Search

CA extern

Lenalidomide (LEN) maintenance (MT) post autologous stem cell transplantation (ASCT) is standard of care in newly diagnosed multiple myeloma (MM) but has not been compared to other agents in clinical trials. We retrospectively compared bortezomib (BTZ; n = 138) or LEN (n = 183) MT from two subsequent GMMG phase III trials. All patients received three cycles of BTZ-based triplet induction and post-ASCT MT. BTZ MT (1.3 mg/m2 i.v.) was administered every 2 weeks for 2 years. LEN MT included two consolidation cycles (25 mg p.o., days 1–21 of 28 day cycles) followed by 10–15 mg/day for 2 years. The BTZ cohort more frequently received tandem ASCT (91% vs. 33%) due to different tandem ASCT strategies. In the LEN and BTZ cohort, 43% and 46% of patients completed 2 years of MT as intended (p = 0.57). Progression-free survival (PFS; HR = 0.83, p = 0.18) and overall survival (OS; HR = 0.70, p = 0.15) did not differ significantly with LEN vs. BTZ MT. Patients with n = 54 vs. BTZ: n = 84), LEN MT significantly improved PFS (HR = 0.61, p = 0.04) but not OS (HR = 0.46, p = 0.09). In conclusion, the significant PFS benefit after eliminating the impact of different tandem ASCT rates supports the current standard of LEN MT after ASCT.

We investigated subclonal cytogenetic aberrations (CA) detected by interphase fluorescence in situ hybridization (iFISH) in patients with newly diagnosed multiple myeloma (MM) enrolled in the Haemato Oncology Foundation for Adults in the Netherlands (HOVON)-65/German-Speaking MM Group (GMMG)-HD4 phase 3 trial. Patients were either treated with 3 cycles of vincristine, Adriamycin, and dexamethasone or bortezomib, Adriamycin, and dexamethasone and then thalidomide or bortezomib maintenance after tandem autologous transplantation. Subclones were defined either by presence of different copy numbers of the same chromosome loci and/or CA present in at least 30% less and maximally 2/3 of cells compared with the main clone CA. Patients with subclones harbored more frequently high risk (31.0%) or hyperdiploid main clone aberrations (24.8%) than patients with t(11;14) in the main clone (10.1%). Gains and deletions of c-MYC were the only CA that occurred more frequently as subclone (8.1%/20.5%) than main clone (6.2%/3.9%, respectively). Treatment with bortezomib completely overcame the negative prognosis of high-risk CA in patients without subclones, but not in patients with additional subclonal CA. High-risk patients treated without bortezomib showed dismal outcome whether subclones were present or not. Cytogenetic heterogeneity defined by subclonal CA is of major prognostic significance in newly diagnosed MM patients treated with bortezomib within the HOVON-65/GMMG-HD4 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]. After a median follow-up of more than 11 years, non-inferiority of single versus tandem HDM/ASCT was demonstrated using the planned non-inferiority threshold of 15% of the 2-year EFS rate. Neither EFS (P = 0·53) nor overall survival (OS) (P = 0·33) differences were observed in the ITT population. In the tandem arm, 26% (n = 47/181) of patients refused a second HDM/ASCT due to non-medical reasons. A per-protocol (PP) analysis, including patients who received the intervention (single/tandem HDM/ASCT: n = 156/93) and patients who did not receive a second HDM/ASCT due to medical reasons (12%, n = 22/181), did not yield differences in EFS (P = 0·61) or OS (P = 0·16). In the ITT and PP set of the tandem arm, the rates of complete responses increased from first to second HDM/ASCT (both P = 0·04). Ten-year OS for the entire ITT was 34% (95% confidence interval: 29-40%). OS after first relapse was significantly shortened in the tandem arm (P = 0·04). In this study single HDM/ASCT was non-inferior to tandem HDM/ASCT in MM.

Introduction The inclusion of "novel" agents including proteasome inhibitors or IMiD-derivatives in the treatment of multiple myeloma significantly improves patient survival. Results of several study groups suggest incorporating at least one "novel agent" in first-line treatment before and after high-dose chemotherapy (HDT) followed by autologous stem cell transplantation. Here we address four main questions: First, what determines (excellent) long-term survival for different treatment regimen? Second, can we show benefit of novel agents for all patients and molecular subentities, including low risk? Third, can the prognostic impact of molecular entities be explained by different association with response, proliferation, and renal impairment? Fourth, does it matter regarding long-term survival by which agents, i.e. "old" vs. "new", a response was reached? Patients and Methods Patients were included in the prospective phase III HOVON-65/GMMG-HD4-trial (German part, n=354) randomizing VAD-induction, autologous tandem-transplantation and thalidomide-maintenance vs. PAD-induction, tandem-transplantation and bortezomib-maintenance. Plasma cells after CD138-purification were subjected to interphase fluorescence in-situ hybridization and gene expression profiling using Affymetrix U133 2.0 DNA-microarrays. Median follow-up (time to censoring) was 93 months. Results Low proliferation, revised-ISS I and cyto-ISS I delineate excellent long-term survival (70-75% after eight years, both arms). Molecular entities are associated with proliferation-rate, i.e. higher (del17p13, del8p21, del13q14, 1q21+, t(4;14)) or lower proliferation (hyperdiploidy), and response: bad response/survival in case of del17p, bad response/no survival impact (t(11;14)), and good response/bad survival (1q21+, t(4;14), and del13q), depending on the treatment regimen. Thus, it does not hold true that good response = good survival if patients are substratified according to their molecular background. Renal insufficiency is associated with 1q21+, del17p13, and t(4;14). For patients with ≥1 of the chromosomal aberrations del17p13, t(4;14), 1q21+ (i.e. cytogenetic high risk, 27.5% of patients) or renal insufficiency (10.6%), risk is abrogated; in absence of these risk features, no benefit could be shown. Patients reaching a near complete remission or better (≥nCR) with VAD-based regimen, HDT followed by thalidomide maintenance show significantly better survival compared to those reaching ≥nCR after bortezomib-based induction/HDT followed by bortezomib maintenance treatment. Conclusions Taken together, adversely prognostic molecular entities are associated with proliferation but can show association with better or adverse remission. Bortezomib-based upfront treatment abrogates chromosomal high-risk aberrations and renal insufficiency; however, no long-term survival-benefit is evident for those without these risk factors or low proliferation, i.e. the majority of patients. Responses achieved by different regimen are not equal in transmission in long-term survival. Responses (≥nCR) are not equivalent regarding their biological and prognostic role in patients with different molecular background and different treatment regimen. Disclosures Seckinger: Celgene: Research Funding; Sanofi: Research Funding; EngMab: Research Funding. Salwender:Novartis: Honoraria, Other: travel suppport, Research Funding; Amgen: Honoraria, Other: travel suppport, Research Funding; Bristol-Myers Squibb: Honoraria, Other: travel suppport, Research Funding; Celgene: Honoraria, Other: travel suppport, Research Funding; Takeda: Honoraria; Janssen: Honoraria, Other: travel support, Research Funding. Scheid:Celgene: Honoraria; Janssen: Honoraria. Knauf:Janssen: Consultancy; AbbVie: Consultancy; Celgene: Consultancy, Honoraria; Gilead Sciences: Consultancy; Roche: Consultancy; Amgen: Consultancy, Honoraria; Mundipharma: Consultancy. Duehrsen:AbbVie: Consultancy, Honoraria; Amgen: Research Funding; Janssen: Honoraria; Celgene: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Gilead: Consultancy, Honoraria. Dürig:Roche: Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria; Celgene: Honoraria. Schmidt-Wolf:Janssen: Research Funding; Novartis: Research Funding. Haenel:Novartis: Honoraria; Amgen: Honoraria; Roche: Honoraria; Takeda: Honoraria. Raab:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Sonneveld:Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Karyopharm: Honoraria, Research Funding; BMS: Honoraria, Research Funding. Blau:Celgene: Other: Advisory board, Research Funding; Janssen: Other: Advisory board, Research Funding; Amgen: Other: Advisory board; Takeda: Other: Advisory board; Novartis: Other: Advisory boards; BMS: Other: Advisory board. Hillengass:Takeda: Honoraria, Other: Advisory Board; BMS: Honoraria, Other: Advisory Board; Celgene: Consultancy, Honoraria, Other: Advisory Board, Research Funding; amgen: Consultancy, Honoraria, Other: Advisory Board; Sanofi: Research Funding; Janssen: Honoraria, Other: Advisory Board; Novartis: Honoraria, Other: Advisory Board. Weisel:Amgen, BMS, Celgene, Janssen, and Takeda: Honoraria; Amgen, Celgene, Janssen, and Sanofi: Research Funding; Amgen, BMS, Celgene, Janssen, Juno, Sanofi, and Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees. Goldschmidt:Chugai: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Takeda: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Mundipharma: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Research Funding; Adaptive Biotechnology: Consultancy; ArtTempi: Honoraria. Hose:Celgene: Honoraria, Research Funding; EngMab: Research Funding; Sanofi: Research Funding.

