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Journal of Clinical Oncology : Official... Jan 2024The GMMG-CONCEPT trial investigated isatuximab, carfilzomib, lenalidomide, and dexamethasone (Isa-KRd) in transplant-eligible (TE) and transplant-noneligible (TNE)...
PURPOSE
The GMMG-CONCEPT trial investigated isatuximab, carfilzomib, lenalidomide, and dexamethasone (Isa-KRd) in transplant-eligible (TE) and transplant-noneligible (TNE) patients with newly diagnosed multiple myeloma (NDMM) with exclusively high-risk disease for whom prospective trials are limited, aiming to induce minimal residual disease (MRD) negativity.
METHODS
This academic, investigator-initiated, multicenter, phase II trial enrolled patients with high-risk NDMM (HRNDMM) defined by mandatory International Staging System stage II/III combined with del17p, t(4;14), t(14;16), or more than three 1q21 copies as high-risk cytogenetic aberrations (HRCAs). Patients received Isa-KRd induction/consolidation and Isa-KR maintenance. TE patients received high-dose melphalan. TNE patients received two additional Isa-KRd cycles postinduction. This prespecified interim analysis (IA) reports the primary end point, MRD negativity (<10, next-generation flow), at the end of consolidation. The secondary end point was progression-free survival (PFS).
RESULTS
Among 125 patients with HRNDMM (TE-intention-to-treat [ITT]-IA, 99; TNE-ITT, 26) of the IA population for the primary end point, the median age was 58 (TE-ITT-IA) and 74 (TNE-ITT) years. Del17p was the most common HRCA (TE, 44.4%; TNE, 42.3%); about one third of evaluable TE/TNE patients presented two or more HRCAs, respectively. The trial met its primary end point with MRD negativity rates after consolidation of 67.7% (TE) and 54.2% (TNE) of patients. Eighty-one of 99 TE-ITT-IA patients reached MRD negativity at any time point (81.8%). MRD negativity was sustained for ≥1 year in 62.6% of patients. With a median follow-up of 44 (TE) and 33 (TNE) months, median PFS was not reached in either arm.
CONCLUSION
Isa-KRd effectively induces high rates of sustainable MRD negativity in the difficult-to-treat HRNDMM population, regardless of transplant status, translating into a median PFS that was not yet reached after 44/33 months.
Topics: Humans; Middle Aged; Multiple Myeloma; Lenalidomide; Prospective Studies; Dexamethasone; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37753960
DOI: 10.1200/JCO.23.01696 -
Journal of Clinical Oncology : Official... Apr 2024Outcomes for patients with newly diagnosed multiple myeloma (NDMM) are heterogenous, with overall survival (OS) ranging from months to over 10 years.
PURPOSE
Outcomes for patients with newly diagnosed multiple myeloma (NDMM) are heterogenous, with overall survival (OS) ranging from months to over 10 years.
METHODS
To decipher and predict the molecular and clinical heterogeneity of NDMM, we assembled a series of 1,933 patients with available clinical, genomic, and therapeutic data.
RESULTS
Leveraging a comprehensive catalog of genomic drivers, we identified 12 groups, expanding on previous gene expression-based molecular classifications. To build a model predicting individualized risk in NDMM (IRMMa), we integrated clinical, genomic, and treatment variables. To correct for time-dependent variables, including high-dose melphalan followed by autologous stem-cell transplantation (HDM-ASCT), and maintenance therapy, a multi-state model was designed. The IRMMa model accuracy was significantly higher than all comparator prognostic models, with a c-index for OS of 0.726, compared with International Staging System (ISS; 0.61), revised-ISS (0.572), and R2-ISS (0.625). Integral to model accuracy was 20 genomic features, including 1q21 gain/amp, del 1p, loss, translocations, APOBEC mutational signatures, and copy-number signatures (reflecting the complex structural variant chromothripsis). IRMMa accuracy and superiority compared with other prognostic models were validated on 256 patients enrolled in the GMMG-HD6 (ClinicalTrials.gov identifier: NCT02495922) clinical trial. Individualized patient risks were significantly affected across the 12 genomic groups by different treatment strategies (ie, treatment variance), which was used to identify patients for whom HDM-ASCT is particularly effective versus patients for whom the impact is limited.
