Elias K. Mai

Baseline characteristics, chromosomal alterations, and treatment affecting prognosis of deletion 17p in newly diagnosed myeloma.

Deletion 17p13, del(17p), is associated with poor outcome in myeloma but some patients show long‐term survival. With the current study we intended to identify factors impacting outcome of such high risk patients. We analyzed 110 newly diagnosed, symptomatic patients with del(17p) detected by fluorescence in situ hybridization (FISH) in CD138‐purified myeloma cells to identify prognostic factors for survival. Age >65 years, ISS III, and elevated LDH negatively impacted survival. Patients with subclonal (10–60% of plasma cells) del(17p) had longer progression‐free survival (PFS) than patients with del(17p) in >60% of plasma cells (26 vs. 19 months, P = 0.03). Additional gain of 1q21 was associated with shorter PFS (17 vs. 25 months, P = 0.01). Hyperdiploidy did not ameliorate impact of del(17p), but gain 19q13 predicted longer PFS (30 vs. 18 months, P = 0.01) and overall survival (50 vs. 29 months, P = 0.01). Multivariate analysis in transplant eligible patients (≤65 years) revealed better survival for patients treated with upfront autologous transplantation (hazard ratio, [95% confidence interval]: 0.15 [0.04, 0.58], P = 0.006). Application of maintenance therapy was associated with better survival in transplant‐eligible patients (0.30 [0.09, 0.99], P = 0.05). We demonstrate heterogeneous outcome of patients with del(17p) according to baseline characteristics and treatment. 19q13 should be included in routine FISH panel, since gains were associated with better survival. Am. J. Hematol. 91:E473–E477, 2016.

Single versus tandem high-dose melphalan followed by autologous blood stem cell transplantation in multiple myeloma: long-term results from the phase III GMMG-HD2 trial.

The prospective, randomized phase III trial GMMG‐HD2 aimed at demonstrating non‐inferiority of single (Arm A) versus tandem (Arm B) high‐dose melphalan followed by autologous transplantation (HDM/ASCT) with regard to 2‐year event‐free survival (EFS) in newly‐diagnosed multiple myeloma (MM) and included 358 evaluable patients [Intention‐to‐treat population, (ITT), single/tandem HDM/ASCT: n = 177/181].

A magnetic resonance imaging-based prognostic scoring system to predict outcome in transplant-eligible patients with multiple myeloma

Diffuse and focal bone marrow infiltration patterns detected by magnetic resonance imaging have been shown to be of prognostic significance in all stages of monoclonal plasma cell disorders and have, therefore, been incorporated into the definition of the disease. The aim of this retrospective analysis was to develop a rapidly evaluable prognostic scoring system, incorporating the most significant information acquired from magnetic resonance imaging. Therefore, the impact of bone marrow infiltration patterns on progression-free and overall survival in 161 transplant-eligible myeloma patients was evaluated. Compared to salt and pepper/minimal diffuse infiltration, moderate/severe diffuse infiltration had a negative prognostic impact on both progression-free survival (P<0.001) and overall survival (P=0.003). More than 25 focal lesions on whole-body magnetic resonance imaging or more than seven on axial magnetic resonance imaging were associated with an adverse prognosis (progression-free survival: P=0.001/0.003 and overall survival: P=0.04/0.02). A magnetic resonance imaging-based prognostic scoring system, combining grouped diffuse and focal infiltration patterns, was formulated and is applicable to whole-body as well as axial magnetic resonance imaging. The score identified high-risk patients with median progression-free and overall survival of 23.4 and 55.9 months, respectively (whole-body-based). Multivariate analyses demonstrated that the magnetic resonance imaging-based prognostic score stage III (high-risk) and adverse cytogenetics are independent prognostic factors for both progression-free and overall survival (whole-body-based, progression-free survival: hazard ratio=3.65, P<0.001; overall survival: hazard ratio=5.19, P=0.005). In conclusion, we suggest a magnetic resonance imaging-based prognostic scoring system which is a robust, easy to assess and interpret parameter summarizing significant magnetic resonance imaging findings in transplant-eligible patients with multiple myeloma.

Association between magnetic resonance imaging patterns and baseline disease features in multiple myeloma: analyzing surrogates of tumour mass and biology.