In the multicentre prospective randomized HD2002 trial, rituximab maintenance therapy (375 mg/m(2) every 3 months for 2 years) versus observation was evaluated for CD20(+) B-cell lymphoma. Out of 321 patients [161 randomized to the treatment group (TG), 160 to the observation group (OG)], 295 data sets were evaluable for statistical analysis. Estimated 5-year relapse-free survival (RFS) was 81% in the TG and 70% in the OG (logrank test, P = 0·047). In the diffuse large B-cell lymphoma (DLBCL) subgroup (n = 152), 5-year RFS was excellent, at 87% in the TG and 84% in the OG (logrank test, P = 0·35). Of note, only in male patients of the DLBCL subgroup was RFS significantly superior in the TG in comparison to the OG (5-year RFS: 88% vs. 74%; logrank test, P = 0·05). Cox regression analysis showed a significant interaction between treatment and gender regarding overall survival (OS) (P = 0·006) and RFS (P = 0·02), with a lower hazard in females than males in the OG [OS: hazard ratio (HR) (female:male) = 0·11; 95% confidence interval (CI) = 0·00-1·03; RFS: HR (female:male) = 0·27; 95% CI = 0·05-0·97], and no significant differences between males and females in the TG. We conclude that Rituximab maintenance therapy improves survival in male patients with DLBCL.

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

Background Harvest of more than one CD34+ stem cell transplant has become the standard, to ensure the option for a second autologous transplantation in patients with relapsed or progressive multiple myeloma (MM). Additional administration of the CXCR-4 inhibitor plerixafor has been shown to increase the efficiency of CD34+ stem cell harvest. However, the algorithm when to apply plerixafor is still under debate. Study Design and Methods In this retrospective study, 46 MM patients were categorized into four groups according to their CD34+ stem cell count in peripheral blood (PB) and mobilization with or without plerixafor: Group A comprised poor mobilizers with CD34+ cell counts of fewer than 20 × 106/L in PB. Group B included inadequate mobilizers with CD34+ cell counts of 20 × 106/L or more in PB and a low CD34+ stem cell yield in the first leukapheresis session. Patients receiving plerixafor preemptively (Group A1) and as a rescue strategy (Group B1) were compared to patients continuing stem cell collection with granulocyte–colony-stimulating factor alone (Groups A2 and B2). Results In both, the preemptive and the rescue settings, plerixafor enhanced the CD34+ stem cell yield significantly. Poor mobilization and administration of plerixafor was not associated with delayed engraftment. Conclusion Our data demonstrate that administration of plerixafor is safe and effective and facilitates a significantly higher CD34+ stem cell harvest. Based on the presented data, we propose an algorithm for the use of plerixafor for CD34+ stem cell mobilization and harvesting in poor mobilizing myeloma patients.

Patients with multiple myeloma and dialysis-dependent renal failure have dismal outcomes. In this retrospective analysis of a case series, we evaluated 27 consecutive patients, all of whom required haemodialysis at the time of first-line induction therapy with either bortezomib or a standard regimen followed by high-dose chemotherapy and auto-SCT. The overall response rate was significantly better after bortezomib-based induction before auto-SCT (83% vs 36%, P=0.02) and at day +100 post auto-SCT (100% vs 58%, P=0.01). Bortezomib also prolonged EFS and furthermore, a trend towards a shorter time on haemodialysis was observed in the bortezomib group at a median of 6.1 months (0.2-68.2 months) vs 17.1 months (0.7-94.3 months, P=0.38) in patients who had received vincristine, adriamycin, dexamethasone or vincristine, adriamycin, dexamethasone-like induction regimens. These data demonstrate the superior efficacy of bortezomib-based induction therapy in transplant-eligible patients with end-stage renal failure.

While extensive data demonstrated that plerixafor improves stem cell harvest in difficult-to-mobilize patients, economic concerns limit a broader application. We retrospectively assessed the effect of an early plerixafor rescue regimen for mobilization in patients with multiple myeloma. Patients were intended for high-dose chemotherapy followed by autologous peripheral blood stem cell transplantation (ABSCT) and therefore received cyclophosphamide-based mobilization chemotherapy and consecutive stimulation with granulocyte colony-stimulating factor (G-CSF). Fifteen patients with poor stem cell harvest in the first leukapheresis session received plerixafor. Data were compared with a matched historic control group of 45 patients who also had a poor stem cell yield in the first apheresis session, but continued mobilization with G-CSF alone. Patients in the plerixafor group collected significantly more CD34+ cells in total (median 4.9 vs. 3.7 [range 1.6–14.1 vs. 1.1–8.0] × 106 CD34+ cells /kg bw; P

Background: Novel agents such as IMIDs and proteasome inhibitors have substantially changed the therapeutic landscape in the first line treatment of multiple myeloma (MM). Better response rates and prolonged progression-free survival have lead to an improvement in overall survival (OS) with median values well beyond 5 years. Therefore to assess whether first line therapy strategies have an impact on the prognosis for patients with MM, long-term results of clinical trials with follow up covering >10 years are necessary. Methods: The HOVON-65/GMMG-HD4 study is a prospective randomized trial testing bortezomib+adriamycin+dexamethasone (PAD) for 3 cycles as induction prior to high-dose chemotherapy (HDT) and autologous stem cell transplantation compared to vincristine+adriamycin+dexamethasone (VAD) in the control arm. After one (HOVON) or two (GMMG) HDT maintenance was given for 2 years consisting of bortezomib every 2 weeks in the PAD arm and thalidomide 50 mg daily in the VAD arm. The study results were initially reported in 2012 (1) and with a median follow up of 91 months in 2018 (2). In this analysis we present OS results after a median follow up of 137 months. All hazard ratios (HR) are given with 95% confidence intervals (CI). Results: Overall survival at 12 years was 32% (CI 27-37%) in the VAD arm versus 36% (CI 31-41%) in the PAD arm without significant difference in the univariate Cox model (HR 0.87, CI 0.73 - 1.03, p=0. 11 or in multivariate Cox model including ISS stage and treatment arm (HR 0.87, CI 0.73 - 1.04, p=0.12; the primary analysis) as specified in the study protocol. When other factors including age, sex, ISS stage, WHO performance status, Immunoglobulin-type, Durie and Salmon-stage, LDH, del 13q, study group and renal impairment (RI, defined as serum creatinine ≥ 2 mg/dl) were added to the Cox model, treatment in the PAD arm was a significant factor for improved OS (HR 0.84, CI 0.7 - 1.0, p=0.048). Of the remaining factors age (HR 1.02, CI 1.01 - 1.03, p=0.002), female sex (HR 0.83, CI 0.69 - 0.99, p=0.044), ISS stage (HR 1.19, CI 1.04 - 1.35, p=0.01), WHO performance status (HR 1.32, CI 1.17 - 1.48, pULN (HR 1.44, CI 1.14 - 1.82, p=0.002), del 13q (HR 1.42, CI 1.17 - 1.73, p Discussion: Long-term results of the HOVON-65/GMMG-HD4 trial show that one third of patients receiving HDT with either thalidomide-based or bortezomib-based maintenance are still alive at 12 years. In contrast to earlier analyses with shorter follow up (1,2) the use of bortezomib in the induction and maintenance treatment provided a significant OS benefit when adjusting for other risk in a multivariate Cox model, although not in the primary analysis. A particular OS benefit was found in patients with RI receiving bortezomib before and after HDT and this could completely abolish the negative prognostic impact of RI. Similarly bortezomib used in combination with tandem-HDT improved OS in patients with del17p so that more than a third of these patients with high-risk MM survived more than 10 years. Our results underline that despite the growing options for treatment at relapse the choice of an optimal first-line therapy is of critical prognostic importance, in particular for patients with high-risk myeloma. References: 1) Sonneveld et al., J Clin Oncol, 2012; 30:2946-2955 2) Goldschmidt et al., Leukemia 2018; 32: 383-390 Figure 1 Disclosures Scheid: Bristol Myers Squibb: Honoraria; Celgene: Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Bertsch:Celgene: Other: travel support; Sanofi: Other: travel support. Zweegman:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding. Weisel:Celgene: Consultancy, Honoraria, Research Funding; Juno: Consultancy; Bristol-Myers Squibb: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Research Funding; GSK: Honoraria; Adaptive Biotech: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria. Kersten:Gilead: Honoraria; Kite Pharma: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Novartis: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding; Miltenyi: Honoraria; Roche: Honoraria, Research Funding; Takeda Oncology: Research Funding; Celgene: Honoraria, Research Funding. Mai:Mundipharma: Other: travel support; Takeda: Honoraria, Other: travel support, Research Funding; Janssen: Consultancy, Honoraria, Other: travel support; Celgene: Consultancy, Honoraria, Other: travel support. Hillengass:Amgen: Consultancy, Honoraria; Janssen: Honoraria. Stilgenbauer:AbbVie, AstraZeneca, Celgene, Gilead Sciences, Inc., GSK, Hoffmann La-Roche, Janssen, Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Broyl:Celgene, amgen, Janssen,Takeda: Honoraria. Bos:Kiadis Pharma: Other: Shareholder (of Cytosen, acquired by Kiadis); Celgene: Research Funding. Dührsen:Amgen: Consultancy, Honoraria, Research Funding; CPT: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Roche: Honoraria, Research Funding; Teva: Honoraria; Novartis: Consultancy, Honoraria; Alexion: Honoraria; Gilead: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Honoraria; Celgene: Research Funding. Salwender:Celgene: Honoraria, Other: Travel or accommodations; Sanofi: Honoraria, Other: Travel or accommodations; Takeda: Honoraria, Other: Travel or accommodations; Bristol-Myers Squibb: Honoraria, Other: Travel or accommodations; AbbVie: Honoraria; Amgen: Honoraria, Other: Travel or accommodations; Janssen Cilag: Honoraria, Other: Travel or accommodations. Goldschmidt:Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Molecular Partners: Research Funding; Dietmar-Hopp-Stiftung: Research Funding; Mundipharma: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; John-Hopkins University: Research Funding; Amgen: Consultancy, Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Chugai: Honoraria, Research Funding; John-Hopkins University: Research Funding; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MSD: Research Funding; Janssen: Consultancy, Research Funding. Sonneveld:Amgen: Honoraria, Research Funding; BMS: Honoraria; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Karyopharm: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; SkylineDx: Research Funding. OffLabel Disclosure: bortezomib maintenance thalidomide maintenance

