Search

A randomized inter-group trial comparing more intensive treatment strategies to a common standard arm 3 + 7 (CSA) was conducted in patients with non-M3 AML. Untreated patients ≥ 60 years were allocated to the CSA (n = 132) or to the study group arms (n = 1154) of the AMLCG (TAD/HAM versus HAM/HAM ± G-CSF followed by TAD and maintenance) and the OSHO (intermediate-dose ara-C/mitoxantrone followed by ara-C/mitoxantrone). Median age of the 1147 eligible patients was 69 (range 60–87) years. CR/CRi status at 90 days was not significantly different between the CSA (54% (95%CI: 45–64)) and the study group arms (53% (95%CI: 47–60) and 59% (95%CI: 58–63)). The five-year event-free survival (EFS) probability (primary endpoint) was 6.2% (95%CI: 2.7–14.0) in the CSA, 7.6% (95%CI: 4.5–12.8) in study group A and 11.1% (95%CI: 9.0–13.7) in B. The 5-year OS was 17.2% (95%CI: 11.0–26.9), 17.0% (95%CI: 2.0–23.9), and 19.5% (95%CI: 16.7–22.8) in CSA, study group A and B, respectively. Neither study group differed significantly from the CSA regarding EFS, OS, or relapse-free survival. In multivariate analyses, allocation to the treatment strategy was not significantly associated with the time-to-event endpoints. The evaluation of more intensive treatment strategies did not show clinically relevant outcome differences when compared to CSA.

Personalized medicine aims to match the right drug with the right patient by using specific features of the individual patient's tumor. However, current strategies of personalized therapy matching provide treatment opportunities for less than 10% of patients with cancer. A promising method may be drug profiling of patient biopsy specimens with single-cell resolution to directly quantify drug effects. We prospectively tested an image-based single-cell functional precision medicine (scFPM) approach to guide treatments in 143 patients with advanced aggressive hematologic cancers. Fifty-six patients (39%) were treated according to scFPM results. At a median follow-up of 23.9 months, 30 patients (54%) demonstrated a clinical benefit of more than 1.3-fold enhanced progression-free survival compared with their previous therapy. Twelve patients (40% of responders) experienced exceptional responses lasting three times longer than expected for their respective disease. We conclude that therapy matching by scFPM is clinically feasible and effective in advanced aggressive hematologic cancers.Significance:This is the first precision medicine trial using a functional assay to instruct n-of-one therapies in oncology. It illustrates that for patients lacking standard therapies, high-content assay-based scFPM can have a significant value in clinical therapy guidance based on functional dependencies of each patient's cancer.See related commentary by Letai, p. 290.This article is highlighted in the In This Issue feature, p. 275

Bei der Impfung handelt es sich um eine der erfolgreichsten medizinischen Maßnahmen, die bereits Millionen von Menschen das Leben gerettet hat. Die Impfung ist besonders wichtig bei Patienten mit einem Multiplen Myelom, deren Infektionsrisiko aufgrund der krankheitsinhärenten Immunsuppression sowie der immunsuppressiven Wirkung der Therapie erhöht ist. Daher sollten alle geeigneten Maßnahmen ergriffen werden, um eine wirksame Immunantwort gegen weitverbreitete Krankheitserreger wie Influenza, Pneumokokken, das Varicella-Zoster-Virus sowie gegen Bakterien und Viren (Haemophilus influenzae, Meningokokken und Hepatitis), die häufig ein erhebliches Risiko für Patienten mit einem Multiplen Myelom darstellen, anzuregen. Patienten nach autologer und insbesondere nach allogener Transplantation haben stark reduzierte Antikörpertiter und benötigen daher ein breiteres Impfspektrum. Die Impfreaktion ist bei Myelom-Patienten oft weniger stark ausgeprägt als in der Allgemeinbevölkerung, sodass entweder die Messung der Antikörpertiter nach der Impfung und/oder eine Wiederholungsimpfung erforderlich ist. In dieser Arbeit stellen wir die Daten zusammen, die zur Impfung von Patienten mit Multiplem Myelom existieren, und geben Empfehlungen für die klinische Praxis.

Antiapoptotic Bcl-2 family members have recently (re)emerged as key drug targets in cancer, with a tissue- and tumor-specific activity profile of available BH3 mimetics. In multiple myeloma, MCL-1 has been described as a major gatekeeper of apoptosis. This discovery has led to the rapid establishment of clinical trials evaluating the impact of various MCL-1 inhibitors. However, our understanding about the clinical impact and optimal use of MCL-1 inhibitors is still limited. We therefore explored mechanisms of acquired MCL-1 inhibitor resistance and optimization strategies in myeloma. Our findings indicated heterogeneous paths to resistance involving baseline Bcl-2 family alterations of proapoptotic (BAK, BAX, and BIM) and antiapoptotic (Bcl-2 and MCL-1) proteins. These manifestations depend on the BH3 profile of parental cells that guide the enhanced formation of Bcl-2:BIM and/or the dynamic (ie, treatment-induced) formation of Bcl-xL:BIM and Bcl-xL:BAK complexes. Accordingly, an unbiased high-throughput drug-screening approach (n = 528) indicated alternative BH3 mimetics as top combination partners for MCL-1 inhibitors in sensitive and resistant cells (Bcl-xL>Bcl-2 inhibition), whereas established drug classes were mainly antagonistic (eg, antimitotic agents). We also revealed reduced activity of MCL-1 inhibitors in the presence of stromal support as a drug-class effect that was overcome by concurrent Bcl-xL or Bcl-2 inhibition. Finally, we demonstrated heterogeneous Bcl-2 family deregulation and MCL-1 inhibitor cross-resistance in carfilzomib-resistant cells, a phenomenon linked to the MDR1-driven drug efflux of MCL-1 inhibitors. The implications of our findings for clinical practice emphasize the need for patient-adapted treatment protocols, with the tracking of tumor- and/or clone-specific adaptations in response to MCL-1 inhibition.

