Publications by authors named "Katja Weisel"

184 Publications

Daratumumab plus lenalidomide and dexamethasone in transplant-ineligible newly diagnosed multiple myeloma: frailty subgroup analysis of MAIA.

Leukemia 2022 Jan 2. Epub 2022 Jan 2.

Department of Hematology, Amsterdam UMC, Vrije Universiteit Amsterdam, Cancer Center Amsterdam, Amsterdam, The Netherlands.

In the phase 3 MAIA study of patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM), daratumumab plus lenalidomide/dexamethasone (D-Rd) improved progression-free survival (PFS) versus lenalidomide/dexamethasone (Rd). We present a subgroup analysis of MAIA by frailty status. Frailty assessment was performed retrospectively using age, Charlson comorbidity index, and baseline Eastern Cooperative Oncology Group performance status score. Patients were classified as fit, intermediate, non-frail (fit + intermediate), or frail. Of the randomized patients (D-Rd, n = 368; Rd, n = 369), 396 patients were non-frail (D-Rd, 196 [53.3%]; Rd, 200 [54.2%]) and 341 patients were frail (172 [46.7%]; 169 [45.8%]). After a 36.4-month median follow-up, non-frail patients had longer PFS than frail patients, but the PFS benefit of D-Rd versus Rd was maintained across subgroups: non-frail (median, not reached [NR] vs 41.7 months; hazard ratio [HR], 0.48; P < 0.0001) and frail (NR vs 30.4 months; HR, 0.62; P = 0.003). Improved rates of complete response or better and minimal residual disease (10) negativity were observed for D-Rd across subgroups. The most common grade 3/4 treatment-emergent adverse event in non-frail and frail patients was neutropenia (non-frail, 45.4% [D-Rd] and 37.2% [Rd]; frail, 57.7% and 33.1%). These findings support the clinical benefit of D-Rd in transplant-ineligible NDMM patients enrolled in MAIA, regardless of frailty status.
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http://dx.doi.org/10.1038/s41375-021-01488-8DOI Listing
January 2022

Lymphocytopenia and Anti-CD38 Directed Treatment Impact the Serological SARS-CoV-2 Response after Prime Boost Vaccination in Patients with Multiple Myeloma.

J Clin Med 2021 Nov 24;10(23). Epub 2021 Nov 24.

The Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, University Cancer Center Hamburg, 20251 Hamburg, Germany.

Even though several SARS-CoV-2 vaccines have shown high effectiveness in the prevention of COVID-19 in healthy subjects, vaccination response in patients with plasma-cell-related disorders (PCD) remains widely unknown. Here, we report on an analysis describing the serological response after prime-boost SARS-CoV-2 vaccination in PCD patients, as compared to a healthy control group, and on possible influencing factors of serological responses. Blood samples were analyzed for the presence of quantitative anti-SARS-CoV-2 spike RBD Ig. A total of 82 patients were included; 67 received mRNA-, eight vector-based and four heterologous vaccinations. SARS-CoV-2 antibody titers (SP-AbT) were assessed in a mean of 23 days (SD ± 11 days) after the first and in a mean 21 days (SD ± 9) after prime-boost vaccination. A positive SP-AbT was detected in 31.9% of PCD patients after the first vaccination, and in 88.9% (44/49) after prime-boost vaccination, which was significantly less likely than that in the control group (100%, 78/78) ( = 0.008). Furthermore, we have been able to validate our previously suggested threshold of 30 CD19+ B lymphocytes/µL as being predictive for SP-AbT development. Despite anti-CD38 directed therapy, quadruplet treatment, higher age and missing deep remission, which correlated negatively with SP-AbT appearance, SP-AbT formation is possible in a majority of myeloma patients after prime-boost vaccination.
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http://dx.doi.org/10.3390/jcm10235499DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8658197PMC
November 2021

Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for patients with relapsed or refractory multiple myeloma (CANDOR): updated outcomes from a randomised, multicentre, open-label, phase 3 study.

Lancet Oncol 2022 Jan 3;23(1):65-76. Epub 2021 Dec 3.

National and Kapodistrian University of Athens, School of Medicine, Athens, Greece.

Background: Despite recent advances in therapeutic options, there remains an unmet need for treating patients with relapsed or refractory multiple myeloma, especially in those previously exposed or refractory to lenalidomide. This updated efficacy and safety analysis from the phase 3 CANDOR study compared carfilzomib, daratumumab, and dexamethasone (KdD) with carfilzomib and dexamethasone (Kd) in patients with relapsed or refractory multiple myeloma.

Methods: In this updated analysis of the randomised, multicentre, open-label, phase 3 CANDOR study, patients (aged ≥18 years) with relapsed or refractory multiple myeloma, at least a partial response to between one and three previous therapies, and Eastern Cooperative Oncology Group performance status of 0-2, were recruited from 102 medical centres globally and randomly assigned (2:1) by interactive voice or web response software to receive KdD or Kd. Participants were stratified by disease stage, previous proteasome inhibitor or anti-CD38 antibody exposure, and number of previous therapies. All patients received intravenous infusions of carfilzomib twice per week at 56 mg/m (20 mg/m on days 1 and 2 during cycle 1) on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle. Daratumumab (8 mg/kg) was administered intravenously on days 1 and 2 of cycle 1 and at 16 mg/kg weekly for the remaining doses of the first two cycles, then every 2 weeks for four cycles (cycles 3-6), and every 4 weeks thereafter. Patients received 40 mg dexamethasone weekly (20 mg for patients >75 years old). This analysis was a preplanned interim analysis for overall survival; however, at the time of data cutoff, overall survival data were not mature. The primary endpoint was progression-free survival. Here, we provide updated progression-free survival data, assessed centrally by Onyx Response Computer Algorithm in the intention-to-treat population, with 11 months additional follow-up. Adverse events were assessed in the safety population, which included all participants who received at least one dose of trial treatment. CANDOR is registered with ClinicalTrials.gov, NCT03158688, and is active but not recruiting.

