Search

BACKGROUND Patients with multiple myeloma (MM) have high information needs due to the complexity of the disease and variety of treatments. Digital voice assistants provide support in daily life and can be a convenient tool that even older patients can use to access health information. Voice assistants may therefore be useful in providing digital health services to meet the information needs of patients with MM. OBJECTIVE We aim to describe and report on the development, content, and functionality of the first Amazon Alexa voice assistant skill for patients with MM in Germany with the goal of empowering and educating patients. Further, we share data on skill usage and first learnings. METHODS In a cocreation workshop with MM patient organizations and MM medical experts in Germany, Takeda Oncology discussed the development and content of the Alexa skill Multiple Myeloma. Patient information on MM disease, diagnostics, and therapy was presented in a question-and-answer format, reviewed by experts, and programmed into the skill. Additionally, a search function for finding patient support groups within a perimeter of 200 km around the users and a myeloma quiz functionality with multiple-choice questions were integrated into the skill. Aggregated retrospective data on the total number of skill installations and skill usage were retrieved from an Amazon Alexa developer account, and a web-based patient survey was conducted on the Takeda Oncology website. RESULTS The Alexa skill Multiple Myeloma was launched in September 2019. It was available free of charge on the German Amazon Alexa skill store between September 2019 and March 2022 and could be used with devices featuring the Amazon Alexa voice assistant. Since the launch in September 2019 and up to July 2021, a total of 141 users have installed the skill. Between July 2020 and July 2021, a total of 189 skill sessions with 797 utterances were analyzed. The most popular inquiries were searches for patient support groups near the users (58/797, 7.3%), followed by inquiries about information on MM disease (53/797, 6.6%) and the quiz (43/797, 5.4%). The web-based survey on voice assistant usage and the feedback on the Alexa skill Multiple Myeloma were collected from 24 participants and showed that 46% (11/24) of participants would recommend the Alexa skill. Nonusers of voice assistants (11/24, 46%) stated that data protection concerns (7/11, 64%) and a lack of need (6/11, 55%) were the most important factors of not using voice assistants. CONCLUSIONS The Alexa skill Multiple Myeloma offers patient-friendly and expert-reviewed answers and explanations for medical terms related to MM disease, diagnostics, and therapy, as well as connections to patient support groups and a quiz functionality. In the future, the skill can be extended with new content and functionalities, such as medication adherence support.

Simple Summary High-dose chemotherapy and autologous stem cell transplantation (HDCT/ASCT) is a standard treatment in patients with newly diagnosed multiple myeloma (MM). At relapse, salvage HDCT/ASCT is a treatment option in patients with sufficient benefit from frontline HDCT/ASCT, but no evidence is currently available regarding its role in the era of triplet regimens combining the most active drug classes for relapsed MM. To evaluate the outcome after salvage HDCT/ASCT following re-induction treatment with carfilzomib/lenalidomide/dexamethasone (KRD) and to identify prognostic factors, we conducted a retrospective analysis of patients that had previously undergone frontline HDCT/ASCT. We found that deep remissions achieved with KRd followed by salvage autologous transplantation were associated with favorable PFS and were enhanced by maintenance treatment. Salvage autologous transplantation after state-of-the-art triplet re-induction was a safe and effective strategy for RRMM patients that may offer the chance to avoid refractoriness to multiple novel agents at the next relapse. Abstract Salvage high-dose chemotherapy and autologous stem cell transplantation (HDCT/ASCT) is a treatment option for relapsed and/or refractory multiple myeloma (RRMM). No data are available on salvage HDCT/ASCT following re-induction treatment with state-of-the-art triplet regimens. We retrospectively report on 44 patients receiving salvage HDCT/ASCT following re-induction with carfilzomib/lenalidomide/dexamethasone (KRd). All patients received frontline HDCT/ASCT with median time to progression (TTP1) of 2.9 (1.2–13.5) years, enabling paired comparison of frontline and salvage HDCT/ASCT. After re-induction and before salvage transplant, 25/44 patients (57%) attained ≥ very good partial response (VGPR), which increased to 34/44 (77%) at best response after salvage HDCT/ASCT. Median progression-free survival (PFS) was 23.3 months from salvage HDCT/ASCT. Patients with ≥ VGPR at the time of salvage HDCT/ASCT and those receiving maintenance treatment post salvage HDCT/ASCT had significantly superior PFS (hazard ratio (HR) 0.19, p = 0.001 and HR 0.20, p = 0.009). In patients achieving at least an equal depth of response before salvage HDCT/ASCT as before frontline HDCT/ASCT, PFS after salvage HDCT/ASCT was comparable to the frontline situation (p = 0.3). This is the first report of state-of-the-art triplet re-induction and salvage HDCT/ASCT for RRMM after frontline transplantation. Deep remissions achieved with KRd translate into prolonged PFS following salvage HDCT/ASCT and are enhanced by maintenance treatment.

