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New Therapies and Therapeutic Approaches in Multiple Myeloma
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New Therapies and Therapeutic Approaches in Multiple Myeloma

A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Oncology".

Deadline for manuscript submissions: closed (31 July 2020) | Viewed by 62624

Special Issue Editors

Prof. Dr. Nicola Giuliani

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Guest Editor
Department of Medicine and Surgery, University of Parma, Via Gramsci 14, 43126 Parma, Italy
Interests: multiple myeloma; hematologic cancers; plasma cell biology; bone lesions; bone microenvironment; angiogenesis; smoldering myeloma; monoclonal gammopathy of uncertain significance; hypoxia; monoclonal antibodies; immunomodulatory drugs; proteasome inhibitors
Special Issues, Collections and Topics in MDPI journals
Dr. Francesca Gay

E-Mail Website
Guest Editor
Myeloma Unit, Division of Hematology, University of Torino, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino, 10126 Torino, Italy
Interests: myeloma; plasma cell discrasia; autologous stem cell transplant; immunotherapies
Dr. Sara Bringhen

E-Mail Website
Guest Editor
Division of Haematology, University of Turin, Turin, Italy
Interests: multiple myeloma; target therapies; immunotherapies; elderly patients; frailty

Special Issue Information

Dear Colleagues,

Multiple myeloma (MM) is a hematological malignancy characterized by high tendency to relapse and to develop drug resistance. Despite the recent introduction of new drugs in the therapeutic armamentarium, MM remains an incurable disease. New therapies and new therapeutic approaches need to improve the survival of MM patients. In recent years, the development and the use of monoclonal antibodies against different cell surface antigens overexpressed by MM cells such as CD38, SLAMF7, and BCMA has helped to change the therapeutic paradigm of MM. New possible therapeutic targets for immunotherapy or the use of CAR T cell technology are under clinical investigation, with very promising results. Moreover, selective drug inhibitors such as those anti-BCL-2 and MCL-1 apoptotic proteins or against the nuclear transport exportin (selinexor) are under experimental and clinical investigation.

In the last few years, new therapeutic approaches have been developed. The prolongation of the duration of the treatment and the introduction of the concept of continuous and of maintenance treatment have significantly expanded the results obtained with the first-line treatment, with a consequent improvement of the survival of MM patients. Moreover, combination treatment using both the main class of drugs as proteasome inhibitors and immunomodulatory drugs and monoclonal antibodies seems to extremely prolong the duration of the response of MM patients. Finally, growing evidence indicates the quality of the response to the therapy, evaluated by the minimal residual disease (MRD), is the most important end point related to the duration of remission and the survival. An MRD-driven therapeutic approach could be the optimal strategy for the future in MM patients.

This Special Issue will address the most recent and relevant scientific findings regarding advances in the treatment of MM.

Prof. Dr. Nicola Giuliani
Dr. Francesca Gay
Dr. Sara Bringhen
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Journal of Clinical Medicine is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Multiple myeloma
  • New drugs
  • Monoclonal antibody
  • Immunotherapy
  • Minimal residual disease
  • Drug combinations

Published Papers (17 papers)

