Response to daratumumab-retreatment in patients with multiple myeloma.

Daratumumab is an effective therapy in multiple myeloma (MM). We assessed whether daratumumab retreatment may re-induce significant responses and which patients do benefit the most. We hypothesized, that there is effective synergism between daratumumab and alternating antimyeloma drug combinations during retreatment and that retreatment is safe and effective. Here, we analyzed 293 consecutive MM patients receiving daratumumab at our institution from 2016 until 2023 retrospectively, and compared responses, side effects and survival of the first daratumumab treatment line and its retreatment. We identified 22/293 (8%) patients with daratumumab retreatment. These patients showed an advanced age and ISS/R-ISS stages, and ≥ 3 lines of prior antimyeloma therapy in 91%. Of note, the median durations of the first and subsequent daratumumab treatment were similarly long. We confirmed a therapy break between daratumumab lines as advantageous. Daratumumab retreatment was effective, with responses declining only gradually from its first use to subsequent first and second retreatment with 64%, 46% and 43%, respectively. Interestingly, comparable progression free survival rates were observed with 11.5, 12 months and not reached, respectively. Consistently, adverse events per daratumumab line did not increase. Our findings suggest that well-selected daratumumab-exposed MM patients may show rewarding responses to daratumumab retreatment, the more with alternating antimyeloma combinations, initial good response and CD38-antibody-treatment pauses, thereby proving CD38-antibody-retreatment as feasible, effective and non-toxic. Confirmatory studies are required to further validate our results.

Optimizing individualized therapy decision-making in multiple myeloma (MM): integration and impact of the Revised Myeloma Comorbidity Index in the MM-tumor board.

Multiple Myeloma (MM) is a hematological disease predominantly affecting elderly patients. The complexity of current treatment necessitates individualized approaches. Therein, functional assessment (FA) tools, such as the Revised Comorbidity Index (R-MCI) at our University- and Comprehensive Cancer Center Freiburg, play a crucial role. This study aimed to determine (a) the implementation of the R-MCI in our MM-tumor board (MM-TB), (b) its impact on treatment guidance at baseline and (c) potential changes during follow-up. This exploratory study investigated R-MCI coverage and distribution in a cohort of patients with multiple TB presentations. Among them, a follow-up patient cohort undergoing subsequent MM-therapy was analyzed to determine treatment adjustments and changes in patients' condition measured by R-MCI alterations. During our 3-year assessment period, 565 patients were presented in our MM-TB, totaling 1256 TB-presentations. In the multiple TB presentation cohort, the median number of TB presentations was 3 (range: 2-12). R-MCI scores within the MM-TB were available in 94%, whereas in 6%, the R-MCI had not been integrated. Among these, potential failure to identify the need for treatment modifications was determined. In the follow-up cohort, patient characteristics were typical for referral/university centers. Dose reductions were performed in 55% and were more prevalent among patients with ≥ 4 vs. lesser TB presentations. Most patients (55%) showed a fitness stabilization or improvement via follow-up R-MCI. R-MCI integration in MM-TB exceeded > 90%, indicating its successful integration for treatment support. Our results underscore its value in guiding therapy decisions, providing a comprehensive assessment beyond age considerations.

Physical activity and exercise motivation of multiple myeloma patients: a prospective cross-sectional study.

