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Expert Review of Hematology Jun 2017Treatment of multiple myeloma has undergone profound changes in the past years thanks to the increased understanding of the biology of the disease and the new treatment... (Review)
Review
Treatment of multiple myeloma has undergone profound changes in the past years thanks to the increased understanding of the biology of the disease and the new treatment options. New drugs and effective approaches are currently available for the treatment of multiple myeloma, including immunomodulatory agents, proteasome inhibitors and autologous stem cell transplantation. Areas covered: We have described the recent updated criteria to start treatment in multiple myeloma and summarized clinical data from major studies including most recent agents. Particularly, results with pomalidomide, carfilzomib, ixazomib, monoclonal antibodies such as elotuzumab, daratumumab, and checkpoint inhibitors have been reported. Both transplant and non-transplant settings have been covered. Expert commentary: Despite the successful improvement in overall survival and time to relapse, multiple myeloma still remains incurable. Therefore, there is still an unmet need for new treatment strategies with novel mechanisms of action, like monoclonal antibodies, novel immunomodulators, and novel proteasome inhibitors. Implementation of these novel drugs in rationally designed therapies with a good balance of efficacy and safety should be carefully considered in order to improve outcome.
Topics: Autografts; Disease-Free Survival; Humans; Immunologic Factors; Multiple Myeloma; Proteasome Inhibitors; Stem Cell Transplantation; Survival Rate
PubMed: 28504554
DOI: 10.1080/17474086.2017.1326814 -
BMJ Case Reports Apr 2020In patients who experience relapse of multiple myeloma, upwards of 30% can have extramedullary disease. The presence of extramedullary multiple myeloma is typically...
In patients who experience relapse of multiple myeloma, upwards of 30% can have extramedullary disease. The presence of extramedullary multiple myeloma is typically associated with adverse cytogenetics and a poor prognosis. Organs most commonly involved include the liver, skin, central nervous system, pleural effusions, kidney, lymph nodes, and pancreas. We present the case of a 53-year-old man with IgA kappa multiple myeloma with the adverse cytogenetic findings of t(4;14) and 1q21 gain who had achieved a stringent complete (sCR) response after initial therapy with carfilzomib, lenalidomide and dexamethasone. Stringent complete response is defined as the normalization of the free light chain ratio in the serum and an absence of clonal cells in the bone marrow in additiion to criteria needed to achieve complete response. Prior to undergoing a planned autologous stem cell transplant, this patient experienced cardiac tamponade secondary to extramedullary relapse of his multiple myeloma which was limited to the pericardium. In response, his treatment regimen was transitioned to pomalidomide, bortezomib, dexamethasone and cyclophosphamide for three cycles after which he again achieved sCR and ultimately underwent autologous stem cell transplant. Post-transplant consolidation therapy was administered in the form of pomalidomide, bortezomib and dexamethasone, followed by pomalidomide and bortezomib maintenance, which he has continued to receive for 3 years without evidence of disease progression.
Topics: Attitude to Health; Cardiac Tamponade; Combined Modality Therapy; Disease-Free Survival; Drug Therapy, Combination; Hematopoietic Stem Cell Transplantation; Humans; Male; Middle Aged; Multiple Myeloma; Neoplasm Recurrence, Local; Pericardium; Transplantation, Autologous
PubMed: 32332043
DOI: 10.1136/bcr-2019-233340 -
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 -
PharmacoEconomics Feb 2018The National Institute for Health and Care Excellence (NICE), as part of the institute's single technology appraisal (STA) process, invited the manufacturer of... (Review)
Review
Pomalidomide with Dexamethasone for Treating Relapsed and Refractory Multiple Myeloma Previously Treated with Lenalidomide and Bortezomib: An Evidence Review Group Perspective of an NICE Single Technology Appraisal.