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Research

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10 pages, 1664 KiB  
Communication
Optimizing the Outcome of Anti-Myeloma Treatment with Daratumumab
by Torben Plesner
J. Clin. Med. 2021, 10(5), 1002; https://doi.org/10.3390/jcm10051002 - 2 Mar 2021
Viewed by 2613
Abstract
A search of the scientific literature for Daratumumab and myeloma gives more than 600 results (January 2021), which reflects the interest and activity around this antibody, an interest that was also reflected by the assignment of breakthrough designation for Daratumumab as a treatment [...] Read more.
A search of the scientific literature for Daratumumab and myeloma gives more than 600 results (January 2021), which reflects the interest and activity around this antibody, an interest that was also reflected by the assignment of breakthrough designation for Daratumumab as a treatment for multiple myeloma by FDA in 2013. The high expectations have been supported and met due to a very active clinical development program, and our insight into Daratumumab’s modes of action have been expanded by a concomitant, systematic activity of translational research. The scope of this article is to point to some areas where the outcome of treatment with Daratumumab for multiple myeloma may be improved with a focus on areas such as when to initiate treatment with Daratumumab, the use of supportive treatment, duration of therapy and some general thoughts about anti-myeloma treatment as a two-step process involving initial de-bulking followed by reprogramming of the host’s immune system and immune-mediated control of myeloma. Full article
(This article belongs to the Special Issue New Therapies and Therapeutic Approaches in Multiple Myeloma)
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10 pages, 2134 KiB  
Article
Circulating Soluble Urokinase-Type Plasminogen Activator Receptor Levels Reflect Renal Function in Newly Diagnosed Patients with Multiple Myeloma Treated with Bortezomib-Based Induction
by Evangelos Terpos, Ioannis Ntanasis-Stathopoulos, Gerasimos-Petros Papassotiriou, Efstathios Kastritis, Alexandra Margeli, Nikolaos Kanellias, Evangelos Eleutherakis-Papaiakovou, Magdalini Migkou, Despina Fotiou, Maria Roussou, Maria Gavriatopoulou, Panagiotis Malandrakis, Erasmia Psimenou, Ioannis Papassotiriou and Meletios A. Dimopoulos
J. Clin. Med. 2020, 9(10), 3201; https://doi.org/10.3390/jcm9103201 - 3 Oct 2020
Cited by 1 | Viewed by 1731
Abstract
(1) Background: Soluble urokinase-type plasminogen activator receptor (suPAR) has been implicated in the pathogenesis of kidney disease in different disease settings. The aim of this study was to investigate a possible link between suPAR circulating levels and renal impairment (RI) in newly diagnosed [...] Read more.
(1) Background: Soluble urokinase-type plasminogen activator receptor (suPAR) has been implicated in the pathogenesis of kidney disease in different disease settings. The aim of this study was to investigate a possible link between suPAR circulating levels and renal impairment (RI) in newly diagnosed patients with symptomatic multiple myeloma (NDMM) before and after frontline therapy with bortezomib-based regimens. (2) Methods: We studied 47 NDMM patients (57% males, median age 69.5 years) before the administration of anti-myeloma treatment and at best response to bortezomib-based therapy. suPAR was measured in the serum of all patients and of 24 healthy matched controls, using an immuno-enzymatic assay (ViroGates, Denmark). (3) Results: suPAR levels were elevated in NDMM patients at diagnosis compared to healthy individuals (p < 0.001). suPAR levels strongly correlated with disease stage (p-ANOVA < 0.001). suPAR levels both at diagnosis and at best response negatively correlated with estimated glomerular filtration rate (eGFR) values (p < 0.001). Interestingly, no significance changes in suPAR levels were observed at best response compared to baseline values (p = 0.31) among 18 responding patients with baseline eGFR < 50 mL/min/1.73 m2. (4) Conclusions: SuPAR levels reflect renal function in NDMM patients treated with bortezomib-based induction. Responders may have elevated circulating suPAR levels, possibly reflecting persistent kidney damage, despite their renal response. Full article
(This article belongs to the Special Issue New Therapies and Therapeutic Approaches in Multiple Myeloma)
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16 pages, 4004 KiB  
Article
Clinical Benefit of Long-Term Disease Control with Pomalidomide and Dexamethasone in Relapsed/Refractory Multiple Myeloma Patients
by Marina Silvia Parisi, Salvatore Leotta, Alessandra Romano, Vittorio Del Fabro, Enrica Antonia Martino, Valeria Calafiore, Rachele Giubbolini, Uros Markovic, Valerio Leotta, Mary Ann Di Giorgio, Daniele Tibullo, Francesco Di Raimondo and Concetta Conticello
J. Clin. Med. 2019, 8(10), 1695; https://doi.org/10.3390/jcm8101695 - 16 Oct 2019
Cited by 8 | Viewed by 3075
Abstract
Background: We retrospectively analysed relapsed/refractory MM (RRMM) patients treated with pomalidomide and dexamethasone (PomaD) either in real life, or previously enrolled in an interventional (STRATUS, MM-010) or currently enrolled in an observational study (MM-015) to provide further insights on safety and tolerability and [...] Read more.
Background: We retrospectively analysed relapsed/refractory MM (RRMM) patients treated with pomalidomide and dexamethasone (PomaD) either in real life, or previously enrolled in an interventional (STRATUS, MM-010) or currently enrolled in an observational study (MM-015) to provide further insights on safety and tolerability and clinical efficacy. Methods: Between July 2013 and July 2018, 76 RRMM patients (including 33 double refractory MM) received pomalidomide 4 mg daily given orally on days 1–21 of each 28-day cycle, and dexamethasone 40 mg weekly (≤75 years) or 20 mg weekly for patients aged > 75 years. In nine patients a third agent was added to increase the response: Cyclophosphamide (in two fit patients) or clarithromycin (in seven frail patients). Patients received subcutaneous filgrastim as part of the prophylaxis regimen for neutropenia. Results: A median number of six (range 2–21) PomaD cycles were given. The regimen was well tolerated with grade 3–4 haematological and non-haematological adverse events in 39 (51%) and 25 (33%) patients, respectively. In patients who developed serious AE, pomalidomide dose reduction (11%, 14%) or definitive discontinuation (18%, 23%) were applied. All patients have been evaluated for response within the first two cycles. The disease control rate (DCR), i.e., those patients that had a response equal or better than stable disease (≥ SD), was high (89%), with 44% overall response rate (ORR) after six cycles. The achieved best responses were complete remission (CR, 5%), very good partial remission (VGPR, 4%), partial remission (PR, 35%), minimal response (MR, 7%), and stable disease (SD, 38%). After a median follow up of 19.6 months, median progression free survival was 9.4 months, and overall survival (OS) was 19.02 months. Univariate analysis showed that double refractory patients, or who received more than three previous lines had shorter PFS. At 18 months, regardless of the depth of response, patients with a disease control of at least six months, defined as maintenance of a best clinical and/or biochemical response to treatment for almost six months, had prolonged PFS (35.3% versus 20.6%, p = 0.0003) and OS (81.2% versus 15.9%, p < 0.0001) Conclusions: Our findings indicate that PomaD is a safe and well-tolerated regimen in real-life, associated with prolonged PFS and OS with acceptable toxicity. Moreover, Pd induced disease control in most intensively pre-treated patients and some of them achieved longer PFS than that obtained with the previous treatment. Full article
(This article belongs to the Special Issue New Therapies and Therapeutic Approaches in Multiple Myeloma)
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Review