Personalized medicine aims to match the right drug with the right patient by using specific features of the individual patient's tumor. However, current strategies of personalized therapy matching provide treatment opportunities for less than 10% of patients with cancer. A promising method may be drug profiling of patient biopsy specimens with single-cell resolution to directly quantify drug effects. We prospectively tested an image-based single-cell functional precision medicine (scFPM) approach to guide treatments in 143 patients with advanced aggressive hematologic cancers. Fifty-six patients (39%) were treated according to scFPM results. At a median follow-up of 23.9 months, 30 patients (54%) demonstrated a clinical benefit of more than 1.3-fold enhanced progression-free survival compared with their previous therapy. Twelve patients (40% of responders) experienced exceptional responses lasting three times longer than expected for their respective disease. We conclude that therapy matching by scFPM is clinically feasible and effective in advanced aggressive hematologic cancers. Significance: This is the first precision medicine trial using a functional assay to instruct n-of-one therapies in oncology. It illustrates that for patients lacking standard therapies, high-content assay-based scFPM can have a significant value in clinical therapy guidance based on functional dependencies of each patient's cancer. See related commentary by Letai, p. 290. This article is highlighted in the In This Issue feature, p. 275

Relapse of acute leukemia is a frequent complication with uncertain outcome and poorly defined risk factors. From 1621 patients entered into two prospective clinical trials (AML02; n = 740 and AML04; n = 881), 74.2% reached complete remission (CR) 1 after induction(s) and 59 patients after additional induction ± hematopoietic cell transplantation (HCT). Of the non-refractory patients, 48.4% with a median age of 63 (range 17–85) years relapsed. Relapses occurred within 6 months after CR in 46.5%, between 7 and 18 months in 38.7%, and after 18 months in 14.8% of patients. Relapse treatment resulted in CR2 in 39% of patients depending upon age (54.5% of ≤ 60 and 28.6% of > 60 years), duration of CR1, and treatment of relapse. Overall survival (OS) was 10.9 (7.4–16.2) %, but OS after HCT ± intensive chemotherapy (ICT) was 39.3% (31.8–48.6) at 5 years and not different in younger and older patients. Donor lymphocyte infusion ± chemotherapy and ICT alone resulted only in OS of 15.4% and of 5%, respectively. Independent favorable factors for OS were long CR1 duration, and HCT, while non-monosomal disease was beneficial for OS in elderly patients. Leukemia-free survival [LFS; 24.9 (19.5–31.7) % at 10 years] was affected by similar risk factors. In a competing risk model, the relapse incidence at 5 years was 53.5 ± 3.5% and the non-relapse mortality rate 21.7 ± 2.9%. Lower relapse incidence was observed in patents with HCT, long CR1 duration, and female gender. Risk factors for non-relapse mortality were HCT in younger and type of AML in elderly patients. In conclusion, allogeneic HCT ± IC improved the results in relapsed AML in younger and elderly patients. Increasing CR2 rates and HCT frequency will be the challenge for the next years. Relapse of the disease remains the major problem. Supplementary Information The online version contains supplementary material available at 10.1007/s00277-021-04565-1.

We report on a 47-year-old patient suffering from bilateral gonalgia, weight loss and night sweats without fever of several months' duration. Diagnostic work-up for infectious and autoimmune diseases showed no abnormal results. A CT scan showed extensive foci of sclerosis throughout the axial skeleton. In the trephine biopsy, foamy cell infiltrates were found with expression of histiocytic markers without expression of Langerhans cell markers. Molecular analysis revealed a low allelic BRAF V600E and BCOR mutation. The diagnosis of Erdheim-Chester disease (ECD) was made. The histologic findings and molecular findings, the clinical and radiologic presentation before and 6 months after therapy as well as possible differential diagnoses of this very rare disease are discussed.Wir präsentieren eine 47 Jahre alte Patientin mit seit mehreren Monaten bestehender bilateraler Gonalgie, Gewichtsverlust und Nachtschweiß ohne Fieber. Eine durchgeführte Infektions- und Autoimmundiagnostik ist negativ ausgefallen. Der CT-Scan zeigt ausgedehnte Skleroseherde im gesamten Achsenskelett. In der Beckenkammbiopsie finden sich Schaumzellinfiltrate mit Expression histiozytärer Marker ohne Expression von Langerhans-Zell-Markern. Molekulargenetisch werden eine niedrigallelige BRAF-V600E- und eine BCOR-Mutation nachgewiesen. Die Diagnose einer Erdheim-Chester-Erkrankung (ECD) wird gestellt und eine Therapie mit dem Kinaseinhibitor Vemurafenib gestartet. Diskutiert werden die histologischen und molekulargenetischen Befunde, die klinische und radiologische Präsentation vor und 3 Monate nach Therapie sowie mögliche Differenzialdiagnosen dieser sehr seltenen Erkrankung.

Alterations in the human microbiome have been linked to several malignant diseases. Here, we investigated the oral microbiome of 79 patients with relapsed/refractory multiple myeloma (MM) treated with ixazomib-thalidomide-dexamethasone. Increased alpha diversity (Shannon index) at the phylum level was associated with longer progression-free survival (PFS) (10.2 vs 8.5 months

Patients with multiple myeloma frequently present with substantial immune impairment and an increased risk for infections and infection-related mortality. The risk for infection with SARS-CoV-2 virus and resulting mortality is also increased, emphasising the importance of protecting patients by vaccination. Available data in patients with multiple myeloma suggest a suboptimal anti-SARS-CoV-2 immune response, meaning a proportion of patients are unprotected. Factors associated with poor response are uncontrolled disease, immunosuppression, concomitant therapy, more lines of therapy, and CD38 antibody-directed and B-cell maturation antigen-directed therapy. These facts suggest that monitoring the immune response to vaccination in patients with multiple myeloma might provide guidance for clinical management, such as administration of additional doses of the same or another vaccine, or even temporary treatment discontinuation, if possible. In those who do not exhibit a good response, prophylactic treatment with neutralising monoclonal antibody cocktails might be considered. In patients deficient of a SARS-CoV-2 immune response, adherence to measures for infection risk reduction is particularly recommended. This consensus was generated by members of the European Multiple Myeloma Network and some external experts. The panel members convened in virtual meetings and conducted an extensive literature research and evaluated recently published data and work presented at meetings, as well as findings from their own studies. The outcome of the discussions on establishing consensus recommendations for COVID-19, This study has been funded by the Austrian Forum against Cancer, which covered in part expenses for interaction between authors and for secretarial support.

