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Open AccessEditorial

The Road to a Cure: Emerging Treatments for Multiple Myeloma

by Jo Caers

Cancers 2020, 12(12), 3593; https://doi.org/10.3390/cancers12123593 - 1 Dec 2020

Viewed by 2492

Abstract

During 50 years of intensive research, we have learnt about the pathophysiology of multiple myeloma (MM) and improved the management of this disease [...] Full article

(This article belongs to the Special Issue Emerging Treatment Strategies for Multiple Myeloma)

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Research

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17 pages, 2866 KiB

Open AccessArticle

AT-101 Enhances the Antitumor Activity of Lenalidomide in Patients with Multiple Myeloma

by Sikander Ailawadhi, Ricardo D. Parrondo, Navnita Dutta, Bing Han, Gina Ciccio, Yesesri Cherukuri, Victoria R. Alegria, Betsy R. LaPlant, Vivek Roy, Taimur Sher, Brett Edwards, Stephanie Lanier, Alak Manna, Keisha Heslop, Thomas Caulfield, Emir Maldosevic, Peter Storz, Rami Manochakian, Yan Asmann, Asher A. Chanan-Khan and Aneel Paulus Show full author list Hide full author list

Cancers 2023, 15(2), 477; https://doi.org/10.3390/cancers15020477 - 12 Jan 2023

Cited by 3 | Viewed by 2706

Abstract

Bcl-2 and Mcl-1 proteins play a role in multiple myeloma (MM) cell survival, for which targeted inhibitors are being developed. AT-101 is an oral drug, which disrupts Bcl-2 and Mcl-1 function, impedes mitochondrial bioenergetic processes and induces apoptosis in MM cells. When combined [...] Read more.

Bcl-2 and Mcl-1 proteins play a role in multiple myeloma (MM) cell survival, for which targeted inhibitors are being developed. AT-101 is an oral drug, which disrupts Bcl-2 and Mcl-1 function, impedes mitochondrial bioenergetic processes and induces apoptosis in MM cells. When combined with lenalidomide and dexamethasone (Rd), AT-101 significantly reduced tumor burden in an in vivo xenograft model of MM. These data provided rationale for a phase I/II study to establish the effective dose of AT-101 in combination with Rd (ARd regimen) in relapsed/refractory MM. A total of 10 patients were enrolled, most with high-risk cytogenetics (80%) and prior stem cell transplant (70%). Three patients were lenalidomide-refractory, 2 were bortezomib-refractory and 3 were daratumumab-refractory. The ARd combination was well tolerated with most common grade 3/4 adverse events being cytopenia’s. The overall response rate was 40% and clinical benefit rate was 90%. The median progression free survival was 14.9 months (95% CI 7.1-NE). Patients responsive to ARd showed a decrease in Bcl-2:Bim or Mcl-1:Noxa protein complexes, increased CD8+ T and NK cells and depletion of T and B-regulatory cells. The ARd regimen demonstrated an acceptable safety profile and promising efficacy in patients with relapsed/refractory MM prompting further investigation in additional patients. Full article

(This article belongs to the Special Issue Emerging Treatment Strategies for Multiple Myeloma)

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20 pages, 4464 KiB

Open AccessArticle

Balancing the CD38 Expression on Effector and Target Cells in Daratumumab-Mediated NK Cell ADCC against Multiple Myeloma

by Margaux Lejeune, Elodie Duray, Matthias Peipp, Béatrice Clémenceau, Frédéric Baron, Yves Beguin and Jo Caers

Cancers 2021, 13(12), 3072; https://doi.org/10.3390/cancers13123072 - 20 Jun 2021

Cited by 7 | Viewed by 4109

Abstract

Multiple myeloma (MM) is an incurable cancer characterized by the proliferation and accumulation of monoclonal plasma cells in the bone marrow. The monoclonal anti-CD38 daratumumab has taken a central place in the different treatment regimens for newly diagnosed and relapsed, refractory myeloma. In [...] Read more.