To identify variants for multiple myeloma risk, we conducted a genome-wide association study with validation in additional series totaling 4,692 individuals with multiple myeloma (cases) and 10,990 controls. We identified four risk loci at 3q26.2 (rs10936599, P = 8.70 × 10(-14)), 6p21.33 (rs2285803, PSORS1C2, P = 9.67 × 10(-11)), 17p11.2 (rs4273077, TNFRSF13B, P = 7.67 × 10(-9)) and 22q13.1 (rs877529, CBX7, P = 7.63 × 10(-16)). These data provide further evidence for genetic susceptibility to this B-cell hematological malignancy, as well as insight into the biological basis of predisposition.

Although functionally competent cytotoxic, T cells are frequently observed in malignant diseases, they possess little ability to react against tumor cells. This phenomenon is particularly apparent in multiple myeloma. We here demonstrate that cytotoxic T cells reacted against myeloma antigens when presented by autologous dendritic cells, but not by myeloma cells. We further show by gene expression profiling and flow cytometry that, similar to many other malignant tumors, freshly isolated myeloma cells expressed several carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) at varying proportions. Binding and crosslinking of CEACAM-6 by cytotoxic T cells inhibited their activation and resulted in T-cell unresponsiveness. Blocking of CEACAM-6 on the surface of myeloma cells by specific monoclonal antibodies or CEACAM-6 gene knock down by short interfering RNA restored T-cell reactivity against malignant plasma cells. These findings suggest that CEACAM-6 plays an important role in the regulation of CD8+ T-cell responses against multiple myeloma; therefore, therapeutic targeting of CEACAM-6 may be a promising strategy to improve myeloma immunotherapy.

Administration of bisphosphonates (BPs) is an essential supportive treatment for reducing bone-related complications in cancer. Deterioration of renal function is one possible side effect of BPs as well as a clinical feature in multiple myeloma. It has been suggested that the nephrotoxicity of different BPs may differ. We performed a retrospective evaluation of renal function in 201 myeloma patients undergoing myeloablative chemotherapy and treatment with ibandronate (I), pamidronate (P), or zoledronate (Z) for up to 36 months. There was no significant deterioration in mean creatinine clearance (CreaCl) in the entire cohort. The percentage of patients experiencing a decrease in CreaCl ≥ 25 % from baseline was 33.0 % in the I group, 44.4 % in the P group and 21.4 % in the Z group, respectively. CreaCl at baseline (P

BACKGROUND Therapeutic options for patients with recurrent multiple myeloma after autologous stem cell transplantation (ASCT) include novel agents, conventional chemotherapy, or salvage ASCT with no standard of care. METHODS A total of 200 patients with multiple myeloma who developed disease recurrence after treatment with upfront ASCT and received an autologous retransplantation as salvage therapy at the study center over a period of 15 years were retrospectively reviewed. The objective of the current study was to evaluate the role of salvage ASCT in terms of efficacy, particularly taking into account the impact of novel agents. RESULTS The median progression-free survival (PFS) and overall survival after salvage ASCT were 15.2 months and 42.3 months, respectively. The overall response rate (a partial response or greater) was 80.4% at day 100, excluding 6 patients who died before assessment. Factors associated with improved PFS and overall survival after salvage ASCT included an initial PFS of > 18 months after upfront ASCT, bortezomib-containing or lenalidomide-containing therapies for reinduction, response to reinduction, and an International Staging System stage of I before salvage ASCT. CONCLUSIONS Salvage ASCT is capable of achieving sustained disease control in patients with multiple myeloma. The use of lenalidomide and bortezomib for reinduction has improved the results after salvage ASCT, suggesting that novel agents and salvage ASCT are complementary rather than alternative treatment approaches. Cancer 2013;119:2438-2446. © 2013 American Cancer Society.

Sorafenib is a small molecular inhibitor of several tyrosine protein kinases, including vascular endothelial growth factor receptor, platelet-derived growth factor receptor and rapidly accelerated fibrosarcoma kinases, targeting signal transduction and angiogenic pathways. It is approved for the treatment of advanced renal cell carcinoma and hepatocellular carcinoma. The objectives of this prospective phase II trial were to assess the activity and tolerability of sorafenib in patients with recurrent or refractory myeloma. In total, 11 patients were enrolled. Patients received 2 × 200 mg of sorafenib orally twice daily until completing 13 full cycles or disease progression. Of the side effects, 8.8% grade 3 and 1.1% grade 4 occurred. Sorafenib treatment was effective in two patients who achieved a partial response and a continuous stable disease with duration of 24.4 months and 6.9 month, respectively. Further clinical investigations are recommended to investigate sorafenib single agent activity in myeloma subgroups with ras-/BRAF-/vascular endothelial growth factor receptor pathway activation and combination therapy approaches. Copyright © 2013 John Wiley & Sons, Ltd.

Serological analyses within epidemiological cohort and case-control studies indicate to an association between HBV infection and risk of multiple myeloma (MM). To verify the relationship with an independent approach, we investigated the correlation between HBV positivity and chromosomal aberrations within 680 patients of the National Center for Tumor Diseases Heidelberg for which the serological HBV status (HBsAg and anti-HBc) and FISH data for five gains (1q21, 9q34, 11q23, 15q22, 19q13), five losses (6q21, 8p21, 13q14, 17p13, 22q11), and three IgH translocations [t(4,14), t(11,14), t(14,16)] were available. Deletion of 8p21 and 13q14 were shown associated with HBV positivity within hepatocellular carcinoma in other investigations. In the present evaluation, the odds ratio for loss of 8p21 was significantly elevated (OR = 2.74, 95% CL = 1.36-5.50, P = 0.0048) and for loss of 13q14 non-significantly increased (OR = 1.40, 95% CL = 0.74-2.65) in anti-HBc positive patients. The results provide further support for a role of HBV infection in the pathogenesis of MM.

In 2011 and 2012, a large outbreak of respiratory syncytial virus (RSV) infections affecting 57 laboratory-confirmed patients occurred in an adult hematology unit in Heidelberg, Germany. During the outbreak investigation, we performed molecular genotyping of RSV strains to differentiate between single versus multiple introductions of the virus into the unit. Furthermore, we assessed the time of viral shedding of consecutive samples from the patients in order to better understand the possible impact of prolonged shedding for outbreak control management. We used subtype-specific reverse transcription-PCR on nasopharyngeal and bronchoalveolar specimens for routine diagnostics and for measuring the viral shedding period. Samples of 47 RSV-infected patients involved in the outbreak were genotyped by sequence analysis and compared to samples from RSV-infected hospitalized children representing the timing of the annual RSV epidemic in the community. Molecular investigation of the virus strains from clinical samples revealed a unique cluster with identical nucleotide sequences of RSV type A (RSV A outbreak strain) for 41 patients, while 3 patients were infected with different RSV A (nonoutbreak) strains and three other patients with RSV type B. Outbreak strains were identified in samples from November 2011 until January 2012, while nonoutbreak strains were from samples coinciding with the community epidemic in February and March 2012. Median duration of viral shedding time was 24.5 days (range, 1 to 168 days) with no difference between outbreak and nonoutbreak strains ( P = 0.45). Our investigation suggests a single introduction of the RSV A outbreak strain into the unit that spread among the immunocompromised patients. Prolonged viral shedding may have contributed to nosocomial transmission and should be taken into account in the infection control management of RSV outbreaks in settings with heavily immunosuppressed patients.

