Chimeric antigen receptor T in the treatment of multiple myeloma – state of the art and future directions

In spite of the introduction of several new drugs in the last 10 years, multiple myeloma (MM) remains incurable. Thus, an adoptive cellular therapy using chimeric antigen receptor T (CART), a strategy to increase the frequency of tumor-directed and functionally active T cells targeting antigens present on the cancer cell, might change the treatment in MM as it did in lymphoma and ALL. There are several targets for CART therapy in MM on different levels of development, which are discussed in the manuscript. B-cell maturation antigen (BCMA) being tested in the studies of phase 1–2 is the most promising, but so far CART has not been approved in the cure of MM and remains an experimental approach. The hematological society is facing a new technology which with its potential ability to cure MM, in spite of its complexity, cost, and toxicity, will definitely and soon change the landscape of myeloma in Europe and world-wide

“Translational research” in multiple myeloma – Polish opportunity to accelerate?

Although multiple myeloma still remains an incurable disease, the introduction of new drugs like thalidomide, bortezomib and lenalidomide, and recently carfilzomib and pomalidomide (not in the EU) has significantly prolonged life of patients with multiple myeloma. One of the key factors affecting the dramatic improvement in the effectiveness of the therapy is the development of so-called translational research which is defined by intensive laboratory work, mainly based on molecular studies, focused on the extremely fast introduction of this knowledge in clinical practice. The use of modern methods of molecular biology by identifying new therapeutic targets in preclinical studies has allowed the introduction of new particles such as perifosine or elotuzumab for clinical trials, which will probably result in their rapid introduction into everyday clinical practice. “Translational research” is also used in the work on the optimization of treatment with substances already registered as exemplified by studies using GEP and proteomics. Consolidated and consistent actions of hematological centers in Poland, in cooperation with the Polish non-clinical research centers, as well as with foreign institutions, given the large clinical population of patients with multiple myeloma, it is a huge Polish opportunity to develop knowledge about the disease. This will give a chance to people for easier access to modern forms of therapy to ultimately make myeloma from “incurable” to “chronic” disease

Outpatient CAR-T therapy

Chimeric antigen receptor T (CAR-T) therapy has recently revolutionized the treatment of aggressive lymphomas and acute lymphoblastic leukemia, and will soon do the same for myeloma and other hematological malignancies. Due to the risk of potentially life-threatening complications such as cytokine release syndrome (CRS) and immune effector cell associated neurological syndrome (ICANS), patients have been hospitalized for the time when those symptoms may have occurred. However, due to improved prognostic factors, diagnostics and treatment of CRS and ICANS, it is possible that in the near future certain groups of patients will be treated with CAR as outpatients. That would allow broader access to CAR therapy, lowering overall costs and improving patient quality of life. Patient selection for outpatient CAR treatment is a topic that has been extensively discussed but, even based on the experience we already have, can already be effectively performed. CAR as an outpatient could be particularly useful for younger patients with a low tumor burden who have an educated caregiver and whose CAR center is logistically capable of providing outpatient care

Role of transplantation in treatment of multiple myeloma in era of novel agents

Multiple myeloma (MM) is a B-cell malignancy characterized by clonal proliferation of plasma cells. Despite the introduction of novel agents such as immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies, high-dose chemotherapy with autologous transplantation remains the primary treatment for patients with newly diagnosed multiple myeloma. This review presents the results of clinical trials assessing the effectiveness and safety of various kinds of transplantation such as single, allogeneic, tandem and salvage. Nowadays, in the era of access to new therapies, the following questions should be asked: when is the best time to perform autologous transplantation? What is the significance of allogeneic or tandem transplantation? Is the use of a second or third salvage transplant justified? Will chimeric antigen receptor T-cell (CAR-T) therapy become a valuable therapeutic method in MM? In this article, we will try to answer these questions

Optimization of treatment of patients with plasma cell myeloma with high cytogenetic risk in Poland