Multiple myeloma (MM) is an incurable cancer characterized by the proliferation and accumulation of monoclonal plasma cells in the bone marrow. The monoclonal anti-CD38 daratumumab has taken a central place in the different treatment regimens for newly diagnosed and relapsed, refractory myeloma. In this study, we correlated the NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC) and potential fratricide induced by daratumumab with CD38-expression levels on both effector and target cells. We show that CD38 expression can be modulated by adding all-trans retinoic acid (ATRA) or interferon-α to MM cells to further fine-tune these effects. In addition, we observed that ADCC becomes inefficient when fratricide occurs and both ADCC and fratricide depend on the balance between CD38 expression on effector and target cells. However, the addition of adjuvants (retinoic acid or interferon-α) to myeloma cells or the inhibition of fratricide using a CD38-blocking nanobody on NK-cells can reverse this balance towards ADCC and thus promote lysis of target cells by ADCC. ATRA and interferon-α increased the CD38 expression at the surface of MM cells about three-fold and two-fold, respectively. This increase was of interest for MM cells with low CD38 expression, that became susceptible to daratumumab-mediated ADCC after preincubation. A CD38-blocking nanobody prevented the binding of daratumumab to these NK-cells and blunted the fratricidal effect on effector NK cells. In conclusion, our study highlights the importance of a balanced CD38 expression on target and effector cells and attempts to alter this balance will affect the susceptibility of MM cells towards daratumumab-mediated ADCC. Full article

(This article belongs to the Special Issue Emerging Treatment Strategies for Multiple Myeloma)

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18 pages, 2994 KiB

Open AccessArticle

Therapeutic Targeting of Protein Disulfide Isomerase PDIA1 in Multiple Myeloma

by Metis Hasipek, Dale Grabowski, Yihong Guan, Raghunandan Reddy Alugubelli, Anand D. Tiwari, Xiaorong Gu, Gabriel A. DeAvila, Ariosto S. Silva, Mark B. Meads, Yvonne Parker, Daniel J. Lindner, Yogen Saunthararajah, Kenneth H. Shain, Jaroslaw P. Maciejewski, Frederic J. Reu, James G. Phillips and Babal K. Jha

Cancers 2021, 13(11), 2649; https://doi.org/10.3390/cancers13112649 - 28 May 2021

Cited by 13 | Viewed by 5243

Abstract

Multiple myeloma is a genetically complex hematologic neoplasia in which malignant plasma cells constantly operate at the maximum limit of their unfolded protein response (UPR) due to a high secretory burden of immunoglobulins and cytokines. The endoplasmic reticulum (ER) resident protein disulfide isomerase, [...] Read more.

Multiple myeloma is a genetically complex hematologic neoplasia in which malignant plasma cells constantly operate at the maximum limit of their unfolded protein response (UPR) due to a high secretory burden of immunoglobulins and cytokines. The endoplasmic reticulum (ER) resident protein disulfide isomerase, PDIA1 is indispensable for maintaining structural integrity of cysteine-rich antibodies and cytokines that require accurate intramolecular disulfide bond arrangement. PDIA1 expression analysis from RNA-seq of multiple myeloma patients demonstrated an inverse relationship with survival in relapsed or refractory disease, supporting its critical role in myeloma persistence. Using a structure-guided medicinal chemistry approach, we developed a potent, orally bioavailable small molecule PDIA1 inhibitor CCF642-34. The inhibition of PDIA1 overwhelms the UPR in myeloma cells, resulting in their apoptotic cell death at doses that do not affect the normal CD34⁺ hematopoietic stem and progenitor cells. Bortezomib resistance leads to increased PDIA1 expression and thus CCF642-34 sensitivity, suggesting that proteasome inhibitor resistance leads to PDIA1 dependence for proteostasis and survival. CCF642-34 induces acute unresolvable UPR in myeloma cells, and oral treatment increased survival of mice in the syngeneic 5TGM1 model of myeloma. Results support development of CCF642-34 to selectively target the plasma cell program and overcome the treatment-refractory state in myeloma. Full article

