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  1. Article: Antibody-Drug Conjugates for Multiple Myeloma: Just the Beginning, or the Beginning of the End?

    Ray, Upasana / Orlowski, Robert Z

    Pharmaceuticals (Basel, Switzerland)

    2023  Volume 16, Issue 4

    Abstract: Multiple myeloma is a malignancy of immunoglobulin-secreting plasma cells that is now often treated in the newly diagnosed and relapsed and/or refractory settings with monoclonal antibodies targeting lineage-specific markers used either alone or in ... ...

    Abstract Multiple myeloma is a malignancy of immunoglobulin-secreting plasma cells that is now often treated in the newly diagnosed and relapsed and/or refractory settings with monoclonal antibodies targeting lineage-specific markers used either alone or in rationally designed combination regimens. Among these are the anti-CD38 antibodies daratumumab and isatuximab, and the anti-Signaling lymphocytic activation molecule family member 7 antibody elotuzumab, all of which are used in their unconjugated formats. Single-chain variable fragments from antibodies also form a key element of the chimeric antigen receptors (CARs) in the B-cell maturation antigen (BCMA)-targeted CAR T-cell products idecabtagene vicleucel and ciltacabtagene autoleucel, which are approved in the advanced setting. Most recently, the bispecific anti-BCMA and T-cell-engaging antibody teclistamab has become available, again for patients with relapsed/refractory disease. Another format into which antibodies can be converted to exert anti-tumor efficacy is as antibody-drug conjugates (ADCs), and belantamab mafodotin, which also targets BCMA, represented the first such agent that gained a foothold in myeloma. Negative results from a recent Phase III study have prompted the initiation of a process for withdrawal of its marketing authorization. However, belantamab remains a drug with some promise, and many other ADCs targeting either BCMA or other plasma cell surface markers are in development and showing potential. This contribution will provide an overview of some of the current data supporting the possibility that ADCs will remain a part of our chemotherapeutic armamentarium against myeloma moving forward, and also highlight areas for future development.
    Language English
    Publishing date 2023-04-14
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2193542-7
    ISSN 1424-8247
    ISSN 1424-8247
    DOI 10.3390/ph16040590
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Clinical trial design change implementation for inclusive studies.

    Espinoza-Gutarra, Manuel R / Aiello, Jack / Orlowski, Robert Z / Ailawadhi, Sikander

    The Lancet. Haematology

    2023  Volume 10, Issue 12, Page(s) e953–e954

    MeSH term(s) Humans ; Clinical Trials as Topic
    Language English
    Publishing date 2023-11-10
    Publishing country England
    Document type Journal Article
    ISSN 2352-3026
    ISSN (online) 2352-3026
    DOI 10.1016/S2352-3026(23)00336-8
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Letter--Incorporating Real-World Evidence and Patient Value Criteria into Value-Based Frameworks for Relapsed/Refractory Multiple Myeloma.

    Orlowski, Robert Z

    Journal of managed care & specialty pharmacy

    2018  Volume 24, Issue 5, Page(s) 487

    Abstract: Disclosures: Orlowski has received research funding from Amgen, BioTheryX, Bristol-Myers Squibb ...

    Abstract Disclosures: Orlowski has received research funding from Amgen, BioTheryX, Bristol-Myers Squibb, Celgene Corporation, and Takeda Pharmaceuticals; honoraria from Amgen, Bristol-Myers Squibb, Celgene Corporation, Janssen, Millennium Pharmaceuticals, and Onyx Pharmaceuticals; and is a member of advisory boards for Amgen, Bristol-Myers Squibb, Celgene Corporation, Incyte, Kite, Legend Biotech, Sanofi-Aventis, and Takeda Pharmaceuticals.
    MeSH term(s) Administration, Oral ; Antineoplastic Combined Chemotherapy Protocols/pharmacology ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Drug Resistance, Neoplasm ; Evidence-Based Medicine/methods ; Humans ; Multiple Myeloma/drug therapy ; Neoplasm Recurrence, Local/drug therapy ; Patient Preference ; Treatment Outcome
    Language English
    Publishing date 2018-04-24
    Publishing country United States
    Document type Letter
    ISSN 2376-1032
    ISSN (online) 2376-1032
    DOI 10.18553/jmcp.2018.24.5.487
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: MUC20 regulated by extrachromosomal circular DNA attenuates proteasome inhibitor resistance of multiple myeloma by modulating cuproptosis.