Introduction Carfilzomib-based induction therapy is highly effective in newly diagnosed pts with multiple myeloma (NDMM), but information on quality of life (QoL) during first line and maintenance therapy is not available. Here, we analyze patient-reported QoL in transplant-non eligible (TNE) NDMM pts randomized to either KTd or KRd induction therapy followed by second randomization to carfilzomib maintenance, or control. Patients and Methods At time of analysis, 101 TNE pts with NDMM had been enrolled, but QoL data documented for ≥ 2 cycles were available in 78 pts so far (median age: 75 years, ISS stage I: 26.6%, II: 35.4%, III: 38.0%, ECOG status 0: 51.9%, 1: 48.1%). Patients were randomized to either 9 cycles KTd or KRd, and subsequently (46 pts with ≥PR) to either carfilzomib maintenance therapy (d1 and 15) or to control for 12 months. Carfilzomib was administered twice weekly (27mg/m2) during cycles 1 and 2, and thereafter weekly at a dose of 56mg/m2. Thalidomide was given daily at 100mg (50mg in pts ≥75 years), lenalidomide at 25mg, d1-21 per 4 week cycle, and dexamethasone at 40 mg (20mg in pts ³75 years) once weekly. QoL was assessed by the QoL questionnaire EORTC QLQ-C30. Assessments were done at baseline, and monthly thereafter for 21 months. A two-sided t-test was used for comparison with the general population. Wilcoxon signed-rank tests were applied to evaluate differences in QoL dimensions within the treatment groups. A clinically meaningful improvement has been defined as a change of ≥10 score points. Results Comparison with the general population : Mean scores for health-related global QoL (54.1±22.6) and physical functioning (61.2±25.0) were significantly lower in pts compared to those reported for the general population of similar age (67.2±20.6, p Induction therapy: Health-related global QoL showed a clinically relevant improvement during carfilzomib-based induction therapy in both treatment groups (KRd: 54.5±19.9 to 65.0±20.2, p=0.10, KTd 53.6±24.8 to 68.2 ± 19.4, p=0.04), but a statistically significant increase in score points was noted in the KTd arm only. For physical functioning, a clinically relevant improvement was noted solely in pts on KRd, but the increase was not statistically significant (59.2 ± 22 to 73.2 ± 23.8, p=0.15), while during KTd no relevant changes were noted. Further clinically relevant improvements during induction therapy were observed for role functioning (KTd: 45 ± 39.3 to 61.6 ± 33.5, p=0.08, KRD: 51.5 ± 34.9 to 66.7 ± 30.1, p=0.29), emotional functioning (KTd: 61.2 ± 27.4 to 73.2 ± 20.5, p=0.04, KRd: 58.3 ± 23.2 to 73 ± 26.7, p=0.10), and pain with a statistically significant decrease in respective scores in both arms (KTd: 47.7 ± 37.4, to 24.2 ± 26.1, p=0.01, KRd: 54.8 ± 33.2 to 20.8 ± 21.5, p Maintenance phase: Pts randomized to carfilzomib maintenance showed no clinically relevant change in health-related QoL score (70.3± 17 to 63.9±25.3), similar to the findings in the untreated controls, which showed a clinically not relevant improvement in scores (66.7.±21.0 to 75.9±18.8). The scores for physical functioning remained rather stable during the maintenance period and values at end of therapy or observation appeared similar between the carfilzomib (77.1±21.6) and the control group (83.7±25.4). Conclusion Health-related global QoL and physical functioning in our pts with TNE NDMM was significantly impaired at start of therapy compared to the general population. During carfilzomib-based induction TX, clinically meaningful improvements in health-related global QoL, physical (only in KTd), emotional, role, and social (only in KRd) functioning, and pain were achieved. Neuropathy worsened during KTd. Maintenance treatment with carfilzomib was well tolerated without a clinically relevant change during the treatment period or statistical significant difference to the untreated controls. Disclosures Ludwig: Seattle Genetics: Other: Advisory Boards; Sanofi: Other: Advisory Boards, Speakers Bureau; Bristol Myers: Other: Advisory Boards, Speakers Bureau; Janssen: Other: Advisory Boards, Speakers Bureau; Celgene: Speakers Bureau; Amgen: Other: Advisory Boards, Research Funding, Speakers Bureau; Takeda: Research Funding. Podar:Amgen, BMS-Celgene, Janssen, Roche: Consultancy, Honoraria, Research Funding. Willenbacher:Amgen, Janssen, Takeda, BMS-Celgene: Consultancy, Honoraria, Research Funding. Petzer:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite-Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Schreder:BMS-Celgene, Amgen: Consultancy. Agis:Janssen: Honoraria, Research Funding; Amgen: Honoraria; BMS: Honoraria; Celgene: Honoraria; Takeda: Honoraria. Greil:Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; Daiichi Sankyo, Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; MSD Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; Astra zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; BMS/celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding. OffLabel Disclosure: Use of Carfilzomib in myeloma first-line treatment

Background Ixazomib-revlimid-dexamethason showed significant activity in relapsed/refractory multiple myeloma (RRMM). Here, we evaluate ixazomib in combination with thalidomide and dexamethasone for induction treatment followed by ixazomib maintenance therapy in RRMM patients. Methods Ninety patients have been included. Ixazomib–thalidomide–dexamethasone (4 mg, day 1, 8, 15; 100 mg daily; and 40 mg weekly) was scheduled for eight cycles followed by maintenance with ixazomib for one year. Results The overall response rate was 51.1%, 23.3% achieved CR or VGPR and 10% MR resulting in a clinical benefit rate of 61.1%. In patients completing ≥2 cycles, the rates were 60.5%, 27.6% and 68.4%, respectively. Median progression-free survival (PFS) was 8.5 months in all, and 9.4 months in those completing ≥2 cycles. Response rates, PFS and overall survival (OS) were similar in patients with and without t(4;14) and/or del(17p), but PFS and OS was significantly shorter in patients with gain of 1q21. Multivariate regression analysis revealed gain of 1q21 as the most important factor associated with OS. Ixazomib maintenance resulted in an upgrade in the depth of response in 12.4% of patients. Grade 3/4 toxicities were relatively rare. Conclusions Ixazomib–thalidomide–dexamethasone followed by ixazomib maintenance therapy is active and well tolerated in patients with RRMM. Trial registration number NCT02410694