(This article belongs to the Special Issue Emerging Treatment Strategies for Multiple Myeloma)

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Review

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14 pages, 647 KiB

Open AccessReview

Upfront or Deferred Autologous Stem Cell Transplantation for Newly Diagnosed Multiple Myeloma in the Era of Triplet and Quadruplet Induction and Minimal Residual Disease/Risk-Adapted Therapy

by Clifton C. Mo, Monique A. Hartley-Brown, Shonali Midha and Paul G. Richardson

Cancers 2023, 15(24), 5709; https://doi.org/10.3390/cancers15245709 - 5 Dec 2023

Cited by 3 | Viewed by 2102

Abstract

The standards of care for the initial treatment of patients with newly diagnosed multiple myeloma (NDMM) who are eligible for high-dose melphalan and autologous stem cell transplantation (HDM-ASCT) include highly active triplet and quadruplet regimens based on proteasome inhibitors, immunomodulatory drugs, and monoclonal [...] Read more.

The standards of care for the initial treatment of patients with newly diagnosed multiple myeloma (NDMM) who are eligible for high-dose melphalan and autologous stem cell transplantation (HDM-ASCT) include highly active triplet and quadruplet regimens based on proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies. These regimens are resulting in improved outcomes and increasingly high rates of minimal residual disease (MRD)-negative responses without HDM-ASCT as part of the upfront therapy. Furthermore, recent randomized studies have shown that, while transplant-based approaches as a frontline therapy result in significantly longer progression-free survival compared to non-transplant approaches, this has not translated into an overall survival benefit. Given these developments, and in the context of the treatment burden of undergoing HDM-ASCT, in addition to the acute toxicities and long-term sequelae of HDM, which are associated with the genotoxicity of melphalan, there is an increasing rationale for considering deferring upfront HDM-ASCT in select transplant-eligible patients and saving it as a treatment option for later salvage therapy. Here, we review the latest clinical trial data on upfront or deferred HDM-ASCT and on the activity of quadruplet induction regimens, including rates of MRD-negative responses, and summarize emerging treatment approaches in the upfront setting such as the use of MRD-directed therapy and alternatives to HDM-ASCT. Full article

(This article belongs to the Special Issue Emerging Treatment Strategies for Multiple Myeloma)

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14 pages, 638 KiB

Open AccessReview

Updates in the Use of BCL-2-Family Small Molecule Inhibitors for the Treatment of Relapsed/Refractory Multiple Myeloma

by Ricardo D. Parrondo, Aneel Paulus and Sikander Ailawadhi

Cancers 2022, 14(14), 3330; https://doi.org/10.3390/cancers14143330 - 8 Jul 2022

Cited by 5 | Viewed by 2650

Abstract

Despite considerable advances in the treatment of multiple myeloma over the past decade, progression of disease is inevitable, and patients ultimately succumb to relapsed and refractory disease. Efficacious therapeutic regimens that target the key biological pathways that are essential for malignant plasma cell [...] Read more.

Despite considerable advances in the treatment of multiple myeloma over the past decade, progression of disease is inevitable, and patients ultimately succumb to relapsed and refractory disease. Efficacious therapeutic regimens that target the key biological pathways that are essential for malignant plasma cell survival are necessary in the efforts to improve patient survival outcomes. The Bcl-2 family of proteins comprise oncogenes that promote myeloma cell survival by conferring resistance to apoptosis. These proteins are frequently upregulated in myeloma cells, thus making them attractive therapeutic targets. Several small molecule inhibitors of Bcl-2-family proteins are currently in clinical development for the treatment of relapsed/refractory multiple myeloma. Venetoclax, a Bcl-2-specific inhibitor, has generated the most clinical data and has shown promising results in patients with multiple myeloma harboring the t (11;14) translocation. Venetoclax has shown efficacy when combined with anti-CD38 monoclonal antibodies, immunomodulatory drugs, and proteasome inhibitors. Several other Bcl-2 inhibitors are in clinical development, as are inhibitors of Mcl-1, a Bcl-2-family oncoprotein that is perhaps more critical for myeloma cell survival than Bcl-2. This review will summarize the latest clinical data regarding the clinical development of Bcl-2-family protein inhibitors in the treatment of relapsed/refractory multiple myeloma. Full article