    Wang, Xiaobin / Shi, Yingqing / Shi, Hua / Liu, Xiaoyu / Liao, Aijun / Liu, Zhuogang / Orlowski, Robert Z / Zhang, Rui / Wang, Huihan

    Journal of experimental & clinical cancer research : CR

    2024  Volume 43, Issue 1, Page(s) 68

    Abstract: Background: Proteasome inhibitors (PIs) are one of the most important classes of drugs for the treatment of multiple myeloma (MM). However, almost all patients with MM develop PI resistance, resulting in therapeutic failure. Therefore, the mechanisms ... ...

    Abstract Background: Proteasome inhibitors (PIs) are one of the most important classes of drugs for the treatment of multiple myeloma (MM). However, almost all patients with MM develop PI resistance, resulting in therapeutic failure. Therefore, the mechanisms underlying PI resistance in MM require further investigation.
    Methods: We used several MM cell lines to establish PI-resistant MM cell lines. We performed RNA microarray and EccDNA-seq in MM cell lines and collected human primary MM samples to explore gene profiles. We evaluated the effect of MUC20 on cuproptosis of PI-resistant MM cells using Co-immunoprecipitation (Co-IP), Seahorse bioenergetic profiling and in vivo assay.
    Results: This study revealed that the downregulation of Mucin 20 (MUC20) could predict PI sensitivity and outcomes in MM patients. Besides, MUC20 attenuated PI resistance in MM cells by inducing cuproptosis via the inhibition of cyclin-dependent kinase inhibitor 2 A expression (CDKN2A), which was achieved by hindering MET proto-oncogene, receptor tyrosine kinase (MET) activation. Moreover, MUC20 suppressed MET activation by repressing insulin-like growth factor receptor-1 (IGF-1R) lactylation in PI-resistant MM cells. This study is the first to perform extrachromosomal circular DNA (eccDNA) sequencing for MM, and it revealed that eccDNA induced PI resistance by amplifying kinesin family member 3 C (KIF3C) to reduce MUC20 expression in MM.
    Conclusion: Our findings indicated that MUC20 regulated by eccDNA alleviates PI resistance of MM by modulating cuproptosis, which would provide novel strategies for the treatment of PI-resistant MM.
    MeSH term(s) Humans ; Proteasome Inhibitors/pharmacology ; Multiple Myeloma/drug therapy ; Multiple Myeloma/genetics ; Oncogenes ; Cytoplasm ; Antiviral Agents ; DNA ; DNA, Circular ; Kinesins ; Mucins
    Chemical Substances Proteasome Inhibitors ; Antiviral Agents ; DNA (9007-49-2) ; DNA, Circular ; KIF3C protein, human ; Kinesins (EC 3.6.4.4) ; MUC20 protein, human ; Mucins
    Language English
    Publishing date 2024-03-05
    Publishing country England
    Document type Journal Article
    ZDB-ID 803138-1
    ISSN 1756-9966 ; 0392-9078
    ISSN (online) 1756-9966
    ISSN 0392-9078
    DOI 10.1186/s13046-024-02972-6
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Pharmacodynamics and pharmacokinetics of proteasome inhibitors for the treatment of multiple myeloma.

    Baljevic, Muhamed / Orlowski, Robert Z

    Expert opinion on drug metabolism & toxicology

    2019  Volume 15, Issue 6, Page(s) 459–473

    Abstract: ... ...