Background Clinical progress in patients with high-risk multiple myeloma (MM) is limited and median survival remains at less than two years. Overexpression of cell cycle and proliferation-related genes is frequently observed in high-risk MM and novel treatment strategies for these patients are urgently needed. While the demand for pyrimidines is saturated via salvage pathways in resting cells, proliferating cells depend on the de novo synthesis of pyrimidines to meet the high demand for nucleotides. We therefore speculated that this pathway represents an attractive target in proliferation-associated high-risk myeloma. Methods In silico analysis of publicly available gene expression data sets was used to analyze CTP Synthase 1 (CTPS1) expression in different MM subgroups. In vitro, CTPS1 was evaluated as a target via generation of CRISPR/Cas9 CTPS1 knock-out cell lines. Apoptosis induction, cell cycle analysis and membrane potential of the cells were analyzed by flow cytometry. Additionally, the CTPS1 inhibitor STP938 (Step Pharma) was tested in 12 MM cell lines for its anti-myeloma properties. Uridine and cytidine rescue experiments were used to confirm the specificity of the compound. Previously established resistance models to pomalidomide and carfilzomib were used to demonstrate the efficacy of STP938 in advanced disease stages. Results In silico gene expression analysis revealed an upregulation of CTPS1 in MM and plasma cell leukemia patients compared to healthy-donor bone marrow plasma cells. Additionally, CTPS1 was found to be upregulated in patients with a proliferative gene expression pattern and high expression levels were linked to poor patient outcome. In vitro, stable CTPS1 knock-out clones failed to proliferate in the absence of exogenous cytidine which can be recycled via the nucleotide salvage pathway. Proliferation inhibition was accompanied by induction of an S-phase cell cycle arrest and apoptosis. The highly specific CTPS1 inhibitor STP938 showed potent inhibition of cell viability in 6 out of 12 cell lines. In accordance with the results obtained in genetic perturbation experiments we observed apoptosis induction, S phase arrest, and loss of mitochondrial membrane potential upon treatment with STP938. Addition of mM concentrations of exogenous cytidine, but not uridine, protected MM cell lines from apoptosis underlining the specificity of STP938. Importantly, the compound remained effective in models resistant to carfilzomib and pomalidomide. Conclusions Our in silico data establish CTPS1 as a potential novel target for proliferation associated high-risk disease. In vitro, the essential role of CTPS1 was confirmed by CRISPR/Cas9 deletion and the CTPS1 inhibitor STP938 was found to be highly efficacious in inducing apoptosis in several myeloma cell lines. Pre-clinical experiments have thus confirmed the drugability of CTPS1 and therefore strongly support the further evaluation of STP938.

Vaccination is one of the most successful medical interventions that has saved the life of millions of people. Vaccination is particularly important in patients with multiple myeloma, who have an increased risk of infections due to the disease-inherent immune suppression, and because of the immune suppressive effects of therapy. Hence, all appropriate measures should be exploited, to elicit an effective immune response to common pathogens like influenza, pneumococci, varicella zoster virus, and to those bacteria and viruses (haemophilus influenzae, meningococci, and hepatitis) that frequently may pose a significant risk to patients with multiple myeloma. Patients after autologous, and specifically after allogeneic transplantation have severely reduced antibody titers, and therefore require a broader spectrum of vaccinations. Response to vaccination in myeloma often is less vigorous than in the general population, mandating either measurement of the postvaccination antibody titers and/or repeating the vaccination. Here, we compile the existing data on vaccination in multiple myeloma and provide recommendations for clinical practice. ispartof: LEUKEMIA vol:35 issue:1 pages:31-44 ispartof: location:England status: published

TO THE EDITOR: A focus on defining genomic mutations at the whole population level in cancer may underestimate clonal plasticity in the tumor genome and how it generates genetic variation between individual single cells (SCs). This may have an impact on understanding cancer evolution and biological

At the 2017 American Society of Hematology Meeting promising data were presented reflecting the impressing advances of clinical research in multiple myeloma. In fit patients eligible for autologous stem cell transplantation new induction regimens showed high response and minimal residual disease negativity rates. Again the important role of autologous stem cell transplantation was pointed out especially for patients with high risk cytogenetics. In the relapsed setting intensified combination therapies are related with improvement of PFS (progression free survival) and even OS (overall survival). Concerning maintenance therapy significant benefits in all standard, high and ultra-high risk groups of patients could be demonstrated. New developements like Selinexor, Filanesib and CAR (chimeric antigen receptor) T cells showed impressing results in a heavily pretreated population.