Findings: Between June 13, 2017, and June 25, 2018, 466 patients were enrolled, of whom 312 received KdD and 154 received Kd. At data cutoff (June 15, 2020), median follow-up was 27·8 months (IQR 25·6-29·5) for KdD and 27·0 months (13·2-28·6) for Kd. Median progression-free survival was 28·6 months (95% CI 22·7-not estimable [NE]) in the KdD group and 15·2 months (11·1-19·9) in the Kd group (hazard ratio 0·59 [95% CI 0·45-0·78], log-rank p<0·0001). Treatment-emergent adverse events in the safety population were consistent with the primary analysis. Grade 3 or worse treatment-emergent adverse events occurred in 268 (87%) patients in the KdD group and 116 (76%) in the Kd group; most commonly thrombocytopenia (76 [25%] vs 25 [16%], respectively), hypertension (65 [21%] vs 23 [15%]), pneumonia (54 [18%] vs 14 [9%]), and anaemia (53 [17%] vs 23 [15%]). Serious adverse events occurred in 194 (63%) patients with KdD and 76 (50%) with Kd. Adverse events leading to death occurred in 27 (9%) patients in the KdD group and seven (5%) in the Kd group; most commonly septic shock (five [2%] vs one (1%]) and pneumonia (four [1%] vs none). No new treatment-related deaths have occurred since the primary analysis.

Interpretation: A clear, maintained progression-free survival benefit of KdD over Kd with longer follow-up was confirmed, making KdD an emerging standard-of-care for patients with relapsed or refractory multiple myeloma.

Funding: Amgen and Janssen.
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http://dx.doi.org/10.1016/S1470-2045(21)00579-9DOI Listing
January 2022

Comparative Efficacy of Ciltacabtagene Autoleucel in CARTITUDE-1 vs Physician's Choice of Therapy in the Long-Term Follow-Up of POLLUX, CASTOR, and EQUULEUS Clinical Trials for the Treatment of Patients with Relapsed or Refractory Multiple Myeloma.

Clin Drug Investig 2022 Jan 25;42(1):29-41. Epub 2021 Nov 25.

Hematology Department, University College Hospital, London, UK.

Background And Objective: Ciltacabtagene autoleucel (cilta-cel) is a novel agent being investigated in the single-arm CARTITUDE-1 trial (NCT03548207) for patients with relapsed or refractory multiple myeloma who are triple-class exposed to an immunomodulatory drug, proteasome inhibitor, and an anti-CD38 monoclonal antibody. The objective of this study was to evaluate the comparative efficacy of cilta-cel vs physician's choice of treatment, as no head-to-head trials have been conducted.

Methods: An external control arm for CARTITUDE-1 was created from patients in the long-term follow-up for three clinical trials of daratumumab (POLLUX, CASTOR, and EQUULEUS) who satisfied the eligibility criteria of CARTITUDE-1. These patients received physician's choice of treatment following the discontinuation of study drugs. Inverse probability of treatment weighting was used to align the external control and CARTITUDE-1 populations on important baseline characteristics. Overall response rate, complete response or better rate, progression-free survival, time to next treatment, and overall survival were assessed. Several sensitivity analyses were conducted.

Results: After propensity score weighting, baseline characteristics were comparable between cohorts. Patients showed improved results with cilta-cel vs physician's choice of treatment: overall response rate (relative risk: 2.95 [95% confidence interval (CI) 2.27, 3.84; p < 0.0001]), complete response or better (relative risk: 111.70 [95% CI 29.08, 429.06; p < 0.0001]), progression-free survival (hazard ratio [HR]: 0.24 [95% CI 0.15, 0.37; p < 0.0001]), time to next treatment (HR: 0.14 [95% CI 0.09, 0.22; p < 0.0001]), and overall survival (HR: 0.21 [95% CI 0.13, 0.35; p < 0.0001]). Results were consistent across all sensitivity analyses.

Conclusions: Cilta-cel showed superior efficacy compared with physician's choice of treatment, making it a promising new treatment option for patients with triple-class exposed relapsed or refractory multiple myeloma.
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http://dx.doi.org/10.1007/s40261-021-01100-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8755696PMC
January 2022

Bone Marrow-Resident Vδ1 T Cells Co-express TIGIT With PD-1, TIM-3 or CD39 in AML and Myeloma.

Front Med (Lausanne) 2021 8;8:763773. Epub 2021 Nov 8.

Department of Oncology, Hematology and Bone Marrow Transplantation With Section Pneumology, Hubertus Wald University Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

γδ T cells represent a unique T cell subpopulation due to their ability to recognize cancer cells in a T cell receptor- (TCR) dependent manner, but also in a non-major histocompatibility complex- (MHC) restricted way via natural killer receptors (NKRs). Endowed with these features, they represent attractive effectors for immuno-therapeutic strategies with a better safety profile and a more favorable anti-tumor efficacy in comparison to conventional αβ T cells. Also, remarkable progress has been achieved re-activating exhausted T lymphocytes with inhibitors of co-regulatory receptors e.g., programmed cell death protein 1 (PD-1), T cell immunoreceptor with Ig and ITIM domains (TIGIT) and of the adenosine pathway (CD39, CD73). Regarding γδ T cells, little evidence is available. This study aimed to immunophenotypically characterize γδ T cells from patients with diagnosed acute myeloid leukemia (AML) in comparison to patients with multiple myeloma (MM) and healthy donors (HD). The frequency, differentiation, activation, and exhaustion status of bone marrow- (BM) derived γδ T cells from patients with AML ( = 10) and MM ( = 11) were assessed in comparison to corresponding CD4 and CD8 T cells and peripheral blood- (PB) derived γδ T cells from HDs ( = 16) using multiparameter flow cytometry. BM-infiltrating Vδ1 T cells showed an increased terminally differentiated cell population (TEMRAs) in AML and MM in comparison to HDs with an aberrant subpopulation of CD27CD45RA cells. TIGIT, PD-1, TIM-3, and CD39 were more frequently expressed by γδ T cells in comparison to the corresponding CD4 T cell population, with expression levels that were similar to that on CD8 effector cells in both hematologic malignancies. In comparison to Vδ2 T cells, the increased frequency of PD-1-, TIGIT-, TIM-3, and CD39 cells was specifically observed on Vδ1 T cells and related to the TEMRA Vδ1 population with a significant co-expression of PD-1 and TIM-3 together with TIGIT. Our results revealed that BM-resident γδ T cells in AML and MM express TIGIT, PD-1, TIM-3 and CD39. As effector population for autologous and allogeneic strategies, inhibition of co-inhibitory receptors on especially Vδ1 γδ T cells may lead to re-invigoration that could further increase their cytotoxic potential.
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http://dx.doi.org/10.3389/fmed.2021.763773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8606547PMC
November 2021

Current Treatment Approaches to Newly Diagnosed Multiple Myeloma.

Oncol Res Treat 2021 16;44(12):690-699. Epub 2021 Nov 16.