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15 pages, 232 KiB  
Review
Future Directions in Maintenance Therapy in Multiple Myeloma
by Sarah A. Holstein, Vera J. Suman, Jens Hillengass and Philip L. McCarthy
J. Clin. Med. 2021, 10(11), 2261; https://doi.org/10.3390/jcm10112261 - 24 May 2021
Cited by 7 | Viewed by 3558
Abstract
Autologous stem cell transplantation (ASCT) has been a backbone of therapy for newly diagnosed patients with multiple myeloma eligible for high-dose therapy for decades. Survival outcomes have continued to improve over time, in part because of the incorporation of highly effective induction regimens [...] Read more.
Autologous stem cell transplantation (ASCT) has been a backbone of therapy for newly diagnosed patients with multiple myeloma eligible for high-dose therapy for decades. Survival outcomes have continued to improve over time, in part because of the incorporation of highly effective induction regimens prior to ASCT as well as post-ASCT maintenance therapy. Randomized phase III clinical trials have helped establish lenalidomide maintenance as a standard of care. However, as nearly all patients will eventually experience disease relapse, there continues to be significant interest in developing novel maintenance strategies to improve upon lenalidomide maintenance. In this review, we summarize the available evidence for the use of immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies as post-ASCT maintenance therapies as well as discuss future directions and unanswered questions in the field. Full article
(This article belongs to the Special Issue New Therapies and Therapeutic Approaches in Multiple Myeloma)
17 pages, 311 KiB  
Review
What Is New in the Treatment of Smoldering Multiple Myeloma?
by Niccolo’ Bolli, Nicola Sgherza, Paola Curci, Rita Rizzi, Vanda Strafella, Mario Delia, Vito Pier Gagliardi, Antonino Neri, Luca Baldini, Francesco Albano and Pellegrino Musto
J. Clin. Med. 2021, 10(3), 421; https://doi.org/10.3390/jcm10030421 - 22 Jan 2021
Cited by 8 | Viewed by 3218
Abstract
Smoldering multiple myeloma (SMM), an asymptomatic plasma cell neoplasm, is currently diagnosed according to the updated IMWG criteria, which reflect an intermediate tumor mass between monoclonal gammopathy of undetermined significance (MGUS) and active MM. However, SMM is a heterogeneous entity and individual case [...] Read more.
Smoldering multiple myeloma (SMM), an asymptomatic plasma cell neoplasm, is currently diagnosed according to the updated IMWG criteria, which reflect an intermediate tumor mass between monoclonal gammopathy of undetermined significance (MGUS) and active MM. However, SMM is a heterogeneous entity and individual case may go from an “MGUS-like” behavior to “early MM” with rapid transformation into symptomatic disease. This wide range of clinical outcomes poses challenges for prognostication and management of individual patients. However, initial studies showed a benefit in terms of progression or even survival for early treatment of high-risk SMM patients. While outside of clinical trials the conventional approach to SMM generally remains that of close observation, these studies raised the question of whether early treatment should be offered in high-risk patients, prompting evaluation of several different therapeutic approaches with different goals. While delay of progression to MM with a non-toxic treatment is clearly achievable by early treatment, a convincing survival benefit still needs to be proven by independent studies. Furthermore, if SMM is to be considered less biologically complex than MM, early treatment may offer the chance of cure that is currently not within reach of any active MM treatment. In this paper, we present updated results of completed or ongoing clinical trials in SMM treatment, highlighting areas of uncertainty and critical issues that will need to be addressed in the near future before the “watch and wait” paradigm in SMM is abandoned in favor of early treatment. Full article
(This article belongs to the Special Issue New Therapies and Therapeutic Approaches in Multiple Myeloma)
16 pages, 931 KiB  
Review
CAR T-Cells in Multiple Myeloma Are Ready for Prime Time
by Paula Rodríguez-Otero, Felipe Prósper, Ana Alfonso, Bruno Paiva and Jesús F. San Miguel
J. Clin. Med. 2020, 9(11), 3577; https://doi.org/10.3390/jcm9113577 - 6 Nov 2020
Cited by 16 | Viewed by 3953
Abstract
The survival of patients with multiple myeloma (MM) has been dramatically improved in the last decade thanks to the incorporation of second-generation proteasome inhibitors (PI), immunomodulatory drugs (IMID), and, more recently, anti-CD38 monoclonal antibodies (MoAb). Nevertheless, still, a major proportion of MM patients [...] Read more.
The survival of patients with multiple myeloma (MM) has been dramatically improved in the last decade thanks to the incorporation of second-generation proteasome inhibitors (PI), immunomodulatory drugs (IMID), and, more recently, anti-CD38 monoclonal antibodies (MoAb). Nevertheless, still, a major proportion of MM patients will relapse, underscoring the need for new therapies in this disease. Moreover, survival in patients failing the current standard of care regimens (including PI, IMIDs, and anti-CD38 MoAb), which is now defined as triple-class refractory, remains dismal, and new drugs with different mechanism of action are needed. B-cell maturation antigen (BCMA)-targeted therapies and in particular chimeric antigen receptor T cell (CAR T-cell) treatment have emerged as promising platforms to overcome refractoriness to conventional drugs. In this manuscript, we review the current available data regarding CAR T-cell therapy for MM, with a special focus on target selection, clinical results, limitations, and future strategies. Full article
(This article belongs to the Special Issue New Therapies and Therapeutic Approaches in Multiple Myeloma)
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15 pages, 295 KiB  
Review
Three Drug Combinations in the Treatment of Fit Elderly Multiple Myeloma Patients
by Hélène Gardeney, Arthur Bobin, Cécile Gruchet, Florence Sabirou, Anthony Lévy, Laly Nsiala, Laura Cailly, Cécile Tomowiak, Jose Torregrosa, Niels Moya, Cyrille Hulin, Xavier Leleu and Stéphanie Guidez
J. Clin. Med. 2020, 9(11), 3554; https://doi.org/10.3390/jcm9113554 - 4 Nov 2020
Cited by 2 | Viewed by 2139
Abstract
The multiple myeloma (MM) non transplant eligible (NTE) population is growing in line with the aging of the population in Western countries. Historically, this population has been known for having a greater risk of treatment related toxicity, and therefore drug development was slow [...] Read more.
The multiple myeloma (MM) non transplant eligible (NTE) population is growing in line with the aging of the population in Western countries. Historically, this population has been known for having a greater risk of treatment related toxicity, and therefore drug development was slow and rather oriented towards the improvement of safety profile than the optimization of disease control. However, NTE MM patients, at least for the fit/non frail patients in recent years, seemed to have benefited more from a less palliative care to improve the depth of response and then prolong survival. NTE MM being a quite heterogeneous population, there are still a number of groups of patients that are in need of more efficient therapy, avoiding unnecessary toxicity, particularly for the frail patients. The use of triplet regimen with a melphalan-prednisone (MP) backbone has long been the standard of care for NTE MM, often dedicated to non-frail patients. New standards of care, triplet, and even quadruplet combinations, are emerging on the basis of the MP backbone but also on the more recently approved lenalidomide-dexamethasone (Rd) backbone. These developments were largely possible in line with the development of antibody-based immunotherapies (IT) in MM. The objective to improve outcomes with an acceptable safety profile will see other key therapeutic developments such as the dropping of dexamethasone early in the disease course or various attempts to allow permanent treatment discontinuation with a prolonged disease control. In that context, it is possible that immunomonitoring, minimal residual disease (MRD), and genomic risk-adaptation will become key elements of the treatment decisions on triplet-based regimens. Full article
(This article belongs to the Special Issue New Therapies and Therapeutic Approaches in Multiple Myeloma)
9 pages, 220 KiB  
Review
Role of Imaging in the Evaluation of Minimal Residual Disease in Multiple Myeloma Patients
by Elena Zamagni, Paola Tacchetti, Simona Barbato and Michele Cavo
J. Clin. Med. 2020, 9(11), 3519; https://doi.org/10.3390/jcm9113519 - 31 Oct 2020
Cited by 20 | Viewed by 2445
Abstract
The International Myeloma Working Group (IMWG) recently introduced the evaluation of minimal residual disease (MRD) within the multiple myeloma (MM) response criteria, and MRD negativity assessed inside and outside the bone marrow is currently considered the most powerful predictor of favorable long-term outcomes. [...] Read more.
