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Cancers Jun 2021This review article outlines the current development of emerging treatment strategies for primary central nervous system lymphoma, a rare brain tumor with, thus far,... (Review)
Review
This review article outlines the current development of emerging treatment strategies for primary central nervous system lymphoma, a rare brain tumor with, thus far, limited therapeutic options. Small molecule targeted tyrosine kinase inhibitors, immunomodulatory agents, and immune checkpoint inhibitors will be discussed. The mechanisms of action, results of completed clinical studies, ongoing clinical trials, and future perspectives are summarized. Among the most promising clinical developments in the field of CNS lymphomas is ibrutinib, an inhibitor of Bruton's tyrosine kinase, which relays activation of nuclear factor kappa B upon integration of constitutive B cell receptor and Toll-like receptor signals. Down-stream of nuclear factor kappa B, the thalidomide analogs lenalidomide and pomalidomide exert immunomodulatory functions and are currently explored against CNS lymphomas. Finally, immune checkpoint inhibitors, such as drugs targeting the PD-1 pathway, may become novel therapeutic options to unleash anti-tumor immunity in patients with primary CNS lymphoma.
PubMed: 34203062
DOI: 10.3390/cancers13123073 -
Anti-cancer Drugs Jan 2024Daratumumab is an anti-CD38 mAb, used frequently in combination with lenalidomide and pomalidomide. No studies compared daratumumab plus lenalidomide and dexamethasone...
Daratumumab is an anti-CD38 mAb, used frequently in combination with lenalidomide and pomalidomide. No studies compared daratumumab plus lenalidomide and dexamethasone (DRd) to daratumumab plus pomalidomide and dexamethasone (DPd) in lenalidomide-exposed multiple myeloma. We identified 504 consecutive multiple myeloma patients who received daratumumab at Mayo Clinic between January 2015 and April 2019. We excluded patients who received daratumumab in the first line, received more than four lines of therapy prior to daratumumab use, did not receive lenalidomide prior to daratumumab, or had an unknown status of lenalidomide exposure, and patients who received daratumumab combinations other than DRd or DPd. We examined the impact of using DRd compared to DPd on progression-free survival (PFS) and overall survival (OS) in patients with relapsed/refractory multiple myeloma. Out of 504 patients, 162 received DRd or DPd and were included; 67 were lenalidomide-exposed and 95 were lenalidomide-refractory. DRd was used in 76 (47%) and DPd in 86 (53%) patients. In lenalidomide-exposed multiple myeloma, there was no difference in median PFS; 34.2 months [95% confidence interval (CI), 22.8-44.6] for DRd compared to 25.2 months (95% CI, 4.9-35.3) for DPd, P = 0.2. In lenalidomide-refractory multiple myeloma, there was no difference in median PFS; 18.6 months (95% CI, 13-32) for DRd compared to 9 months (95% CI, 5.2-14.6) for DPd, P = 0.09. No difference in median OS was observed in DRd compared to DPd. Our study shows combining daratumumab with lenalidomide in patients with prior lenalidomide use is a viable and effective treatment option.
Topics: Humans; Multiple Myeloma; Lenalidomide; Dexamethasone; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37067996
DOI: 10.1097/CAD.0000000000001520 -
Communications Biology Nov 2021Pomalidomide and lenalidomide are immunomodulatory agents that were derived from thalidomide. Cereblon (CRBN) is a common direct target of thalidomide and related...
Pomalidomide and lenalidomide are immunomodulatory agents that were derived from thalidomide. Cereblon (CRBN) is a common direct target of thalidomide and related compounds and works as a Cullin Ring 4 E3 ubiquitin ligase (CRL4) with DDB1, CUL4, and ROC1. The substrate specificity of CRL4 is modulated by thalidomide-related compounds. While lenalidomide is approved for the treatment of several diseases including multiple myeloma, 5q- syndrome, mantle cell lymphoma, and follicular lymphoma, pomalidomide is approved only for the treatment of lenalidomide-resistant multiple myeloma. Here we show that PLZF/ZBTB16 and its fusion proteins are pomalidomide-dependent neosubstrates of CRL4. PLZF joins to RARα or potentially other partner genes, and the translocation causes leukemias, such as acute promyelocytic leukemia and T-cell acute lymphoblastic leukemia. We demonstrate that pomalidomide treatment induces PLZF-RARα degradation, resulting in antiproliferation of leukemic cells expressing PLZF-RARα. This study highlights a potential therapeutic role of pomalidomide as a degrader of leukemogenic fusion proteins.