Department of Hematology, Oncology and Bone Marrow Transplantation with Section of Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Background: Multiple myeloma is a so far incurable malignant plasma cell disorder. During the past 2 decades, treatment paradigms substantially changed when novel drugs were introduced initially in treatment of relapsed disease and subsequently also in first-line treatment.

Summary: Up to now, first-line treatment differs between patients initially classified as transplant eligible and those who are considered as nontransplant eligible. Transplant-eligible patients receive a primary proteasome inhibitor (PI)-based induction which is being combined with an immunomodulating agent and a CD38-directed monoclonal antibody followed by high-dose melphalan therapy and autologous stem cell transplantation with subsequent maintenance treatment with lenalidomide. Patients who are considered as nontransplant eligible receive upfront treatment preferentially with a continuous combination treatment either with a CD38-directed monoclonal antibody in combination with the immunomodulating agent lenalidomide or a lenalidomide-PI combination followed by lenalidomide maintenance. Key Messages: Primary goal of the initiated treatment is to induce a rapid and deep remission which ideally leads to an eradication of the residual plasma cell clone in sense of a minimal residual disease negativity. Achievement of long-term remission with limited toxicity despite continuous treatment strategies and maintenance or improvement of life-quality is key. Despite successful treatment options, specific difficult-to-treat subgroups, especially patients with high-risk myeloma remain with inferior prognosis and a clear unmet need for novel therapeutic strategies. Future concepts will evaluate cellular treatments and other innovative immunotherapies in first-line treatment in curative intention.
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http://dx.doi.org/10.1159/000520504DOI Listing
December 2021

MCT1 is a predictive marker for lenalidomide maintenance therapy in multiple myeloma.

Blood Adv 2022 Jan;6(2):515-520

Department of Medicine III, Klinikum rechts der Isar, and.

Biomarkers that predict response to lenalidomide maintenance therapy in patients with multiple myeloma (MM) have remained elusive. We have shown that immunomodulatory drugs (IMiDs) exert anti-MM activity via destabilization of MCT1 and CD147. In this study, cell samples of 654 patients with MM who received lenalidomide (n = 455), thalidomide (n = 98), or bortezomib (n = 101) maintenance were assessed by gene expression profiling and RNA sequencing, followed by correlation of MCT1 and CD147 expression with data for progression-free survival (PFS) and overall survival (OS). Patients with high expression levels of MCT1 showed significantly reduced PFS (31.9 months vs 48.2 months in MCT1high vs MCT1low; P = .03) and OS (75.9 months vs not reached [NR] in MCT1high vs MCT1low; P = .001) in cases with lenalidomide maintenance, whereas MCT1 expression had no significant impact on PFS or OS in cases with bortezomib maintenance. We validated the predictive role of MCT1 for IMiD-based maintenance in an independent cohort of patients who received thalidomide (OS, 83.6 months vs NR in MCT1high vs MCT1low; P = .03). Functional validation showed that MCT1 overexpression in human MM cell lines significantly reduced the efficacy of lenalidomide, whereas no change was observed with bortezomib treatment, either in vitro or in a MM xenograft model. Our findings have established MCT1 expression as a predictive marker for response to lenalidomide-based maintenance in patients with MM.
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http://dx.doi.org/10.1182/bloodadvances.2021005532DOI Listing
January 2022

COVID-19 vaccination in patients with multiple myeloma: a consensus of the European Myeloma Network.

Lancet Haematol 2021 Dec 28;8(12):e934-e946. Epub 2021 Oct 28.

Department of Hematooncology, University Hospital Ostrava and Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic.

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 vaccination in patients with multiple myeloma was condensed into this Review.
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http://dx.doi.org/10.1016/S2352-3026(21)00278-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8553271PMC
December 2021

COVID-19 and seasonal influenza: a comparative analysis in patients with hematological malignancies.

Leuk Lymphoma 2021 Oct 20:1-8. Epub 2021 Oct 20.

Department of Oncology, Hematology and Bone Marrow Transplantation with Division of Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

The severity and mortality of COVID-19 and seasonal influenza were recently compared in the general population but not in patients with hematological malignancies. We analyzed the clinical courses of 79 patients with hematological malignancies and diagnosis of either SARS-CoV-2 ( = 29) or influenza A or B infections ( = 50) who were admitted or were already under treatment in the Department of Oncology, Hematology and Stem cell Transplantation at the University Medical Center Hamburg-Eppendorf, Germany, between 1 January 2012 and 31 January 2021. For COVID-19, we observed significantly higher rates of acute respiratory distress syndrome with 48% (14/29) compared to 14% (7/50) in the influenza group ( = 0.001) as well as a significantly higher virus-associated 90-day mortality (41% vs. 12%,  = 0.005). Based on our results, we conclude that infections with SARS-CoV-2 are more severe than influenza A or B in patients with hematological malignancies.
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http://dx.doi.org/10.1080/10428194.2021.1992626DOI Listing
October 2021

Daratumumab, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone alone in newly diagnosed multiple myeloma (MAIA): overall survival results from a randomised, open-label, phase 3 trial.

Lancet Oncol 2021 11 13;22(11):1582-1596. Epub 2021 Oct 13.

Levine Cancer Institute/Atrium Health, Charlotte, NC, USA.

Background: In the primary analysis of the phase 3 MAIA trial (median follow-up 28·0 months), a significant improvement in progression-free survival was observed with daratumumab plus lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in transplantation-ineligible patients with newly diagnosed multiple myeloma. Here, we report the updated efficacy and safety results from a prespecified interim analysis for overall survival.

Methods: MAIA is an ongoing, multicentre, randomised, open-label, phase 3 trial that enrolled patients at 176 hospitals in 14 countries across North America, Europe, the Middle East, and the Asia-Pacific region. Eligible patients were aged 18 years or older, had newly diagnosed multiple myeloma, had an Eastern Cooperative Oncology Group performance status score of 0-2, and were ineligible for high-dose chemotherapy with autologous stem-cell transplantation because of their age (≥65 years) or comorbidities. Patients were randomly assigned (1:1) using randomly permuted blocks (block size 4) by an interactive web response system to receive 28-day cycles of intravenous daratumumab (16 mg/kg, once per week during cycles 1-2, once every 2 weeks in cycles 3-6, and once every 4 weeks thereafter) plus oral lenalidomide (25 mg on days 1-21 of each cycle) and oral dexamethasone (40 mg on days 1, 8, 15, and 22 of each cycle; daratumumab group) or lenalidomide and dexamethasone alone (control group). Randomisation was stratified by International Staging System disease stage, geographical region, and age. Neither patients nor investigators were masked to treatment assignment. The primary endpoint was progression-free survival, which was centrally assessed, and a secondary endpoint was overall survival (both assessed in the intention-to-treat population). The safety population included patients who received at least one dose of the study treatment. The results presented here are from a prespecified interim analysis for overall survival, for which the prespecified stopping boundary was p=0·0414. This trial is registered with ClinicalTrials.gov, NCT02252172.