Bone marrow plasma cell infiltration is a crucial parameter of disease activity in monoclonal plasma cell disorders. Until now, the only way to quantify such infiltration was bone marrow biopsy or aspiration. Diffusion-weighted imaging (DWI) is a magnetic resonance imaging-technique that may mirror tissue cellularity by measuring random movements of water molecules. To investigate if DWI is capable of assessing bone marrow cellularity in monoclonal plasma cell disease, we investigated 56 patients with multiple myeloma or monoclonal gammopathy of undetermined significance, and 30 healthy controls using DWI of the pelvis and/or the lumbar spine. In 25 of 30 patients who underwent biopsy, bone marrow trephine and DWI could be compared. Of the patients with symptomatic disease 15 could be evaluated after systemic treatment. There was a positive correlation between the DWI-parameter apparent diffusion coefficient (ADC) and bone marrow cellularity as well as micro-vessel density (P

International audience; Over the past decade, treatment options for patients with multiple myeloma (MM) have improved substantially, resulting in better response rates and prolonged overall survival (OS). Nevertheless, MM remains a challenging disease, especially if renal insufficiency (RI) or extensive pre-treatment aggravates the assignment of the optimal treatment schedule. In this retrospective study, we analyzed the outcome of lenalidomide plus dexamethasone in 167 patients with relapsed or refractory MM with focus on RI. The baseline creatinine clearance (CL) was normal in 94 patients (CL ≥ 80 ml/min), while RI was observed in 73 patients, including 40 patients with mild RI (50 ≤ CL 2 previous treatment lines. OS was not significantly different between patients with normal and impaired renal function. In contrast, the number of previous treatment lines (2 vs.

As more efficient agents for stem cell mobilization are being developed, there is an urgent need to define which patient population might benefit from these novel drugs. For a precise and prospective definition of "poor mobilization" (PM), we have analyzed the efficiency of mobilization in patients intended to receive autologous transplantation at our center in the past 6 years. Between January 2003, and December 2008, 840 patients with the following diagnoses were scheduled to undergo leukapheresis: multiple myeloma (MM, n = 602) and non-Hodgkin lymphoma (NHL, n= 238). Most patients mobilized readily: close to 85% of the patients had a level of 20/microL to500/microL of CD34(+) cells at the peak of stimulation. Of the 840 patients, 129 (15.3%) were considered to be PMs, defined as patients who had a peak concentration of20/microL of CD34(+) cells upon stimulation with granulocyte-colony stimulating factor (G-CSF) subsequent to induction chemotherapy appropriate for the respective disease. Among them, 38 (4.5%) patients had CD34(+) levels between 11 and 19/microL at maximum stimulation, defined as "borderline" PM, 49 (5.8%) patients had CD34(+) levels between 6 and 10/microL, defined as "relative" PM, and 42 patients (5%) with levels of5/microL, defined as "absolute" PM. There was no difference in the incidence of PM between patients with MM versus those with NHL. Sex, age, body weight (b.w.) and previous irradiation therapy did not make any significant difference. Only the total number of cycles of previous chemotherapy (P = .0034), and previous treatment with melphalan (Mel; P = .0078) had a significant impact on the ability to mobilize. For the good mobilizers, the median time to recovery of the white blood cells (WBCs) to 1.0/nL or more was 13 days with a range of 7 to 22 days, whereas for the PM group it was 14 days with a range of 8 to 37 days. This difference was statistically not significant. The median time to recovery of the platelets counts to an unmaintained level of20/nL was 11 days with a range of 6 to 17 days for the good mobilizers, whereas for the PM it was 11 days with a range of 7 to 32 days. Again, this difference was not significant. The majority of the patients today intended for autologous transplantations were able to mobilize readily. As long asor =2.0 x 10(6) of CD34(+) cells/kg b.w. have been collected, PM was not associated with inferior engraftment.

Chromosomal abnormalities have been shown to play a major role in disease evolution of multiple myeloma. Specific changes in interphase cells can be detected by fluorescent in situ hybridization, which overcomes the problem of the lack of dividing cells required for conventional cytogenetics.We analyzed the prognostic value of 12 frequent chromosomal abnormalities detected by fluorescent in situ hybridization in a series of patients (n=315) with newly diagnosed, symptomatic multiple myeloma. All patients underwent frontline autologous stem cell transplantation according to the GMMG-HD3- or GMMG-HD4-trial protocols or analogous protocols.Univariate statistical analyses revealed that the presence of del(13q14), del(17p13), t(4;14), +1q21 and non-hyperdiploidy was associated with adverse progression-free and overall survival rates independently of the International Staging System (ISS) classification. Multivariate analyses showed that only t(4;14) and del(17p13) retained prognostic value for both progression-free and overall survival. According to the presence or absence of t(4;14) and del(17p13) and the patients' International Staging System classification, the cohort could be stratified into three distinct groups: a group with a favorable prognosis [absence of t(4;14)/del(17p13) and ISS I], a group with a poor prognosis [presence of t(4;14)/del(17p13) and ISS II/III] and a group with an intermediate prognosis (all remaining patients). The probabilities of overall survival at 5 years decreased from 72% in the favorable prognostic group to 62% (hazard ratio 2.4; P=0.01) in the intermediate and 41% (hazard ratio 5.6; P0.001) in the poor prognostic groups.These results have implications for risk-adapted management for patients with multiple myeloma undergoing high-dose chemotherapy followed by autologous stem cell transplantation and suggest that new treatment concepts are urgently needed for patients who belong to the poor prognosis group. As targeted therapies evolve, different treatment options might have variable success, depending on the underlying genetic nature of the clone.

The introduction of rituximab into the primary treatment of malignant lymphomas of the B cell lineage has had a major impact on the management of these diseases. In addition, prolonged exposure to rituximab as maintenance therapy has been beneficial in patients with follicular lymphoma and mantle cell lymphoma. For the individual patient, the effect of any prolonged antitumor therapy on the quality of life (QoL) is a very important question. However, so far, the question whether rituximab maintenance therapy may impair QoL in patients with non-Hodgkin's lymphoma remains unanswered. To investigate this subject, we have performed a prospective randomized trial of rituximab maintenance therapy (8 cycles rituximab 375 mg/m(2) every 3 months) versus observation in patients with CD20+B cell non-Hodgkin's lymphoma in our institution. Between July 2002 and December 2005, 122 patients were included into the trial. QoL was assessed with the standardized questionnaires EORTC-QLQ-C30, EuroQol-5D, and EuroQol-5D (VAS) in 91 patients. After statistical analysis with the exact Wilcoxon rank sum test, we found no significant differences of the QoL between the rituximab treatment group and the observation group. We conclude that rituximab maintenance therapy seems to be safe and does not impair quality of life in this patient population.

Thalidomide, an agent with antiangiogenic and immunomodulatory properties, is therapeutically effective in multiple myeloma, leprosy, and autoimmune diseases. The most common clinical toxicities of thalidomide are constipation, neuropathy, fatigue, sedation, rash, tremor, and edema. We here describe for the first time a patient who developed leukocytoclastic vasculitis during therapy with thalidomide. Of the 260 patients treated with thalidomide in our institution, this is the first patient who developed autoimmune disease. We conclude that patients with malignant disorders who are treated with thalidomide should be carefully monitored for the development of autoimmune disorders. Whether autoimmune phenomena also occur during treatment with new drugs such as PS-341 or potent immunomodulatory agents remains to be evaluated.

Angiogenesis is defined as the formation of new capillaries from preexisting blood vessels and plays an important role in the progression of solid tumors. Recently a similar relationship has been described in several hematologic malignancies. Expression of the angiogenic peptides vascular endothelial growth factor (VEGF) and basic fibroblast growth factor correlates with clinical characteristics in leukemia and non-Hodgkin's-lymphoma and the serum/plasma concentrations serve as predictors of poor prognosis. Increased bone marrow microvessels in multiple myeloma (MM) are correlated with decreased overall survival. Thalidomide which has antiangiogenic effects and direct cytotoxic effects was found to be effective in MM, myelodysplastic syndrome and acute myeloid leukemia (AML). Preliminary data indicate activity of VEGF-tyrosine kinase inhibitors in AML. Clinical research is now aimed at testing antiangiogenic treatment strategies in several hematologic neoplasms as well as identifying the best candidate patients for specific approaches.

