Investigation of Rare Non-Coding Variants in Familial Multiple Myeloma.

Multiple myeloma (MM) is a plasma cell malignancy whereby a single clone of plasma cells over-propagates in the bone marrow, resulting in the increased production of monoclonal immunoglobulin. While the complex genetic architecture of MM is well characterized, much less is known about germline variants predisposing to MM. Genome-wide sequencing approaches in MM families have started to identify rare high-penetrance coding risk alleles. In addition, genome-wide association studies have discovered several common low-penetrance risk alleles, which are mainly located in the non-coding genome. Here, we further explored the genetic basis in familial MM within the non-coding genome in whole-genome sequencing data. We prioritized and characterized 150 upstream, 5' untranslated region (UTR) and 3' UTR variants from 14 MM families, including 20 top-scoring variants. These variants confirmed previously implicated biological pathways in MM development. Most importantly, protein network and pathway enrichment analyses also identified 10 genes involved in mitogen-activated protein kinase (MAPK) signaling pathways, which have previously been established as important MM pathways.

Response Improvement Rather than Response Status after First Autologous Stem Cell Transplantation Is a Significant Prognostic Factor for Survival Benefit from Tandem Compared with Single Transplantation in Multiple Myeloma Patients.

High-dose chemotherapy and autologous stem cell transplantation (ASCT) have provided effective treatment for patients with newly diagnosed multiple myeloma for more than 3 decades; however, which patients will benefit from tandem ASCT compared with single ASCT remains unclear. Here we retrospectively analyzed 978 trial and nontrial patients who underwent single or tandem ASCT in Heidelberg or other German-Speaking Myeloma Multicenter Group centers. Our results show that response improvement after first ASCT is a significant prognostic factor for progression-free survival benefit from tandem versus single ASCT (multivariable analysis, P = .002; hazard ratio, .64; 95% confidence interval, .48 to .85; P for interaction = .02). The depth of response after first ASCT and the cytogenetic profile did not have a significant prognostic effect on survival benefit from tandem ASCT. Our results suggest that it is not the response depth, but rather the response improvement after first ASCT is of prognostic significance regarding the benefit of tandem ASCT versus single ASCT.

Salvage therapy versus upfront autologous stem cell transplantation in multiple myeloma patients with progressive disease after first-line induction therapy.

It is a matter of debate whether myeloma patients with progressive disease (PD) after induction should receive salvage therapy or proceed directly to autologous stem cell transplantation. We performed a retrospective analysis of 1599 patients treated between 1991 and 2016 at the University Hospital of Heidelberg and other centers. Deepening of response through salvage therapy did not lead to better progression-free or overall survival (PD versus salvage therapy patients: HR = 0.71, 95% CI [0.28, 1.80], p = 0.5 and HR = 0.77, 95% CI [0.30, 1.95], p = 0.6, respectively), neither in patients treated with novel agents (HR = 0.66, 95% CI [0.23, 1.85], p = 0.4 and HR = 0.76, 95% CI [0.27, 2.15], p = 0.6) nor older regimens (HR = 0.86, 95% CI [0.36, 2.07], p = 0.7 and HR = 0.8, 95% CI [0.34, 1.91], p = 0.6). Therefore, primary nonresponders might benefit from a direct transplant rather than salvage induction, although the analyzed salvage therapy cohort was small (n = 23) and cytogenetics was not included in the multivariable analysis.

Familial Cancer: How to Successfully Recruit Families for Germline Mutations Studies? Multiple Myeloma as an Example.

INTRODUCTION: Identification of germline mutations related to an increased cancer risk enables diagnostic, preventive, and therapeutic measures for individuals carrying the disease variant. However, recruitment of families for studies on these mutations can be challenging. Herein we present some of the obstacles that can arise during such studies. We suggest solutions for overcoming or avoiding these difficulties, enabling an efficient and ethically correct family recruitment. PATIENTS AND METHODS: We describe a study on germline mutations associated with familial risk of multiple myeloma using next-generation sequencing of the whole genome. To date, the study has recruited 54 participants/16 families from different centers in Germany. It was performed at the University Hospital of Heidelberg and German Cancer Research Center. RESULTS: We were confronted with ethical/psychological concerns of patients and family members, a large number of ineligible families, a profound time investment by the participants and the study team, incidental findings, and participants' death. We present solutions to these difficulties such as: knowledge of and adherence to the laws protecting participants' rights, an exact clarification of the inclusion and exclusion criteria, a clear division of tasks within members of the study team, a collaboration with general practitioners/oncologists and patients' support groups, a detailed and understandable informed consent including information about incidental findings, and a choice of a representative in case of participant's death. CONCLUSION: A successful recruitment for studies on familial cancer is challenging, yet possible. It can be facilitated by applying the previously mentioned strategies.

Efficacy and tolerability of the histone deacetylase inhibitor panobinostat in clinical practice.

The histone deacetylase inhibitor panobinostat has shown efficacy in phase-II and phase-III trials for multiple myeloma and has recently received market approval in combination with bortezomib and dexamethasone. Here, we retrospectively report our single center experience with panobinostat/bortezomib/dexamethasone (FVD) in a heavily pretreated patient population (n = 24) with a high degree of refractoriness to proteasome inhibitors (PI) and immunomodulatory drugs (IMiD). Median age was 67 years (range 49-87) and the median number of prior therapies was 5 (range 2-17). Fourteen patients (58%) had high-risk cytogenetic aberrations. Thirteen (54%) and 21 (88%) patients were refractory to PIs and IMiDs, respectively. Twelve patients (50%) were refractory to bortezomib and 7 (29%) to carfilzomib; 6 patients (25%) were refractory to both bortezomib and carfilzomib. In 21 patients evaluable for response, overall response rate (ORR; ≥PR) was 33% (7/21) and 81% (17/21) achieved at least stable disease. Median progression-free survival (PFS) and overall survival were 3.5 and 9.8 months, respectively. Significant differences between bortezomib-sensitive and -refractory patients were observed. In bortezomib-sensitive patients, median PFS was 6.3 months compared to 2.3 months in bortezomib-refractory patients (P < .001). Median overall survival was not reached vs 4.8 months (P = .046) in bortezomib-sensitive and bortezomib-refractory patients, respectively. The only patient refractory to carfilzomib but sensitive to bortezomib achieved very good partial remission and PFS of 6.3 months, suggesting discrete mechanisms of resistance to different PIs. As expected, thrombocytopenia and fatigue/asthenia occurred in nearly all patients (96% and 83%, respectively). Diarrhea was observed in only 19% of patients which compares favorably with the high rates of diarrhea reported in the PANORAMA trials. With panobinostat dose reductions in 67% of patients, FVD was tolerated by the majority of patients. In conclusion, FVD showed efficacy in a heavily pretreated, high-risk multiple myeloma population with a high degree of patients refractory to novel agents including PIs.