Topics: Adaptor Proteins, Signal Transducing; Amino Acid Sequence; HEK293 Cells; Humans; Promyelocytic Leukemia Zinc Finger Protein; Sequence Alignment; Thalidomide; Ubiquitin-Protein Ligases
PubMed: 34764413
DOI: 10.1038/s42003-021-02801-y -
Biochemical Pharmacology Oct 2021Thalidomide is an antiinflammatory, antiangiogenic and immunomodulatory agent which has been used for the treatment of erythema nodosum leprosum and multiple myeloma. It...
Thalidomide is an antiinflammatory, antiangiogenic and immunomodulatory agent which has been used for the treatment of erythema nodosum leprosum and multiple myeloma. It has also been employed in treating complex regional pain syndromes. The current study aimed to reveal the molecular mechanisms underlying thalidomide-induced pain antihypersensitive effects in neuropathic pain. Thalidomide gavage, but not its more potent analogs lenalidomide and pomalidomide, inhibited mechanical allodynia and thermal hyperalgesia in neuropathic pain rats induced by tight ligation of spinal nerves, with ED values of 44.9 and 23.5 mg/kg, and E values of 74% and 84% MPE respectively. Intrathecal injection of thalidomide also inhibited mechanical allodynia and thermal hyperalgesia in neuropathic pain. Treatment with thalidomide, lenalidomide and pomalidomide reduced peripheral nerve injury-induced proinflammatory cytokines (TNFα, IL-1β and IL-6) in the ipsilateral spinal cords of neuropathic rats and LPS-treated primary microglial cells. In contrast, treatment with thalidomide, but not lenalidomide or pomalidomide, stimulated spinal expressions of IL-10 and β-endorphin in neuropathic rats. Particularly, thalidomide specifically stimulated IL-10 and β-endorphin expressions in microglia but not astrocytes or neurons. Furthermore, pretreatment with the IL-10 antibody blocked upregulation of β-endorphin in neuropathic rats and cultured microglial cells, whereas it did not restore thalidomide-induced downregulation of proinflammatory cytokine expression. Importantly, pretreatment with intrathecal injection of the microglial metabolic inhibitor minocycline, IL-10 antibody, β-endorphin antiserum, and preferred or selective μ-opioid receptor antagonist naloxone or CTAP entirely blocked thalidomide gavage-induced mechanical antiallodynia. Our results demonstrate that thalidomide, but not lenalidomide or pomalidomide, alleviates neuropathic pain, which is mediated by upregulation of spinal microglial IL-10/β-endorphin expression, rather than downregulation of TNFα expression.
Topics: Animals; Cells, Cultured; Dose-Response Relationship, Drug; Immunosuppressive Agents; Interleukin-10; Male; Microglia; Neuralgia; Rats; Rats, Wistar; Signal Transduction; Thalidomide; beta-Endorphin
PubMed: 34390739
DOI: 10.1016/j.bcp.2021.114727 -
Cancers Feb 2024Multi-agent regimens incorporating immunomodulatory (IMiD) agents such as thalidomide, lenalidomide, and pomalidomide have become the preferred standard of care for the... (Review)
Review
Multi-agent regimens incorporating immunomodulatory (IMiD) agents such as thalidomide, lenalidomide, and pomalidomide have become the preferred standard of care for the treatment of patients with multiple myeloma (MM), resulting in improved survival outcomes. Currently, there are three IMiD agents approved for the treatment of MM: thalidomide, lenalidomide, and pomalidomide. Lenalidomide is commonly used to treat patients with newly diagnosed MM and as maintenance therapy following stem cell transplant or after disease relapse. Pomalidomide, the focus of this review, is approved in patients with relapsed/refractory MM (RRMM). Despite survival benefits, IMiD agents each have different safety profiles requiring consideration both prior to starting therapy and during treatment. Adverse event (AE) management is essential, not only to ensure treatment adherence and thus ensure optimal efficacy but also to maintain patient quality of life. Here, we discuss AEs associated with pomalidomide and present five clinically relevant hypothetical case studies in patients with RRMM to provide scenario-driven guidance regarding treatment selection and AE prevention and management in the clinical setting. Lastly, as new treatment approaches continue to be explored in MM, we also discuss novel cereblon E3 ligase modulator (CELMoD™) agents including iberdomide (CC-220) and mezigdomide (CC-92480).