CONCLUSION
Integrating clinical, demographic, genomic, and therapeutic data, to our knowledge, we have developed the first individualized risk-prediction model enabling personally tailored therapeutic decisions for patients with NDMM.
Topics: Humans; Multiple Myeloma; Prognosis; Melphalan; Hematopoietic Stem Cell Transplantation; Genomics; Transplantation, Autologous; Retrospective Studies
PubMed: 38194610
DOI: 10.1200/JCO.23.01277 -
Annals of Clinical and Translational... Nov 2023Myasthenia gravis (MG) is an autoantibody-mediated neuromuscular junction disorder involving the acetylcholine receptors on the motor endplate. The safety and response...
OBJECTIVE
Myasthenia gravis (MG) is an autoantibody-mediated neuromuscular junction disorder involving the acetylcholine receptors on the motor endplate. The safety and response to high-dose chemotherapy (HDIT) and autologous hematopoietic cell transplantation (HCT) were assessed in a patient with severe refractory MG.
METHODS
As part of a pilot study of HDIT/HCT for patients with treatment-resistant autoimmune neurological disorders, a patient with severe refractory MG underwent treatment. After mobilization of hematopoietic stem cells with rituximab, prednisone, and G-CSF, the patient had HDIT consisting of carmustine, etoposide, cytarabine, melphalan, and rabbit antithymocyte globulin, followed by autologous HCT. The effect of treatment on the autoantibody to the acetylcholine receptor (AChR) was assessed.
RESULTS
The patient had been diagnosed with AChR antibody-positive MG 14 years before HDIT/HCT and had failed thymectomy, therapeutic plasma exchange, and multiple immunomodulatory agents. The Myasthenia Gravis Foundation of America (MGFA) clinical classification was IVb before HDIT/HCT. She tolerated HDIT/HCT well and started to improve clinically within days of treatment. At both 1 and 2 years after HDIT/HCT, patients remained symptom-free. After HDIT/HCT, AChR-binding autoantibodies persisted, and the relative frequency of immune cell subtypes shifted.
INTERPRETATION
HDIT/HCT induced a complete response of disease activity in a patient with severe refractory MG. This response may suggest that a cell-mediated etiology may be a significant contributing factor in refractory MG cases. A phase 2 clinical trial is warranted to establish if HDIT/HCT can be an effective therapy for severe refractory MG and to gain a further understanding of disease pathogenesis.
Topics: Female; Humans; Hematopoietic Stem Cell Transplantation; Pilot Projects; Treatment Outcome; Transplantation, Autologous; Myasthenia Gravis; Receptors, Cholinergic; Autoantibodies
PubMed: 37726935
DOI: 10.1002/acn3.51898 -
HemaSphere Oct 2023We conducted a registry analysis including adult acute myeloid leukemia (AML) patients in remission who had received thiotepa, busulfan, and fludarabine (TBF) or...
Thiotepa-busulfan-fludarabine Compared to Treosulfan-based Conditioning for Haploidentical Transplant With Posttransplant Cyclophosphamide in Patients With Acute Myeloid Leukemia in Remission: A Study From the Acute Leukemia Working Party of the EBMT.
We conducted a registry analysis including adult acute myeloid leukemia (AML) patients in remission who had received thiotepa, busulfan, and fludarabine (TBF) or treosulfan-based (Treo) conditioning for haplo-hematopoietic stem cell transplant (HSCT) with posttransplant cyclophosphamide (PTCy) between 2010 and 2020. A total of 1123 patients met the inclusion criteria (968 received TBF and 155 received Treo). A 1:1 matched-pair analysis was performed on 142 TBF and 142 Treo patients. In the Treo group, 68% of patients received treosulfan at a dose ≥36 g/m and 54% of patients received a second alkylator (thiotepa or melphalan). We observed a trend toward increased incidence of grade II-IV acute (a) graft-versus-host disease (GVHD) at 180 days in the TBF group compared with Treo (29% versus 20%; = 0.08), while incidence of grade III-IV aGVHD was not statistically different. Similarly, the incidence of chronic (c) GVHD was not statistically different in the 2 groups. Incidence of nonrelapse mortality at 2 years was 19% in TBF and 14% in Treo ( = 0.4). Relapse incidence at 2 years was not statistically different in the 2 groups (16% and 18% in TBF and Treo, respectively; = 0.9). Leukemia-free survival, overall survival, and GVHD-free, relapse-free survival was 65% versus 68% ( = 0.6), 73% versus 76% ( = 0.5), and 54% versus 53% ( = 0.8) in TBF versus Treo, respectively. In conclusion, we did not find a significant difference between the 2 conditioning in the present study; Treo and TBF represent 2 valid alternative regimens for haplo-HSCT with PTCy for AML in remission.
