). The Danish guidelines recommend salvage HDM-ASCT for relapse later than 18 months. This study only includes a few patients treated with new drugs in clinical trials. Fluorescent in situ hybridization at diagnosis was introduced as a standard procedure in 2012. Statistical calculations were performed using R version 3.2.3 (R Foundation for Statistical Computing, Vienna, * Annette J. Vangsted Annette.juul.vangsted@regionh.dk

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.

The majority of newly diagnosed myeloma patients do not fulfill the inclusion criteria in clinical phase III trials

Real-world data (RWD) are important as randomized clinical trials (RCT) have strict inand exclusion criteria that do not allow evaluation of the effect and toxicity of new drugs or treatment modalities in patients that do not fulfill these criteria. Since 2005, clinical data on all newly diagnosed multiple myeloma (MM) patients have been registered in the Danish Multiple Myeloma Registry (DMMR) [1, 2]. The Danish National guidelines for treatment of MM, are based on the results of phase III RCT (www.myeloma.dk). The median overall survival (OS) for patients above 65 years registered in DMMR in 2009–2014 is less as compared to the Hovon 87 trial (32.9 months (mo.) versus 48 mo.) [3, 4]. In patients eligible for high-dose melphalan with autologous stem cell transplantation (HDM-ASCT) the median OS in the DMMR was 74 mo. in 2009–2014 (Abstract 1946 EHA 2016). A review of OS for patients treated in HDM-ASCT RCT describe a 3-year OS of 80% and 75% in patients treated with and without bortezomib, respectively [5]. In the DMMR, 3-year OS was 77% in the calendar period 2009–2013 [4]. The worse OS of the elderly in the DMMR let us to compare OS for patients registered in DMMR who fulfilled the inclusion and exclusion criteria in phase III RCT with OS for those patients who did not. Furthermore, we analyzed the fraction of population-based cohort of newly diagnosed elderly and younger myeloma patients that fulfill the inclusion and exclusion criteria. Four recent phase III RCTs for MM patients ineligible for HDM-ASCT (Hovon 87 trial [3]; VISTA trial [6]; FIRST trial [7]; and the SWOG S0777 trial [8]) and four recent phase III RCTs in MM patients eligible for HDMASCT at diagnosis (STaMINA trial [9]; IFM2013-04 trial [10]; IFM DFCI 2009 trial [11], and the Hovon95/EMN02 trial [12]) were used and 11 inclusion and exclusion criteria, reported in at least 3 out of 4 trials, were selected (Supplementary Tables S1 and S2). The three inclusion criteria were CRAB, measurable disease, and bone marrow plasma cells (PLC) ≥ 10%, and the eight exclusion criteria were kidney failure, WHO performance status (PS) > 2, AL amyloidosis, acute myocardial infarction (AMI) within last 6 months, human immunodeficiency virus (HIV), hepatitis B or C, cancer within 5 years (excluding stage 0–1 cervical cancer, some skin cancers), severe comorbidity (congestive heart failure (CHF), dementia, severe diabetes, moderate, or severe liver disease, hemiplegia) [2] (Supplementary Table S3). The validated DMMR has been described [1]. ICD-10 codes from the Danish National Patient Registry (DNPR) were used (Supplementary Table S3) [2]. In the relapse setting, thalidomide was introduced in 1999, bortezomib in 2003, lenalidomide in 2005, pomalidomide in 2014, carfilzomib, elotuzumab, and daratumumab in 2016, and ixazomib in 2017 [13, 14]. Combination treatment including thalidomide, bortezomib, and lenalidomide are now treatment options at diagnosis. Clinical data from 2189 MM patients at diagnosis were collected from DMMR and DNPR between 1 January 2005 and 31 December 2013 (Supplementary Table S3) [1, 2]. * Annette J. Vangsted annette.juul.vangsted@regionh.dk