We aimed at demonstrating non-inferiority of bortezomib/cyclophosphamide/dexamethasone (VCD) compared to bortezomib/doxorubicin/dexamethasone (PAd) induction therapy with respect to very good partial response rates or better (⩾VGPR) in 504 newly diagnosed, transplant-eligible multiple myeloma patients. VCD was found to be non-inferior to PAd with respect to ⩾VGPR rates (37.0 versus 34.3%, P=0.001). The rates of progressive disease (PD) were 0.4% (VCD) versus 4.8% (PAd; P=0.003). In the PAd arm, 11 of 12 patients with PD had either renal impairment (creatinine ⩾2 mg/dl) at diagnosis or the cytogenetic abnormality gain 1q21, whereas no PD was observed in these subgroups in the VCD arm. Leukocytopenia/neutropenia (⩾3°) occurred more frequently in the VCD arm (35.2% versus 11.3%, P

Previous studies demonstrated the relevance of focal lesions (FL) in whole-body magnetic resonance imaging (wb-MRI) at the initial workup of patients with smoldering multiple myeloma (SMM). The aim of this study was to assess the effects of longitudinal wb-MRIs on progression into multiple myeloma (MM). Sixty-three patients with SMM were analyzed who received at least two wb-MRIs for follow-up before progression into MM. Radiological progressive disease (MRI-PD) was defined as detection of new FL or increase in diameter of existing FL and a novel or progressive diffuse infiltration. Radiological stable disease (MRI-SD) was defined by no change compared with the prior MRI. Patients were followed-up every 3-6 months, including a serological and clinical evaluation. One Hundred and eighty-two wb-MRIs were analyzed. MRI-PD occurred in 31 patients (49%), and 25 (40%) patients developed MM. MRI-PD was highly significantly associated with progression into MM, regardless of findings at the initial MRI. In multivariate analysis, MRI-PD remained a risk factor, independent of relevant baseline parameters like serum monoclonal protein or ⩾95% aberrant plasma cells in the bone marrow. Patients with MRI-SD had no higher risk of progression, even when FL were present at the initial MRI. Therefore, MRI is suitable for the follow-up of patients with SMM.

Contains fulltext : 137125.pdf (Publisher’s version ) (Open Access) Renal impairment is frequent in patients with multiple myeloma and is correlated with an inferior prognosis. This analysis evaluates the prognostic role of renal impairment in patients with myeloma treated with bortezomib before and after autologous stem cell transplantation within a prospective randomized phase III trial. Eight hundred and twenty-seven newly diagnosed myeloma patients in the HOVON-65/GMMG-HD4 trial were randomized to receive three cycles of vincristine, adriamycin, dexamethasone (VAD) or bortezomib, adriamycin, dexamethasone (PAD) followed by autologous stem cell transplantation and maintenance with thalidomide 50 mg daily (VAD-arm) or bortezomib 1.3 mg/m(2) every 2 weeks (PAD-arm). Baseline serum creatinine was less than 2 mg/dL (Durie-Salmon-stage A) in 746 patients and 2 mg/dL or higher (stage B) in 81. In myeloma patients with a baseline creatinine >/= 2 mg/dL the renal response rate was 63% in the VAD-arm and 81% in the PAD-arm (P=0.31). The overall myeloma response rate was 64% in the VAD-arm versus 89% in the PAD-arm with 13% complete responses in the VAD-arm versus 36% in the PAD-arm (P=0.01). Overall survival at 3 years for patients with a baseline creatinine >/= 2 mg/dL was 34% in the VAD-arm versus 74% in the PAD-arm (P/= 2 mg/dL or

Chromosomal aberrations of plasma cells are well established pathogenetic and prognostic factors in multiple myeloma, but their prognostic implication in systemic light chain (AL) amyloidosis is unclear. Therefore, the aim of this study was to identify prognostic cytogenetic risk factors by interphase FISH in a series of 103 consecutive AL amyloidosis patients treated uniformly with melphalan/dexamethasone as first-line therapy. Detection of gain of 1q21 was predictive for a poor overall survival (OS) (median 12.5 versus 38.2 months, p = 0.002). Hematologic event free survival (hem EFS) for gain of 1q21 was 5.0 versus 8.5 months in median (p = 0.08) and haematologic remission rates (≥VGPR) after three cycles were 5% versus 25% (p = 0.06). Most important, in multivariate concordance analyses the adverse prognosis carried by gain of 1q21 was retained as an independent prognostic factor (OS: p = 0.003, average hazard ratio (AHR) = 3.64, hemEFS: p = 0.008, AHR = 2.35), along with the well established Mayo cardiac staging. Patients with t(11;14) had a longer median OS with 38.2 months versus 17.5 months, though no statistical significance was reached. Deletion 13q14 and hyperdiploidy turned out to be prognostically neutral. In conclusion, we have identified gain of 1q21 as an independent adverse prognostic factor in AL amyloidosis patients treated with standard chemotherapy.

Introduction: Multiple myeloma is a heterogeneous disease with survival ranging from months to more than 10 years. Cytogenetic abnormalities (CA) detected by fluorescence in situ hybridization (FISH) are of major prognostic significance, since e.g. patients with del(17p), t(4;14) or gain 1q21 show dismal outcome. We evaluated CA at primary diagnosis and relapse to investigate clonal evolution in patients treated with upfront autologous stem cell transplantation (ASCT). Methods: We identified 128 patients with paired samples at primary diagnosis before the start of therapy (1st FISH) and at relapse after ASCT (2nd FISH). Forty-four patients were initially treated within the GMMG HD4 trial which compared 3 cycles of conventional induction chemotherapy (Arm A) with a bortezomib-based induction therapy (Arm B) followed by tandem ASCT and thalidomide (Arm A) or bortezomib (Arm B) maintenance. Eighty-four non-study patients (NSP) treated outside clinical trials were included who had received comparable induction therapies (bortezomib: n=45, thalidomide: n=11, other: n=28) before ASCT. FISH was performed on purified plasma cells using probes for 1q21, 5p15, 5q35, 8p21, 9q34, 11q23, 13q14, 15q22, 17p13 and 19q13, immunoglobulin H (IgH) translocations, t(11;14), t(4;14) and t(14;16). McNemar`s test was used to assess differences between FISH assessments. Kaplan-Meier method and Cox regression were used to analyze survival differences between patients without CA or with CA only at 1st, 2nd or both FISH assessments. Last follow-up for the whole cohort was performed in 06/2016. Results: Median time to first progression for the whole cohort was 27.0 months (HD4: 29.8 months; NSP: 25.5 months). There were no significant differences in CA as well as remission after induction therapy or ASCT between the HD4 and NSP cohort. The number of patients with high-risk CA was significantly higher after relapse (odds ratio (OR): 6.33; 95% confidence interval (CI): 1.86, 33.42; p Conclusion: We demonstrate clonal evolution and a higher incidence of high-risk CA at relapse after ASCT in a homogeneously treated group of patients. The most common translocations in myeloma are highly conservative. High-risk CA can emerge on a subclonal level during disease progression or might evolve from initially present subclones which results in similar dismal outcome Disclosures Merz: Celgene: Other: Travel grant; Janssen: Other: Travel grant. Hose:Sanofi: Research Funding; EngMab: Research Funding; Celgene: Other: personal fees outside this work. Bertsch:Janssen: Research Funding; Celgene: Research Funding; Chugai: Research Funding. Schmidt-Wolf:Janssen: Research Funding; Novartis: Research Funding. Scheid:Novartis: Other: funding outside this work; Celgene: Other: funding outside this work; Janssen: Other: funding outside this work. Weisel:Amgen: Consultancy, Honoraria; Novartis: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Onyx: Consultancy; Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria. Goldschmidt:Janssen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Chugai: Consultancy, Research Funding; Onyx: Consultancy; Millenium: Consultancy; BMS: Other: fees outside this work. Hillengass:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Research Funding; Amgen: Consultancy, Honoraria; BMS: Honoraria; Celgene: Honoraria; Novartis: Research Funding.

Background High-dose therapy (HDT) with autologous stem cell transplantation (ASCT) is considered the standard of care for multiple myeloma (MM) patients 65 years is currently uncertain, especially since the introduction of novel agents for induction and maintenance therapy. Furthermore, there are no conclusive data available on risk assessment in elderly patients treated with HDT. Patients and methods We retrospectively analyzed 202 patients ≥60 years with newly diagnosed MM who underwent ASCT at our institution. Patients were stratified by age into three groups (60–64, 65–69 and 70–75 years). For safety assessment, we compared data about hospitalization, hematopoetic reconstitution and early mortality. Remission before and after ASCT was analyzed according to age and application of novel agents. Event-free (EFS) and overall survival (OS) were analyzed to identify impact of age, remission before/after ASCT and maintenance therapy as well as ISS score and cytogenetic aberrations on outcome in elderly patients. Results The assessment of safety, remission before/after ASCT as well as EFS and OS showed no significant differences between the three groups (median EFS: 60–64 years: 27 months; 65–69 years: 23 months; 70–75 years: 23 months; median OS: not reached). Patients receiving novel agents as part of induction therapy achieved significantly higher nCR + CR rates than patients treated without novel agents. In Cox regression analysis, ISS and cytogenetics as well as remission after ASCT had the highest prognostic impact on EFS and OS. Maintenance therapy was associated with longer EFS in uni- and multivariate analyses. Conclusion ASCT is feasible for selected patients >65 and >70 years without increased mortality. Age at transplantation has no prognostic significance on outcome after ASCT. Novel agents during induction therapy and maintenance therapy improves outcome of older patients eligible for ASCT. ISS and cytogenetic analysis should be carried out routinely for risk assessment.