Findings: Between March 18, 2015, and Jan 15, 2017, 952 patients were assessed for eligibility, of whom 737 patients were enrolled and randomly assigned to the daratumumab group (n=368) or the control group (n=369). At a median follow-up of 56·2 months (IQR 52·7-59·9), median progression-free survival was not reached (95% CI 54·8-not reached) in the daratumumab group versus 34·4 months (29·6-39·2) in the control group (hazard ratio [HR] 0·53 [95% CI 0·43-0·66]; p<0·0001). Median overall survival was not reached in either group (daratumumab group, 95% CI not reached-not reached; control group, 95% CI 55·7-not reached; HR 0·68 [95% CI 0·53-0·86]; p=0·0013). The most common (>15%) grade 3 or higher treatment-emergent adverse events were neutropenia (197 [54%] patients in the daratumumab group vs 135 [37%] patients in the control group), pneumonia (70 [19%] vs 39 [11%]), anaemia (61 [17%] vs 79 [22%]), and lymphopenia (60 [16%] vs 41 [11%]). Serious adverse events occurred in 281 (77%) patients in the daratumumab group and 257 (70%) patients in the control group. Treatment-related deaths occurred in 13 (4%) patients in the daratumumab group and ten (3%) patients in the control group.

Interpretation: Daratumumab plus lenalidomide and dexamethasone increased overall survival and progression-free survival in patients ineligible for stem-cell transplantation with newly diagnosed multiple myeloma. There were no new safety concerns. Our results support the frontline use of daratumumab plus lenalidomide and dexamethasone for patients with multiple myeloma who are ineligible for transplantation.

Funding: Janssen Research & Development.
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http://dx.doi.org/10.1016/S1470-2045(21)00466-6DOI Listing
November 2021

Prognostic Impact of Serum Free Light Chain Ratio Normalization in Patients with Multiple Myeloma Treated within the GMMG-MM5 Trial.

Cancers (Basel) 2021 Sep 28;13(19). Epub 2021 Sep 28.

Department of Medicine V, Hematology, Oncology and Rheumatology, University of Heidelberg, 69120 Heidelberg, Germany.

We investigated the prognostic impact of time-dependent serum free light chain ratio (FLCr) normalization in 590 patients with secretory multiple myeloma (MM) during first-line treatment within the German-Speaking Myeloma Multicenter Group MM5 trial. Serum free light chains (sFLC) were assessed by the Freelite test at baseline, after induction, mobilization, autologous blood stem cell transplantation, consolidation and every three months during maintenance or follow up within two years after the start of maintenance. The proportion of patients with a normal or normalized FLCr increased from 3.6% at baseline to 23.2% after induction and 64.7% after consolidation. The achievement of FLCr normalization at any one time before the start of maintenance was associated with significantly prolonged progression-free survival (PFS) ( < 0.01, hazard ratio (HR) = 0.61, 95% confidence interval (95% CI) = 0.47-0.79) and overall survival (OS) ( = 0.02, HR = 0.67, 95% CI = 0.48-0.93) in multivariable time-dependent Cox regression analyses. Furthermore, reaching immune reconstitution, defined as the normalization of uninvolved immunoglobulins, before maintenance was associated with superior PFS ( = 0.04, HR = 0.77, 95% CI = 0.60-0.99) and OS ( = 0.01, HR = 0.59, 95% CI = 0.41-0.86). We conclude that FLCr normalization during therapy is an important favorable prognostic factor in MM. Therefore, we recommend serial measurements of sFLC during therapy until achieving FLCr normalization, even in patients with secretory MM.
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http://dx.doi.org/10.3390/cancers13194856DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8507729PMC
September 2021

Pomalidomide, bortezomib, and dexamethasone at first relapse in lenalidomide-pretreated myeloma: A subanalysis of OPTIMISMM by clinical characteristics.

Eur J Haematol 2022 Jan 22;108(1):73-83. Epub 2021 Sep 22.

National and Kapodistrian University of Athens, Athens, Greece.

Objective: We evaluated the efficacy and safety of pomalidomide, bortezomib, and dexamethasone (PVd) vs bortezomib and dexamethasone (Vd) by age, renal function, and high-risk cytogenetic abnormalities in lenalidomide-pretreated patients with multiple myeloma at first relapse.

Methods: OPTIMISMM was a phase 3, multicenter, open-label, randomized study (NCT01734928; N = 559). The primary endpoint was progression-free survival (PFS).

Results: Overall, 226 patients had received one prior line of therapy. PVd significantly prolonged PFS vs Vd in patients aged ≤65 years (median, 22.0 vs 13.1 months; P = .0258) and >65 years (median, 17.6 vs 9.9 months; P = .0369). Median PFS in patients with renal impairment (RI; creatinine clearance <60 mL/min) was 15.1 months with PVd vs 9.5 months with Vd (hazard ratio [HR], 0.67 [95% CI, 0.34-1.34]). In patients without RI, median PFS was 22.0 vs 13.1 months (HR, 0.45 [95% CI, 0.27-0.76]). In patients with high-risk cytogenetics, median PFS was 14.7 vs 9.9 months (HR, 0.39 [95% CI, 0.13-1.17]). PVd significantly improved overall response rate vs Vd in all subgroups. The safety profile of PVd was consistent with previous reports.

Conclusions: These findings confirmed the benefits of PVd at first relapse, including in patients with poor prognostic factors.
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http://dx.doi.org/10.1111/ejh.13706DOI Listing
January 2022

Quality of life analyses in patients with multiple myeloma: results from the Selinexor (KPT-330) Treatment of Refractory Myeloma (STORM) phase 2b study.

BMC Cancer 2021 Sep 6;21(1):993. Epub 2021 Sep 6.

Lineberger Comprehensive Cancer Center at University of North Carolina-Chapel Hill, Chapel Hill, USA.