BACKGROUND: Multiple myeloma (MM) is the second most common hematological malignancy with its prevalence increasing. Patients with symptomatic MM can show numerous comorbidities, affecting their quality of life (QoL). Physical activity (PA) may improve QoL but is not a standardized intervention of comprehensive cancer centers (CCCs). Since data on the PA of patients with MM are scarce, we aimed to prospectively assess fitness levels and patients' motivation to join PA-interventions at our CCC. METHODS: We generated an exercise questionnaire to interview consecutive patients MM. We prospectively collected data on (a) past and current PA, defined by the World Health Organization (WHO) recommendations, (b) knowledge on exercise effects, (c) exercise motivation, and (d) willingness to participate in PA-interventions. Demographics, comorbidities, response, progression-free survival (PFS), and overall survival (OS) were assessed in 211 symptomatic patients MM. RESULTS: While our patients were elderly and most showed bone involvement, their PA was similar to healthy individuals. Aerobic PA (≥ 60 minutes/week) was performed by 65%, and 25% exercised ≥ 150 minutes/week. WHO PA recommendations were fulfilled by 17% of patients. No sport activities or complete physical inactivity were observed in 35% and 16%, respectively. Notably, 38% were motivated to join MM-specific sport interventions. Self-reported knowledge of PA-induced benefits for patients cancer was high (82%), but only 27% knew which exercises were safe to perform. CONCLUSION: This study provides an overview of the PA of patients MM. Our results suggest that the PA of patients MM might not be much lower than in the age-matched general population.

The proteogenomic landscape of multiple myeloma reveals insights into disease biology and therapeutic opportunities.

Multiple myeloma (MM) is a plasma cell malignancy of the bone marrow. Despite therapeutic advances, MM remains incurable, and better risk stratification as well as new therapies are therefore highly needed. The proteome of MM has not been systematically assessed before and holds the potential to uncover insight into disease biology and improved prognostication in addition to genetic and transcriptomic studies. Here we provide a comprehensive multiomics analysis including deep tandem mass tag-based quantitative global (phospho)proteomics, RNA sequencing, and nanopore DNA sequencing of 138 primary patient-derived plasma cell malignancies encompassing treatment-naive MM, plasma cell leukemia and the premalignancy monoclonal gammopathy of undetermined significance, as well as healthy controls. We found that the (phospho)proteome of malignant plasma cells are highly deregulated as compared with healthy plasma cells and is both defined by chromosomal alterations as well as posttranscriptional regulation. A prognostic protein signature was identified that is associated with aggressive disease independent of established risk factors in MM. Integration with functional genetics and single-cell RNA sequencing revealed general and genetic subtype-specific deregulated proteins and pathways in plasma cell malignancies that include potential targets for (immuno)therapies. Our study demonstrates the potential of proteogenomics in cancer and provides an easily accessible resource for investigating protein regulation and new therapeutic approaches in MM.

Myosteatosis in multiple myeloma: a key determinant of survival beyond sarcopenia.

OBJECTIVE: Fatty infiltration of skeletal muscle (Myosteatosis) is associated with increased frailty, decreased muscle and mobility function, which seems fairly prevalent in multiple myeloma (MM) patients. This study aimed to determine the prognostic value of myosteatosis assessed by CT for progression-free survival (PFS) and overall survival (OS). MATERIALS AND METHODS: This IRB-approved cohort study included patients with newly diagnosed MM who were treated at a single university hospital and received CT at baseline. Geriatric assessment was performed via International Myeloma Working Group frailty score and Revised Myeloma Comorbidity Index. Myosteatosis was determined through measurement of paravertebral muscle radiodensity. Statistical analyses included uni- and multivariable Cox proportional hazard models and the Kaplan-Meier-method. RESULTS: A total of 226 newly diagnosed MM patients (median age: 65 years [range: 29-89], 63% males, mean BMI: 25 [14-42]) were analyzed. The prevalence of myosteatosis was 51%. Muscle radiodensity was significantly decreased in individuals with International Staging System stage III vs. I (p < 0.001), indicating higher fatty muscle infiltration in patients with advanced disease. Both PFS and OS were significantly decreased in patients with myosteatosis (PFS: median 32.0 months (95% CI 20.5.5-42.2) vs. 66.4 months without myosteatosis (95% CI 42.5-not reached), p < .001); OS: median 58.6 (95% CI 51.3-90.2) vs. not reached, p < .001). Myosteatosis remained an independent predictor of OS in multivariable analyses (HR: 1.98; 95%-CI: 1.20-3.27). CONCLUSION: Myosteatosis seems fairly prevalent in patients with newly diagnosed MM and associated with impaired overall survival. Prospective clinical trials are required to better understand the role of myosteatosis in MM patients.