PubMed: 38473381
DOI: 10.3390/cancers16051023 -
Hematology (Amsterdam, Netherlands) Dec 2023Although multiple myeloma is still incurable, an abundance of novel treatments have become available for relapsed and or refractory multiple myeloma (RRMM). Direct... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Although multiple myeloma is still incurable, an abundance of novel treatments have become available for relapsed and or refractory multiple myeloma (RRMM). Direct head-to-head comparisons between the novel treatments are lacking. We performed a network meta-analysis to evaluate immediate effects such as response quality of current novel-drugs combined therapeutic regimens, with the aim to identify treatments that could be more effective than others in RRMM.
METHODS
We searched Cochrane Library, PubMed, Embase, and Web of Science for randomized controlled clinical trials receiving novel-drugs combined treatments as means of interventions. The primary endpoint was objective response rates (ORRs). We used the surface under the cumulative ranking curve (SUCRA) to sequence treatments. Totally, 22 randomized controlled trials were identified for final evaluation. With the aim to include all regimens within one network analysis, we divided the treatment schemes into 13 categories according to the use of novel drugs.
RESULTS
Carfilzomib-, daratumumab-, and isatuximab-based treatments had better ORRs than bortezomib combined dexamethasone and lenalidomide combined dexamethasone. Daratumumab- and isatuximab-based treatments had better ORRs than pomalidomide combined dexamethasone. According to the SUCRA, daratumumab- and isatuximab-based triple-drug regimens had higher probabilities of achieving better ORRs, followed by carfilzomib, elotuzumab, venetoclax, selinexor, ixazomib, vorinostat, pomalidomide, panobinostat, lenalidomide.
CONCLUSIONS
Our network meta-analysis performed a complete review of the ORRs of all current available novel-drugs based regimens for RRMM. By using the clinical data all from randomized controlled studies, daratumumab- and isatuximab-based treatments were identified to be the best treatments receiving better response quality.
Topics: Humans; Multiple Myeloma; Lenalidomide; Network Meta-Analysis; Bortezomib; Dexamethasone; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37343159
DOI: 10.1080/16078454.2023.2225342 -
Journal of Clinical Medicine Apr 2020Antibodies targeting CD38 are rapidly changing the treatment landscape of multiple myeloma (MM). CD38-directed antibodies have several mechanisms of action. Fc-dependent... (Review)
Review
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.
PubMed: 32331242
DOI: 10.3390/jcm9041195 -
BMC Cancer Jul 2022Pomalidomide in combination with dexamethasone has demonstrated positive results in patients with relapsed or refractory multiple myeloma (RRMM), but no data are...
Efficacy and safety of pomalidomide and low-dose dexamethasone in Chinese patients with relapsed or refractory multiple myeloma: a multicenter, prospective, single-arm, phase 2 trial.
BACKGROUND
Pomalidomide in combination with dexamethasone has demonstrated positive results in patients with relapsed or refractory multiple myeloma (RRMM), but no data are available in China. We conducted a multicenter, single-arm trial to examine the efficacy and safety of bioequivalent generic pomalidomide plus low-dose dexamethasone in Chinese RRMM patients.
METHODS
Adult (≥ 18 years of age) RRMM patients who progressed after at least two previous treatments, including bortezomib and lenalidomide, were eligible. Pomalidomide was given orally at 4 mg/day on days 1 to 21 of a 28-day cycle. Dexamethasone was given at 40 mg/day (either orally or intravenously; 20 mg/day at 75 years or older) on days 1, 8, 15, and 22 of each cycle. Treatment continued until disease progression or intolerable adverse events (AEs). The primary end point was objective response rate (ORR).
RESULTS
Seventy-four patients were enrolled between February 2017 and February 2019. All patients had progressed within 60 days of their last therapy. 74.3% of the patients were resistant to lenalidomide, 31.1% had renal insufficiency and 33.8% had high-risk cytogenetic RRMM. The median follow-up duration was 33.0 months (range 31.1-34.8 months). The ORR was 37.8% in the overall analysis, 32.7% in lenalidomide-refractory patients, 36.0% in patients with high-risk cytogenetics and 34.8% in RRMM patients with renal impairment. The median progression-free survival was 5.7 months (95% CI 3.7-8.8 months). The median overall survival was 24.3 months (95% CI 14.4-41.1 months). The most common grade 3 and 4 treatment-emergent adverse events (TEAEs) were neutropenia (63.5%), leukopenia (37.8%), thrombocytopenia (28.4%), and anemia (31.1%). Pulmonary infection (27.0%) was the most frequent grade 3 and 4 nonhematologic TEAE. No previously unreported AEs were observed. No venous thromboembolism was reported.