Background: Selinexor is an oral, selective nuclear export inhibitor. STORM was a phase 2b, single-arm, open-label, multicenter trial of selinexor with low dose dexamethasone in patients with penta-exposed relapsed/refractory multiple myeloma (RRMM) that met its primary endpoint, with overall response of 26% (95% confidence interval [CI], 19 to 35%). Health-related quality of life (HRQoL) was a secondary endpoint measured using the Functional Assessment of Cancer Therapy - Multiple Myeloma (FACT-MM). This study examines impact of selinexor treatment on HRQoL of patients treated in STORM and reports two approaches to calculate minimal clinically important differences for the FACT-MM.

Methods: FACT-MM data were collected at baseline, on day 1 of each 4-week treatment cycle, and at end of treatment (EOT). Changes from baseline were analyzed for the FACT-MM total score, FACT-trial outcome index (TOI), FACT-General (FACT-G), and the MM-specific domain using mixed-effects regression models. Two approaches for evaluating minimal clinically important differences were explored: the first defined as 10% of the instrument range, and the second based on estimated mean baseline differences between Eastern Cooperative Oncology Group performance status (ECOG PS) scores. Post-hoc difference analysis compared change in scores from baseline to EOT for treatment responders and non-responders.

Results: Eighty patients were included in the analysis; the mean number of prior therapies was 7.9 (standard deviation [SD] 3.1), and mean duration of myeloma was 7.6 years (SD 3.4). Each exploratory minimal clinically important difference threshold yielded consistent results whereby most patients did not experience HRQoL decline during the first six cycles of treatment (range: 53.9 to 75.7% for the first approach; range: 52.6 to 72.9% for the second). Treatment responders experienced less decline in HRQoL from baseline to EOT than non-responders, which was significant for the FACT-G, but not for other scores.

Conclusion: The majority of patients did not experience decline in HRQoL based on minimal clinically important differences during early cycles of treatment with selinexor and dexamethasone in the STORM trial. An anchor-based approach utilizing patient-level data (ECOG PS score) to define minimal clinically important differences for the FACT-MM gave consistent results with a distribution-based approach.

Trial Registration: This trial was registered on ClinicalTrials.gov under the trial-ID NCT02336815 on January 8, 2015.
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http://dx.doi.org/10.1186/s12885-021-08453-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419947PMC
September 2021

Post-Vaccination Anti-SARS-CoV-2-Antibody Response in Patients with Multiple Myeloma Correlates with Low CD19+ B-Lymphocyte Count and Anti-CD38 Treatment.

Cancers (Basel) 2021 Jul 28;13(15). Epub 2021 Jul 28.

University Cancer Center Hamburg, Department of Oncology, Hematology and Bone Marrow Transplantation, Section of Pneumology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany.

Few data are available regarding the efficacy of anti-SARS-CoV-2 vaccines in patients with hematological malignancies, and particular, plasma cell neoplasia. This ongoing single-center study aimed to describe the level of post-vaccination anti-SARS-CoV-2-antibodies depending on B lymphocyte count, current therapy, and remission status of patients with multiple myeloma and related plasma cell dyscrasia, after the first dose of anti-SARS-CoV-2 vaccination. The 82 patients included in this study received SARS-CoV-2 vaccines (including mRNA- and vector-based vaccines) as a routine measure. After the first vaccination, a positive SARS-CoV-2 spike protein antibody titer (SP-AbT) was detected in 23% of assessable patients. SARS-CoV-2 SP-AbT was significantly higher in patients with higher CD19+ B lymphocyte counts. A cut-off value of ≥30 CD19+ B cells/µL was significantly positive correlating with higher SARS-CoV-2 SP-AbT. In contrast, current treatment with anti-CD38-antibodies has led to significantly reduced SP-AbT titers. Furthermore, in multivariable linear regression, higher age and insufficiently controlled disease significantly correlated negatively with SARS-CoV-2 SP-AbT. Conversely, treatment with immunomodulatory drugs did not harm the development of antibody titers. Based on our results, the majority of myeloma patients respond poorly after receiving the first dose of any anti-SARS-CoV-2 vaccination and need booster vaccination.
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http://dx.doi.org/10.3390/cancers13153800DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8345197PMC
July 2021

Longer term outcomes with single-agent belantamab mafodotin in patients with relapsed or refractory multiple myeloma: 13-month follow-up from the pivotal DREAMM-2 study.

Cancer 2021 Nov 27;127(22):4198-4212. Epub 2021 Jul 27.

Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.

Background: On the basis of the DREAMM-2 study (ClinicalTrials.gov identifier NCT03525678), single-agent belantamab mafodotin (belamaf) was approved for patients with relapsed or refractory multiple myeloma (RRMM) who received ≥4 prior therapies, including anti-CD38 therapy. The authors investigated longer term efficacy and safety outcomes in DREAMM-2 after 13 months of follow-up among patients who received belamaf 2.5 mg/kg.

Methods: DREAMM-2 is an ongoing, phase 2, open-label, 2-arm study investigating belamaf (2.5 or 3.4 mg/kg) in patients with RRMM who had disease progression after ≥3 lines of therapy and were refractory to immunomodulatory drugs and proteasome inhibitors and refractory and/or intolerant to an anti-CD38 therapy. The primary outcome was the proportion of patients that achieved an overall response, assessed by an independent review committee.

Results: As of January 31, 2020, 10% of patients still received belamaf 2.5 mg/kg. Thirty-one of 97 patients (32%; 97.5% confidence interval [CI], 21.7%-43.6%) achieved an overall response, and 18 responders achieved a very good partial response or better. Median estimated duration of response, overall survival, and progression-free survival were 11.0 months (95% CI, 4.2 months to not reached), 13.7 months (95% CI, 9.9 months to not reached), and 2.8 months (95% CI, 1.6-3.6 months), respectively. Response and survival outcomes in patients who had high-risk cytogenetics or renal impairment were consistent with outcomes in the overall population. Outcomes were poorer in patients with extramedullary disease. In patients who had a clinical response and prolonged dose delays (>63 days; mainly because of corneal events), 88% maintained or deepened responses during their first prolonged dose delay. Overall, there were no new safety signals during this follow-up.

Conclusions: Extended follow-up confirms sustained clinical activity without new safety signals with belamaf in this heavily pretreated patient population with RRMM.
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http://dx.doi.org/10.1002/cncr.33809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8597112PMC
November 2021

Outcome of a Real-World Patient Cohort with Secondary CNS Lymphoma Treated with High-Intensity Chemoimmunotherapy and Autologous Stem Cell Transplantation.

Oncol Res Treat 2021 21;44(7-8):375-381. Epub 2021 Jul 21.