Purpose The aim of this study was to analyze chromosomal aberrations in terms of frequency and impact on time to progression in patients with smoldering multiple myeloma (SMM) on the background of clinical prognostic factors. Patients and Methods The chromosomal abnormalities 1q21, 5p15/5q35, 9q34, 13q14.3, 15q22, 17p13, t(11;14)(q13;q32), and t(4;14)(p16.3;q32) were assessed in CD138-purified myeloma cells by interphase fluorescent in situ hybridization (iFISH) alongside clinical parameters in a consecutive series of 248 patients with SMM. Results The high-risk aberrations in active myeloma (ie, del(17p13), t(4;14), and +1q21) present in 6.1%, 8.9%, and 29.8% of patients significantly confer adverse prognosis in SMM with hazard ratios (HRs) of 2.90 (95% CI, 1.56 to 5.40), 2.28 (95% CI, 1.33 to 3.91), and 1.66 (95% CI, 1.08 to 2.54), respectively. Contrary to the conditions in active myeloma, hyperdiploidy, present in 43.3% of patients, is an adverse prognostic factor (HR, 1.67; 95% CI, 1.10 to 2.54). Percentage of malignant bone marrow plasma cells assessed by iFISH and combination of M-protein and plasma cell infiltration as surrogates of tumor load significantly confer adverse prognosis with HRs of 4.37 (95% CI, 2.79 to 6.85) and 4.27 (95% CI, 2.77 to 6.56), respectively. In multivariate analysis, high-risk aberrations, hyperdiploidy, and surrogates of tumor load are independently prognostic. Conclusion The high-risk chromosomal aberrations del(17p13), t(4;14), and +1q21 are adverse prognostic factors in SMM just as they are in active myeloma, independent of tumor mass. Hyperdiploidy is the first example for an adverse prognostic factor in SMM of opposite predictiveness in active myeloma. Risk association of chromosomal aberrations is not only a priori treatment dependent (predictive) but is also an intrinsic property of myeloma cells (prognostic).

Radiological skeletal survey or computed tomography are currently applied to assess bone diseases in patients with monoclonal plasma cell disorders. Whole-body magnetic resonance imaging (whole-body MRI) allows detecting the infiltration of clonal cells in nearly the whole bone marrow compartment even before bone destruction has occurred. Those MRI results (i.e., patterns of bone marrow infiltration) have been demonstrated to be of prognostic significance in patients with symptomatic as well as asymptomatic multiple myeloma. We have therefore analyzed the findings of whole-body MRI in 137 consecutive individuals with monoclonal gammopathy of undetermined significance (MGUS). A focal infiltration pattern was detected in 23.4% of patients. Presence and number of focal lesions as well as value of M-Protein were of independent prognostic significance for progression into a symptomatic disease requiring systemic treatment (P=0.02; P

Interferon (INF)-α was the maintenance treatment of choice after autologous stem cell transplantation in multiple myeloma in the past, but currently Thalidomide is commonly used. In this prospective study, the implications of the various types of maintenance therapy on the patients T cell pattern and activation status were assessed. T cells were analyzed for expression of surface molecules, cytokine secretion, the presence of regulatory T cells, and the specific activation against the multiple myeloma antigen HM1.24. T cells from 69 multiple myeloma patients were analyzed: 19 patients were treated with IFN-α; 26 were treated with Thalidomide; and 24 patients received no maintenance therapy. Specific T cell activation with an immunogenic HLA-A2 + –restricted peptide from the myeloma-associated antigen HM1.24 was impaired in the Thalidomide group. In accordance with this observation, there was a trend toward a higher amount of regulatory T cells in the Thalidomide group. Furthermore, patients treated with IFN-α showed high rates of naive T cells, whereas a high rate of effector memory T cells was observed in the Thalidomide group. Importantly, after cessation of Thalidomide therapy, this effect was reversible in the CD8 compartment. In conclusion, Thalidomide maintenance therapy has profound implications on T cell pattern and activation status, which compromise antigen specific antitumor immunity.

A number of specific chromosomal abnormalities define the subgroups of multiple myeloma. In a meta-analysis of two genome-wide association studies of multiple myeloma including a total of 1,661 affected individuals, we investigated risk for developing a specific tumor karyotype. The t(11;14)(q13;q32) translocation in which CCND1 is placed under the control of the immunoglobulin heavy chain enhancer was strongly associated with the CCND1 c.870G>A polymorphism (P = 7.96 x 10(-11)). These results provide a model in which a constitutive genetic factor is associated with risk of a specific chromosomal translocation.

In multiple myeloma, focal lesions, as well as diffuse and variegated infiltration patterns, can be detected by magnetic resonance imaging. In the current study, we compared treatment response in 100 myeloma patients with changes in infiltration patterns in whole body magnetic resonance imaging before and after autologous stem cell transplantation. We found an agreement between serological response and changes in imaging (P

In patients with multiple myeloma (MM), risk stratification by chromosomal abnormalities may enable a more rational selection of therapeutic approaches. In the present study, we analyzed the prognostic value of 12 chromosomal abnormalities in a series of 354 MM patients treated within the HOVON-65/GMMG-HD4 trial. Because of the 2-arm design of the study, we were able to analyze the effect of a bortezomib-based treatment before and after autologous stem cell transplantation (arm B) compared with standard treatment without bortezomib (arm A). For allanalyzed chromosomal aberrations, progression-free survival (PFS) and overall survival (OS) were at least equal or superior in the bortezomib arm compared with the standard arm. Strikingly, patients with del(17p13) benefited the most from the bortezomib-containing treatment: the median PFS in arm A was 12.0 months and in arm B it was 26.2 months ( P = .024); the 3 year-OS for arm A was 17% and for arm B it was 69% ( P = .028). After multivariate analysis, del(17p13) was an independent predictor for PFS ( P < .0001) and OS ( P < .0001) in arm A, whereas no statistically significant effect on PFS ( P = .28) or OS ( P = .12) was seen in arm B. In conclusion, the adverse impact of del(17p13) on PFS and OS could be significantly reduced by bortezomib-based treatment, suggesting that long-term administration of bortezomib should be recommended for patients carrying del(17p13). This trial is registered at the International Standard Randomised Controlled Trial Number Register as [ISRCTN64455289][1]. [1]: /external-ref?link_type=ISRCTN&access_num=ISRCTN64455289