    Abstract Introduction
    MeSH term(s) Animals ; Antineoplastic Agents/administration & dosage ; Antineoplastic Agents/pharmacokinetics ; Antineoplastic Agents/pharmacology ; Biomarkers, Tumor/metabolism ; Drug Resistance, Neoplasm ; Humans ; Medication Adherence ; Multiple Myeloma/drug therapy ; Multiple Myeloma/pathology ; Proteasome Inhibitors/administration & dosage ; Proteasome Inhibitors/pharmacokinetics ; Proteasome Inhibitors/pharmacology ; Quality of Life
    Chemical Substances Antineoplastic Agents ; Biomarkers, Tumor ; Proteasome Inhibitors
    Language English
    Publishing date 2019-04-08
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 2214462-6
    ISSN 1744-7607 ; 1742-5255
    ISSN (online) 1744-7607
    ISSN 1742-5255
    DOI 10.1080/17425255.2019.1621839
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: New Drugs in Multiple Myeloma.

    Kunacheewa, Chutima / Orlowski, Robert Z

    Annual review of medicine

    2019  Volume 70, Page(s) 521–547

    Abstract: Multiple myeloma is diagnosed in over 100,000 patients each year worldwide, has an increasing incidence and prevalence in many regions, and follows a relapsing course, making it a significant and growing healthcare challenge. Recent basic, translational, ...

    Abstract Multiple myeloma is diagnosed in over 100,000 patients each year worldwide, has an increasing incidence and prevalence in many regions, and follows a relapsing course, making it a significant and growing healthcare challenge. Recent basic, translational, and clinical studies have expanded our therapeutic armamentarium, which now consists of alkylating agents, corticosteroids, deacetylase inhibitors, immunomodulatory agents, monoclonal antibodies, and proteasome inhibitors. New drugs in these categories, and additional agents, including both small and large molecules, as well as cellular therapies, are under development that promise to further expand our capabilities and bring us closer to the cure of this plasma cell dyscrasia.
    MeSH term(s) Antibodies, Monoclonal/therapeutic use ; Antineoplastic Agents/therapeutic use ; Clinical Trials, Phase II as Topic ; Drug Approval ; Female ; Forecasting ; Humans ; Immunologic Factors/therapeutic use ; Male ; Multiple Myeloma/diagnosis ; Multiple Myeloma/drug therapy ; Multiple Myeloma/mortality ; Precision Medicine/methods ; Precision Medicine/trends ; Proteasome Inhibitors/therapeutic use ; Risk Assessment ; Severity of Illness Index ; Survival Rate ; Treatment Outcome ; United States ; United States Food and Drug Administration
    Chemical Substances Antibodies, Monoclonal ; Antineoplastic Agents ; Immunologic Factors ; Proteasome Inhibitors
    Language English
    Publishing date 2019-01-29
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 207930-6
    ISSN 1545-326X ; 0066-4219
    ISSN (online) 1545-326X
    ISSN 0066-4219
    DOI 10.1146/annurev-med-112017-091045
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article: The future of proteasome inhibitors in relapsed/refractory multiple myeloma.

    Orlowski, Robert Z

    Oncology (Williston Park, N.Y.)

    2014  Volume 25 Suppl 2, Page(s) 56–64

    Abstract: The ubiquitin-proteasome pathway was first validated as a target for cancer therapy with the demonstration of the activity of the boronic acid proteasome inhibitor (PI) bortezomib (Velcade) against relapsed and relapsed/refractory multiple myeloma. ... ...