PubMed: 37746158
DOI: 10.1097/HS9.0000000000000952 -
Cancers Aug 2023Multiple myeloma (MM) is a plasma cell malignancy characterized by several genetic abnormalities, including chromosomal translocations, genomic deletions and gains, and... (Review)
Review
Multiple myeloma (MM) is a plasma cell malignancy characterized by several genetic abnormalities, including chromosomal translocations, genomic deletions and gains, and point mutations. DNA damage response (DDR) and DNA repair mechanisms are altered in MM to allow for tumor development, progression, and resistance to therapies. Damaged DNA rarely induces an apoptotic response, given the presence of ataxia-telangiectasia mutated () loss-of-function or mutations, as well as deletions, mutations, or downregulation of tumor protein p53 (TP53) and tumor protein p73 (TP73). Moreover, DNA repair mechanisms are either hyperactive or defective to allow for rapid correction of the damage or permissive survival. Medications used to treat patients with MM can induce DNA damage, by either direct effects (mono-adducts induced by melphalan), or as a result of reactive oxygen species (ROS) production by proteasome inhibitors such as bortezomib. In this review, we will describe the mechanisms of DDR and DNA repair in normal tissues, the contribution of these pathways to MM disease progression and other phenotypes, and the potential therapeutic opportunities for patients with MM.
PubMed: 37627183
DOI: 10.3390/cancers15164155 -
Scientific Reports Aug 2023Breast cancer is the second most common type of cancer worldwide and the leading cause of cancer death in women. Dietary bioactive compounds may act at different stages...
Breast cancer is the second most common type of cancer worldwide and the leading cause of cancer death in women. Dietary bioactive compounds may act at different stages of carcinogenesis, including tumor initiation, promotion, and progression. Spices have been used for thousands of years and have many bioactive compounds with chemopreventive and chemotherapeutic properties. Curcumin has a multitude of beneficial biological properties, including anti-inflammatory and anticancer effects. This study investigated the effects of cotreatment with curcumin and the chemotherapeutic drug melphalan in cultured MDA-MB-231 breast cancer cells. When used alone, both curcumin and melphalan had a cytotoxic effect on breast cancer cells. Combined treatment with 11.65 µM of curcumin and 93.95 µM of melphalan (CURC/MEL) reduced cell viability by 28.64% and 72.43% after 24 h and 48 h, respectively. CURC/MEL reduced the number of colony-forming units and increased ROS levels by 1.36-fold. CURC/MEL alter cell cycle progression, induce apoptosis, and upregulate caspases-3, -7, and -9, in MDA-MB-231 cells. Cotreatment with curcumin and melphalan have anti-breast cancer cells effects and represent a promising candidate for clinical testing.
Topics: Female; Humans; Melphalan; Curcumin; Breast Neoplasms; Cell Cycle Checkpoints; Apoptosis
PubMed: 37596331
DOI: 10.1038/s41598-023-40535-5 -
Blood Advances Jun 2023The overall survival (OS) has improved significantly in multiple myeloma (MM) over the last decade with the use of proteasome inhibitor and immunomodulatory drug-based...
The overall survival (OS) has improved significantly in multiple myeloma (MM) over the last decade with the use of proteasome inhibitor and immunomodulatory drug-based combinations, followed by high-dose melphalan and autologous hematopoietic stem cell transplantation (auto-HSCT) and subsequent maintenance therapies in eligible newly diagnosed patients. However, clinical trials using auto-HSCT followed by lenalidomide maintenance have shown an increased risk of second primary malignancies (SPM), including second hematological malignancies (SHM). We evaluated the impact of SPM and SHM on progression-free survival (PFS) and OS in patients with MM after auto-HSCT using CIBMTR registry data. Adult patients with MM who underwent first auto-HSCT in the United States with melphalan conditioning regimen from 2011 to 2018 and received maintenance therapy were included (n = 3948). At a median follow-up of 37 months, 175 (4%) patients developed SPM, including 112 (64%) solid, 36 (20%) myeloid, 24 (14%) SHM, not otherwise specified, and 3 (2%) lymphoid malignancies. Multivariate analysis demonstrated that SPM and SHM were associated with an inferior PFS (hazard ratio [HR] 2.62, P < .001 and HR 5.01, P < .001, respectively) and OS (HR 3.85, P < .001 and HR 8.13, P < .001, respectively). In patients who developed SPM and SHM, MM remained the most frequent primary cause of death (42% vs 30% and 53% vs 18%, respectively). We conclude the development of SPM and SHM leads to a poor survival in patients with MM and is an important survivorship challenge. Given the median survival for MM continues to improve, continued vigilance is needed to assess the risks of SPM and SHM with maintenance therapy post-auto-HSCT.