Background Rapid induction of remission is a favorable factor in pts with Hodgkin's disease and DLBCL. In MM, only few data are available on the impact of response kinetics on outcome in newly diagnosed transplant ineligible MM pts. Recently, (Abstract EP971, EHA 2021) we described a significant correlation between time to response and progression-free survival (PFS) and overall survival in this patient population. Response and time to response depend on several factors such as the biology of the underlying myeloma clone(s), the activity of the treatment regimen, and on the composition of the bone marrow immune environment. Here, we evaluated possible interconnections between the bone marrow immune environment at baseline and the time to response to therapy in a series of pts randomized to either 9 cycles KRd or KTd induction therapy followed by a second randomization to carfilzomib maintenance or observation. Patients and Methods Composition of the immune environment at baseline was analyzed in 55 pts with newly diagnosed transplant ineligible MM enrolled in a randomized phase II trial (AGMT_MM 02). Median age: 74 years (range: 58-84 years), ISS I: 21.8%, ISS II: 41.8%, and ISS III: 36.4%, cytogenetics: 30.9% high risk, 40% standard risk, 29.1% unknown, ECOG Status 0: 54.5%, 1: 45.6%. Treatment: Carfilzomib : Cycle 1 day 1+2: 20mg/m 2, days 8+9 and 15+16: 27 mg/m 2 ; Cycle 2 day 1,2,8,9,15 + 16: 27 mg/m 2 Cycle 3-9: 56mg/m 2 on days 1, 8 and 15. Lenalidomide: 25mg p.o. on days 1-21/cycle or thalidomide: 100 mg p.o. on days 1-28; in pts ≥75 years of age 50mg p.o. on days 1-28, dexamethasone: 40 mg p.o. on days 1, 8, 15, 22 (± 1 day), in pts ≥ 75 years of age 20 mg p.o. this treatment was administered for nine cycles. Thereafter, pts were randomized to carfilzomib maintenance at last tolerated dose on days 1+15 or to observation for 12 cycles. BM samples were stained with 3 different antibody combinations for the analysis of T, B and NK cells (T cells: CD45RA, CD127, CD8, TCRgd, CD25, CD197, CD4, CD3, B/NK cells: CD57, CCR7, CD314, CD85j, CD62L, CD3, CD16, CD56, CD335, HLADR, CD337). We used a semi-automated pipeline to unveil full cellular diversity based on unbiased clustering. The median and range of each cellular subgroup was calculated and compared between pts with short or longer time to response (< or ≥119 days (median)). Statistical significance of these comparisons was calculated using the Wilcoxon test. Results Median FU was 20.5 months. Twenty of the 55 pts achieved a CR (36.7%) and 16 (57.1%) of the 28 who had MRD testing were shown to be MRD negative at a sensitivity of 10 -6. Twenty-three pts achieved a VGPR (41.8%), while only 12 pts achieved a PR (21.8%). Pts were subdivided into two groups according to time to best response. Group A (n=26), median time 56 (26-112) days, group B (n=29), 265 (119-675) days. PFS was significantly longer in group B (19.1 months vs not reached, p=0.007), while for OS only a trend for better survival was noted for group B pts (median survival not reached, p=0.129). High numbers of total CD3 + cells (p=0.033) and CD4 T cells with a CD 197 loCD45RA -CD127 + phenotype (p=0.022) were associated with longer time to best response and longer PFS. An opposite result was noted for the following T cell subsets, which correlated with a shorter time to best response and shorter PFS: CD56 + T cells with (p=0.01) or without (p=0.024) HLADR and CD8 Naïve CD127 + T cells (p=0.041). Diverse results were noted when the NK cell compartment was analyzed. Higher levels of circulatory CD314 - (p Conclusion Our data show significant correlations between the composition of bone marrow immune cells at start of therapy with time to best response and PFS in newly diagnosed transplant ineligible MM pts uniformly treated with carfilzomib-based therapy. High numbers of total lymphocytes CD3 and CD4 Tcells with a CD197 loCD45RA -CD127 + phenotype correlated with significantly longer PFS and longer time to response. Furthermore, higher numbers of specific NK subsets such as those with a circulatory phenotype, correlated with better outcome. These results highlight the prognostic potential of immune monitoring and the interconnection between specific subsets of the immune environment with the course of the disease. Figure 1 Figure 1. Disclosures Greil: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Daiichi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Sandoz: Honoraria, Research Funding. Podar: Amgen Inc.: Consultancy, Honoraria; Janssen Pharmaceuticals: Consultancy, Honoraria; Roche Pharmaceuticals: Research Funding; Celgene: Consultancy, Honoraria. Petzer: Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite-Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sandoz: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene-BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Saegen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Zojer: Celgene-BMS, Amgen, Takeda, Sanofi, Janssen: Consultancy, Speakers Bureau. Schreder: BMS-Celgene, Amgen: Consultancy. Melchardt: Abbvie, Celgene, Novartis: Honoraria. Knop: BMS/Celgene: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; Janssen: Consultancy; Oncopeptides: Consultancy; Pfizer: Consultancy; Sanofi: Consultancy. Paiva: Bristol-Myers Squibb-Celgene, Janssen, and Sanofi: Consultancy; Adaptive, Amgen, Bristol-Myers Squibb-Celgene, Janssen, Kite Pharma, Sanofi and Takeda: Honoraria; Celgene, EngMab, Roche, Sanofi, Takeda: Research Funding. Ludwig: Janssen, Celgene-BMS, Sanofi, Seattle Genetics: Consultancy, Speakers Bureau; Amgen, Takeda: Consultancy, Research Funding, Speakers Bureau. OffLabel Disclosure: Carfilzomib in first-line therapy

Background Accurate measurement of heterogeneity and reconstruction of evolutionary pathways are key to decipher clonal dynamics in tumour origins. Although bulk population genetic sequencing data has been used extensively to understand the life history of tumours, sequencing single cell DNA is likely to provide a much higher resolution of clonal dynamics and yield new insights into competing cellular populations with different genotypes. This is of significant importance when clonal evolution from a benign state to malignant disease is being considered, such as in the clonal evolution of MGUS to multiple myeloma (MM). Methods To this end, we further refined a multiple displacement amplification-based single cell whole-exome sequencing (scWES) protocol and applied it to examine MM cells (2 cases), and in one of these cases, probed evolution from a pre-existing MGUS stage in a paired setting. Single tumour cells were isolated from CD138+CD38+ fluorescence-activated cell sorted populations and CD3+ for T cells as germline controls. We developed a novel computational pipeline to accurately call somatic SNVs/indels and copy number aberration (CNA) events in the form of loss-of-heterozygosity (LOH) and gains in each single cell, identified drivers at the genome-wide level and reconstructed the tumour phylogeny while estimating and accounting for allelic dropout (N=176 single cells, 25× each cell). Results By focusing on the patient that allowed comparison of single cells at pre- and post-malignancy states, we show that pre-malignant subclones can be readily identified, and strikingly that malignant cells arise and expand from one of the MGUS subclones in the combined tumour phylogeny. Conclusions These results suggest that this scWES based method is a pragmatic approach to investigate clonal dynamics by allowing: 1) the analysis of genetic heterogeneity at the genome-wide level (much higher resolution than targeted panels), and 2) at low sequencing costs across large set of cells when compared with whole genome sequencing-based methods.