    Abstract The ubiquitin-proteasome pathway was first validated as a target for cancer therapy with the demonstration of the activity of the boronic acid proteasome inhibitor (PI) bortezomib (Velcade) against relapsed and relapsed/refractory multiple myeloma. Another generation of PIs is now entering the clinical arena; this includes intravenous agents such as carfilzomib, CEP-18770, and marizomib, and oral drugs such as MLN9708 and ONX 0912. These novel agents will likely first be used for patients with disease that has either relapsed or been refractory to prior therapy (including bortezomib-based regimens) because of their ability to overcome drug resistance, or will be used in patients who are intolerant of, or are not candidates for bortezomib. Preclinical studies also suggest that PIs may act synergistically with other conventional and novel agents, or even with one another in rationally designed combination regimens. In addition, other inhibitors that selectively target only the immunoproteasome and not the constitutive proteasome, as well as agents that bind to noncatalytic proteasome subunits, are emerging as potential drug candidates. Taken together, it seems likely that we have only begun to appreciate the full potential of inhibition of the proteasome. This article extrapolates our current knowledge into an algorithm for the future use of these inhibitors against multiple myeloma.
    MeSH term(s) Boronic Acids/therapeutic use ; Bortezomib ; Humans ; Multiple Myeloma/drug therapy ; Proteasome Inhibitors/therapeutic use ; Pyrazines/therapeutic use ; Recurrence
    Chemical Substances Boronic Acids ; Proteasome Inhibitors ; Pyrazines ; Bortezomib (69G8BD63PP)
    Language English
    Publishing date 2014-07-29
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 1067950-9
    ISSN 0890-9091
    ISSN 0890-9091
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article: Novel Anti-B-cell Maturation Antigen Alpha-Amanitin Antibody-drug Conjugate HDP-101 Shows Superior Activity to Belantamab Mafodotin and Enhanced Efficacy in Deletion 17p Myeloma Models.

    Singh, Ram Kumar / Jones, Richard J / Shirazi, Fazal / Qin, Li / Zou, Jianxuan / Hong, Samuel / Wang, Hua / Lee, Hans C / Patel, Krina K / Wan, Jie / Choudhary, Rajan Kumar / Kuiatse, Isere / Pahl, Andreas / Orlowski, Robert Z

    Research square

    2024  

    Abstract: B-cell maturation antigen (BCMA) plays a pathobiologic role in myeloma and is a validated target with five BCMA-specific therapeutics having been approved for relapsed/refractory disease. However, these drugs are not curative, and responses are inferior ... ...

    Abstract B-cell maturation antigen (BCMA) plays a pathobiologic role in myeloma and is a validated target with five BCMA-specific therapeutics having been approved for relapsed/refractory disease. However, these drugs are not curative, and responses are inferior in patients with molecularly-defined high-risk disease, including those with deletion 17p (del17p) involving the tumor suppressor
    Language English
    Publishing date 2024-01-11
    Publishing country United States
    Document type Preprint
    DOI 10.21203/rs.3.rs-3843028/v1
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: Why proteasome inhibitors cannot ERADicate multiple myeloma.

    Orlowski, Robert Z

    Cancer cell

    2013  Volume 24, Issue 3, Page(s) 275–277

    Abstract: Proteasome inhibitors are key parts of our armamentarium against multiple myeloma, but the disease can become resistant through poorly defined mechanisms. In this issue of Cancer Cell, Leung-Hagesteijn and colleagues describe XBP1s(-) subpopulations of ... ...

    Abstract Proteasome inhibitors are key parts of our armamentarium against multiple myeloma, but the disease can become resistant through poorly defined mechanisms. In this issue of Cancer Cell, Leung-Hagesteijn and colleagues describe XBP1s(-) subpopulations of tumor cells that are resistant to bortezomib and may account for therapeutic failures in the clinic.
    MeSH term(s) DNA-Binding Proteins/deficiency ; Drug Resistance, Neoplasm/genetics ; Humans ; Multiple Myeloma/drug therapy ; Multiple Myeloma/genetics ; Proteasome Inhibitors/therapeutic use ; Regulatory Factor X Transcription Factors ; Transcription Factors/deficiency ; X-Box Binding Protein 1
    Chemical Substances DNA-Binding Proteins ; Proteasome Inhibitors ; Regulatory Factor X Transcription Factors ; Transcription Factors ; X-Box Binding Protein 1 ; XBP1 protein, human
    Language English
    Publishing date 2013-09-13
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Comment
    ZDB-ID 2078448-X
    ISSN 1878-3686 ; 1535-6108
    ISSN (online) 1878-3686
    ISSN 1535-6108
    DOI 10.1016/j.ccr.2013.08.014
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: Novel agents for multiple myeloma to overcome resistance in phase III clinical trials.

