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Multidrug Therapies Containing Monoclonal Antibodies for Multiple Myeloma 2024
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Multidrug Therapies Containing Monoclonal Antibodies for Multiple Myeloma 2024

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmacology".

Deadline for manuscript submissions: closed (15 December 2024) | Viewed by 17287

Special Issue Editor

Dr. Massimo Offidani

E-Mail Website
Guest Editor
AOU delle Marche, 60126 Torrette (AN), Italy
Interests: multiple myeloma; monoclonal gammapathy; immunotherapy; transplant
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Treatment of multiple myeloma (MM) continues to evolve, and immunotherapy has now entered its therapeutic armamentarium. In particular, monoclonal antibodies (MoAbs), such as elotuzumab, daratumumab, and isatuximab in combinations with proteasome inhibitors (PI) and immunomodulatory agents (IMiDs), successfully used for relapsed–relapsed MM, have been used in frontline therapy in both transplant-eligible and -non-eligible patients. Elotuzumab in combination with lenalidomide and dexamethasone (Rd), and subsequently, daratumumab with Rd and with bortezomib and dexamethasone (Vd) were the first to be approved for the treatment of relapsed–refractory MM (rrMM). Recently, another anti-CD38 MoAb named isatuximab was approved by the FDA in combination with pomalidomide–dexamethasone for rrMM. Daratumumab, in combination with bortezomib, melphalan, and prednisone (VMP) as well as with lenalidomide and dexamethasone (Rd), has just been approved for the treatment of newly diagnosed MM patients not eligible for transplantation, since these regimens have been shown to definitely induce better results compared with standard therapies. In transplant-eligible patients, many trials comparing standard treatments with regimens containing elotuzumab, daratumumab, and isatuximab are either ongoing or have concluded with very encouraging results. The new frontier of immunotherapy of MM  includes bispecific and conjugated MoAbs, a very promising active area of experimental trials for rrMM patients in which preliminary results are rather favorable. It can be argued that passive and active immunotherapy will make MM a chronic disease or will cure an increasing fraction of MM patients.

Dr. Massimo Offidani
Guest Editor

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Keywords

  • multiple myeloma
  • monoclonal antibodies
  • immunotherapy

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Published Papers (8 papers)