The 7th Heidelberg Myeloma Workshop was held on April 5th and 6th, 2019 at the University Hospital Heidelberg. Main topics of the meeting were (1) diagnostics and prognostic factors, (2) role of immunotherapy in multiple myeloma (MM), (3) current therapy of MM, (4) biology and genomics of MM as well as (5) novel treatment concepts. A debate on the status of minimal residual disease (MRD) driven therapy was held. Diagnostics and treatment of newly diagnosed and relapsed MM are continuously evolving. While advances in the field of (single cell) genetic analysis now allow for characterization of the disease at an unprecedented resolution, immunotherapeutic approaches and MRD testing are at the forefront of the current clinical trial landscape.

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.

The role of salvage high-dose chemotherapy and autologous stem cell transplantation (sHDCT/ASCT) for relapsed and/or refractory multiple myeloma (RRMM) in the era of continuous novel agent treatment has not been defined. This randomized, open-label, phase III, multicenter trial randomized patients with 1st-3rd relapse of multiple myeloma (MM) to a transplant arm (n = 139) consisting of 3 Rd (lenalidomide 25 mg, day 1-21; dexamethasone 40 mg, day 1, 8, 15, and 22; 4-week cycles) reinduction cycles, sHDCT (melphalan 200 mg/m2), ASCT, and lenalidomide maintenance (10 mg/day) or to a control arm (n = 138) of continuous Rd. Median PFS was 20.7 months in the transplant and 18.8 months in the control arm (HR 0.87; 95% CI 0.65-1.16; p = 0.34). Median OS was not reached in the transplant and 62.7 months in the control arm (HR 0.81; 95% CI 0.52-1.28; p = 0.37). Forty-one patients (29%) did not receive the assigned sHDCT/ASCT mainly due to early disease progression, adverse events, and withdrawal of consent. Multivariate landmark analyses from the time of sHDCT showed superior PFS and OS (p = 0.0087/0.0057) in patients who received sHDCT/ASCT. Incorporation of sHDCT/ASCT into relapse treatment with Rd was feasible in 71% of patients and did not significantly prolong PFS and OS on ITT analysis while patients who received sHDCT/ASCT may have benefitted.

Measles viruses derived from the live-attenuated Edmonton-B vaccine lineage are currently investigated as novel anti-cancer therapeutics. In this context, tumor specificity and oncolytic potency are key determinants of the therapeutic index. Here, we describe a systematic and comprehensive analysis of a recently developed post-entry targeting strategy based on the incorporation of microRNA target sites (miRTS) into the measles virus genome. We have established viruses with target sites for different microRNA species in the 3′ untranslated regions of either the N, F, H, or L genes and generated viruses harboring microRNA target sites in multiple genes. We report critical importance of target-site positioning with proximal genomic positions effecting maximum vector control. No relevant additional effect of six versus three miRTS copies for the same microRNA species in terms of regulatory efficiency was observed. Moreover, we demonstrate that, depending on the microRNA species, viral mRNAs containing microRNA target sites are directly cleaved and/or translationally repressed in presence of cognate microRNAs. In conclusion, we report highly efficient control of measles virus replication with various miRTS positions for development of safe and efficient cancer virotherapy and provide insights into the mechanisms underlying microRNA-mediated vector control. Keywords: measles virus, oncolytic viruses, vector engineering, vector safety, microRNAs, microRNA target sites, post-entry targeting

Background: A low platelet count before mobilization has recurrently been identified as risk factor for poor mobilization. Methods: To determine the relevance of this finding for peripheral blood stem cell (PBSC) mobilization, including pre-emptive or rescue plerixafor in the case of poor mobilization, we retrospectively analyzed all patients undergoing PBSC collection at our institution between January 2014 and December 2015 (n = 380). Results: In total, 99% of the patients (377/380) successfully collected a minimum of 2 × 106 CD34+ cells/kg body weight sufficient for a single transplant. Rescue or pre-emptive plerixafor was administered to 11% of the patients (42/380). No correlations between the platelet count before mobilization and the number of peripheral blood CD34+ cells or the CD34+ cell collection result were detected in the entire population or the subgroups according to diagnosis (newly diagnosed multiple myeloma, relapsed multiple myeloma, lymphoma, amyloid light-chain amyloidosis, sarcoma, or germ cell tumor). However, patients requiring pre-emptive or rescue plerixafor had a significantly lower platelet count before mobilization (217/nl vs. 245/nl; p = 0.004). Conclusion: With the current state of the art PBSC mobilization strategies, the platelet count before mobilization was not associated with the CD34+ cell collection result but was associated with the need for pre-emptive or rescue application of plerixafor.