(This article belongs to the Special Issue Emerging Treatment Strategies for Multiple Myeloma)

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15 pages, 637 KiB

Open AccessReview

The Use of Oncolytic Viruses in the Treatment of Multiple Myeloma

by Georgia Stewart, Andrew Chantry and Michelle Lawson

Cancers 2021, 13(22), 5687; https://doi.org/10.3390/cancers13225687 - 13 Nov 2021

Cited by 7 | Viewed by 3535

Abstract

Multiple myeloma accounts for 1% of all new cancers worldwide. It is the second most common haematological malignancy and has a low five-year survival rate (53.2%). Myeloma remains an incurable disease and is caused by the growth of malignant plasma cells in the [...] Read more.

Multiple myeloma accounts for 1% of all new cancers worldwide. It is the second most common haematological malignancy and has a low five-year survival rate (53.2%). Myeloma remains an incurable disease and is caused by the growth of malignant plasma cells in the bone marrow. Current anti-myeloma therapies (conventional chemotherapies, immunomodulatory drugs i.e., thalidomide and its’ analogues, proteasome inhibitors, monoclonal antibodies, and radiotherapy) initially substantially debulk tumour burden, but after a period of remission ‘plateau phase’ disease invariably relapses due to tumour recrudescence from foci of minimal residual disease (MRD) and accumulating drug resistance. Therefore, there is a compelling clinical need for the development of novel treatment regimens to target MRD and effectively eliminate all remaining tumour cells. This review will discuss the potential use of oncolytic virus (OV) therapies in the treatment of myeloma. Specifically, it will focus on preclinical studies using DNA viruses (adenovirus (Ad), vaccinia virus (VV), myxoma virus (MYXV), and herpes simplex virus (HSV)), RNA viruses (reovirus (reo), coxsackie virus, measles virus (MV) and bovine viral diarrhoea virus (BVDV), and vesicular stomatitis virus (VSV)), and on four types of viruses (VV, reo, MV-NIS and VSV-IFNβ-NIS) that have been assessed clinically in a small number of myeloma patients. Full article

(This article belongs to the Special Issue Emerging Treatment Strategies for Multiple Myeloma)

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18 pages, 28711 KiB

Open AccessReview

Treatment of Patients with Monoclonal Gammopathy of Clinical Significance

by David F. Moreno, Laura Rosiñol, María Teresa Cibeira, Joan Bladé and Carlos Fernández de Larrea

Cancers 2021, 13(20), 5131; https://doi.org/10.3390/cancers13205131 - 13 Oct 2021

Cited by 12 | Viewed by 7605

Abstract

Monoclonal gammopathy of undetermined significance (MGUS) is defined as the presence of a monoclonal protein (M-protein) produced by a small amount of plasma cells. The majority of patients remain asymptomatic; however, a fraction of them develop clinical manifestations related to the monoclonal gammopathy [...] Read more.

Monoclonal gammopathy of undetermined significance (MGUS) is defined as the presence of a monoclonal protein (M-protein) produced by a small amount of plasma cells. The majority of patients remain asymptomatic; however, a fraction of them develop clinical manifestations related to the monoclonal gammopathy despite not fulfilling criteria of multiple myeloma or other lymphoproliferative disorder. These patients constitute an emerging clinical issue coined as monoclonal gammopathy of clinical significance (MGCS). The mechanisms involved are poorly understood, and literature is scarce regarding management. The clinical spectrum involves symptoms related to renal, neurologic, skin, ocular, or bleeding manifestations, requiring a multidisciplinary approach. Treatment strategies rely on the basis of symptomatic disease and the M-protein isotype. In this review, we focus on MGCS other than renal, as the latter was earliest recognized and better known. We review the literature and discuss management from diagnosis to treatment based on illustrative cases from daily practice. Full article