Plasma cell myeloma (PCM) is a hematologic malignancy that derives from mature B cells. The prognosis of patients with PCM is highly dependent on the presence of cytogenetic aberrations. Determination of cytogenetic risk enables informing patients about their prognosis and allows for individual choice of therapy. In Poland, cytogenetic risk assessment is a fully reimbursed procedure, and it is recommended to perform such an examination in every diagnosed patient. Therapy of patients with high cytogenetic risk should be planned with consideration of tandem autotransplantation of hematopoietic cells in eligible patients. In patients with refractory or relapsed PCM, treatment with ixazomib in combination with lenalidomide and dexamethasone appears to remove cytogenetic risk

Ixazomib in patients with relapsed/refractory multiple myeloma

Ixazomib is a new agent registered in combination with lenalidomide and dexamethasone for the treatment of adult patients with multiple myeloma who have received at least one prior therapy. The drug is the first oral proteasome inhibitor. Registration data show improvement in progression-free survival time (20.6 vs 14.7 months, p=0.01) but recent analysis in Asian population also in overall survival (25.8 vs 15.8 months, HR=0.419, p=0.001) what placed with lack of ixazomib incremental toxicity may implicate clinical importance of the treatment in relapsed or refractory multiple myeloma. Oral dosing of the triplet regimen may decrease the number and duration of hospitalizations that allows for better social functioning and occupational performance, and thus impacts daily disease perception

Safety and cost effectiveness of outpatient autologous hematopoietic stem cell transplantation for multiple myeloma — single-center experience of a pilot Early Discharge Program

Introduction: Multiple myeloma (MM) is the leading indication for autologous stem cell transplantation (ASCT), with over 12,000 transplants per year in Europe. Due to low toxicity, an entirely outpatient procedure or an early discharge after ASCT can be considered as alternatives to inpatient transplantation. Thus, we launched an Early Discharge Program (EDP) for patients qualified for ASCT due to MM who were under 60 years of age, without significant comorbidities, who had a caregiver available 24/7, and who lived within a 60-minute drive of our hospital. Material and methods: Patients spent 72 hours in the hospital being administered melphalan 200 mg/m2 intravenous followed by an infusion of hematopoietic stem cells. They were eventually discharged and remained under outpatient care. The program was launched in September 2019 and was temporarily halted due to the coronavirus disease 19 (COVID-19) pandemic in early 2020. Five patients were enrolled to the EDP. Results: Non-hematological toxicity was mild and manageable in an outpatient setting. Only one patient was readmitted due to exacerbation of ulcerative colitis that was probably not related to ASCT. We observed neither infections nor bleeding. Due to hematological toxicity, three of the five patients received platelet transfusion on the 6th day after ASCT as outpatients. No packed erythrocytes were transfused. The EDP demonstrated lower costs compared to an inpatient approach. Conclusions: We believe that early discharge, which is an intermediate step to full at-home transplantation due to patients’ wellbeing, reduction of infections caused by resistant microorganisms, and costs, will eventually replace a full inpatient procedure for a significant population of patients suffering from multiple myeloma and indeed other diseases

CAR-T cell therapy – toxicity and its management

Chimeric antigen receptor T-cell (CAR-T) therapy is an effective new treatment for hematologic malignancies. Two anti-CD19 CAR-T products, namely axicabtagene ciloleucel and tisagenlecleucel, have been approved for the management of relapsed/refractory large B-cell lymphoma after two lines of systemic therapy. Additionally, tisagenlecleucel is indicated for refractory acute lymphoblastic leukemia in pediatric patients and young adults up to 25 years of age. CAR-T cells are undoubtedly a major breakthrough therapy in hematooncology resulting in up to 90% response rate with durable remissions in population with refractory high-risk disease. However, there are serious side effects resulting from CAR-T therapy, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Manifestations of CRS mostly include fever, hypotension, hypoxia, and end organ dysfunction. Neurologic toxicities are diverse and include encephalopathy, cognitive defects, dysphasia, seizures, and cerebral edema. Since the symptoms are potentially severe, practitioners need to familiarize themselves with the unique toxicities associated with these therapies. In this article, we present a practical guideline for diagnosis, grading and management of CRS and CAR-T neurotoxicity. In addition, infectious complications and late toxicities including prolonged cytopenias and hypogammaglobulinemia are discussed