In multiple myeloma (MM), the synergy between immunomodulatory drugs (IMiDs) and monoclonal antibodies (MABs) has been demonstrated in several pivotal trials. However, disease refractory to either class of compounds remains a major therapeutic challenge. We here report on 3 heavily pretreated MM patients who were refractory to pomalidomide as well as to MABs against CD38 (daratumumab) or CD20 (rituximab), respectively, but who responded to retreatment with the same agents in combination. Responses were durable with PFS of 7, 10 (ongoing), and 30 months from initiation of combination treatment. The combination of IMiDs with MABs directed against MM cell surface antigens can overcome refractoriness to both agents.

BACKGROUND Granulocyte–colony-stimulating factor (G-CSF) originators such as filgrastim (Neupogen) and lenograstim (Granocyte) are widely used for peripheral blood stem cell (PBSC) mobilization. In recent years, biosimilar agents have been approved for the same indications. The aim of this retrospective study was to compare the mobilization efficiency of the three G-CSF variants originator filgrastim, lenograstim, and the biosimilar Filgrastim Hexal in a homogeneous group of multiple myeloma (MM) patients in first-line therapy. STUDY DESIGN AND METHODS Overall mobilization data of 250 patients with MM were included. Of these patients, 74 (30%), 131 (52%), and 45 (18%) were mobilized with originator filgrastim, biosimilar Filgrastim Hexal, or lenograstim, respectively, at a dose of 5 to 10 µg/kg body weight subcutaneously starting from Day 5 after chemomobilization with CAD (cyclophosphamide, doxorubicin, dexamethasone) until completion of PBSC collection. RESULTS All but one patient reached the collection goal of a minimum of at least 2 × 106 CD34+ cells/kg body weight during a median of one (range, one to three) leukapheresis session. No significant differences in CD34+ mobilization and collection yields between the filgrastim-mobilized (median, 10.5; range, 2.7-40.4), Filgrastim Hexal–mobilized (median, 9.9; range, 0.2-26.0), and lenograstim-mobilized (median, 10.7; range, 3.1-27.9 CD34+ cells × 106/kg body weight) patients were observed. CONCLUSION Concerning the clinically relevant efficiencies of PBSC mobilization and in terms of reaching the individual collection target, this retrospective study did not detect any significant differences between the three G-CSF variants in the analyzed patient cohort.

Objective Analysis of the efficiency and toxicity of cyclophosphamide-based stem cell mobilization in patients with relapsed multiple myeloma (RMM). Methods Peripheral blood stem cells (PBSCs) were mobilized with high dose cyclophosphamide (2 g/m2 daily on days 1 and 2) and G-CSF plus pre-emptive/rescue plerixafor in RMM patients (first to third relapse) treated within the ReLApsE trial of the German-Speaking Myeloma Multicenter Group (GMMG). Results Mobilization was initiated with high-dose cyclophosphamide (HD-CY) and G-CSF in 30 patients. Fifteen patients received additional pre-emptive/rescue administration of plerixafor. Stem cell collection was successful (≥2×106 CD34+ cells per kg bw) in 77% (23/30 patients). Patients with prior high-dose melphalan collected a significantly lower median total number of PBSCs than patients without prior high-dose melphalan (3.3×106 vs 17×106 CD34+ cells/kg bw). Toxicity of HD-CY was frequent with 12 serious adverse events (SAE) in 37% of patients (11/30 patients). Infections accounted for the majority of SAE reports. In two patients, SAEs were lethal (septic shock). Conclusions These data proof feasibility of PBSC collection at relapse but emphasize the importance of collection and storage of additional PBSC transplants during first-line treatment when mobilization is more efficient and less toxic.