Background: The well-described prognostic impact of tumor characteristics and biology in multiple myeloma (MM), such as the combination of cytogenetics, the International Staging System (ISS) and lactate dehydrogenase (LDH, Moreau et. al., JCO, 2014) as well as frailty (Palumbo et al., Blood, 2015) significantly influence patient outcomes. However, only limited data on the impact of infections during therapy exist (Rajkumar et al., Lancet Oncology, 2010). Therefore, we hypothesized that severe infections during induction therapy (IT) in transplant-eligible MM influence dosage of therapies, treatment responses after IT and survival. Patients and Methods: From 05/2005 until 05/2008, 399 patients were randomly assigned to receive IT with either three cycles of VAD (vincristine, VIN, i.v. 0.4mg, days 1-4; doxorubicine, DOXO, i.v. 9mg/m2, days 1-4; dexamethasone, DEX, p.o. 40mg, days 1-4, 9-12, 17-20; n=201, arm A) or PAD (bortezomib, BTZ, i.v. 1.3mg/m2, days 1, 4, 8, 11; DOXO i.v. 9mg/m2, days 1-4; DEX p.o. 40mg, days 1-4, 9-12, 17-20; n=194, arm B), followed by high-dose melphalan (HDM) and autologous stem cell transplantation (ASCT) and either thalidomide (arm A) or bortezomib (arm B) maintenance within the German part of the joint GMMG-HD4/HOVON65 trial (Sonneveld et al., JCO, 2012). After exclusion of ineligible patients, 395 patients (99.0%) were evaluable for analyses. Any severe infection (equal or greater grade 3, according to the Common Terminology Criteria for Adverse Events, Version 4.0) during IT (at least once, defined from first until last date of application of IT medication) occurred in 105 patients (VAD n=53/198 and PAD n=52/192, 26.9% of all patients, missing data n=5). Results: Among patients with a severe infection during IT in the VAD and PAD arms, total DEX and DOXO doses (equal dosage in VAD/PAD group) were significantly lower (median DEX dose (mg/m2): 689.0 [77.7, 1014.1] vs. 742.3 [0.0, 1324.1], p Overall survival (OS) was significantly shortened in patients with at least one severe infection during IT (median OS: 81.8 months vs. not reached, p=0.04, Figure 1A). OS plots diverged in the early period of observation (< 3 months), driven by infection-related deaths (n=8). A landmark analysis 3 months after registration demonstrated approximated survival curves without significant differences in OS (median OS: 78.8 months vs. not reached, p=0.30, Figure 1B). Similarly, progression-free survival (PFS) was shortened, though not significantly (median PFS: 30.2 vs. 35.0 months, p=0.08). However, since not just death accounts as PFS event, the impact of infection-related deaths on PFS remains smaller than on OS. Accordingly, landmark analyses after 3 months from registration showed again closer survival curves (median PFS: 28.5 vs. 32.4 months, p=0.36). Conclusions: Severe infections have a critical impact on the applied doses of IT and outcome in the early, vulnerable phases of MM therapy. OS for transplant-eligible MM patients with severe infections during IT was significantly shortened, mainly driven by early infection-related deaths (< 3 months). A reduction of DEX doses during PAD/PAd IT in the subsequent GMMG study generation (GMMG-HD4/HOVON65: 480mg/cycle to GMMG-MM5: 240mg/cycle) and the recommendation of antibiotic/antiviral prophylaxis throughout the whole IT led to a reduced rate of severe infections of 12% (PAd) in the GMMG-MM5 trial. Further analyses are needed to elucidate how severe infections can be avoided, and whether there is an overlap between the subgroup of patients with severe infections during IT and patients with known adverse prognostic factors or reduced fitness/pre-existing conditions. (A) Overall survival and (B) landmark analysis on overall survival 3 months after start of induction therapy of patients with or without at least one severe infection (equal or greater grade 3) during induction therapy. Figure 1. Impact of severe infections on overall survival. Figure 1. Impact of severe infections on overall survival. Disclosures Mai: Janssen-Cilag: Other: Travel Grant; Onyx: Other: Travel Grant; Mundipharma: Other: Travel Grant; Celgene: Other: Travel Grant. Salwender:Celgene: Honoraria; Janssen Cilag: Honoraria; Bristol Meyer Sqibb: Honoraria; Amgen: Honoraria; Novartis: Honoraria. Pfreundschuh:Roche: Honoraria; Amgen, Roche, Spectrum: Research Funding; Boehringer Ingelheim, Celegene, Roche, Spectrum: Other: Advisory board. Duehrsen:Janssen: Honoraria. Hillengass:Janssen-Cilag: Honoraria, Other: Travel support; Celgene: Honoraria, Other: Travel support; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Other: Travel support; Sanofi: Research Funding. Scheid:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees. Weisel:BMS: Consultancy, Honoraria, Other: Travel Support; Onyx: Consultancy, Honoraria; Janssen Pharmaceuticals: Consultancy, Honoraria, Other: Travel Support, Research Funding; Celgene: Consultancy, Honoraria, Other: Travel Support, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel Support; Novartis: Other: Travel Support; Noxxon: Consultancy. Blau:MSD: Honoraria; Celgene: Honoraria, Research Funding; AMGEN: Honoraria; JAZZ pharm: Honoraria; BMS: Honoraria; Shire: Honoraria; Baxalta: Honoraria; Janssen: Honoraria, Research Funding. Goldschmidt:Onyx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millenium: Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Chugai: Honoraria, Research Funding, Speakers Bureau.

Thalidomide (Thal) is a drug with antiangiogenic, anti-inflammatory, and immunomodulatory properties that was found to inhibit the production of tumor necrosis factor-α (TNF-α) in vitro. We studied single nucleotide polymorphisms at positions −308 and −238 of the TNF-α gene promoter and measured the corresponding TNF-α cytokine levels in 81 patients (pts) with refractory and relapsed multiple myeloma (MM) who were treated with Thal. In myeloma pts carrying the TNF-238A allele (n = 8), we found a correlation with higher pretreatment TNF-α levels in peripheral blood (P = .047). After Thal administration, this TNF-238A group had a prolonged 12-month progression-free and overall survival of 86% and 100% versus 44% and 84% (P = .003 andP = .07) in pts with the TNF-238G allele, respectively. These findings suggest that regulatory polymorphisms of the TNF-α gene can affect TNF-α production and predict the outcome after Thal therapy, particularly in those MM pts who are genetically defined as “high producers” of TNF-α.

In multiple myeloma (MM) pathogenesis, hyperdiploidy and nonhyperdiploidy are recognized as 2 major cytogenetic pathways. Here, we assessed the role of hyperdiploidy in 426 patients with monoclonal plasma cell disorders, among them 246 patients with AL amyloidosis (AL), by interphase fluorescence in situ hybridization. Hyperdiploidy was defined by a well-established score requiring trisomies for at least 2 of the 3 chromosomes 5, 9, and 15. The hyperdiploidy frequency in AL was a mere 11% compared with 30% in monoclonal gammopathy of undetermined significance (P < .001) and 46% in AL with concomitant MM I (P < .001). Overall, hyperdiploidy was associated with an intact immunoglobulin, κ light chain restriction, higher age, and bone marrow plasmacytosis, but was unrelated to the organ involvement pattern in AL. Clustering of 6 major cytogenetic aberrations in AL by an oncogenetic tree model showed that hyperdiploidy and t(11;14) were almost mutually exclusive, whereas gain of 1q21 favored hyperdiploidy. Deletion 13q14 and secondary IgH translocations were equally distributed between ploidy groups. We conclude that the interphase fluorescence in situ hybridization–based hyperdiploidy score is also a feasible tool to delineate hyperdiploid patients in early-stage monoclonal gammopathies and that the cytogenetic pathogenetic concepts developed in MM are transferable to AL.

Bortezomib is a proteasome inhibitor demonstrating substantial activity in multiple myeloma. One of its key toxicities is peripheral neuropathy, which is reversible in most patients. The possibility that bortezomib might in rare cases induce severe neuropathies by auto-inflammatory mechanisms remains controversial. We report here the case of a 65-year-old female myeloma patient who was initially treated with bortezomib, doxorubicin, and dexamethasone (PAD). At the end of the second cycle of PAD, the patient presented with a rapid and severe onset of paresis of the left arm, accompanied by progressive sensory neuropathy and increasing neuropathic pain. After an extensive neurological work-up, including electrophysiological and laboratory evaluations as well as magnet resonance tomography imaging, we diagnosed an inflammatory autoimmune neuropathy, presumably induced by bortezomib, with accentuation of the left arm nerve plexus. We subsequently initiated regular treatment with polyvalent immunoglobulins, which gradually improved the neurological symptoms. In conclusion, the identification of an inflammatory autoimmune neuropathy, presumably associated with bortezomib, is a rare but important complication. An extensive neurological examination should be performed in patients who develop severe or unusual sensory or motor deficits under therapy with bortezomib, so as to differentiate autoimmune from toxic neuropathies, as therapeutic strategies differ for each.

Abstract 2987 Background. We have recently shown HIF1A to be expressed in 95.4% of CD138-purified myeloma cell samples from previously untreated patients (n= 329), with significantly higher [lower] expression in case of presence of t(4,14) [hyperdiploidy] vs. patients without the respective aberration. This makes HIF1A an interesting target in myeloma treatment. Additionally, we have shown about 40% of myeloma cell samples to have a proliferation-index above the median plus three standard-deviations of normal bone-marrow plasma cells, and we and others have proven proliferation to be associated with adverse prognosis in myeloma. Here, we report on 2 members of a novel class of sulfonanilides, their preclinical activity and pharmacology, and their dual mechanism of action, targeting HIF1A-signaling and inducing apoptosis via cell cycle arrest and tubulin depolymerization. Patients and Methods. The effect of the novel sulfonanilides ELR510444 and ELR510552 on the proliferation of 20 human myeloma cell lines and the survival of 5 primary myeloma cell-samples cultured within their microenvironment were tested. The results of efficacy studies in in two murine models (RPMI8226-xenograft-model and 5T33-model) are also presented. The mechanism of action was investigated using a variety of in-vitro assays (see below). Results. Preclinical activity in Myeloma. i) The sulfonanilides ELR510444 and ELR510552 completely inhibit proliferation of 20/20 tested myeloma cell lines at low nM concentrations and ii) induce apoptosis in 5/5 primary myeloma cell-samples at 6.4 – 32 nM concentration, without major effect on the bone marrow microenvironment. iii) They significantly inhibit tumor growth (xenograft; RPMI8226 mouse model, 6 mg p.o. bid for ELR510444, 15 mg p.o. bid for ELR510552) and bone marrow infiltration (5T33-model; ELR510444, 6 mg/kg p.o. bid × 4d, rest 3d (cycle)). Mechanism of action. Apoptosis induction and G2/M-block. i) Both compounds lead to caspase-3/7 activation and subsequent apoptosis with cellular EC50 values of 50–100 nM. ii) The compounds induce an initial cellular arrest in G2/M and a significant tubulin depolymerizing effect, followed by an increase in a sub-G1 (apoptotic) population after 24h. HIF1A-inhibition. i) Both compounds show a potent inhibition of HIF1A signaling in a cell based reporter assay (HRE-bla HCT-116) at EC50s of 1–25nM, whereas ii) at concentrations of 1 μ M, neither of the compounds shows an effect in assay systems monitoring the JAK/STAT, NFκB, PI3K/AKT/FOXO or Wnt/β-catenin-signaling pathways. iii) Kinase inhibition profiling showed no significant inhibition at 1μ M in two assays assessing 100 (Invitrogen) and 442 (Ambit) kinases, respectively. Pre-clinical pharmacology. Single dose exposure of 25 mg p.o. yields a maximum concentration of 1.1 μ M with a half life time of 3.6 hours (ELR510444) and 2.7 μ M and 6.6 h (ELR510552) in mice, respectively. The compounds are well-tolerated at levels that are significantly above the in vitro EC50 in all myeloma cell lines and primary samples tested. Conclusion. ELR510444 and ELR510552 are very active on all tested myeloma cell lines and primary myeloma cells without major impact on the bone marrow microenvironment, and show activity in two different mouse models. The compounds inhibit HIF1A-signaling and induce apoptosis via cell cycle arrest and tubulin depolymerization. Preclinical pharmacology data show favorable in vivo profiles with exposure levels in mice significantly higher than concentrations required for in vitro activity. Therefore, this novel class of compounds represents a promising weapon in the therapeutic arsenal against multiple myeloma entering a phase I/II trial within the next year. Disclosures: Leber: ELARA Pharmaceuticals GmbH: Employment. Janssen:ELARA Pharmaceuticals GmbH: Employment. Lewis:ELARA Pharmaceuticals GmbH: Employment. Schultes:ELARA Pharmaceuticals GmbH: Employment.