(This article belongs to the Special Issue Emerging Treatment Strategies for Multiple Myeloma)

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25 pages, 2197 KiB

Open AccessReview

Treatment Strategy for Multiple Myeloma to Improve Immunological Environment and Maintain MRD Negativity

by Kazuhito Suzuki, Kaichi Nishiwaki and Shingo Yano

Cancers 2021, 13(19), 4867; https://doi.org/10.3390/cancers13194867 - 28 Sep 2021

Cited by 9 | Viewed by 4013

Abstract

Improving the immunological environment and eradicating minimal residual disease (MRD) are the two main treatment goals for long-term survival in patients with multiple myeloma (MM). Immunomodulatory drugs (IMiDs), monoclonal antibody drugs (MoAbs), and autologous grafts for autologous stem cell transplantation (ASCT) can improve [...] Read more.

Improving the immunological environment and eradicating minimal residual disease (MRD) are the two main treatment goals for long-term survival in patients with multiple myeloma (MM). Immunomodulatory drugs (IMiDs), monoclonal antibody drugs (MoAbs), and autologous grafts for autologous stem cell transplantation (ASCT) can improve the immunological microenvironment. ASCT, MoAbs, and proteasome inhibitors (PIs) may be important for the achievement of MRD negativity. An improved immunological environment may be useful for maintaining MRD negativity, although the specific treatment for persistent MRD negativity is unknown. However, whether the ongoing treatment should be continued or changed if the MRD status remains positive is controversial. In this case, genetic, immunophenotypic, and clinical analysis of residual myeloma cells may be necessary to select the effective treatment for the residual myeloma cells. The purpose of this review is to discuss the MM treatment strategy to “cure MM” based on currently available therapies, including IMiDs, PIs, MoAbs, and ASCT, and expected immunotherapies, such as chimeric antigen receptor T cell (CAR-T) therapy, via improvement of the immunological environment and maintenance of MRD negativity. Full article

(This article belongs to the Special Issue Emerging Treatment Strategies for Multiple Myeloma)

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24 pages, 1347 KiB

Open AccessReview

The Agony of Choice—Where to Place the Wave of BCMA-Targeted Therapies in the Multiple Myeloma Treatment Puzzle in 2022 and Beyond

by Irene Strassl, Martin Schreder, Normann Steiner, Jakob Rudzki, Hermine Agis, Tina Künz, Nino Müser, Wolfgang Willenbacher, Andreas Petzer, Peter Neumeister and Maria Theresa Krauth

Cancers 2021, 13(18), 4701; https://doi.org/10.3390/cancers13184701 - 19 Sep 2021

Cited by 8 | Viewed by 5387

Abstract

Since the introduction of first-generation proteasome inhibitors and immunomodulatory agents, the multiple myeloma (MM) treatment landscape has undergone a remarkable development. Most recently, immunotherapeutic strategies targeting the B cell maturation antigen (BCMA) entered the clinical stage providing access to highly anticipated novel treatment [...] Read more.

Since the introduction of first-generation proteasome inhibitors and immunomodulatory agents, the multiple myeloma (MM) treatment landscape has undergone a remarkable development. Most recently, immunotherapeutic strategies targeting the B cell maturation antigen (BCMA) entered the clinical stage providing access to highly anticipated novel treatment strategies. At present, numerous different approaches investigate BCMA as an effective multi-modal target. Currently, BCMA-directed antibody–drug conjugates, bispecific and trispecific antibodies, autologous and allogeneic CAR-T cell as well as CAR-NK cell constructs are either approved or in different stages of clinical and preclinical development for the treatment of MM. This armamentarium of treatment choices raises several challenges for clinical decision making, particularly in the absence of head-to-head comparisons. In this review, we provide a comprehensive overview of BCMA-targeting therapeutics, deliver latest updates on clinical trial data, and focus on potential patient selection criteria for different BCMA-targeting immunotherapeutic strategies. Full article