Znaczenie minimalnej choroby resztkowej w szpiczaku plazmocytowym — Stanowisko Polskiego Konsorcjum Szpiczakowego

Introducing substantial numbers of new drugs in treatment armamentarium for plasma cell myeloma (PCM) has improved the depth and duration of achieved responses as well as prolongation of overall survival. Although complete responses (CR) are significantly more common with novel therapies, a majority of patients still relapse. This may be due to small populations of clonal plasma cells persisting after treatment; the phenomenon known as minimal residual disease (MRD). The prognostic role of MRD in patients with CR has been confirmed by numerous clinical trials, andrecently MRD assessment has become a routine tool for evaluating how effective the latest drugs and therapy protocols are. Furthermore, the updated response criteria of IMWG (International Myeloma Working Group) have included response categories based on MRD evaluation with modern techniques characterized by at least 10–5 sensitivity: i.e. next generation flow and next generation sequencing. In this paper, we discuss the current role of MRD in PCM, with particular emphasis on the methodology of assessing MRD by flow cytometry. In the opinion of the Polish Myeloma Consortium members, dissemination and standardization of MRD assessment in PCM may lead to improvement of PCM therapy in Poland. Wprowadzenie do terapii szpiczaka plazmocytowego (PCM) znacznej liczby nowych leków pozwoliło na poprawę głębokości uzyskiwanych odpowiedzi, a w konsekwencji na wydłużenie okresu remisji i przeżycia chorych. Mimo wyższego obecnie odsetka całkowitych remisji (CR) u większości pacjentów dochodzi jednak do nawrotu choroby, co może być tłumaczone pozostawaniem po zakończeniu leczenia niewielkich populacji klonalnych plazmocytów w szpiku kostnym, określanych mianem minimalnej choroby resztkowej (MRD). Prognostyczne znaczenie występowania MRD u chorych w CR potwierdzono w wielu badaniach klinicznych, a ocena MRD stała się w ostatnim czasie rutynowym narzędziem w ocenie skuteczności najnowszych leków i schematów terapii. Ponadto w najnowszych kryteriach odpowiedzi IMWG (International Myeloma Working Group) z 2016 roku wprowadzono kategorie odpowiedzi oparte na badaniu MRD oznaczanej z czułością co najmniej 10–5 najnowocześniejszymi technikami diagnostycznymi — cytometrii przepływowej nowej generacji i sekwencjonowania nowej generacji. W pracy podsumowano aktualne znaczenie oceny MRD u chorych na PCM, ze szczególnym uwzględnieniem metodyki oceny MRD techniką cytometrii przepływowej. W opinii Polskiego Konsorcjum Szpiczakowego upowszechnienie i standaryzacja oceny MRD w PCM może się przyczynić do poprawy wyników leczenia chorych na ten nowotwór w Polsce

Autologous stem cell transplantation as consolidation therapy for patients with peripheral T cell lymphoma in first remission : long-term outcome and risk factors analysis

This report is a retrospective analysis of 65 patients with peripheral T cell lymphoma (PTCL), who underwent high-dose therapy and autologous hematopoietic stem cell transplantation (autoHCT) as a consolidation of first response achieved with either induction or salvage chemotherapy. We intended to determine the prognostic factors that influenced outcome after autoHCT and to define the predictive value of the scoring systems most often applied for transplant outcomes. Nineteen patients in either complete or partial remission underwent autoHCT after induction chemotherapy. Forty-six patients received second-line chemotherapy as a consolidation of partial response after induction chemotherapy (n = 34) or as a salvage therapy after primary induction failure (n = 12), and thereafter proceeded to autoHCT. Finally, the 36 patients were in complete remission, and 29 in partial remission at autoHCT. The median follow-up of survivors was 53 months (range 7–157 months). The 5-year overall survival and progression-free survival for all patients were 61.5 % (95 % CI 47.0–74.2 %) and 59.4 % (95 % CI 46.1–71.5 %), respectively. In multivariate analysis, bone marrow involvement at diagnosis and less than partial remission after induction chemotherapy were factors independently predictive for overall survival and progression-free survival. The prognostic index for PTCL could reliably stratify the prognosis of PTCL in this analysis