Treatment of high-risk patients is a major challenge in multiple myeloma. This is especially true for patients assigned to the gene expression profiling-defined proliferation subgroup. Although recent efforts have identified some key players of proliferative myeloma, genetic interactions and players that can be targeted with clinically effective drugs have to be identified in order to overcome the poor prognosis of these patients. We therefore examined maternal embryonic leucine zipper kinase (MELK) for its implications in hyper-proliferative myeloma and analyzed the activity of the MELK inhibitor OTSSP167 both in vitro and in vivo. MELK was found to be significantly overexpressed in the proliferative subgroup of myeloma. This finding translated into poor overall survival in patients with high vs. low MELK expression. Enrichment analysis of upregulated genes in myeloma cells of MELKhigh patients confirmed the strong implications in myeloma cell proliferation. Targeting MELK with OTSSP167 impaired the growth and survival of myeloma cells, thereby affecting central survival factors such as MCL-1 and IRF4. This activity was also observed in the 5TGM.1 murine model of myeloma. OTSSP167 reduced bone marrow infiltration and serum paraprotein levels in a dose-dependent manner. In addition, we revealed a strong link between MELK and other proliferation-associated high-risk genes (PLK-1, EZH2, FOXM1, DEPDC1) and MELK inhibition also impaired the expression of those genes. We therefore conclude that MELK is an essential component of a proliferative gene signature and that pharmacological inhibition of MELK represents an attractive novel approach to overcome the poor prognosis of high-risk patients with a proliferative expression pattern.

The patient described here presented with relapsed multiple myeloma progressing after therapy with immunomodulatory agents (thalidomide and lenalidomide) and proteasome inhibitors (bortezomib and carfilzomib). Eventually, the patient achieved an excellent response to the combination of panobinostat, bortezomib and dexamethasone, overcoming resistance to proteasome inhibitors and achieving a sustained VGPR (very good partial remission), which was consolidated with high-dose melphalan and autologous stem-cell transplantation.

Immunomodulatory drugs (IMiDs) are a cornerstone in the treatment of multiple myeloma (MM), but specific markers to predict outcome are still missing. Recent work pointed to a prognostic role for IMiD target genes (e.g. CRBN). Moreover, indirect activity of IMiDs on immune cells correlated with outcome, raising the possibility that cell populations in the bone marrow (BM) microenvironment could serve as biomarkers. We therefore analysed gene expression levels of six IMiD target genes in whole BM samples of 44 myeloma patients treated with lenalidomide-dexamethasone. Expression of CRBN (R = 0.30, P = .05), IKZF1 (R = 0.31, P = .04), IRF4 (R = 0.38, P = .01), MCT-1 (R = 0.30, P = .05), and CD147 (R = 0.38, P = .01), but not IKZF3 (R = −0.15, P = .34), was significantly associated with response. Interestingly, IKZF1 expression was elevated in BM environmental cells and thus selected for further investigation by multicolor flow cytometry. High IKAROS protein levels in total BM mononuclear cells (median OS 83.4 vs. 32.2 months, P = .02), CD19+ B cells (median OS 71.1 vs. 32.2 months, P = .05), CD3+ CD8+ T cells (median OS 83.4 vs 19.0 months, P = .008) as well as monocytes (median OS 53.9 vs 18.0 months, P = .009) were associated with superior overall survival (OS). In contrast, IKAROS protein expression in MM cells was not predictive for OS. Our data therefore corroborate the central role of immune cells for the clinical activity of IMiDs and built the groundwork for prospective analysis of IKAROS protein levels in distinct cell populations as a potential biomarker for IMiD based therapies.

The field of myeloma has been very dynamic in the last 10 years. Indeed, in no other hematological malignancy has progress been so rapid. In Europe, five new myeloma drugs were approved in the 2‑year period during 2015–2016. This has already had a profound impact on the way we approach treatment of relapsed disease. In the near future, the results of trials evaluating some of these very new substances in first-line treatment will be available and hopefully will show a further improvement of disease control over what has already been achieved with current upfront protocols.

Background The depth of response to myeloma therapy shows significant variation between individual patients. Responsiveness depends on the activity of the treatment regimen, the genetic aberrations of the predominant myeloma clone(s), and on the composition of the bone marrow environment, particularly of the immune compartment, in patients treated with drugs having broad immune effects. Here, we evaluated possible relationships between multiple immune cells and response to therapy in a series of newly diagnosed patients randomized to either carfilzomib-lenalidomide-dexamethasone or to carfilzomib-thalidomide-dexamethasone. Patients and Methods Forty-one patients with newly diagnosed multiple myeloma enrolled in a randomized phase II trial (AGMT_MM 02) with baseline bone marrow phenotyping were enrolled. Median age: 74 years (range: 58-84 years), R-ISS I: 23.8%, R-ISS II: 33.3%, and R-ISS III: 42.9%, IgG: 57.1%, IgA: 21.4%, light chain only: 19.0%, IgM: 2.4%, ECOG Status 0: 42.9%, 1: 57.1%. Treatment: Carfilzomib : Cycle 1 day 1+2: 20mg/m2, days 8+9 and 15+16: 27 mg/m2 ; Cycle 2 day 1,2,8,9,15 + 16: 27 mg/m2 Cycle 3-9: 56mg/m2 on days 1, 8 and 15. Lenalidomide: 25mg p.o. on days 1-21/cycle or thalidomide: 100 mg p.o. on days 1-28; in patients ≥75 years of age 50mg p.o. on days 1-28, dexamethasone: 40 mg p.o. on days 1, 8, 15, 22 (± 1 day), in patients ≥ 75 years of age 20 mg p.o. this treatment was administered for nine cycles. Thereafter, patients were randomized to carfilzomib maintenance at last tolerated dose on days 1+15 or to control for 12 cycles. BM samples were stained with 3 different antibody combinations for the analysis of T, B and NK cells (T cells: CD45RA, CD127, CD8, TCRgd, CD25, CD197, CD4, CD3, B/NK cells: CD57, CCR7, CD314, CD85j, CD62L, CD3, CD16, CD56, CD335, HLADR, CD337) using sample preparation protocols standardized by EuroFlow. We used a semi-automated pipeline to unveil full cellular diversity based on unbiased clustering. The median and range of each cellular subgroup was calculated in patients with CR and compared with results obtained in non-CR patients. Statistical significance of these comparisons was calculated using the Wilcoxon test. Results Median follow up is 15.9 months. Thirteen of the 41 patients achieved a CR (31.7%) and 9 (75%) of the 12 who had MRD testing were shown to be MRD negative at a sensitivity of 10-6. Nine (22.0%) of the 41 patients did already progress. High numbers of total B cells (p=0.011), B-cells expressing CD62L (p=0.027), CD4+ CD127+ central memory T cells (p=0.009), and CD337+ (p=0.012), or adaptive CD57lo (p=0.002) cytotoxic NK cells were significantly associated with achievement of CR. By contrast, lower numbers of T-NK cells (CD3+CD56+) (p=0.006), CD127- double-negative T cells (CD4- CD8-) (p=0.013), CD85j+ tissue resident immunoregulatory NK cells (p=0.002) and CD56+CD57+ (p=0.002) and CD56+ HLADR+ (p=0.003) T cells correlated significantly with achievement of CR. Significant correlations were also noted when NK cell subsets were analyzed for a possible association with progressive disease. Higher numbers of CD85j+ tissue resident immunoregulatory NK cells (p=0.001) were associated with progressive disease. In contrast, higher numbers of canonical cytotoxic NK cells (p=0.015) and CD314+ circulating immunoregulatory NK cells (p=0.033) correlated with sustained response. Conclusion Our data show significant correlations between the composition of bone marrow immune cells with achievement of CR and sustained response in newly diagnosed patients uniformly treated with carfilzomib-based therapy. High cytotoxic NK cell and B-cell, and low CD56+ T cell numbers among others were associated with deep response to carfilzomib-based therapy. Furthermore, higher numbers of specific NK cell subsets (CD85j+, CD57lo), correlated with disease progression while for other NK cell subtypes (canonical cytotoxic NK cells and CD314+ circulating immunoregulatory) a correlation with sustained response was noted. This study paves the way towards clinically relevant immune monitoring, whereby a holistic and unbiased assessment of the immune tumor microenvironment is connected with patients' treatment, depth of response and outcome. Disclosures Greil: Daiichi Sankyo, Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; MSD Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; Astra zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; BMS/celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding. Podar:Amgen, BMS-Celgene, Janssen, Roche: Consultancy, Honoraria, Research Funding. Petzer:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite-Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Agis:Janssen: Honoraria, Research Funding; Amgen: Honoraria; BMS: Honoraria; Celgene: Honoraria; Takeda: Honoraria. Schreder:BMS-Celgene, Amgen: Consultancy. Paiva:Janssen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Kite: Consultancy; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding; SkylineDx: Consultancy; Takeda: Consultancy, Honoraria, Research Funding; Roche: Research Funding; Adaptive: Honoraria; Amgen: Honoraria. Ludwig:Bristol Myers: Other: Advisory Boards, Speakers Bureau; Sanofi: Other: Advisory Boards, Speakers Bureau; Seattle Genetics: Other: Advisory Boards; Takeda: Research Funding; Amgen: Other: Advisory Boards, Research Funding, Speakers Bureau; Celgene: Speakers Bureau; Janssen: Other: Advisory Boards, Speakers Bureau. OffLabel Disclosure: Use of Carfilzomib in myeloma first-line treatment