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Research

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12 pages, 622 KiB  
Article
Efficacy and Safety of Isatuximab, Carfilzomib, and Dexamethasone (IsaKd) in Multiple Myeloma Patients at the First Relapse After Autologous Stem Cell Transplantation and Lenalidomide Maintenance: Results from the Multicenter, Real-Life AENEID Study
by Nicola Sgherza, Olga Battisti, Paola Curci, Concetta Conticello, Salvatore Palmieri, Daniele Derudas, Candida Germano, Enrica Antonia Martino, Giuseppe Mele, Roberta Della Pepa, Francesca Fazio, Anna Mele, Bernardo Rossini, Giulia Palazzo, Daniela Roccotelli, Simona Rasola, Maria Teresa Petrucci, Domenico Pastore, Giuseppe Tarantini, Fabrizio Pane, Massimo Gentile, Francesco Di Raimondo, Emanuela Resta and Pellegrino Mustoadd Show full author list remove Hide full author list
Pharmaceuticals 2025, 18(4), 595; https://doi.org/10.3390/ph18040595 - 19 Apr 2025
Cited by 1 | Viewed by 849 | Correction
Abstract
Background: In the randomized, phase-3 IKEMA trial, the triplet isatuximab, carfilzomib, and dexamethasone (IsaKd) demonstrated superior clinical benefit compared to those of carfilzomib and dexamethasone alone in patients with relapsed/refractory multiple myeloma after 1–3 prior treatments. Methods: Our real-world, AENEID study [...] Read more.
Background: In the randomized, phase-3 IKEMA trial, the triplet isatuximab, carfilzomib, and dexamethasone (IsaKd) demonstrated superior clinical benefit compared to those of carfilzomib and dexamethasone alone in patients with relapsed/refractory multiple myeloma after 1–3 prior treatments. Methods: Our real-world, AENEID study aimed to evaluate the efficacy and safety of IsaKd in patients who relapsed after frontline lenalidomide treatment, poorly represented in the IKEMA trial. Specifically, in the present multicenter analysis, we enrolled eighty-two patients who received, between April 2022 and September 2024 and outside of clinical trials, at least one cycle of IsaKd as a second-line treatment at the first relapse after induction therapy, autologous stem cell transplantation (ASCT), and lenalidomide maintenance. Results: After a median follow-up time of 12.9 months (range, 1–77), the overall response rate, at least a very good partial response rate, and median progression-free survival time were 79.3%, 56.1%, and 24.4 months, respectively. This slightly lower performance compared to that in the IKEMA study may be attributed to the well-known poor prognostic impact of lenalidomide refractoriness (len-R), developed by all our patients during maintenance therapy, and to a higher proportion of patients with extramedullary disease present in our series, which was identified as the only factor significantly affecting the PFS in multivariable analysis. The median overall survival was not reached, as in the pivotal trial, while the 1-year survival probability was 85.1%. Regarding the safety profile, our findings were consistent with those of the IKEMA trial, with no new safety signals reported. Conclusions: These real-world data support the use of IsaKd as a valuable option for len-R MM patients relapsing after the first-line therapy, including ASCT and lenalidomide maintenance. Full article
(This article belongs to the Special Issue Multidrug Therapies Containing Monoclonal Antibodies for Multiple Myeloma 2024)
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16 pages, 704 KiB  
Article
Unravelling Transplant-Ineligible Newly Diagnosed Multiple Myeloma Treatment in Real-World Practice in Spain: The CARINAE Study
by Felipe de Arriba de la Fuente, Mercedes Gironella Mesa, Miguel Teodoro Hernández García, Juan Alonso Soler Campos, Susana Herráez Rodríguez, María José Moreno Belmonte, Teresa Regueiro López, Miriam González-Pardo, María Casanova Espinosa and on behalf of the CARINAE Study Investigators
Pharmaceuticals 2024, 17(10), 1272; https://doi.org/10.3390/ph17101272 - 26 Sep 2024
Viewed by 1440
Abstract
Real-world evidence on the impact of monoclonal antibodies as first-line treatment in Spain is limited. This observational, retrospective and prospective, multicenter, descriptive study included 117 transplant-ineligible newly diagnosed multiple myeloma (TIE-NDMM) patients divided into Group A, who received no daratumumab standard regimens, and [...] Read more.
Real-world evidence on the impact of monoclonal antibodies as first-line treatment in Spain is limited. This observational, retrospective and prospective, multicenter, descriptive study included 117 transplant-ineligible newly diagnosed multiple myeloma (TIE-NDMM) patients divided into Group A, who received no daratumumab standard regimens, and the DVMP group (daratumumab, bortezomib, melphalan, and prednisone treatment). More than 90% of the patients in Group A received bortezomib, lenalidomide, or a combination of them. The median follow-up time for Group A was 38.2 months in comparison to 25.8 months for the DVMP group (p < 0.0001). The rate of DVMP patients that experienced disease progression or death from any cause was 36.8%, compared to 67.3% of Group A patients at 36 months of follow-up. The DVMP group had a higher 36-month progression-free survival (PFS) rate (52.9% vs. 31.7%). During the retrospective period, 73.0% of patients reported adverse drug reactions, while in the prospective period, 40.5% experienced adverse events, with no clinical differences between groups. The study supports the use of daratumumab regimens in frontline therapy based on real-world data. The findings provide valuable insights into the clinical outcomes of daratumumab therapy, which can help physicians make informed decisions regarding the optimal treatment approach for this patient population. Full article
(This article belongs to the Special Issue Multidrug Therapies Containing Monoclonal Antibodies for Multiple Myeloma 2024)
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Review