    Orlowski, Robert Z

    Seminars in oncology

    2013  Volume 40, Issue 5, Page(s) 634–651

    Abstract: The incorporation of novel agents such as bortezomib and lenalidomide into initial therapy for multiple myeloma has improved the response rate of induction regimens. Also, these drugs are being increasingly used in the peri-transplant setting for ... ...

    Abstract The incorporation of novel agents such as bortezomib and lenalidomide into initial therapy for multiple myeloma has improved the response rate of induction regimens. Also, these drugs are being increasingly used in the peri-transplant setting for transplant-eligible patients, and as part of consolidation and/or maintenance after front-line treatment, including in transplant-ineligible patients. Together, these and other strategies have contributed to a prolongation of progression-free survival (PFS) and overall survival (OS) in myeloma patients, and an increasing proportion are able to sustain a remission for many years. Despite these improvements, however, the vast majority of patients continue to suffer relapses, which suggests a prominent role for either primary, innate drug resistance, or secondary, acquired drug resistance. As a result, there remains a strong need to develop new proteasome inhibitors and immunomodulatory agents, as well as new drug classes, which would be effective in the relapsed and/or refractory setting, and overcome drug resistance. This review will focus on novel drugs that have reached phase III trials, including carfilzomib and pomalidomide, which have recently garnered regulatory approvals. In addition, agents that are in phase II or III, potentially registration-enabling trials will be described as well, to provide an overview of the possible landscape in the relapsed and/or refractory arena over the next 5 years.
    MeSH term(s) Antibodies, Monoclonal, Humanized/therapeutic use ; Antineoplastic Agents/therapeutic use ; Benzamides ; Clinical Trials, Phase III as Topic ; Disease-Free Survival ; Drug Resistance, Neoplasm ; Histone Deacetylase Inhibitors/therapeutic use ; Humans ; Hydroxamic Acids/therapeutic use ; Immunologic Factors/therapeutic use ; Indoles/therapeutic use ; Multiple Myeloma/drug therapy ; Oligopeptides/therapeutic use ; Panobinostat ; Phosphorylcholine/analogs & derivatives ; Phosphorylcholine/therapeutic use ; Piperidines ; Proteasome Inhibitors/therapeutic use ; Pyridines ; Remission Induction ; Thalidomide/analogs & derivatives ; Thalidomide/therapeutic use ; Thiazoles/therapeutic use ; Treatment Outcome ; Vorinostat
    Chemical Substances Antibodies, Monoclonal, Humanized ; Antineoplastic Agents ; Benzamides ; Histone Deacetylase Inhibitors ; Hydroxamic Acids ; Immunologic Factors ; Indoles ; Oligopeptides ; Piperidines ; Proteasome Inhibitors ; Pyridines ; Thiazoles ; Phosphorylcholine (107-73-3) ; elotuzumab (1351PE5UGS) ; perifosine (2GWV496552) ; Thalidomide (4Z8R6ORS6L) ; Vorinostat (58IFB293JI) ; carfilzomib (72X6E3J5AR) ; Panobinostat (9647FM7Y3Z) ; pomalidomide (D2UX06XLB5) ; masitinib (M59NC4E26P)
    Language English
    Publishing date 2013-10-16
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 189220-4
    ISSN 1532-8708 ; 0093-7754
    ISSN (online) 1532-8708
    ISSN 0093-7754
    DOI 10.1053/j.seminoncol.2013.07.007
    Database MEDical Literature Analysis and Retrieval System OnLINE

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