Department of Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Background: Aggressive non-Hodgkin lymphomas with secondary central nervous system (CNS) involvement bear a dismal prognosis. Optimal treatment remains so far unclear, and effective treatment options remain an unmet clinical need. Remission rates are in general low, resulting in rapid relapses and palliative care in the majority of patients. High-intensity treatment combining effective CNS-directed chemoimmunotherapy with autologous stem cell transplantation was shown in a recent phase 2 trial to induce durable remissions. Here, we report the outcome of the first real-world patient cohort treated according to the published protocol.

Methods: We retrospectively identified 17 HIV-negative lymphoma patients with secondary CNS involvement, either at first diagnosis or at relapse of lymphoma, treated according to the study protocol published by Ferreri et al. [J Clin Oncol. 2015] at two university medical centers in Germany. Treatment consisted of four cycles of chemoimmunotherapy with a consolidating autologous stem cell transplantation. Adverse events and overall outcome were assessed.

Results: Five patients had CNS involvement at first diagnosis and 12 patients at relapse of lymphoma. A complete response was achieved in 9 patients. Median survival was 11 months. Five patients died of septic complications and 4 patients succumbed to progression or relapse of disease.

Conclusions: The outcome of our real-world cohort emphasizes the possible toxic character of the treatment protocol by Ferreri et al. [J Clin Oncol. 2015]. Further improvement in treatment regimens is still an unmet need.
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http://dx.doi.org/10.1159/000517531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8495762PMC
September 2021

Prognostic value of minimal residual disease negativity in myeloma: combined analysis of POLLUX, CASTOR, ALCYONE, MAIA.

Blood 2021 Jul 21. Epub 2021 Jul 21.

Dana-Farber Cancer Institute, Boston, Massachusetts, United States.

We explored minimal residual disease (MRD) in relapsed/refractory multiple myeloma (RRMM) and transplant-ineligible newly diagnosed multiple myeloma (TIE NDMM) using data from four phase 3 studies (POLLUX, CASTOR, ALCYONE, and MAIA). Each study previously demonstrated that daratumumab-based therapies improved MRD-negativity rates and reduced the risk of disease progression or death by approximately half versus standards of care. We conducted a large-scale pooled analysis for associations between patients achieving complete response (CR) or better with MRD-negative status, and progression-free survival (PFS). MRD was assessed via next-generation sequencing (10‒5 threshold). Patient-level data were pooled from all four studies, and for patients with TIE NDMM plus patients with RRMM who received ≤2 prior lines of therapy (≤2PL). PFS was evaluated by response and MRD status. Median follow-up (months) was: POLLUX, 54.8; CASTOR, 50.2; ALCYONE, 40.1; and MAIA, 36.4. Patients who achieved ≥CR and MRD negativity had improved PFS versus those who failed to reach CR or were MRD positive (TIE NDMM and RRMM hazard ratio [HR] 0.20, P < .0001; TIE NDMM and RRMM ≤2PL HR 0.20, P < .0001). This benefit occurred irrespective of therapy or disease setting. A time-varying Cox proportional hazard model confirmed that ≥CR with MRD negativity was associated with improved PFS. Daratumumab-based treatment was associated with more patients reaching ≥CR and MRD negativity. These findings represent the first large-scale analysis with robust methodology to support ≥CR with MRD negativity as a prognostic factor for PFS in RRMM and TIE NDMM. These trials were registered at www.ClinicalTrials.gov: NCT02076009/NCT02136134/NCT02195479/NCT02252172.
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http://dx.doi.org/10.1182/blood.2021011101DOI Listing
July 2021

Health-related quality of life outcomes from the CANDOR study in patients with relapsed or refractory multiple myeloma.

Leuk Lymphoma 2021 Dec 26;62(12):3002-3010. Epub 2021 Jun 26.

CHU de Poitiers - La Miletrie, Poitiers, France.

CANDOR (NCT03158688) compared carfilzomib, dexamethasone, and daratumumab (KdD) to carfilzomib and dexamethasone (Kd) in patients with relapsed/refractory multiple myeloma (RRMM). A secondary objective of CANDOR was to evaluate health-related quality of life (HRQoL) scores using the Global Health Status (GHS)/Quality of Life (QoL) domain of the EORTC QLQ-C30. Scores were compared between KdD and Kd using a restricted maximum likelihood-based mixed effects model for repeated measures. GHS/QoL completion rates were >81% for both arms. Higher GHS/QoL scores were observed with KdD versus Kd from Cycle 7-26. The overall least squares mean estimate (95% CI) of the difference between treatment arms was 0.06 (-2.39 to 2.50;  = 0.96). In an exploratory analysis, 55.5% in the KdD arm and 43.0% in the Kd arm improved ≥10 points in GHS/QoL score from baseline. HRQoL was maintained with KdD, consistent with superior clinical benefit observed with KdD versus Kd in patients with RRMM.
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http://dx.doi.org/10.1080/10428194.2021.1941927DOI Listing
December 2021

Real-world comparative effectiveness of triplets containing bortezomib (B), carfilzomib (C), daratumumab (D), or ixazomib (I) in relapsed/refractory multiple myeloma (RRMM) in the US.

Ann Hematol 2021 Sep 10;100(9):2325-2337. Epub 2021 May 10.

Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Multiple available combinations of proteasome inhibitors, immunomodulators (IMIDs), and monoclonal antibodies are shifting the relapsed/refractory multiple myeloma (RRMM) treatment landscape. Lack of head-to-head trials of triplet regimens highlights the need for real-world (RW) evidence. We conducted an RW comparative effectiveness analysis of bortezomib (V), carfilzomib (K), ixazomib (I), and daratumumab (D) combined with either lenalidomide or pomalidomide plus dexamethasone (Rd or Pd) in RRMM. A retrospective cohort of patients initiating triplet regimens in line of therapy (LOT) ≥ 2 on/after 1/1/2014 was followed between 1/2007 and 3/2018 in Optum's deidentified US electronic health records database. Time to next treatment (TTNT) was estimated using Kaplan-Meier methods; regimens were compared using covariate-adjusted Cox proportional hazard models. Seven hundred forty-one patients (820 patient LOTs) with an Rd backbone (VRd, n = 349; KRd, n = 218; DRd, n = 99; IRd, n = 154) and 348 patients (392 patient LOTs) with a Pd backbone (VPd, n = 52; KPd, n = 146; DPd, n = 149; IPd, n = 45) in LOTs ≥2 were identified. More patients ≥75 years received IRd (39.6%), IPd (37.8%), and VRd (36.7%) than other triplets. More patients receiving VRd/VPd were in LOT2 vs other triplets. Unadjusted median TTNT in LOT ≥ 2: VRd, 13.9; KRd, 8.7; IRd, 11.4; DRd, not estimable (NE); and VPd, 12.0; KPd, 6.7; IPd, 9.5 months; DPd, NE. In covariate-adjusted analysis, only KRd vs DRd was associated with a significantly higher risk of next LOT initiation/death (HR 1.72; P = 0.0142); no Pd triplet was significantly different vs DPd in LOT ≥ 2. Our data highlight important efficacy/effectiveness gaps between results observed in phase 3 clinical trials and those realized in the RW.
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http://dx.doi.org/10.1007/s00277-021-04534-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8357697PMC
September 2021

Matching adjusted indirect comparisons of efficacy outcomes for idecabtagene vicleucel (ide-cel, bb2121) versus selinexor + dexamethasone and belantamab mafodotin in relapsed and refractory multiple myeloma.