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17 pages, 953 KiB  
Review
Minimal Residual Disease Significance in Multiple Myeloma Patients Treated with Anti-CD38 Monoclonal Antibodies
by Federico Caroni, Vincenzo Sammartano, Paola Pacelli, Anna Sicuranza, Margherita Malchiodi, Andreea Dragomir, Sara Ciofini, Donatella Raspadori, Monica Bocchia and Alessandro Gozzetti
Pharmaceuticals 2025, 18(2), 159; https://doi.org/10.3390/ph18020159 - 25 Jan 2025
Viewed by 1274
Abstract
Minimal residual disease (MRD) evaluation is a recognized endpoint in clinical trials. Both next-generation flow and sequencing could be used as complementary techniques to detect myeloma cells after therapy to measure the depth of response and novel drug efficacy. Anti-CD38 monoclonal antibodies combined [...] Read more.
Minimal residual disease (MRD) evaluation is a recognized endpoint in clinical trials. Both next-generation flow and sequencing could be used as complementary techniques to detect myeloma cells after therapy to measure the depth of response and novel drug efficacy. Anti-CD38 monoclonal antibodies combined with proteasome inhibitors and immunomodulatory drugs have increased the quality of response in myeloma patients, and MRD evaluation is also entering routine clinical practice in many hematological centers. This review analyzes updated results from recent clinical trials utilizing anti-CD38 monoclonal antibodies such as isatuximab and daratumumab in terms of their responses and MRD data. MRD-driven therapy appears promising for the future of MM patients, and emerging minimally invasive techniques to assess MRD are under investigation as novel potential methods to replace or integrate traditional MRD evaluation. Full article
(This article belongs to the Special Issue Multidrug Therapies Containing Monoclonal Antibodies for Multiple Myeloma 2024)
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20 pages, 268 KiB  
Review
Monoclonal Antibodies in Relapsed-Refractory Multiple Myeloma
by Ilaria Sorgiovanni, Maria Livia Del Giudice, Sara Galimberti and Gabriele Buda
Pharmaceuticals 2025, 18(2), 145; https://doi.org/10.3390/ph18020145 - 22 Jan 2025
Viewed by 1289
Abstract
Multiple myeloma is a malignant hematological tumor characterized by the proliferation of clonal plasma cells in the bone marrow causing organ damage. Despite improved survival rates due to the increasing availability of therapeutic options in recent decades, it remains an incurable disease, with [...] Read more.
Multiple myeloma is a malignant hematological tumor characterized by the proliferation of clonal plasma cells in the bone marrow causing organ damage. Despite improved survival rates due to the increasing availability of therapeutic options in recent decades, it remains an incurable disease, with most patients ultimately relapsing. Consequently, relapsed/refractory multiple myeloma disease (RRMM) has become a treatment priority. Immunotherapy is the backbone of treatment in RRMM, starting with monoclonal antibodies such as elotuzumab, daratumumab, and isatuximab. The aim of this review is summarizing the results of RRMM trials with monoclonal antibodies and of the principal ongoing trials containing them. Additionally, we put a brief focus on novel drugs (such as bispecific antibodies) to provide a better overview. The advent of monoclonal antibodies has been nothing short of a game-changer for multi-refractory patients. It has opened up a whole new world of possibilities, offering myeloma patients a brighter and more hopeful future, even in the face of relapse. Full article
(This article belongs to the Special Issue Multidrug Therapies Containing Monoclonal Antibodies for Multiple Myeloma 2024)
12 pages, 259 KiB  
Review
The Role of Monoclonal Antibodies in the Treatment of Myeloma Kidney Disease
by Daniele Derudas and Sabrina Chiriu
Pharmaceuticals 2024, 17(8), 1029; https://doi.org/10.3390/ph17081029 - 5 Aug 2024
Viewed by 1864
Abstract
Renal failure is one of the most important manifestations of multiple myeloma. It is caused by renal lesions such as cast nephropathy, immunoglobulin deposition disease, AL amyloidosis or other glomerular and/or tubular diseases, mostly due to the toxic effect of free light chains [...] Read more.
Renal failure is one of the most important manifestations of multiple myeloma. It is caused by renal lesions such as cast nephropathy, immunoglobulin deposition disease, AL amyloidosis or other glomerular and/or tubular diseases, mostly due to the toxic effect of free light chains in serum. Renal failure can represent a clinical emergency and is associated with poor outcome in newly diagnosed and relapsed/refractory multiple myeloma patients. Although progression-free survival and overall survival have improved with the introduction of novel agents, renal failure remains a challenge for the treatment of patients with multiple myeloma. Monoclonal antibodies are a component of therapy for newly diagnosed and relapsed/refractory patients and, based on clinical trials and real-world experience, are also safe and effective for subjects with renal failure, even if they are on dialysis. Most of the data are on anti-CD38 and anti-SLAM7 antibodies, but new antibody–drug conjugates such as belantamab mafodotin and bispecific antibodies also appear to be effective in myeloma kidney disease. In the future, we will have to face some challenges, such as defining new criteria for renal response to treatment, defining specific trials for these difficult-to-treat patients and integrating different therapeutic options. Full article