Future progress in the treatment of multiple myeloma (MM) requires both the characterisation of key drivers of the disease and novel, innovative approaches to tackle these vulnerabilities. The present study focussed on the pre-clinical evaluation of a novel drug class, BMI-1 modulators, in MM. We demonstrate potent activity of PTC-028 and PTC596 in a comprehensive set of in vitro and in vivo models, including models of drug resistance and stromal support. Treatment of MM cells with PTC-028 and PTC596 downregulated BMI-1 protein levels, which was found to correlate with drug activity. Surprisingly, BMI-1 was dispensable for the activity of BMI-1 modulators and MM cell growth. Our data rather point to mitotic arrest accompanied by myeloid cell leukaemia-1 (MCL-1) loss as key anti-MM mechanisms and reveal impaired MYC and AKT signalling activity due to BMI-1 modulator treatment. Moreover, we observed a complete eradication of MM after PTC596 treatment in the 5TGM.1 in vivo model and define epigenetic compounds and B cell leukaemia/lymphoma 2 homology domain 3 (BH3) mimetics as promising combination partners. These results bring into question the postulated role of BMI-1 as an essential MM gene and confirm BMI-1 modulators as potent anti-mitotic agents with encouraging pre-clinical activity that supports their rapid translation into clinical trials.

This trial evaluated quality of life (QoL) using the EORTC QLQ-C30 and the EORTC QLQ-MY20 instruments in 90 patients with relapsed/refractory multiple myeloma during induction and maintenance therapy with eight cycles of ixazomib-thalidomide-dexamethasone, followed by 12 months of ixazomib maintenance therapy. When patient's baseline QoL was compared with data of the general population, a significant impairment in health-related QoL, physical, role, and social functioning and several other dimensions, as well as more pain and fatigue, was noted. Induction therapy resulted in significant improvement of pain and worsening of neuropathy, with no significant variation of other parameters. During maintenance treatment, scores for most dimensions including health-related QoL, physical functioning and pain, improved, while for neuropathy no improvement was observed. Time to deterioration (≥10 score points) of health-related QoL, physical functioning, pain, and neuropathy was distinctly shorter than time to progression. Health-related QoL and physical functioning at baseline correlated with overall survival.

[Background]: Maintenance therapy following autologous stem cell transplantation (ASCT) can delay disease progression and prolong survival in patients with multiple myeloma. Ixazomib is ideally suited for maintenance therapy given its convenient once-weekly oral dosing and low toxicity profile. In this study, we aimed to determine the safety and efficacy of ixazomib as maintenance therapy following ASCT. [Methods]: The phase 3, double-blind, placebo-controlled TOURMALINE-MM3 study took place in 167 clinical or hospital sites in 30 countries in Europe, the Middle East, Africa, Asia, and North and South America. Eligible participants were adults with a confirmed diagnosis of symptomatic multiple myeloma according to International Myeloma Working Group criteria who had achieved at least a partial response after undergoing standard-of-care induction therapy followed by high-dose melphalan (200 mg/m²) conditioning and single ASCT within 12 months of diagnosis. Patients were randomly assigned in a 3:2 ratio to oral ixazomib or matching placebo on days 1, 8, and 15 in 28-day cycles for 2 years following induction, high-dose therapy, and transplantation. The initial 3 mg dose was increased to 4 mg from cycle 5 if tolerated during cycles 1–4. Randomisation was stratified by induction regimen, pre-induction disease stage, and response post-transplantation. The primary endpoint was progression-free survival (PFS) by intention-to-treat analysis. Safety was assessed in all patients who received at least one dose of ixazomib or placebo, according to treatment actually received. This trial is registered with ClinicalTrials.gov, number NCT02181413, and follow-up is ongoing. [Findings]: Between July 31, 2014, and March 14, 2016, 656 patients were enrolled and randomly assigned to receive ixazomib maintenance therapy (n=395) or placebo (n=261). With a median follow-up of 31 months (IQR 27·3–35·7), we observed a 28% reduction in the risk of progression or death with ixazomib versus placebo (median PFS 26·5 months [95% CI 23·7–33·8] vs 21·3 months [18·0–24·7]; hazard ratio 0·72, 95% CI 0·58–0·89; p=0·0023). No increase in second malignancies was noted with ixazomib therapy (12 [3%] patients) compared with placebo (eight [3%] patients) at the time of this analysis. 108 (27%) of 394 patients in the ixazomib group and 51 (20%) of 259 patients in the placebo group experienced serious adverse events. During the treatment period, one patient died in the ixazomib group and none died in the placebo group. [Interpretation]: Ixazomib maintenance prolongs PFS and represents an additional option for post-transplant maintenance therapy in patients with newly diagnosed multiple myeloma, This study was sponsored by Millennium Pharmaceuticals, a wholly owned subsidiary of Takeda Pharmaceutical Company.