Immunomodulatory drugs (IMIDs) are very effective in the treatment of multiple myeloma (MM). The description of their cereblon-mediated mechanism of action was a hallmark in MM research. Although the importance of IMID-induced degradation of cereblon-binding proteins is well described in vitro, the prognostic value of their expression levels in MM cells is less clear. Based on recently published data showing somewhat conflicting RNA levels, we analyzed the association between the levels of the Ikaros family zinc finger protein 1 (IKZF1), IKZF3, and karyopherin subunit alpha 2 (KPNA2) proteins measured by flow cytometry and prognostic parameters in 214 newly diagnosed MM patients who were randomized in the GMMG HD6 trial. No statistically significant associations between the expression levels and age, gender, light chain type, International Staging System (ISS) stage or cytogenetic high- and normal risk groups could be identified. Hyperdiploid MM cells expressed significantly higher levels of IKZF1, IKZF3 and KPNA2 than nonhyperdiploid cells. In contrast, translocation t(11;14) was associated with significantly lower expression levels. In conclusion, the observed overexpression of cereblon-binding proteins in MM cells with gain of chromosomes 5, 9, 11, 15, and 19 is consistent with the previously proposed positive regulation of MYC by IKZF1 and IKZF3, as well as MYC activation in hyperdiploid MM cells.

The histone deacetylase inhibitor panobinostat has shown efficacy in phase-II and phase-III trials for multiple myeloma and has recently received market approval in combination with bortezomib and dexamethasone. Here, we retrospectively report our single center experience with panobinostat/bortezomib/dexamethasone (FVD) in a heavily pretreated patient population (n = 24) with a high degree of refractoriness to proteasome inhibitors (PI) and immunomodulatory drugs (IMiD). Median age was 67 years (range 49-87) and the median number of prior therapies was 5 (range 2-17). Fourteen patients (58%) had high-risk cytogenetic aberrations. Thirteen (54%) and 21 (88%) patients were refractory to PIs and IMiDs, respectively. Twelve patients (50%) were refractory to bortezomib and 7 (29%) to carfilzomib; 6 patients (25%) were refractory to both bortezomib and carfilzomib. In 21 patients evaluable for response, overall response rate (ORR; ≥PR) was 33% (7/21) and 81% (17/21) achieved at least stable disease. Median progression-free survival (PFS) and overall survival were 3.5 and 9.8 months, respectively. Significant differences between bortezomib-sensitive and -refractory patients were observed. In bortezomib-sensitive patients, median PFS was 6.3 months compared to 2.3 months in bortezomib-refractory patients (P

Background Despite novel therapeutic agents, most multiple myeloma (MM) patients eventually relapse. Two large phase III trials have shown significantly improved response rates (RR) of lenalidomide/dexamethasone compared with placebo/dexamethasone in relapsed MM (RMM) patients. These results have led to the approval of lenalidomide for RMM patients and lenalidomide/dexamethasone has since become a widely accepted second-line treatment. Furthermore, in RMM patients consolidation with high-dose chemotherapy plus autologous stem cell transplantation has been shown to significantly increase progression free survival (PFS) as compared to cyclophosphamide in a phase III trial. The randomized prospective ReLApsE trial is designed to evaluate PFS after lenalidomide/dexamethasone induction, high-dose chemotherapy consolidation plus autologous stem cell transplantation and lenalidomide maintenance compared with the well-established lenalidomide/dexamethasone regimen in RMM patients. Methods/Design ReLApsE is a randomized, open, multicenter phase III trial in a planned study population of 282 RMM patients. All patients receive three lenalidomide/dexamethasone cycles and - in absence of available stem cells from earlier harvesting - undergo peripheral blood stem cell mobilization and harvesting. Subsequently, patients in arm A continue on consecutive lenalidomide/dexamethasone cycles, patients in arm B undergo high dose chemotherapy plus autologous stem cell transplantation followed by lenalidomide maintenance until discontinuation criteria are met. Therapeutic response is evaluated after the 3rd (arm A + B) and the 5th lenalidomide/dexamethasone cycle (arm A) or 2 months after autologous stem cell transplantation (arm B) and every 3 months thereafter (arm A + B). After finishing the study treatment, patients are followed up for survival and subsequent myeloma therapies. The expected trial duration is 6.25 years from first patient in to last patient out. The primary endpoint is PFS, secondary endpoints include overall survival (OS), RR, time to best response and the influence of early versus late salvage high dose chemotherapy plus autologous stem cell transplantation on OS. Discussion This phase III trial is designed to evaluate whether high dose chemotherapy plus autologous stem cell transplantation and lenalidomide maintenance after lenalidomide/dexamethasone induction improves PFS compared with the well-established continued lenalidomide/dexamethasone regimen in RMM patients. Trial registration: ISRCTN16345835 (date of registration 2010-08-24). Electronic supplementary material The online version of this article (doi:10.1186/s12885-016-2321-2) contains supplementary material, which is available to authorized users.