(This article belongs to the Special Issue Emerging Treatment Strategies for Multiple Myeloma)

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14 pages, 503 KiB

Open AccessReview

PIM Kinases in Multiple Myeloma

by Jian Wu, Emily Chu and Yubin Kang

Cancers 2021, 13(17), 4304; https://doi.org/10.3390/cancers13174304 - 26 Aug 2021

Cited by 19 | Viewed by 4652

Abstract

Multiple myeloma (MM) remains an incurable disease and novel therapeutic agents/approaches are urgently needed. The PIM (Proviral insertion in murine malignancies) serine/threonine kinases have 3 isoforms: PIM1, PIM2, and PIM3. PIM kinases are engaged with an expansive scope of biological activities including cell [...] Read more.

Multiple myeloma (MM) remains an incurable disease and novel therapeutic agents/approaches are urgently needed. The PIM (Proviral insertion in murine malignancies) serine/threonine kinases have 3 isoforms: PIM1, PIM2, and PIM3. PIM kinases are engaged with an expansive scope of biological activities including cell growth, apoptosis, drug resistance, and immune response. An assortment of molecules and pathways that are critical to myeloma tumorigenesis has been recognized as the downstream targets of PIM kinases. The inhibition of PIM kinases has become an emerging scientific interest for the treatment of multiple myeloma and several PIM kinase inhibitors, such as SGI-1776, AZD1208, and PIM447 (formerly LGH447), have been developed and are under different phases of clinical trials. Current research has been focused on the development of a new generation of potent PIM kinase inhibitors with appropriate pharmacological profiles reasonable for human malignancy treatment. Combination therapy of PIM kinase inhibitors with chemotherapeutic appears to create an additive cytotoxic impact in cancer cells. Notwithstanding, the mechanisms by which PIM kinases modulate the immune microenvironment and synergize with the immunomodulatory agents such as lenalidomide have not been deliberately depicted. This review provides a comprehensive overview of the PIM kinase pathways and the current research status of the development of PIM kinase inhibitors for the treatment of MM. Additionally, the combinatorial effects of the PIM kinase inhibitors with other targeted agents and the promising strategies to exploit PIM as a therapeutic target in malignancy are highlighted. Full article

(This article belongs to the Special Issue Emerging Treatment Strategies for Multiple Myeloma)

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21 pages, 1612 KiB

Open AccessReview

Emerging Therapeutic Strategies to Overcome Drug Resistance in Multiple Myeloma

by Lorraine N. Davis and Daniel W. Sherbenou

Cancers 2021, 13(7), 1686; https://doi.org/10.3390/cancers13071686 - 2 Apr 2021

Cited by 32 | Viewed by 5636

Abstract

Multiple myeloma is a malignant plasma cell neoplasm that remains incurable and is ultimately fatal when patients acquire multi-drug resistance. Thus, advancing our understanding of the mechanisms behind drug resistance in multi-relapsed patients is critical for developing better strategies to extend their lifespan. [...] Read more.

Multiple myeloma is a malignant plasma cell neoplasm that remains incurable and is ultimately fatal when patients acquire multi-drug resistance. Thus, advancing our understanding of the mechanisms behind drug resistance in multi-relapsed patients is critical for developing better strategies to extend their lifespan. Here, we review the understanding of resistance to the three key drug classes approved for multiple myeloma treatment: immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies. We consider how the complex, heterogenous biology of multiple myeloma may influence the acquisition of drug resistance and reflect on the gaps in knowledge where additional research is needed to improve our treatment approaches. Fortunately, many agents are currently being evaluated preclinically and in clinical trials that have the potential to overcome or delay drug resistance, including next-generation immunomodulatory drugs and proteasome inhibitors, novel small molecule drugs, chimeric antigen receptor T cells, antibody-drug conjugates, and bispecific antibodies. For each class, we discuss the potential of these strategies to overcome resistance through modifying agents within each class or new classes without cross-resistance to currently available drugs. Full article

(This article belongs to the Special Issue Emerging Treatment Strategies for Multiple Myeloma)

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