AbstractObjectiveTo assess associations between bone marrow infiltration patterns and localization in magnetic resonance imaging (MRI) and baseline clinical/prognostic parameters in multiple myeloma (MM).MethodsWe compared baseline MM parameters, MRI patterns and localization of focal lesions to the mineralized bone in 206 newly diagnosed MM patients.ResultsA high tumour mass (represented by International Staging System stage III) was significantly associated with severe diffuse infiltration (p = 0.015) and a higher number of focal lesions (p = 0.006). Elevated creatinine (p = 0.003), anaemia (p < 0.001) and high LDH (p = 0.001) correlated with severe diffuse infiltration. A salt and pepper diffuse pattern had a favourable prognosis. A higher degree of destruction of mineralized bone (assessed by X-ray or computed tomography) was associated with an increasing number of focal lesions on MRI (p < 0.001). Adverse cytogenetics (del17p/gain1q21/t(4;14)) were associated with diffuse infiltration (p = 0.008). The presence of intraosseous focal lesions exceeding the mineralized bone had a borderline significant impact on prognosis.ConclusionsDiffuse bone marrow infiltration on MRI correlates with adverse cytogenetics, lowered haemoglobin values and high tumour burden in newly diagnosed MM whereas an increasing number of focal lesions correlates with a higher degree of bone destruction. Focal lesions exceeding the cortical bone did not adversely affect the prognosis.Key Points• Diffuse MRI correlates with adverse cytogenetics, lowered haemoglobin and high tumour burden. • Higher numbers of MRI focal lesions correlate with increasing degree of bone destruction. • Focal lesions exceeding the cortical bone borderline significantly influence survival. • Moderate/severe diffuse infiltration and more than 23 focal lesions adversely affect survival.

Analysis of long-term survival in multiple myeloma after first-line autologous stem cell transplantation: impact of clinical risk factors and sustained response

The widespread use of high‐dose therapy and autologous stem cell transplantation (ASCT) as well as the introduction of novel agents have significantly improved outcomes in multiple myeloma (MM) enabling long‐term survival. We here analyze factors influencing survival in 865 newly diagnosed MM patients who underwent first‐line ASCT at our center between 1993 and 2014. Relative survival and conditional survival were assessed to further characterize long‐term survivors. Achievement of complete response (CR) post‐ASCT was associated with prolonged progression‐free survival (PFS) in the whole cohort and with significantly superior overall survival (OS) in the subgroup of patients receiving novel agent‐based induction therapy. Landmark analyses performed at 1, 3, and 5 years post‐ASCT revealed that sustainment of any response had a highly significant influence on survival with no significant differences between sustained CR and sustained inferior responses. Furthermore, outcome was independently improved by administration of maintenance therapy. A subset of patients did experience long‐term survival >15 years. However, conditional survival demonstrated a persistent risk of myeloma‐associated death and cumulative relative survival curves did not show development of a clear plateau, even in prognostically advantageous groups. In conclusion, in this large retrospective study, sustained response after first‐line ASCT was found to be a major prognostic factor for OS independent of depth of sustained response. Administration of maintenance therapy further improved outcome, supporting the hypothesis that interventions to prolong responses achieved post‐ASCT may be essential to reach long‐term survival, especially in the setting of persisting residual disease.

Longitudinal fluorescence in situ hybridization reveals cytogenetic evolution in myeloma relapsing after autologous transplantation

To investigate cytogenetic evolution after upfront autologous stem cell transplantation for newly diagnosed myeloma we retrospectively analyzed fluorescence in situ hybridization results of 128 patients with paired bone marrow samples from the time of primary diagnosis and at relapse. High-risk cytogenetic abnormalities (deletion 17p and/or gain 1q21) occurred more frequently after relapse (odds ratio: 6.33; 95% confidence interval: 1.86–33.42; P<0.001). No significant changes were observed for defined IGH translocations [t(4;14); t(11;14); t(14;16)] or hyperdiploid karyotypes between primary diagnosis and relapse. IGH translocations with unknown partners occurred more frequently at relapse. New deletion 17p and/or gain 1q21 were associated with cytogenetic heterogeneity, since some de novo lesions with different copy numbers were present only in subclones. No distinct baseline characteristics were associated with the occurrence of new high-risk cytogenetic abnormalities after progression. Patients who relapsed after novel agent-based induction therapy had an increased risk of developing high-risk aberrations (odds ratio 10.82; 95% confidence interval: 1.65–127.66; P=0.03) compared to those who were treated with conventional chemotherapy. Survival analysis revealed dismal outcomes regardless of whether high-risk aberrations were present at baseline (hazard ratio, 3.53; 95% confidence interval: 1.53–8.14; P=0.003) or developed at relapse only (hazard ratio, 3.06; 95% confidence interval: 1.09–8.59; P=0.03). Our results demonstrate cytogenetic evolution towards high-risk disease after autologous transplantation and underline the importance of repeated genetic testing in relapsed myeloma (EudraCT number of the HD4 trial: 2004-000944-26).