SPIRIT checklist. (DOC 121Â kb)

Introduction: The German-Speaking Myeloma Multicenter Group (GMMG) has initiated a randomized multicenter phase III trial on the effect of elotuzumab in VRD (bortezomib, lenalidomide, dexamethasone) induction/consolidation and lenalidomide maintenance in patients with newly diagnosed multiple myeloma (GMMG-HD6 trial, NCT02495922). The study compares four cycles induction therapy with VRD vs. VRD + elotuzumab, followed by standard intensification (i.e. mobilization and stem cell transplantation), two cycles consolidation with VRD/VRD + elotuzumab and lenalidomide maintenance +/- elotuzumab. The primary endpoint is determination of the best of four treatment strategies regarding progression-free survival. Here we present a first analysis of stem cell mobilization within this study. Patients and Methods: We performed a retrospective analysis of collection data on all patients who underwent peripheral blood stem cell (PBSC) collection between trial initiation in June 2015 and June 2016. Only patients with completely available datasets in respect of mobilization were considered (n=111). The vast majority of 99 patients (89%) received chemomobilization with CAD (cyclophosphamide, adriamycin, dexamethasone) followed by 5-10 µg G-CSF /kg body weight (bw) /d (starting day +9 until completion of PBSC collection), while in one case (1%) dexamethasone was omitted and in 10 cases (9%) cyclophosphamide mono was administered. One patient underwent steady-state mobilization with G-CSF only (10µg /kg bw /d). 55/111 patients received VRD (50%), whereas the remaining patients received VRD + elotuzumab. According to the recommendations of the study group, PBSCs for three stem cell transplants were to be collected. One transplant ideally consisted of ≥2.5 x10^6 CD34+ cells /kg bw, but in the event of poor mobilization as low as ≥2.0 x10^6 CD34+ cells /kg bw would be considered acceptable. Results: The median number of collected CD34+ cells was 10.4 x10^6 /kg bw (range 2.88 to 23.01 x10^6 /kg bw). Overall, 92 patients (83%) collected ≥7.5 x10^6 CD34+ cells /kg bw and another 12 patients (11%) collected between 6.0 and 7.5 x10^6 CD34+ cells /kg bw, resulting in three transplants, respectively. Only 7 patients (6%) collected below 6.0 x10^6 CD34+ cells /kg bw; 5 of them had been treated in the VRD-arm without elotuzumab. Due to insufficient PBSC mobilization after conventional treatment, 14 patients (13%) received a rescue mobilization with plerixafor, from which 12 patients collected ≥6.0 x10^6 CD34+ cells /kg bw. Overall, 7 serious adverse events (SAEs) occurred during mobilization phase, 4 of them in the study arm with elotuzumab. Conclusions: Cyclophosphamide-based chemomobilization after induction therapy with VRD is feasible. Efficient PBSC collection of ≥6.0 x10^6 CD34+ cells /kg bw could be performed in 104 of 111 patients (94%), with a low incidence of SAEs. The need for rescue mobilization was not higher than that of comparable previous GMMG treatment protocols. The addition of elotuzumab during induction phase did not impede PBSC collection. Disclosures Wuchter: Sanofi-Aventis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Hexal: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Bertsch:Janssen: Research Funding; Celgene: Research Funding; Chugai: Research Funding. Munder:Janssen: Honoraria; Takeda: Honoraria; Amgen: Honoraria; Bristol Myers Squibb: Honoraria. Fenk:Jansen: Honoraria, Other: travel support; Celgene: Honoraria, Other: travel support, Research Funding. Hillengass:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria; Celgene: Honoraria; BMS: Honoraria; Novartis: Research Funding; Sanofi: Research Funding. Raab:Novartis: Consultancy, Research Funding; BMS: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Ho:Sanofi-Aventis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Scheid:Medac: Other: Travel, accomodations or expenses; Baxalta: Honoraria; Amgen: Consultancy; Novartis: Consultancy, Honoraria, Other: Travel, accomodations or expenses; Janssen: Consultancy, Honoraria; Celgene: Other: Travel, accomodations or expenses; BMS: Consultancy, Honoraria. Weisel:Onyx: Consultancy; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Novartis: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria. Goldschmidt:Takeda: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Chugai: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees.