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Since 2006, the European conditional marketing authorization (CMA) aims to facilitate timely patient access to medicinal products for which there is an unmet medical need by accepting less comprehensive data than normally required. The granting of CMA requires a positive benefit-risk balance, unmet medical needs to be fulfilled, likely submission of comprehensive data postauthorization, and the benefit of immediate availability to outweigh the risks of data noncomprehensiveness. Since its first use, more than half of all CMAs represent (hemato-)oncology indications. Therefore, we aimed to investigate the conditions in which CMA has been applied for anticancer medicinal products and whether they have changed over time. We retrospectively assessed the European public assessment reports of the 30 anticancer medicinal products granted CMA in 2006-2020 (51% of all 59 CMAs). Comparison of 2006-2013 to 2014-2020 highlighted increased proportions of proactively requested CMAs (+40%), medicinal products that addressed unmet medical needs by providing a major therapeutic advantage over authorized treatments (+38%), and orphan designated indications (+32%). In contrast, it showed decreased proportions of medicinal products for which a scientific advisory group was consulted (-55%) and phase III randomized controlled trial data were available (-38%). This suggests that applicants and the European Medicines Agency have learned how to use the CMA as a regulatory tool, among others, through better planning and proactive interaction. However, the increasing number of granted CMAs complicates the establishment of unmet medical need and the benefit-risk balance, especially in crowded indications and when only phase II uncontrolled trials are available., (© 2023 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Introduction: Response kinetics is a well-established prognostic marker in acute lymphoblastic leukemia. The situation is not clear in multiple myeloma (MM) despite having a biomarker for response monitoring (monoclonal component [MC])., Materials and Methods: We developed a mathematical model to assess the prognostic value of serum MC response kinetics during 6 induction cycles, in 373 NDMM transplanted patients treated in the GEM2012Menos65 clinical trial. The model calculated a "resistance" parameter that reflects the stagnation in the response after an initial descent., Results: Two patient subgroups were defined based on low and high resistance, that respectively captured sensitive and refractory kinetics, with progression-free survival (PFS) at 5 years of 72% and 59% (HR 0.64, 95% CI 0.44-0.93; P = .02). Resistance significantly correlated with depth of response measured after consolidation (80.9% CR and 68.4% minimal residual disease negativity in patients with sensitive vs. 31% and 20% in those with refractory kinetics). Furthermore, it modulated the impact of reaching CR after consolidation; thus, within CR patients those with refractory kinetics had significantly shorter PFS than those with sensitive kinetics (median 54 months vs. NR; P = .02). Minimal residual disease negativity abrogated this effect. Our study also questions the benefit of rapid responders compared to late responders (5-year PFS 59.7% vs. 76.5%, respectively [P < .002]). Of note, 85% of patients considered as late responders were classified as having sensitive kinetics., Conclusion: This semi-mechanistic modeling of M-component kinetics could be of great value to identify patients at risk of early treatment failure, who may benefit from early rescue intervention strategies., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Achieving and maintaining a high-quality response is the treatment goal for patients with newly diagnosed multiple myeloma (NDMM). The phase 3 PETHEMA/GEM2012 study, in 458 patients aged ≤65 years with NDMM, is evaluating bortezomib (subcutaneous) + lenalidomide + dexamethasone (VRD) for 6 cycles followed by autologous stem cell transplant (ASCT) conditioned with IV busulfan + melphalan vs melphalan and posttransplant consolidation with 2 cycles of VRD. We present grouped response analysis of induction, transplant, and consolidation. Responses deepened over time; in patients who initiated cycle 6 of induction (n = 426), the rates of a very good partial response or better were 55.6% by cycle 3, 63.8% by cycle 4, 68.3% by cycle 5, and 70.4% after induction. The complete response rate of 33.4% after induction in the intent-to-treat (ITT) population, which was similar in the 92 patients with high-risk cytogenetics (34.8%), also deepened with further treatment (44.1% after ASCT and 50.2% after consolidation). Rates of undetectable minimal residual disease (median 3 × 10-6 sensitivity) in the ITT population also increased from induction (28.8%) to transplant (42.1%) and consolidation (45.2%). The most common grade ≥3 treatment-emergent adverse events during induction were neutropenia (12.9%) and infection (9.2%). Grade ≥2 peripheral neuropathy (grouped term) during induction was 17.0%, with a low frequency of grade 3 (3.7%) and grade 4 (0.2%) events. VRD is an effective and well-tolerated regimen for induction in NDMM with deepening response throughout induction and over the course of treatment. This trial was registered at www.clinicaltrials.gov as #NCT01916252 and EudraCT as #2012-005683-10., (© 2019 by The American Society of Hematology.)

Response criteria for multiple myeloma (MM) require monoclonal protein (M-protein)-negative status on both serum immunofixation electrophoresis (sIFE) and urine (uIFE) immunofixation electrophoresis for classification of complete response (CR). However, uIFE is not always performed for sIFE-negative patients. We analyzed M-protein evaluations from 384 MM patients (excluding those with light-chain-only disease) treated in the GEM2012MENOS65 (NCT01916252) trial to determine the uIFE-positive rate in patients who became sIFE-negative posttreatment and evaluate rates of minimal residual disease (MRD)-negative status and progression-free survival (PFS) among patients achieving CR, CR but without uIFE available (uncertain CR; uCR), or very good partial response (VGPR). Among 107 patients with M-protein exclusively in serum at diagnosis who became sIFE-negative posttreatment and who had uIFE available, the uIFE-positive rate was 0%. Among 161 patients with M-protein in both serum and urine at diagnosis who became sIFE-negative posttreatment, 3 (1.8%) were uIFE positive. Among patients achieving CR vs uCR, there were no significant differences in postconsolidation MRD-negative (<10 -6 ; 76% vs 75%; P = .9) and 2-year PFS (85% vs 88%; P = .4) rates; rates were significantly lower among patients achieving VGPR. Our results suggest that uIFE is not necessary for defining CR in MM patients other than those with light-chain-only disease., (© 2019 by The American Society of Hematology.)

Stringent complete response (sCR) criteria are used in multiple myeloma as a deeper response category compared with CR, but prospective validation is lacking, it is not always clear how evaluation of clonality is performed, and is it not known what the relative clinical influence is of the serum free light chain ratio (sFLCr) and bone marrow (BM) clonality to define more sCR. To clarify this controversy, we focused on 94 patients that reached CR, of which 69 (73%) also fulfilled the sCR criteria. Patients with sCR displayed slightly longer time to progression (median, 62 vs 53 months, respectively; P = .31). On analyzing this contribution to the prognosis of sFLCr or clonality, it was found that the sFLCr does not identify patients in CR at distinct risk; by contrast, low-sensitive multiparametric flow cytometry (MFC) immunophenotyping (2 colors), which is equivalent to immunohistochemistry, identifies a small number of patients (5 cases) with high residual tumor burden and dismal outcome; nevertheless, using traditional 4-color MFC, persistent clonal BM disease was detectable in 36% of patients, who, compared with minimal residual disease-negative cases, had a significantly inferior outcome. These results show that the current definition of sCR should be revised., (© 2015 by The American Society of Hematology.)

This study was conducted to determine whether the integration of the Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) and the European Group for Blood and Marrow Transplantation (EBMT) score would improve individual capacity for stratification of high-risk HCT candidates. A total of 442 consecutive patients receiving an allogeneic HCT after reduced-toxicity conditioning was included. Final HCT-CI and EBMT scores were calculated and validated. Then, patients were grouped into a 6-category new combination model according to the HCT-CI (0, 1 to 2, ≥ 3) and EBMT scores (0 to 3, 4 to 7), and the model's predictive capacity was also evaluated. Median HCT-CI and EBMT scores were 3 and 4, respectively. Increased HCT-CI was associated with higher 4-year nonrelapse mortality (NRM) and lower 4-year overall survival (OS), whereas a high EBMT score was associated with higher 4-year NRM. The HCT-CI showed a trend for a better predictive capacity than the EBMT score (c-statistic .6 versus .54, P = .1). According to the new model, patients within HCT-CI of 0 and HCT-CI of 1 to 2 groups had similar risk of NRM independently of their EBMT score. Within the HCT-CI ≥ 3 group, patients with low EBMT score showed lower NRM (25% versus 40%, P = .04) and a trend to higher OS (52% versus 36%, P = .06) than patients with a high EBMT score. Moreover, patients with HCT-CI ≥ 3 and EBMT score 0 to 3 had similar outcomes than those with HCT-CI of 1 to 2. In conclusion, the combination of HCT-CI and the EBMT score is feasible and might contribute to a better identification of high-risk patients, improving selection of best allogeneic HCT candidates., (Copyright © 2014 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Hyperferritinemia has been associated with adverse outcomes after allogeneic hematopoietic cell transplantation (allo-HCT) with myeloablative conditioning. However, its characteristics and impact on the outcome in the reduced-intensity conditioning (RIC) and in the lymphoid malignancy settings are far from clear. The study includes 201 adult patients undergoing allo-HCT with RIC (allo-RIC) for lymphoid malignancies with a median follow-up for survivors of 52 months (range, 3 to 123). Median serum ferritin level at allo-RIC was 379 ng/mL (range, 4 to 10,790). In the multivariate analysis, patients with hyperferritinemia at transplantation (>399 ng/mL) showed lower 4-year overall survival (hazard ratio [HR], 1.8 [95% confidence interval {CI}, 1.2 to 2.8]; P = .008), higher nonrelapse mortality (NRM) (HR, 1.8 [95% CI, 1.1 to 3.2]; P = .03), and higher infection-related mortality (HR, 2.3 [95% CI, 1.1 to 4.8]; P = .02) than patients without hyperferritinemia. Neutrophil and platelet engraftment and 100-day NRM were similar between both groups. The adverse outcome associated with hyperferritinemia seemed higher in patients without major comorbidities and was not influenced by the elevation of acute phase reactants. Our results indicate that high ferritin levels at HCT are associated with an adverse outcome after allo-RIC in patients with lymphoid malignancies., (Copyright © 2013 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Posttransplant cytopenias are a severe complication after allogeneic stem cell transplantation (allo-SCT) and their origin is often multifactorial or unknown. They are frequently refractory to standard therapy, which may include steroids and/or immunoglobulins. Mesenchymal stem cells (MSCs) are an attractive therapeutic tool in the allo-SCT setting for the ability to enhance engraftment as well as acting as immunosuppressants for graft-versus-host disease. There is no prior experience in the literature of the use of MSCs to treat cytopenias after allo-SCT., Case Reports: In this work we report for the first time four cases of refractory posttransplant cytopenias (three patients with thrombocytopenia and one with neutropenia) that were treated with MSCs from a third-party donor. MSCs were expanded from 100 mL of marrow obtained under standard good manufacturing practice conditions. Most patients received more than one cell dose, and median dose of MSCs administered was 1 × 10(6) /kg., Results: All patients recovered normal blood counts, with a mean follow-up of 12.5 months. There were no adverse events related to MSC administration., Conclusion: MSC therapy may contribute to the recovery of refractory posttransplant peripheral cytopenias in patients undergoing allo-SCT., (© 2011 American Association of Blood Banks.)

Liver dysfunction is frequent before allogeneic stem cell transplantation (allo-SCT). However, its characteristics and impact on transplantation outcomes are uncertain, especially in the reduced-intensity conditioning (RIC) setting. We analyzed 455 patients receiving an allo-SCT in 3 Spanish centers. Pretransplantation aspartate aminotransferase (AST), alanine aminotransaminase (ALT), gamma-glutamyl transpeptidase (GGT), alkaline phosphatase (AP), total bilirubin, and international normalized ratio were analyzed. Pretransplantation liver function test abnormalities were found in 94 (22%) patients. The most frequent cause of pretransplantation liver dysfunction was isolated elevation of GGT/AP (n = 49, 53%). Patients with high bilirubin levels before allo-SCT showed higher 4-year nonrelapse mortality (4y-NRM) (hazard ratio [HR] 2 [95% confidence interval [CI] 1.1-3.8] P = .02) and patients with high GGT levels showed higher 100-day NRM and lower 4-year overall survival (OS) (HR 3.4 [95% CI 1.8-6.7] P < .001, and HR 2 [95% CI 1.4-3], P = .001), respectively. High levels of transaminases did not influence on survival or mortality. In conclusion, hepatic dysfunction before allo-SCT is frequent and has an impact on transplantation outcomes. The best indicator of liver dysfunction still has to be determined., (Copyright © 2011 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

The distinction between IgM monoclonal gammopathy of undetermined significance (MGUS), asymptomatic Waldenstrom's macroglobulinemia (WM; aWM), and symptomatic WM (sWM) relies on two features: the presence of infiltration by lymphoplasmacytic lymphoma in the bone marrow (BM) biopsy and the existence of signs or symptoms attributable to the disease. Nevertheless, some patients lack a BM biopsy or it is not conclusive for diagnosis. In this study we have investigated 94 patients with IgM monoclonal gammopathies, in which a BM trephine biopsy and morphological and flow cytometry (FCM) evaluation of BM aspirate were available at diagnosis. We found a clear correlation between BM infiltration of B-lymphocytes assessed by morphology and by FCM with a Pearson correlation of 0.62 (P<.001). Moreover, in the absence of a BM trephine biopsy, the cut-off points that would help in the differential diagnosis between MGUS, aWM, and sWM would be 20% for morphology and 5% for FCM, both assessed in the BM aspirate.

We report a patient with multiple myeloma presenting with a paraspinal plasmacytoma with a marked dissociation between the response obtained in bone marrow (BM) infiltration and that achieved in soft tissue masses. While a complete remission was reached and maintained in BM, extramedullary plasmacytomas were refractory to every line of treatment. Genetic analysis identified the presence of t(4;14) and RB deletion in myeloma cells of both origins. However, a P53 deletion was only detected in plasma cells from extramedullary plasmacytomas. This finding suggests that P53 deletion has a role in the lack of treatment response of extramedullary plasmacytomas.