Impact of prior treatment on selinexor, bortezomib, dexamethasone outcomes in patients with relapsed/refractory multiple myeloma: Extended follow-up subgroup analysis of the BOSTON trial.

OBJECTIVES: To analyze the impact of prior therapies on outcomes with selinexor, bortezomib, and dexamethasone (SVd) versus bortezomib and dexamethasone (Vd) in 402 patients with relapsed/refractory multiple myeloma (RRMM) in the phase 3 BOSTON trial. METHODS: Post hoc analysis of progression-free survival (PFS), overall survival (OS), and safety for lenalidomide-refractory, proteasome inhibitor (PI)-naïve, bortezomib-naïve, and one prior line of therapy (1LOT) patient subgroups. RESULTS: At a median follow-up of over 28 months, clinically meaningful improvements in PFS were noted across all groups with SVd. The median SVd PFS was longer in all subgroups (lenalidomide-refractory: 10.2 vs. 7.1 months, PI-naïve: 29.5 vs. 9.7; bortezomib-naïve: 29.5 vs. 9.7; 1LOT: 21.0 vs. 10.7; p < .05). The lenalidomide-refractory subgroup had longer OS with SVd (26.7 vs. 18.6 months; HR 0.53; p = .015). In all subgroups, overall response and ≥very good partial response rates were higher with SVd. The manageable safety profile of SVd was similar to the overall patient population. CONCLUSIONS: With over 2 years of follow-up, these clinically meaningful outcomes further support the use of SVd in patients who are lenalidomide-refractory, PI-naïve, bortezomib-naïve, or who received 1LOT (including a monoclonal antibody) and underscore the observed synergy between selinexor and bortezomib.

Expression of the chemokine receptor CCR1 decreases sensitivity to bortezomib in multiple myeloma cell lines.

BACKGROUND: The proteasome inhibitor bortezomib is one of the primary therapies used for the haematological malignancy multiple myeloma (MM). However, intrinsic or acquired resistance to bortezomib, via mechanisms that are not fully elucidated, is a barrier to successful treatment in many patients. Our previous studies have shown that elevated expression of the chemokine receptor CCR1 in MM plasma cells in newly diagnosed MM patients is associated with poor prognosis. Here, we hypothesised that the poor prognosis conferred by CCR1 expression is, in part, due to a CCR1-mediated decrease in MM plasma cell sensitivity to bortezomib. METHODS: In order to investigate the role of CCR1 in MM cells, CCR1 was knocked out in human myeloma cell lines OPM2 and U266 using CRISPR-Cas9. Additionally, CCR1 was overexpressed in the mouse MM cell line 5TGM1. The effect of bortezomib on CCR1 knockout or CCR1-overexpressing cells was then assessed by WST-1 assay, with or without CCL3 siRNA knockdown or addition of recombinant human CCL3. NSG mice were inoculated intratibially with OPM2-CCR1KO cells and were treated with 0.7 mg/kg bortezomib or vehicle twice per week for 3 weeks and GFP+ tumour cells in the bone marrow were quantitated by flow cytometry. The effect of CCR1 overexpression or knockout on unfolded protein response pathways was assessed using qPCR for ATF4, HSPA5, XBP1, ERN1 and CHOP and Western blot for IRE1α and p-Jnk. RESULTS: Using CCR1 overexpression or CRIPSR-Cas9-mediated CCR1 knockout in MM cell lines, we found that CCR1 expression significantly decreases sensitivity to bortezomib in vitro, independent of the CCR1 ligand CCL3. In addition, CCR1 knockout rendered the human MM cell line OPM2 more sensitive to bortezomib in an intratibial MM model in NSG mice in vivo. Moreover, CCR1 expression negatively regulated the expression of the unfolded protein response receptor IRE1 and downstream target gene XBP1, suggesting this pathway may be responsible for the decreased bortezomib sensitivity of CCR1-expressing cells. CONCLUSIONS: Taken together, these studies suggest that CCR1 expression may be associated with decreased response to bortezomib in MM cell lines.