Leuk Lymphoma 2021 10 24;62(10):2482-2491. Epub 2021 Apr 24.

Celgene International Sàrl, a Bristol-Myers Squibb Company, Boudry, Switzerland.

Idecabtagene vicleucel (ide-cel, bb2121), a chimeric antigen receptor (CAR) T cell therapy, has been investigated in patients with relapsed and refractory multiple myeloma (RRMM) who have received an immunomodulatory drug, proteasome inhibitor, and anti-CD38 antibody in the single-arm phase 2 KarMMa clinical trial. Two therapies with distinct mechanisms of action - selinexor plus dexamethasone (Sd) and belantamab mafodotin (BM) - are currently approved in the United States for heavily pretreated patients, including those who are triple-class refractory. To compare ide-cel versus Sd and ide-cel versus BM, matching-adjusted indirect comparisons were performed. Ide-cel extended progression-free survival (PFS) and overall survival (OS) versus both Sd and BM (hazard ratio (HR); 95% confidence interval (CI)). PFS: ide-cel versus Sd, 0.46; 0.28-0.75; ide-cel versus BM, 0.45; 0.27-0.77. OS: ide-cel versus Sd, 0.23; 0.13-0.42; ide-cel versus BM, 0.35; 0.14-0.87. These results suggest ide-cel offers clinically meaningful improvements over currently approved regimens for patients with heavily pretreated RRMM.
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http://dx.doi.org/10.1080/10428194.2021.1913143DOI Listing
October 2021

Improving outcomes for patients with relapsed multiple myeloma: Challenges and considerations of current and emerging treatment options.

Blood Rev 2021 09 9;49:100808. Epub 2021 Feb 9.

Jerome Lipper Multiple Myeloma Center, Dana Farber Cancer Institute, Boston, MA, USA.

Despite the recent introduction of new therapies for multiple myeloma (MM), it remains an incurable disease. As MM progresses, patients experience cycles of relapse and remission, with remission periods becoming increasingly shorter as the disease becomes less treatment-sensitive. The treatment of relapsed refractory MM (RRMM) remains a significant clinical challenge. Patients with RRMM are a highly heterogeneous group and choosing the most appropriate treatment requires careful consideration. Furthermore, the number of treatment options for MM is continually growing with no definitive consensus to guide treating clinicians. The emergence of second-generation proteasome inhibitors (e.g., carfilzomib and ixazomib), immunomodulatory drugs (e.g., pomalidomide) and monoclonal antibodies (e.g., isatuximab) has expanded an already complex treatment landscape. This review provides a clear summary of the available treatments for MM and discusses how to tailor treatments to individual patients' needs. Novel treatments currently under clinical development, including venetoclax, melflufen and CAR T-cell therapies, are also discussed.
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http://dx.doi.org/10.1016/j.blre.2021.100808DOI Listing
September 2021

Monoclonal Antibodies and Antibody Drug Conjugates in Multiple Myeloma.

Cancers (Basel) 2021 Mar 29;13(7). Epub 2021 Mar 29.

II Medizinische Klinik und Poliklinik, Universitätsklinikum Hamburg-Eppendorf, 20251 Hamburg, Germany.

Multiple myeloma is the second most common hematologic malignancy. Current treatment strategies are mainly based on immunomodulatory drugs, proteasome inhibitors or combination of both. Novel agents added to these backbone treatments represent a promising strategy in treatment of newly diagnosed as well as relapsed and refractory multiple myeloma patients. In this respect, the incorporation of monoclonal antibodies into standard-of-care regimens markedly improved prognosis of myeloma patients during the last years. More specifically, monoclonal anti-CD38 antibodies, daratumumab and isatuximab, have been implemented into treatment strategies from first-line treatment to refractory disease. In addition, the monoclonal anti-SLAM-F7 antibody elotuzumab in combination with immunomodulatory drugs has improved the clinical outcomes of patients with relapsed/refractory disease. Belantamab mafodotin is the first approved antibody drug conjugate directed against B cell maturation antigen and is currently used as a monotherapy for patients with advanced disease. This review focuses on clinical efficacy and safety of monoclonal antibodies as well as antibody drug conjugates in multiple myeloma.
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http://dx.doi.org/10.3390/cancers13071571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8037134PMC
March 2021

Ixazomib-lenalidomide-dexamethasone in routine clinical practice: effectiveness in relapsed/refractory multiple myeloma.

Future Oncol 2021 Jul 26;17(19):2499-2512. Epub 2021 Mar 26.

Institute of Biostatistics & Analyses, Ltd, Brno, 602 00, Czech Republic.

To evaluate the effectiveness and safety of ixazomib-lenalidomide-dexamethasone (IRd) in relapsed/refractory multiple myeloma in routine clinical practice. Patient-level data from the global, observational INSIGHT MM and the Czech Registry of Monoclonal Gammopathies were integrated and analyzed. At data cut-off, 263 patients from 13 countries were included. Median time from diagnosis to start of IRd was 35.8 months; median duration of follow-up was 14.8 months. Overall response rate was 73%, median progression-free survival, 21.2 months and time-to-next therapy, 33.0 months. Ixazomib/lenalidomide dose reductions were required in 17%/36% of patients; 32%/30% of patients discontinued ixazomib/lenalidomide due to adverse events. The effectiveness and safety of IRd in routine clinical practice are comparable to those reported in TOURMALINE-MM1. NCT02761187 (ClinicalTrials.gov).
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http://dx.doi.org/10.2217/fon-2020-1225DOI Listing
July 2021

Belantamab mafodotin in combination with novel agents in relapsed/refractory multiple myeloma: DREAMM-5 study design.

Future Oncol 2021 06 8;17(16):1987-2003. Epub 2021 Mar 8.

Department of Medical Oncology, Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, MA 02215, USA.

Belantamab mafodotin (belamaf) is a BCMA-targeted antibody-drug conjugate recently approved as monotherapy for adults with relapsed/refractory multiple myeloma who have received ≥4 prior therapies. Belamaf binds to BCMA and eliminates myeloma cells by multimodal mechanisms of action. The cytotoxic and potential immunomodulatory properties of belamaf have led to novel combination studies with other anticancer therapies. Here, we describe the rationale and design of DREAMM-5, an ongoing Phase I/II platform study evaluating the safety and efficacy of belamaf combined with novel agents, including GSK3174998 (OX40 agonist), feladilimab (an ICOS; GSK3359609), nirogacestat (a gamma-secretase inhibitor; PF-03084014) and dostarlimab (a PD-1 blocker) versus belamaf monotherapy for patients with relapsed/refractory multiple myeloma. Clinical trial registration: NCT04126200 (ClinicalTrials.gov).
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http://dx.doi.org/10.2217/fon-2020-1269DOI Listing
June 2021

Treatment of relapsed and refractory multiple myeloma: recommendations from the International Myeloma Working Group.

Lancet Oncol 2021 03;22(3):e105-e118

Rigshospitalet, Copenhagen University, Copenhagen, Denmark.

This Policy Review presents the International Myeloma Working Group's clinical practice recommendations for the treatment of relapsed and refractory multiple myeloma. Based on the results of phase 2 and phase 3 trials, these recommendations are proposed for the treatment of patients with relapsed and refractory disease who have received one previous line of therapy, and for patients with relapsed and refractory multiple myeloma who have received two or more previous lines of therapy. These recommendations integrate the issue of drug access in both low-income and middle-income countries and in high-income countries to help guide real-world practice and thus improve patient outcomes.
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http://dx.doi.org/10.1016/S1470-2045(20)30756-7DOI Listing
March 2021

Idecabtagene Vicleucel in Relapsed and Refractory Multiple Myeloma.

N Engl J Med 2021 02;384(8):705-716

From the Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute (N.C.M.), the Veterans Affairs Boston Healthcare System, Harvard Medical School (N.C.M.), and Massachusetts General Hospital (N.R.), Boston, and bluebird bio, Cambridge (F.P., M.M.) - all in Massachusetts; Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas (L.D.A.); the University of California, San Francisco, San Francisco (N.S.); Icahn School of Medicine at Mount Sinai, New York (D.M.); Sarah Cannon Research Institute and Tennessee Oncology, Nashville (J.B.); Emory School of Medicine, Atlanta (S.L.); Mayo Clinic, Rochester, MN (Y.L.); Hackensack University Medical Center, Hackensack (D.S.), and Bristol-Myers Squibb, Princeton (J.N.C., S.K., P.P., L.H., T.B.C., K.H.) - both in New Jersey; Institut Josep Carreras and Institut Catala d'Oncologia, Hospital Germans Trias i Pujol, Badalona (A.O.), and Clinica Universidad de Navarra, Centro de Investigación Médica Aplicada, Instituto de Investigación Sanitaria de Navarra, Centro de Investigación Biomédica en Red de Cáncer, Pamplona (J.S.-M.) - both in Spain; Centre Hospitalier Universitaire (CHU) de Nantes, Nantes (P.M.), and CHU de Lille, University of Lille, INSERM Unité 1286, Institute for Translational Research in Inflammation, Lille (I.Y.-A.) - both in France; University Hospital Leuven, Leuven, Belgium (M.D.); "Seràgnoli" Institute of Hematology, Bologna University School of Medicine, Bologna (M.C.), the Department of Oncology and Hematology, University of Milan, Milan (A.R.), and Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII, Bergamo (A.R.) - all in Italy; University Hospital of Würzburg, Würzburg (H.E.), University Hospital Heidelberg (H.G.) and the National Center for Tumor Diseases (H.G.), Heidelberg, the University Medical Center Hamburg-Eppendorf, Hamburg (K.W.), and Universitätsklinikum Tübingen, Tübingen (K.W.) - all in Germany; and Princess Margaret Cancer Centre, Toronto (D.R.).

Background: Idecabtagene vicleucel (ide-cel, also called bb2121), a B-cell maturation antigen-directed chimeric antigen receptor (CAR) T-cell therapy, has shown clinical activity with expected CAR T-cell toxic effects in patients with relapsed and refractory multiple myeloma.

Methods: In this phase 2 study, we sought to confirm the efficacy and safety of ide-cel in patients with relapsed and refractory myeloma. Patients with disease after at least three previous regimens including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 antibody were enrolled. Patients received ide-cel target doses of 150 × 10 to 450 × 10 CAR-positive (CAR+) T cells. The primary end point was an overall response (partial response or better); a key secondary end point was a complete response or better (comprising complete and stringent complete responses).

Results: Of 140 patients enrolled, 128 received ide-cel. At a median follow-up of 13.3 months, 94 of 128 patients (73%) had a response, and 42 of 128 (33%) had a complete response or better. Minimal residual disease (MRD)-negative status (<10 nucleated cells) was confirmed in 33 patients, representing 26% of all 128 patients who were treated and 79% of the 42 patients who had a complete response or better. The median progression-free survival was 8.8 months (95% confidence interval, 5.6 to 11.6). Common toxic effects among the 128 treated patients included neutropenia in 117 patients (91%), anemia in 89 (70%), and thrombocytopenia in 81 (63%). Cytokine release syndrome was reported in 107 patients (84%), including 7 (5%) who had events of grade 3 or higher. Neurotoxic effects developed in 23 patients (18%) and were of grade 3 in 4 patients (3%); no neurotoxic effects higher than grade 3 occurred. Cellular kinetic analysis confirmed CAR+ T cells in 29 of 49 patients (59%) at 6 months and 4 of 11 patients (36%) at 12 months after infusion.

Conclusions: Ide-cel induced responses in a majority of heavily pretreated patients with refractory and relapsed myeloma; MRD-negative status was achieved in 26% of treated patients. Almost all patients had grade 3 or 4 toxic effects, most commonly hematologic toxic effects and cytokine release syndrome. (Funded by bluebird bio and Celgene, a Bristol-Myers Squibb company; KarMMa ClinicalTrials.gov number, NCT03361748.).
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http://dx.doi.org/10.1056/NEJMoa2024850DOI Listing
February 2021
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