A systematic classification of death causes in multiple myeloma

The introduction of high-dose therapy followed by autologous blood stem cell transplantation (HDT/ ABSCT) and the novel agents led to continuously improving survival in multiple myeloma (MM). However, the majority of MM patients ultimately relapses or progresses, and deceases of disease related conditions such as severe infections, renal failure or toxicity. Nonetheless, the increasing life expectancy of the MM population might translate into an increase in causes of death (COD) unrelated to MM. The aim of this study was to develop and apply a reliable systematic classification for COD in MM, combining the assessment of a specific COD and a causal link between the COD and MM, MM therapy or unrelated conditions, and to assess the impact of known MM prognostic factors on COD. A number of 818 MM patients, who had received an upfront HDT/ABSCT between June 1992 and October 2013 at the University Hospital Heidelberg, Heidelberg, Germany were included in this single-center, retrospective analysis (Supplemental Table 1). Until April 2014, 483 of the eligible patients were deceased. The median overall survival of the cohort was 5.9 years (Supplemental Figure 1). This analysis was approved by the ethics committee of the University of Heidelberg (Number S-337/2009). All patients gave written informed consent. To construct a systematic COD classification, the process of qualitative content analysis was applied using MAXQDA (VERBI GmbH, Berlin, Germany) (Supplemental Figure 2). A preliminary classification was developed based on the results of a PubMed literature search on COD in MM and existing COD classifications. Next, the preliminary COD classification (Supplemental Figure 3) was examined on the collective to evaluate feasibility and practicality. Based on this initial evaluation, a final, systematic COD classification for MM (Fig. 1) and a corresponding rule-based allocation algorithm (Supplemental Figure 4) were built and applied to our cohort. The final COD classification is hierarchically and systematically structured (Fig. 1). A superordinate system of categories determines the causal link between the COD and MM or side effects of MM therapy and distinguishes the following categories: (1) MM-dependent, (2) MMindependent, (3) not attributable to (1)/(2), and (4) unknown (Fig. 1). In addition, MM-dependent COD (1) are subdivided into (1A) MM progression-related, (1B) therapy-related, and (1C) not attributable to (1A)/(1B). The subordinate system defines COD at four levels of different specificity applying the MedDRA terminology: the System Organ Class (SOC) has the lowest and the Preferred Term (PT) the highest specificity (Fig. 1). According to the developed algorithm, COD were allocated to the different categories by consulting the available medical documentation within 90 days before death (Supplemental Figure 4). Examples for each category can be found in the Supplemental Methods. Additionally, a validity system was developed and applied to the cohort to evaluate the reliability of the consulted medical documentation (Supplemental Methods). Statistical analyses were conducted using R version 3.2.218 and survival package (Supplemental Methods).

Bortezomib-based induction therapy with high or low-dose dexamethasone in newly diagnosed, transplant-eligible multiple myeloma

Elias K. Mai 1 ● Thomas Hielscher ● Uta Bertsch ● Jana Schlenzka ● Hans J. Salwender ● Markus Munder ● Christian Gerecke ● Ulrich Dührsen ● Peter Brossart ● Kai Neben ● Jens Hillengass ● Marc S. Raab ● Maximilian Merz ● Marc-Andrea Baertsch ● Anna Jauch ● Dirk Hose ● Hans Martin ● Hans-Walter Lindemann ● Igor W. Blau ● Christof Scheid ● Katja C. Weisel ● Hartmut Goldschmidt ● for the German-speaking Myeloma Multicenter Group (GMMG)

Cytogenetic aberrations in multiple myeloma are associated with shifts in serum immunoglobulin isotypes distribution and levels

This is a letter to the editors.

Multiples Myelom: Aktuelle Therapiekonzepte und neue Behandlungsstrategien

Beim multiplen Myelom (MM) handelt es sich um eine maligne, lymphoproliferative B-ZellErkrankung, an der jährlich etwa 5500 Menschen in Deutschland neu erkranken. Es gehört damit zu den 20 häu gsten Tumorerkrankungen in Deutschland. Vom MM wird das Plasmozytom unterschieden, ein solitärer, intraoder extramedullärer Plasmazelltumor. Das MM hingegen ist eine systemische Plasmazellerkrankung, vornehmlich der Knochenmarkräume (Abb. 1). Die Indikation zur erapie des MM erfolgt gemäß der CRAB-Kriterien (Tab. 1) bei einer Endorganschädigung (sog. symptomatisches MM). Im Gegensatz zum solitären Plasmozytom ist das multiple Myelom eine systemische Plasmazellerkrankung der Knochenmarkräume Hiervon abzugrenzen sind die monoklonale Gammopathie unklarer Signi kanz (MGUS) und das multiple Smoldering-Myelom („smoldering muliple myeloma“, SMM), bei denen noch keine Endorganschäden vorliegen (Tab. 2, [1]). Di erenzialdiagnostisch kommen das lymphoplasmazytische Lymphom (M. Waldenström), andere maligne Lymphome sowie die AL(„amyloid light-chain“)-Amyloidose in Betracht.