Treatment pattern and outcomes of re-induction therapy prior to stem cell transplantation in patients with relapsed/refractory multiple myeloma in Germany.

There are limited data guiding choice of re-induction therapies for patients with relapsed/refractory multiple myeloma (RRMM) prior to stem cell transplantation (SCT). We performed a retrospective medical chart review of 171 patients with RRMM in Germany who received re-induction therapy in second line (78%; n = 134) or third line (22%; n = 37) prior to re-SCT. Index therapy was defined as first completed re-induction therapy for planned myeloablative conditioning and SCT in second/third line within the eligibility period (1/2016-12/2019). Most common pre-index first line and maintenance therapy used were bortezomib-based combinations (91%; n = 155/171) and lenalidomide (55%; n = 29/53), respectively. Median duration of index therapy line was 9 months; carfilzomib-based combinations were the most widely used in second/third line re-induction therapy (49%; n = 83/171), followed by daratumumab-based combinations (21%; n = 36/171). Overall response rates in second/third line were 87% after re-induction and 96% after SCT; median time to next treatment line after start of index therapy was 31 months; median progression-free survival (PFS) was 29 months; and median overall survival after index date was not reached. Based on these data, re-induction therapy with salvage SCT appears to be beneficial in selected patients with RRMM in clinical practice in Germany, translating into deep responses, long PFS and prolonged time to next treatment.

Functional cure and long-term survival in multiple myeloma: how to challenge the previously impossible.

Multiple myeloma (MM) is a heterogeneous disease with survival ranging from months to decades. The goal of 'cure' remains elusive for most patients, but has been shown to be possible, with durable remission and a transition to a plateau phase (analogous to monoclonal gammopathy of uncertain significance/smoldering myeloma). In this review, two representative cases set the stage to illustrate how this might be possible and what still needs to be determined to achieve functional disease control over a prolonged period. Several developments have emerged, such as improved diagnostics including the definitions and use of SLiM-CRAB criteria and measurable residual disease (MRD) with whole-genome/single-cell sequencing as well as other correlates to better understand disease biology. These advances enable earlier detection, more accurate risk stratification and improved personalized treatment strategies by facilitating analysis of genetic alterations and clonal heterogeneity. Whole-genome sequencing may also identify driver mutations and modes of resistance to immunotherapies as well as other targeted therapies. Today, induction with a CD38 antibody, proteasome inhibitor, immunomodulatory drug, and dexamethasone, potentially followed by autologous stem cell transplantation and lenalidomide maintenance, can be considered standard of care for transplant-eligible (TE) patients with newly diagnosed MM (NDMM). That prolonged disease control and functional cure can be achieved in non-transplant-eligible (NTE) patients is currently emerging as a distinct possibility: data from phase III trials that incorporate a CD38 antibody into the treatment of NTE NDMM patients demonstrate impressive MRD negativity rates that appear sustained over several years. While the long-term durability of chimeric antigen receptor T cells, bi-specific antibodies and other immunotherapies are being evaluated, several clinical trials are now investigating their role in frontline treatment for TE and NTE patients. These trials will address whether chimeric antigen receptor T-cell therapy will replace autologous stem cell transplantation and whether such immunotherapies will represent a truly curative option. We conclude that while cure remains elusive, the concept of operational or functional cure provides a new benchmark to strive for and is an emerging area of active and potentially achievable clinical research for MM.

Identification of clinical factors impacting outcome in patients undergoing autologous hematopoietic cell transplantation after BEAM and TEAM conditioning.