Multiple myeloma was prominently featured during the American Society of Hematology 2015 meeting. Important presentations were related to standards of first-line therapy of myeloma, disease assessment, and treatment of relapsed disease. New innovative treatments for myeloma are emerging, which will likely open new therapeutic avenues in the near future. This review aims to give a brief overview of the topic, focusing on presentations with relevance for clinical practice.

Immune suppression is a hallmark of multiple myeloma (MM), but data on soluble factors involved in the fate of immune effector cells are limited. The CXCR3-binding chemokine monokine induced by interferon-gamma (MIG/CXCL9) has been associated with tumor progression, immune escape, and angiogenesis in several malignancies. We here aimed to evaluate the prognostic relevance of MIG in MM. MIG serum levels were significantly elevated in newly diagnosed MM patients (n = 105) compared to patients with monoclonal gammopathy of undetermined significance (MGUS; n = 17) and healthy controls (n = 37). MIG expression in stromal compartments but not purified MM cells correlated with serum levels. High MIG serum levels were significantly associated with established prognostic markers (international staging system: R = 0.25, p = 0.001; age: R = 0.47, p 0.0001; lactate-dehydrogenase: R = 0.34, p = 0.0005) and poor overall survival (OS) (median OS 17.0 months vs. not reached, p 0.001). A similar association was found for CXCL10 and CXCL11. Multivariate regression analysis indicated MIG as an independent prognostic factor of OS.

The concept of the myeloma stem cell may have important therapeutic implications, yet its demonstration has been hampered by a lack of consistency in terms and definitions. Here, we summarize the current documentation and propose single-cell in vitro studies for future translational studies. By the classical approach, a CD19–/CD45/CD38/CD138+ malignant plasma cell, but not the CD19/CD38–memory B cell compartment, is enriched for tumorigenic cells that initiate myeloma in xenografted immunodeficient mice, supporting that myeloma stem cells are present in the malignant PC compartment. Using a new approach, analysis of c-DNA libraries from CD19/CD27/CD38–single cells has identified clonotypic memory B cell, suggested to be the cell of origin. This is consistent with multiple myeloma being a multistep hierarchical process before or during clinical presentation. We anticipate that further characterization will require single cell geno-and phenotyping combined with clonogenic assays. To implement such technologies, we propose a revision of the concept of a myeloma stem cell by including operational in vitro assays to describe the cellular components of origin, initiation, maintenance, and evolution of multiple myeloma. These terms are in accordance with recent (2012) consensus statements on the definitions, assays, and nomenclature of cancer stem cells, which is technically precise without completely abolishing established terminology. We expect that this operational model will be useful for future reporting of parameters used to identify and characterize the multiple myeloma stem cells. We strongly recommend that these parameters include validated standard technologies, reproducible assays, and, most importantly, supervised prospective sampling of selected biomaterial which reflects clinical stages, disease spectrum, and therapeutic outcome. This framework is key to the characterization of the cellular architecture of multiple myeloma and its use in precision medicine., This work on MMSC and myeloma pathogenesis and classification was supported by research funding from the EU 6th FP to MSCNET (LSHC-CT-2006-037602), the Danish Research Agency (grants no. 99 00 771, 271-05-0286, 271-05-0537, and 22-00-0314; to CHEPRE, #2101-07-0007), the Danish Cancer Society (grants no. DP 07014, DR 07017, and DP 9810009), Novo Nordic Foundation (Senior Fellowship 2001-4), KE Jensen Foundation (2005-2013), the Multiple Myeloma Research Foundation (senior grant 2003-4, contract no. 14).

Mit moderner Induktionstherapie gefolgt von Hochdosistherapie und autologer Transplantation werden heute 5-Jahres-Uberlebensraten von 50–60 % erreicht. Die Transplantation im Rahmen der Erstlinientherapie durfte sich als Standard weiterhin behaupten. Eine Doppeltransplantation kann in Einzelfallen sinnvoll sein, etwa bei Patienten, die wahrend der Induktion nicht zumindest eine VGPR erreichen oder bei Patienten mit 17p-Deletion. Mit Konsolidierungs- bzw. Erhaltungsstrategien lasst sich die Remission vertiefen bzw. die Zeit bis zur Progression verlangern.

Cytogenetic data have established relevance for prognostication in myeloma. Also, certain chromosomal aberrations were associated with an increased risk of progression of smoldering myeloma to active disease. The impact of cytogenetic and molecular data on treatment decisions is however limited. Myeloma patients with a t(4;14) have been shown to benefit from bortezomib treatment, while thalidomide treatment has a detrimental effect in cases with del17p13. The discovery of marked intraclonal heterogeneity has influence on therapeutic concepts to treat plasma cell disease, but so far no relevance for guiding treatment in individual cases. Cereblon is the molecular target of immunomodulatory substances, and expression levels have been linked to treatment outcome under thalidomide, lenalidomide, and pomalidomide treatment. Alternative splicing has been described for cereblon, and relevance of different isoforms for drug sensitivity is currently under study. So far no reliable clinical test exists to predict for response to immunomodulatory substances.