(This article belongs to the Special Issue Multidrug Therapies Containing Monoclonal Antibodies for Multiple Myeloma 2024)
20 pages, 563 KiB  
Review
Monoclonal Antibodies in Smoldering Multiple Myeloma and Monoclonal Gammopathy of Undetermined Significance: Current Status and Future Directions
by Valeria Ferla, Francesca Farina, Tommaso Perini, Magda Marcatti and Fabio Ciceri
Pharmaceuticals 2024, 17(7), 901; https://doi.org/10.3390/ph17070901 - 6 Jul 2024
Viewed by 2621
Abstract
Monoclonal antibodies (MoAbs) targeting several cellular receptors have significantly improved the prognosis of multiple myeloma (MM). Their high effectiveness and safety raise the question of whether earlier therapeutic intervention in monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) influences the [...] Read more.
Monoclonal antibodies (MoAbs) targeting several cellular receptors have significantly improved the prognosis of multiple myeloma (MM). Their high effectiveness and safety raise the question of whether earlier therapeutic intervention in monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) influences the natural course of the disease. MM is preceded by clinically recognized conditions such as MGUS and SMM. Numerous studies are investigating the disease biology and immune profile of SMM and MGUS to unravel the intricate relationship between immunosurveillance and disease progression. The standard approach to MGUS and SMM remains close observation. Early studies indicate benefits in terms of progression or even survival for promptly treating high-risk SMM patients. Ongoing debates are focused on which patients with SMM and MGUS to treat, as well as on determining the optimal therapeutic approach. The first approach aims to cure by attempting to eliminate the pathological clone, while the second approach is preventive, aiming to manage disease progression to active MM and restore the immune system. In this review, we focus on the available and emerging data on early treatment, particularly with MoAbs alone or in combination with other therapies, in SMM and MGUS patients. Full article
(This article belongs to the Special Issue Multidrug Therapies Containing Monoclonal Antibodies for Multiple Myeloma 2024)
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21 pages, 357 KiB  
Review
Novel Immunotherapies and Combinations: The Future Landscape of Multiple Myeloma Treatment
by Sonia Morè, Laura Corvatta, Valentina Maria Manieri, Erika Morsia, Antonella Poloni and Massimo Offidani
Pharmaceuticals 2023, 16(11), 1628; https://doi.org/10.3390/ph16111628 - 19 Nov 2023
Cited by 10 | Viewed by 4204
Abstract
In multiple myeloma impressive outcomes have improved with the introduction of new therapeutic approaches, mainly those including naked monoclonal antibodies such as daratumumab and isatuximab. However, moving to earlier lines of therapy with effective anti-myeloma drugs led to an increase in the number [...] Read more.
In multiple myeloma impressive outcomes have improved with the introduction of new therapeutic approaches, mainly those including naked monoclonal antibodies such as daratumumab and isatuximab. However, moving to earlier lines of therapy with effective anti-myeloma drugs led to an increase in the number of patients who developed multi-refractoriness to them early on. Currently, triple- or multi-refractory MM represents an unmet medical need, and their management remains a complicated challenge. The recent approval of new immunotherapeutic approaches such as conjugated monoclonal antibodies, bispecific antibodies, and CAR T cells could be a turning point for these heavily pretreated patients. Nevertheless, several issues regarding their use are unsolved, such as how to select patients for each strategy or how to sequence these therapies within the MM therapeutic landscape. Here we provide an overview of the most recent data about approved conjugated monoclonal antibody belantamab, mafodotin, bispecific antibody teclistamab, and other promising compounds under development, mainly focusing on the ongoing clinical trials with monoclonal antibody combination approaches in advanced and earlier phases of MM treatment. Full article
(This article belongs to the Special Issue Multidrug Therapies Containing Monoclonal Antibodies for Multiple Myeloma 2024)