Organ dysfunction, including pulmonary function impairment, plays a key role in the choice of conditioning chemotherapy before autologous hematopoietic stem cell transplantation (auto-HSCT). Replacement of BCNU/carmustine as part of BEAM (BCNU/carmustine, etoposide, cytarabine, and melphalan) conditioning protocol by thiotepa (TEAM) reduces pulmonary toxicity while maintaining efficacy. We retrospectively analyzed the association of clinical characteristics, comorbidities, and organ function with outcomes after conditioning with BEAM or TEAM. Three hundred ninety-six patients undergoing auto-HSCT (n = 333 with BEAM; n = 63 with TEAM) at our institution between 2008 and 2021 were included in this study. In the multivariate analysis, CO-diffusion capacity corrected for hemoglobin (DLCOcSB) ≤ 60% of predicted, progressive disease (PD) before auto-HSCT, Karnofsky performance score (KPS) ≤ 80%, HCT-CI score ≥ 4, and cardiac disease before auto-HSCT were associated with decreased overall survival (OS) in patients treated with BEAM. In contrast, only PD before auto-HSCT was identified in patients treated with TEAM. Patients conditioned with BEAM and DLCOcSB ≤ 60% had higher non-relapse mortality, including pulmonary cause of death. In summary, we have identified clinical and pulmonary risk factors associated with worse outcomes in patients conditioned with BEAM compared to TEAM. Our data suggest TEAM conditioning as a valid alternative for patients with comorbidities, including pulmonary dysfunction and/or poorer performance scores, before auto-HSCT.

Clinical phenotype and outcome of persistent SARS-CoV-2 replication in immunocompromised hosts: a retrospective observational study in the Omicron era.

PURPOSE: This study aims to describe clinical, virological and radiological characteristics as well as treatment strategies and outcomes of immunocompromised patients with persistent SARS-CoV-2 replication. METHODS: We performed a retrospective cohort study of immunocompromised patients at the University Medical Center Freiburg between 01/2022 and 05/2023. Patients with substantial immunosuppression and persistent SARS-CoV-2 detection (Ct-value < 30 after 14 days) were included. RESULTS: 36 patients in our cohort reported mainly fever, dyspnoea or continuous cough. Viral load was significantly higher in concurrent samples taken from the lower respiratory tract (Ct-value = 26) than from the upper respiratory tract (Ct-value = 34). Time of detectable viral RNA after start of antiviral treatment was shorter in patients receiving two antivirals (median 15 days vs. 31 days with one antiviral agent). Short-course antiviral therapy (≤ 5 days) was less efficient in reduction of symptoms and viral load than prolonged therapy > 10 days. In 30% (8/27) of patients with repeated CT scans, we found the emergence of chronic pulmonary changes, which were more frequently in patients with B cell depletion (37%, 7/19) compared to patients with organ transplantation (12%, 2/17). CONCLUSION: Ongoing SARS-CoV-2 replication in the lower respiratory tract is a relevant differential diagnosis in patients with severe immunosuppression and continuous cough, fever or dyspnoea even if nasopharyngeal swabs test negative for SARS-CoV-2. Especially in B cell-depleted patients, this may lead to inflammatory or fibrotic-like pulmonary changes, which are partially reversible after inhibition of viral replication. Antiviral therapy seems to be most effective in combination and over a prolonged period of time of > 10 days. TRIAL REGISTRATION NUMBER: DRKS 00027299.

In search for cure of multiple myeloma.

Not available.

Impact of Photon-Counting Detector Computed Tomography on Image Quality and Radiation Dose in Patients With Multiple Myeloma.