The International Myeloma Working Group (IMWG) recently introduced the evaluation of minimal residual disease (MRD) within the multiple myeloma (MM) response criteria, and MRD negativity assessed inside and outside the bone marrow is currently considered the most powerful predictor of favorable long-term outcomes. However, MRD evaluation has thus far relied on flow-cytometry or molecular-based methods, despite the limitations associated with the patchy infiltration of bone marrow (BM) plasma cells and the presence of extra-medullary (EMD). On the contrary, imaging-based sensitive response assessment through the use of functional rather than morphological whole-body (WB) imaging techniques, such as positron emission tomography with computed tomography (PET/CT) and magnetic resonance imaging (MRI), likely is a promising strategy to overcome these limitations in evaluating response to therapy and in the assessment of the MRD status in MM patients. However, despite the significant advances in the development and availability of novel functional imaging techniques for MRD evaluation, a worldwide standardization of imaging criteria for acquisition, interpretation, and reporting is yet to be determined and will be object of future investigations. Full article
(This article belongs to the Special Issue New Therapies and Therapeutic Approaches in Multiple Myeloma)
17 pages, 257 KiB  
Review
Allogeneic Hematopoietic Transplantation for Multiple Myeloma in the New Drugs Era: A Platform to Cure
by Alberto Mussetti, Maria Queralt Salas and Vittorio Montefusco
J. Clin. Med. 2020, 9(11), 3437; https://doi.org/10.3390/jcm9113437 - 26 Oct 2020
Cited by 3 | Viewed by 2400
Abstract
Allogeneic hematopoietic cell transplantation (alloHCT) represents a treatment option for multiple myeloma (MM) patients. As shown in several studies, alloHCT is highly effective, but it is hampered by a high toxicity, mainly related to the graft-versus-host disease (GVHD), a complex immunological reaction ascribable [...] Read more.
Allogeneic hematopoietic cell transplantation (alloHCT) represents a treatment option for multiple myeloma (MM) patients. As shown in several studies, alloHCT is highly effective, but it is hampered by a high toxicity, mainly related to the graft-versus-host disease (GVHD), a complex immunological reaction ascribable to the donor’s immune system. The morbidity and mortality associated with GVHD can weaken the benefits of this procedure. On the other side, the high therapeutic potential of alloHCT is also related to the donor’s immune system, through immunological activity known as the graft-versus-myeloma effect. Clinical research over the past two decades has sought to enhance the favorable part of this balance, along with the reduction in treatment-related toxicity. Frontline alloHCT showed promising results and a potential for a cure in the past. Currently, thanks to the improved results of first-line therapies and the availability of effective second- or third-line salvage therapies, alloHCT is reserved for selected high-risk patients and is considered a clinical option. For donor lymphocyte infusion, bortezomib or lenalidomide have been used as consolidation or maintenance therapies post-transplant—none has become standard of care. For those patients who relapse, the best treatment should be evaluated considering the patient’s clinical status and the previous lines of therapy. The use of newer drugs, such as monoclonal antibodies or other immunotherapies in the post-transplant setting, deserves further investigation. However, acceptable toxicity and a synergic effect with the newer immune system could be hopefully expected. Full article
(This article belongs to the Special Issue New Therapies and Therapeutic Approaches in Multiple Myeloma)
16 pages, 926 KiB  
Review
Melflufen: A Peptide–Drug Conjugate for the Treatment of Multiple Myeloma
by María-Victoria Mateos, Joan Bladé, Sara Bringhen, Enrique M Ocio, Yvonne Efebera, Luděk Pour, Francesca Gay, Pieter Sonneveld, Joachim Gullbo and Paul G. Richardson
J. Clin. Med. 2020, 9(10), 3120; https://doi.org/10.3390/jcm9103120 - 27 Sep 2020
Cited by 35 | Viewed by 7187
Abstract
Despite the availability of new therapies that have led to improved outcomes for patients with multiple myeloma, most patients will eventually relapse. With triplet and even quadruplet combination therapies becoming standard in the first and second line, many patients will have few treatment [...] Read more.