Other

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20 pages, 933 KiB  
Systematic Review
Impact of Anti-CD38 Monoclonal Antibody Therapy on CD34+ Hematopoietic Stem Cell Mobilization, Collection, and Engraftment in Multiple Myeloma Patients—A Systematic Review
by Flavia Bigi, Enrica Manzato, Simona Barbato, Marco Talarico, Michele Puppi, Simone Masci, Ilaria Sacchetti, Roberta Restuccia, Miriam Iezza, Ilaria Rizzello, Chiara Sartor, Katia Mancuso, Lucia Pantani, Paola Tacchetti, Michele Cavo and Elena Zamagni
Pharmaceuticals 2024, 17(7), 944; https://doi.org/10.3390/ph17070944 - 15 Jul 2024
Cited by 2 | Viewed by 2746
Abstract
This systematic review examines the available clinical data on CD34+ cell mobilization, collection, and engraftment in multiple myeloma patients treated with the anti-CD38 monoclonal antibodies daratumumab and isatuximab in clinical trials and in real life. Twenty-six clinical reports were published between 2019 and [...] Read more.
This systematic review examines the available clinical data on CD34+ cell mobilization, collection, and engraftment in multiple myeloma patients treated with the anti-CD38 monoclonal antibodies daratumumab and isatuximab in clinical trials and in real life. Twenty-six clinical reports were published between 2019 and February 2024. Most studies documented lower circulating CD34+ cells after mobilization compared to controls, leading to higher plerixafor requirements. Although collection yields were significantly lower in approximately half of the studies, the collection target was achieved in similar proportions of daratumumab- and isatuximab-treated and nontreated patients, and access to autologous stem cell transplant (ASCT) was comparable. This could be explained by the retained efficacy of plerixafor in anti-CD38 monoclonal antibody-treated patients, while no chemotherapy-based or sparing mobilization protocol proved superior. Half of the studies reported slower hematopoietic reconstitution after ASCT in daratumumab- and isatuximab-treated patients, without an excess of infectious complications. While no direct effect on stem cells was observed in vitro, emerging evidence suggests possible dysregulation of CD34+ cell adhesion after daratumumab treatment. Overall, anti-CD38 monoclonal antibodies appear to interfere with CD34+ cell mobilization, without consistently leading to significant clinical consequences. Further research is needed to elucidate the underlying mechanisms and define optimal mobilization strategies in this patient population. Full article
(This article belongs to the Special Issue Multidrug Therapies Containing Monoclonal Antibodies for Multiple Myeloma 2024)
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