OBJECTIVE: Computed tomography (CT) is an established method for the diagnosis, staging, and treatment of multiple myeloma. Here, we investigated the potential of photon-counting detector computed tomography (PCD-CT) in terms of image quality, diagnostic confidence, and radiation dose compared with energy-integrating detector CT (EID-CT). MATERIALS AND METHODS: In this prospective study, patients with known multiple myeloma underwent clinically indicated whole-body PCD-CT. The image quality of PCD-CT was assessed qualitatively by three independent radiologists for overall image quality, edge sharpness, image noise, lesion conspicuity, and diagnostic confidence using a 5-point Likert scale (5 = excellent), and quantitatively for signal homogeneity using the coefficient of variation (CV) of Hounsfield Units (HU) values and modulation transfer function (MTF) via the full width at half maximum (FWHM) in the frequency space. The results were compared with those of the current clinical standard EID-CT protocols as controls. Additionally, the radiation dose (CTDIvol) was determined. RESULTS: We enrolled 35 patients with multiple myeloma (mean age 69.8 ± 9.1 years; 18 [51%] males). Qualitative image analysis revealed superior scores (median [interquartile range]) for PCD-CT regarding overall image quality (4.0 [4.0-5.0] vs. 4.0 [3.0-4.0]), edge sharpness (4.0 [4.0-5.0] vs. 4.0 [3.0-4.0]), image noise (4.0 [4.0-4.0] vs. 3.0 [3.0-4.0]), lesion conspicuity (4.0 [4.0-5.0] vs. 4.0 [3.0-4.0]), and diagnostic confidence (4.0 [4.0-5.0] vs. 4.0 [3.0-4.0]) compared with EID-CT (P ≤ 0.004). In quantitative image analyses, PCD-CT compared with EID-CT revealed a substantially lower FWHM (2.89 vs. 25.68 cy/pixel) and a significantly more homogeneous signal (mean CV ± standard deviation [SD], 0.99 ± 0.65 vs. 1.66 ± 0.5; P < 0.001) at a significantly lower radiation dose (mean CTDIvol ± SD, 3.33 ± 0.82 vs. 7.19 ± 3.57 mGy; P < 0.001). CONCLUSION: Whole-body PCD-CT provides significantly higher subjective and objective image quality at significantly reduced radiation doses than the current clinical standard EID-CT protocols, along with readily available multi-spectral data, facilitating the potential for further advanced post-processing.

Carfilzomib, lenalidomide and dexamethasone followed by a second ASCT is an effective strategy in first relapse multiple myeloma: a study on behalf of the Chronic malignancies working party of the EBMT.

In the setting of a first relapse of multiple myeloma (MM), a second autologous stem cell transplant (ASCT) following carfilzomib-lenalidomide-dexamethasone (KRd) is an option, although there is scarce data concerning this approach. We performed a retrospective study involving 22 EBMT-affiliated centers. Eligible MM patients had received a second-line treatment with KRd induction followed by a second ASCT between 2016 and 2018. Primary objective was to estimate progression-free survival (PFS) and overall survival (OS). Secondary objectives were to assess the response rate and identify significant variables affecting PFS and OS. Fifty-one patients were identified, with a median age of 62 years. Median PFS after ASCT was 29.5 months while 24- and 36-months OS rates were 92.1% and 84.5%, respectively. Variables affecting PFS were an interval over four years between transplants and the achievement of a very good partial response (VGPR) or better before the relapse ASCT. Our study suggests that a relapse treatment with ASCT after KRd induction is an effective strategy for patients with a lenalidomide-sensitive first relapse. Patients with at least four years of remission after a frontline ASCT and who achieved at least a VGPR after KRd induction appear to benefit the most from this approach.

Prevention and management of adverse events during treatment with bispecific antibodies and CAR T cells in multiple myeloma: a consensus report of the European Myeloma Network.

T-cell redirecting bispecific antibodies (BsAbs) and chimeric antigen receptor T cells (CAR T cells) have revolutionised multiple myeloma therapy, but adverse events such as cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome (ICANS), cytopenias, hypogammaglobulinaemia, and infections are common. This Policy Review presents a consensus from the European Myeloma Network on the prevention and management of these adverse events. Recommended measures include premedication, frequent assessing for symptoms and severity of cytokine release syndrome, step-up dosing for several BsAbs and some CAR T-cell therapies; corticosteroids; and tocilizumab in the case of cytokine release syndrome. Other anti-IL-6 drugs, high-dose corticosteroids, and anakinra might be considered in refractory cases. ICANS often arises concomitantly with cytokine release syndrome. Glucocorticosteroids in increasing doses are recommended if needed, as well as anakinra if the response is inadequate, and anticonvulsants if convulsions occur. Preventive measures against infections include antiviral and antibacterial drugs and administration of immunoglobulins. Treatment of infections and other complications is also addressed.