Despite the availability of new therapies that have led to improved outcomes for patients with multiple myeloma, most patients will eventually relapse. With triplet and even quadruplet combination therapies becoming standard in the first and second line, many patients will have few treatment options after second-line treatment. Melflufen (melphalan flufenamide) is a first-in-class peptide–drug conjugate (PDC) that targets aminopeptidases and rapidly releases alkylating agents into tumor cells. Once inside the tumor cells, melflufen is hydrolyzed by peptidases to release alkylator molecules, which become entrapped. Melflufen showed anti-myeloma activity in myeloma cells that were resistant to bortezomib and the alkylator melphalan. In early phase studies (O-12-M1 and HORIZON [OP-106]), melflufen plus dexamethasone has demonstrated encouraging clinical activity and a manageable safety profile in heavily pretreated patients with relapsed/refractory multiple myeloma, including those with triple-class refractory disease and extramedullary disease. The Phase III OCEAN study (OP-104) is further evaluating melflufen plus dexamethasone in patients with relapsed/refractory multiple myeloma. The safety profile of melflufen is characterized primarily by clinically manageable hematologic adverse events. Melflufen, with its novel mechanism of action, has the potential to provide clinically meaningful benefits to patients with relapsed/refractory multiple myeloma, including those with high unmet needs. Full article
(This article belongs to the Special Issue New Therapies and Therapeutic Approaches in Multiple Myeloma)
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11 pages, 871 KiB  
Review
Monoclonal and Bispecific Anti-BCMA Antibodies in Multiple Myeloma
by Benedetta Dalla Palma, Valentina Marchica, Maria Teresa Catarozzo, Nicola Giuliani and Fabrizio Accardi
J. Clin. Med. 2020, 9(9), 3022; https://doi.org/10.3390/jcm9093022 - 19 Sep 2020
Cited by 14 | Viewed by 4794
Abstract
B-cell maturation antigen (BCMA), a member of the tumor necrosis factor receptor superfamily, is universally expressed by normal and neoplastic plasma cells and plays a critical role in the proliferation, survival and tumor progression in multiple myeloma (MM). B-cell activating factor (BAFF) and [...] Read more.
B-cell maturation antigen (BCMA), a member of the tumor necrosis factor receptor superfamily, is universally expressed by normal and neoplastic plasma cells and plays a critical role in the proliferation, survival and tumor progression in multiple myeloma (MM). B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) have been recognized as proliferation ligands for BCMA in the bone marrow microenvironment. Soluble BCMA levels in the serum correlates with disease phase and tumor burden and is a predictor of progression-free survival (PFS) and overall survival (OS). Recently, the introduction of new monoclonal antibodies against CD38 (Daratumumab and Isatuximab) and SLAM7 (Elotuzumab) has changed the therapeutic approach to MM, improving the response rate and the time to progression, both in newly diagnosed and refractory/relapsed patients. Among the surface antigens on MM cells, BCMA is a suitable target for the design of new antibody-based strategies. Experimental approaches targeting BCMA are currently being investigated and include antibody-drug conjugates (ADCs), bispecific antibodies (bsAbs) and genetically engineered T-cells with chimeric antigen receptors (CAR). In this review we summarize the more recent findings about BCMA biologic rationale as a therapeutic target and report the updated results of preclinical and clinical studies focused on ADCs and bsAbs targeting BCMA. Full article
(This article belongs to the Special Issue New Therapies and Therapeutic Approaches in Multiple Myeloma)
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16 pages, 4163 KiB  
Review
Novel Approaches to Improve Myeloma Cell Killing by Monoclonal Antibodies
by Paola Storti, Federica Costa, Valentina Marchica, Jessica Burroughs-Garcia, Benedetta dalla Palma, Denise Toscani, Rosa Alba Eufemiese and Nicola Giuliani
J. Clin. Med. 2020, 9(9), 2864; https://doi.org/10.3390/jcm9092864 - 4 Sep 2020
Cited by 7 | Viewed by 2873
Abstract
The monoclonal antibodies (mAbs) have significantly changed the treatment of multiple myeloma (MM) patients. However, despite their introduction, MM remains an incurable disease. The mAbs currently used for MM treatment were developed with different mechanisms of action able to target antigens, such as [...] Read more.