Proliferation of malignant plasma cells is a strong adverse prognostic factor in multiple myeloma and simultaneously targetable by available (e.g. tubulin polymerase inhibitors) and upcoming (e.g. aurora kinase inhibitors) compounds.We assessed proliferation using gene expression-based indices in 757 samples including independent cohorts of 298 and 345 samples of CD138-purified myeloma cells from previously untreated patients undergoing high-dose chemotherapy, together with clinical prognostic factors, chromosomal aberrations, and gene expression-based high-risk scores.In the two cohorts, 43.3% and 39.4% of the myeloma cell samples showed a proliferation index above the median plus three standard deviations of normal bone marrow plasma cells. Malignant plasma cells of patients in advanced stages or those harboring disease progression-associated gain of 1q21 or deletion of 13q14.3 showed significantly higher proliferation indices; patients with gain of chromosome 9, 15 or 19 (hyperdiploid samples) had significantly lower proliferation indices. Proliferation correlated with the presence of chromosomal aberrations in metaphase cytogenetics. It was significantly predictive for event-free and overall survival in both cohorts, allowed highly predictive risk stratification (e.g. event-free survival 12.7 versus 26.2 versus 40.6 months, P0.001) of patients, and was largely independent of clinical prognostic factors, e.g. serum β₂-microglobulin, International Staging System stage, associated high-risk chromosomal aberrations, e.g. translocation t(4;14), and gene expression-based high-risk scores.Proliferation assessed by gene expression profiling, being independent of serum-β₂-microglobulin, International Staging System stage, t(4;14), and gene expression-based risk scores, is a central prognostic factor in multiple myeloma. Surrogating a biological targetable variable, gene expression-based assessment of proliferation allows selection of patients for risk-adapted anti-proliferative treatment on the background of conventional and gene expression-based risk factors.

In this study, we investigated the quality of life (QoL) of long-term survivors with Hodgkin lymphoma who received high-dose chemotherapy (HDCT) followed by peripheral blood stem cell transplantation (PBSCT). QoL of this group was compared with QoL of patients who were treated with conventional chemotherapy and with QoL of the healthy German population. Two standardized questionnaires, the EORTC QLQ-C30 and the EQ-5D, including the visual analogue scale (VAS) were applied. A total of 98 patients were included in the study, all of them treated in our institution. Thirty-seven patients who received HDCT with PBSCT between 1986 and 2007 were compared with 61 patients treated with conventional chemotherapy and supplementary radiation between 1998 and 2009. The median follow-up for the HDCT group was 11 years. Statistical analysis with the one-sample t-test shows a reduced QoL of both groups of patients compared to the healthy population. Compared to the group of patients who received conventional chemotherapy, there is a tendency towards reduced QoL in patients with HDCT in all of the three main categories of the EORTC-QLQ-C30. However, these differences were not statistically significant, with the exception of the subcategory of dyspnoea, which was worse in the group that was treated with BCNU containing high-dose protocols. We conclude that the negative impact of both HDCT and conventional therapy on the QoL of long-term survivors with Hodgkin lymphoma should not be underestimated and should lead to the development of less toxic therapy strategies.

Abstract 2722 Poster Board II-698 Background: As the clinical management of patients with bulky disease remains challenging, many centres apply involved-field radiotherapy (IF-RT) after completion of immunochemotherapy. This strategy remains controversial. Patients and Methods: To evaluate the benefit of consolidating IF-RT in addition to immunochemotherapy, we retrospectively analyzed relapse patterns and survival of patients presenting with bulky follicular lymphoma (FL). Bulky disease was defined as abdominal/ mediastinal lymphoma mass >7.5 cm and/ or peripheral lymphoma mass >5 cm. All patients were treated within a prospective randomized trial on 126 patients with FL with six cycles of standard CHOP-chemotherapy in combination with 1, 3 or 6 cycles of Rituximab, followed by consolidating IF-RT in patients with bulky disease. 42 eligible patients with bulky disease were identified and form the foundation of this analysis, of which 26 were irradiated and 16 were not, violating the protocol. Results: With the exception of number of affected nodal regions, there was no significant difference between the irradiated and the non-irradiated group with regards to presenting characteristics (p > .05). Among all patients, bulks were located below the diaphragm in 91%. A second tumour bulk was present in 9 patients (22%). Female to male ratio was 1.3:1, and the median age at diagnosis was 54 years (range 23–73). According to FLIPI, 10% were classified as low risk (0–1), 45% as intermediate risk (2), and 45% as high risk (3–5). B symptoms were absent in 69%. Eleven patients (26 %) had received one course of Rituximab, 17 (41%) three courses and 14 (33%) six courses. There was no significant difference between the irradiated and the non-irradiated group with regards to previous exposure to immunochemotherapy (p = .628). After a median follow-up of 60 months, a total of 21 patients (50%) had progressed or relapsed and 9 patients (21%) had died. With the exception of one patient who died from congestive heart failure following chemotherapy-related cardiomyopathy, the main cause of death was disease progression or relapse. Highly malignant transformation into diffuse large B-cell lymphoma was observed in 5 cases. In the irradiated group, relapse occurred in 12 of 26 patients. Half of these relapses were located within the original bulk or within the bulk plus a new location, and 50% at a new location altogether; 42% occurred within the previously irradiated area. In the non-irradiated group, 9 of 16 patients relapsed. The corresponding rates regarding relapse location were 67% for original plus new location and 33% for new location only. There was no statistically significant difference between exposure to radiotherapy after immunochemotherapy and the likelihood of a relapse per se (p = .751) or at a specific location (p = .66). At the last follow-up, 31% of irradiated patients had achieved CR and 23% PR. Among the non-irradiated group, the corresponding rates were 25% and 19%. There was no significant difference in remission rates at any staging examination throughout the clinical trial between the two treatment groups (p > .05). 6-year progression-free- and overall survival rates were 52% and 80% after IF-RT and 48% and 73% without IF-RT (p = 1.00, p = .68 respectively). Conclusion: In this analysis, there was no difference in relapse rate, relapse location, PFS and OS between patients with bulky FL treated with and without consolidating IF-RT. Although patient numbers are limited, this is the first analysis of its kind conducted in the Rituximab era. Disclosures: No relevant conflicts of interest to declare.

International audience; Genetic instability and cellular proliferation have been associated with Aurora-kinase expression in several cancer entities, including multiple myeloma. Therefore, the expression of Aurora-A, -B and -C was determined by Affymetrix DNA-microarrays in 784 samples including two independent sets of 233 and 345 CD138-purified myeloma-cells from previously untreated myeloma-patients. Chromosomal aberrations were assessed by comprehensive iFISH and proliferation of primary myeloma-cells by propidium-iodine staining. The effect of the clinical Aurora-kinase inhibitor VX680 on proliferation of 20 human-myeloma-cell-lines and survival of 5 primary myeloma-cell-samples was tested. We found Aurora-A and -B to be expressed at varying frequencies in primary myeloma-cells of different patient-cohorts, Aurora-C in testis-samples only. Myeloma-cell samples with detectable vs. absent Aurora-A expression show a significantly higher proliferation rate, but neither a higher absolute number of chromosomal aberrations present (aneuploidy) nor of subclonal aberrations (chromosomal instability). VX680 induces apoptosis in all myeloma-cell-line- and primary myeloma-cell-samples tested. Presence of Aurora-A expression delineates significantly inferior event-free and overall-survival in two independent cohorts of patients undergoing high-dose chemotherapy, independent of conventional prognostic factors, i.e. serum-beta2-microglobulin or ISS-stage. In conclusion, using gene expression profiling, Aurora-kinase inhibitors as promising therapeutic option for newly-diagnosed patients can be tailoredly given to patients with adverse prognosis, expressing Aurora-A.