CONCLUSIONS
Pomalidomide in combination with low-dose dexamethasone is effective and safe in Chinese RRMM patients.
TRIAL REGISTRATION
The study is registered at Chinese Clinical Trial Registry (ChiCTR) ( ChiCTR-OIC-17013234 , first registered on 03/11/2017).
Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Humans; Lenalidomide; Leukopenia; Multiple Myeloma; Prospective Studies; Thalidomide
PubMed: 35778685
DOI: 10.1186/s12885-022-09802-y -
Transplantation and Cellular Therapy Dec 2023Second autologous hematopoietic cell transplantation (AHCT2) is a useful therapeutic modality for fit patients with multiple myeloma who have durable remission after...
Continuous Elotuzumab, Pomalidomide, and Dexamethasone Maintenance Following Second Autologous Transplantation for Multiple Myeloma: Results of a Prospective Phase 2 Multicenter Trial.
Second autologous hematopoietic cell transplantation (AHCT2) is a useful therapeutic modality for fit patients with multiple myeloma who have durable remission after upfront AHCT. Retrospective studies have suggested a significant benefit of incorporating maintenance therapy post-AHCT2, but prospective data on specific regimens are lacking. The purpose of this study was to investigate the use of elotuzumab, pomalidomide, and dexamethasone (EPd) as salvage therapy prior to and maintenance after AHCT2 for relapsed multiple myeloma. This prospective single-arm phase II trial investigating the use of EPd in combination with AHCT2 in patients with relapsed multiple myeloma was conducted at 2 academic centers in North America. The primary outcome was 1-year progression-free survival (PFS). Twenty-five patients were enrolled on the study. Sixteen patients received EPd induction; six patients (38%) progressed during salvage therapy and were removed from the trial prior to AHCT2. Following a planned safety analysis, the protocol was amended, and EPd induction was removed from the study schema. An additional 9 patients underwent induction off-study and were enrolled on trial for AHCT2 and EPd maintenance. A total of 18 patients underwent AHCT2 and received EPd maintenance. Two patients discontinued treatment because of toxicity, one attributed to elotuzumab and the other to pomalidomide. The 1-year PFS was 72%, and the median PFS was 19 months. The study was closed early owing to poor accrual; 6 patients remained on therapy at time of analysis. EPd maintenance after AHCT2 was safe and tolerable. The 1-year PFS and median PFS were similar to values in previous retrospective reports of outcomes following AHCT2. Further studies are needed to define the optimal use of and protocol for AHCT2 in fit patients with relapsed multiple myeloma.
Topics: Humans; Multiple Myeloma; Prospective Studies; Transplantation, Autologous; Retrospective Studies; Dexamethasone
PubMed: 37741459
DOI: 10.1016/j.jtct.2023.09.014 -
Nature Structural & Molecular Biology Apr 2020Thalidomide-dependent degradation of the embryonic transcription factor SALL4 by the CRL4 E3 ubiquitin ligase is a plausible major driver of thalidomide teratogenicity....
Thalidomide-dependent degradation of the embryonic transcription factor SALL4 by the CRL4 E3 ubiquitin ligase is a plausible major driver of thalidomide teratogenicity. The structure of the second zinc finger of SALL4 in complex with pomalidomide, cereblon and DDB1 reveals the molecular details of recruitment. Sequence differences and a shifted binding position relative to Ikaros offer a path to the rational design of cereblon-binding drugs with reduced teratogenic risk.
Topics: Adaptor Proteins, Signal Transducing; Crystallography, X-Ray; DNA-Binding Proteins; Humans; Multiprotein Complexes; Protein Binding; Protein Conformation; Proteolysis; Substrate Specificity; Thalidomide; Transcription Factors; Ubiquitin-Protein Ligases; Ubiquitination
PubMed: 32251415
DOI: 10.1038/s41594-020-0405-9