The monoclonal antibodies (mAbs) have significantly changed the treatment of multiple myeloma (MM) patients. However, despite their introduction, MM remains an incurable disease. The mAbs currently used for MM treatment were developed with different mechanisms of action able to target antigens, such as cluster of differentiation 38 (CD38) and SLAM family member 7 (SLAMF7) expressed by both, MM cells and the immune microenvironment cells. In this review, we focused on the mechanisms of action of the main mAbs approved for the therapy of MM, and on the possible novel approaches to improve MM cell killing by mAbs. Actually, the combination of anti-CD38 or anti-SLAMF7 mAbs with the immunomodulatory drugs significantly improved the clinical effect in MM patients. On the other hand, pre-clinical evidence indicates that different approaches may increase the efficacy of mAbs. The use of trans-retinoic acid, the cyclophosphamide or the combination of anti-CD47 and anti-CD137 mAbs have given the rationale to design these types of combinations therapies in MM patients in the future. In conclusion, a better understanding of the mechanism of action of the mAbs will allow us to develop novel therapeutic approaches to improve their response rate and to overcome their resistance in MM patients. Full article
(This article belongs to the Special Issue New Therapies and Therapeutic Approaches in Multiple Myeloma)
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14 pages, 622 KiB  
Review
Bispecific Antibodies: A New Era of Treatment for Multiple Myeloma
by Xiang Zhou, Hermann Einsele and Sophia Danhof
J. Clin. Med. 2020, 9(7), 2166; https://doi.org/10.3390/jcm9072166 - 9 Jul 2020
Cited by 23 | Viewed by 5579
Abstract
Despite the introduction of novel agents such as proteasome inhibitors, immunomodulatory drugs, and autologous stem cell transplant, multiple myeloma (MM) largely remains an incurable disease. In recent years, monoclonal antibody-based treatment strategies have been developed to target specific surface antigens on MM cells. [...] Read more.
Despite the introduction of novel agents such as proteasome inhibitors, immunomodulatory drugs, and autologous stem cell transplant, multiple myeloma (MM) largely remains an incurable disease. In recent years, monoclonal antibody-based treatment strategies have been developed to target specific surface antigens on MM cells. Treatment with bispecific antibodies (bsAbs) is an immunotherapeutic strategy that leads to an enhanced interaction between MM cells and immune effector cells, e.g., T-cells and natural killer cells. With the immune synapse built by bsAbs, the elimination of MM cells can be facilitated. To date, bsAbs have demonstrated encouraging results in preclinical studies, and clinical trials evaluating bsAbs in patients with MM are ongoing. Early clinical data show the promising efficacy of bsAbs in relapsed/refractory MM. Together with chimeric antigen receptor-modified (CAR)-T-cells, bsAbs represent a new dimension of precision medicine. In this review, we provide an overview of rationale, current clinical development, resistance mechanisms, and future directions of bsAbs in MM. Full article
(This article belongs to the Special Issue New Therapies and Therapeutic Approaches in Multiple Myeloma)
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16 pages, 297 KiB  
Review
Minimal Residual Disease in Multiple Myeloma: State of the Art and Future Perspectives
by Roberto Mina, Stefania Oliva and Mario Boccadoro
J. Clin. Med. 2020, 9(7), 2142; https://doi.org/10.3390/jcm9072142 - 7 Jul 2020
Cited by 13 | Viewed by 3534
Abstract
Minimal residual disease (MRD) detection represents a sensitive tool to appropriately measure the response obtained with therapies for multiple myeloma (MM). The achievement of MRD negativity has superseded the conventional complete response (CR) and has been proposed as a surrogate endpoint for progression-free [...] Read more.
Minimal residual disease (MRD) detection represents a sensitive tool to appropriately measure the response obtained with therapies for multiple myeloma (MM). The achievement of MRD negativity has superseded the conventional complete response (CR) and has been proposed as a surrogate endpoint for progression-free survival and overall survival. Several techniques are available for the detection of MRD inside (next-generation sequencing, flow cytometry) and outside (PET/CT, magnetic resonance) the bone marrow, and their complementary use allows a precise definition of the efficacy of anti-myeloma treatments. This review summarizes MRD data and results from previous clinical trials, highlights open issues related to the role of MRD in MM and discusses how MRD could be implemented in clinical practice to inform on patient prognosis and drive therapeutic decisions. Full article
(This article belongs to the Special Issue New Therapies and Therapeutic Approaches in Multiple Myeloma)
27 pages, 2133 KiB  
Review
Anti-VEGF Drugs in the Treatment of Multiple Myeloma Patients
by Roberto Ria, Assunta Melaccio, Vito Racanelli and Angelo Vacca
J. Clin. Med. 2020, 9(6), 1765; https://doi.org/10.3390/jcm9061765 - 6 Jun 2020
Cited by 19 | Viewed by 4371
Abstract