Topics: Adult; Humans; United States; Multiple Myeloma; Melphalan; Neoplasms, Second Primary; Transplantation, Autologous; Lenalidomide; Hematologic Neoplasms
PubMed: 36827681
DOI: 10.1182/bloodadvances.2022009138 -
Multiple Sclerosis and Related Disorders Aug 2023Autologous hematopoietic stem cell treatment (AHSCT) is considered an effective treatment option for patients with aggressive relapsing-remitting multiple sclerosis...
BACKGROUND
Autologous hematopoietic stem cell treatment (AHSCT) is considered an effective treatment option for patients with aggressive relapsing-remitting multiple sclerosis (RRMS). Still there are few randomized and controlled studies of AHSCT to shed light on the safety and efficacy of the treatment, and therefore experiences from single centers are important.
AIM
To describe the Danish experience with AHSCT regarding patient characteristics, safety, and efficacy.
METHOD
Nationwide retrospective single center study of patients with multiple sclerosis (MS) treated with AHSCT.
RESULTS
A total of 32 patients were treated with AHSCT from May 2011 to May 2021. Seven were treated with carmustine, etoposide, cytarabine arabinoside, and melphalan (BEAM) as well as antithymocyte globulin (ATG). Twenty-five patients were treated with cyclophosphamide (CY) and ATG. In the whole cohort, relapse-free survival (RFS) was 77% (95% CI: 64-94%), worsening-free survival (WFS) was 79% (95% CI: 66-96%), MRI event-free survival (MFS) was 93% (95% CI: 85-100%), and no evidence of disease (NEDA-3) was 69% (95% CI: 54-89%) at the end of year two post-AHSCT. We had no treatment related mortality and only few severe adverse events (AEs).
CONCLUSION
AHSCT of patients with aggressive RRMS was an effective and relatively safe treatment with few serious AEs and no mortality in Danish patients.
Topics: Humans; Multiple Sclerosis, Relapsing-Remitting; Multiple Sclerosis; Retrospective Studies; Treatment Outcome; Hematopoietic Stem Cell Transplantation; Denmark
PubMed: 37364374
DOI: 10.1016/j.msard.2023.104829 -
Molecular Therapy. Methods & Clinical... Sep 2023Hematopoietic stem cell gene therapy has been successfully used for a number of genetic diseases and is also being explored for HIV. However, toxicity of the...
Hematopoietic stem cell gene therapy has been successfully used for a number of genetic diseases and is also being explored for HIV. However, toxicity of the conditioning regimens has been a major concern. Here we compared current conditioning approaches in a clinically relevant nonhuman primate model. We first customized various aspects of the therapeutic approach, including mobilization and cell collection protocols, conditioning regimens that support engraftment with minimal collateral damage, and cell manufacturing and infusing schema that reflect and build on current clinical approaches. Through a series of iterative experiments in two macaque species, we show that busulfan conditioning significantly spares lymphocytes and maintains a superior immune response to mucosal challenge with simian/human immunodeficiency virus, compared to total body irradiation and melphalan regimens. Comparative mobilization experiments demonstrate higher cell yield relative to our historical standard, primed bone marrow and engraftment of CRISPR-edited hematopoietic stem and progenitor cells (HSPCs) after busulfan conditioning. Our findings establish a detailed workflow for preclinical HSPC gene therapy studies in the nonhuman primate model, which in turn will support testing of novel conditioning regimens and more advanced HSPC gene editing techniques tailored to any disease of interest.
PubMed: 37575091
DOI: 10.1016/j.omtm.2023.07.006