The interaction between the bone marrow microenvironment and plasma cells plays an essential role in multiple myeloma progression and drug resistance. The vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) pathway in vascular endothelial cells activates and promotes angiogenesis. Moreover, VEGF activates and promotes [...] Read more.
The interaction between the bone marrow microenvironment and plasma cells plays an essential role in multiple myeloma progression and drug resistance. The vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) pathway in vascular endothelial cells activates and promotes angiogenesis. Moreover, VEGF activates and promotes vasculogenesis and vasculogenic mimicry when it interacts with VEGF receptors expressed in precursor cells and inflammatory cells, respectively. In myeloma bone marrow, VEGF and VEGF receptor expression are upregulated and hyperactive in the stromal and tumor cells. It has been demonstrated that several antiangiogenic agents can effectively target VEGF-related pathways in the preclinical phase. However, they are not successful in treating multiple myeloma, probably due to the vicarious action of other cytokines and signaling pathways. Thus, the simultaneous blocking of multiple cytokine pathways, including the VEGF/VEGFR pathway, may represent a valid strategy to treat multiple myeloma. This review aims to summarize recent advances in understanding the role of the VEGF/VEGFR pathway in multiple myeloma, and mainly focuses on the transcription pathway and on strategies that target this pathway. Full article
(This article belongs to the Special Issue New Therapies and Therapeutic Approaches in Multiple Myeloma)
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20 pages, 798 KiB  
Review
Resistance Mechanisms towards CD38−Directed Antibody Therapy in Multiple Myeloma
by Laurens E. Franssen, Claudia A. M. Stege, Sonja Zweegman, Niels W. C. J. van de Donk and Inger S. Nijhof
J. Clin. Med. 2020, 9(4), 1195; https://doi.org/10.3390/jcm9041195 - 22 Apr 2020
Cited by 31 | Viewed by 7046
Abstract
Antibodies targeting CD38 are rapidly changing the treatment landscape of multiple myeloma (MM). CD38−directed antibodies have several mechanisms of action. Fc−dependent immune effector mechanisms include complement-dependent cytotoxicity (CDC), antibody−dependent cell−mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP) and apoptosis. In addition, direct effects and [...] Read more.
Antibodies targeting CD38 are rapidly changing the treatment landscape of multiple myeloma (MM). CD38−directed antibodies have several mechanisms of action. Fc−dependent immune effector mechanisms include complement-dependent cytotoxicity (CDC), antibody−dependent cell−mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP) and apoptosis. In addition, direct effects and immunomodulatory effects contribute to the efficacy of CD38−directed antibodies. Daratumumab, the first−in−class anti−CD38 monoclonal antibody, is now part of standard treatment regimens of both newly diagnosed as well as relapsed/refractory MM patients. The FDA has recently approved isatuximab in combination with pomalidomide and dexamethasone for relapsed/refractory MM patients after at least two prior therapies. Further, the other CD38−targeting antibodies (i.e., MOR202 and TAK-079) are increasingly used in clinical trials. The shift to front-line treatment of daratumumab will lead to an increase in patients refractory to CD38 antibody therapy already after first−line treatment. Therefore, it is important to gain insight into the mechanisms of resistance to CD38−targeting antibodies in MM, and to develop strategies to overcome this resistance. In the current review, we will briefly describe the most important clinical data and mechanisms of action and will focus in depth on the current knowledge on mechanisms of resistance to CD38-targeting antibodies and potential strategies to overcome this. Full article
(This article belongs to the Special Issue New Therapies and Therapeutic Approaches in Multiple Myeloma)
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2 pages, 170 KiB  
Erratum
Erratum: Mina, R.; et al. Minimal Residual Disease in Multiple Myeloma: State of the Art and Future Perspectives. J. Clin. Med. 2020, 9, 2142
by Roberto Mina, Stefania Oliva and Mario Boccadoro
J. Clin. Med. 2020, 9(8), 2630; https://doi.org/10.3390/jcm9082630 - 13 Aug 2020
Cited by 3 | Viewed by 1274
Abstract
The authors sincerely apologize for the inaccuracies made during the revision that a product line has been associated with the wrong company [...] Full article
(This article belongs to the Special Issue New Therapies and Therapeutic Approaches in Multiple Myeloma)
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