The National Institute for Health and Care Excellence (NICE), as part of the institute's single technology appraisal (STA) process, invited the manufacturer of pomalidomide (POM; Imnovid, Celgene) to submit evidence regarding the clinical and cost effectiveness of the drug in combination with dexamethasone (POM + LoDEX) for the treatment of relapsed and refractory multiple myeloma (RRMM) after at least two regimens including lenalidomide (LEN) and bortezomib (BOR). Kleijnen Systematic Reviews Ltd (KSR) and Erasmus University Rotterdam were commissioned as the Evidence Review Group (ERG) for this submission. The ERG reviewed the evidence submitted by the manufacturer, validated the manufacturer's decision analytic model, and conducted exploratory analyses in order to assess the robustness and validity of the presented clinical and cost-effectiveness results. This paper describes the company submission, the ERG assessment, and NICE's subsequent decisions. The company conducted a systematic review to identify studies comparing POM with comparators outlined in the NICE scope: panobinostat with bortezomib and dexamethasone (PANO + BOR + DEX), bendamustine with thalidomide and dexamethasone (BTD) and conventional chemotherapy (CC). The main clinical effectiveness evidence was obtained from MM-003, a randomized controlled trial (RCT) comparing POM + LoDEX with high-dose dexamethasone (HiDEX; used as a proxy for CC). Additional data from other studies were also used as nonrandomized observational data sources for the indirect treatment comparison of POM + LoDEX with BTD and PANO + BOR + DEX. Covariate or treatment switching adjustment methods were used for each comparison. The model developed in Microsoft Excel 2010 using a semi-Markov partitioned survival structure, submitted in the original submission to NICE for TA338, was adapted for the present assessment of the cost effectiveness of POM + LoDEX. Updated evidence from the clinical-effectiveness part was used for the survival modelling of progression-free survival and overall survival. For POM + LoDEX, the patient access scheme (PAS) discount was applied to the POM price. Three separate comparisons were conducted for each comparator, each comparison using a different dataset and adjustment methods. The ERG identified and corrected some errors, and the corrected incremental cost-effectiveness ratios (ICERs) for POM + LoDEX versus each comparator were presented: approximately £45,000 per quality-adjusted life-year (QALY) gained versus BTD, savings of approximately £143,000 per QALY lost versus PANO + BOR + DEX, and approximately £49,000 per QALY gained versus CC. The ERG also conducted full incremental analyses, which revealed that CC, POM + LoDEX and PANO + BOR + DEX were on the cost-effectiveness frontier. The committee's decision on the technology under analysis deemed that POM + LoDEX should be recommended as an option for treating multiple myeloma in adults at third or subsequent relapse of treatments including both LEN and BOR, contingent on the company providing POM with the discount agreed in the PAS.
Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Cost-Benefit Analysis; Dexamethasone; Humans; Lenalidomide; Multiple Myeloma; Quality-Adjusted Life Years; Randomized Controlled Trials as Topic; Recurrence; Technology Assessment, Biomedical; Thalidomide
PubMed: 29086363
DOI: 10.1007/s40273-017-0581-6 -
Journal of Cancer Research and Clinical... Aug 2023Outcomes of multiple myeloma (MM) patients who are refractory to daratumumab are dismal and no standard of treatment exists for this patients' population. Here, we...
PURPOSE
Outcomes of multiple myeloma (MM) patients who are refractory to daratumumab are dismal and no standard of treatment exists for this patients' population. Here, we investigate the role of pomalidomide combinations in daratumumab-refractory MM patients.
METHODS
We performed a retrospective analysis of myeloma patients treated at four referral centers (three in Germany and one in Italy). Review chart identified 30 patients with relapsed and refractory myeloma, who progressed during treatment with daratumumab and were treated with pomalidomide-based combinations in the subsequent lines of therapy.
RESULTS
Responses improved from 37% with daratumumab to 53% with pomalidomide. Of seven patients with extramedullary MM (EMM), four achieved a clinical stabilization with pomalidomide, including one patient with a long-lasting complete response. Median progression-free survival and overall survival were 6 and 12 months, respectively. Pomalidomide combinations were well tolerated, no patient discontinued treatment due to adverse events.
CONCLUSION
These data show that pomalidomide-based combinations can be an effective and safe salvage regimen for daratumumab-refractory patients, including those with EMM.
Topics: Aged; Aged, 80 and over; Female; Humans; Male; Middle Aged; Angiogenesis Inhibitors; Antibodies, Monoclonal; Antineoplastic Agents; Drug Therapy, Combination; Multiple Myeloma; Recurrence; Salvage Therapy; Thalidomide; Treatment Failure; Progression-Free Survival
PubMed: 36781500
DOI: 10.1007/s00432-023-04637-x -
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 -
Leukemia Dec 2017This phase 1 dose-escalation study evaluated pomalidomide, bortezomib (subcutaneous (SC) or intravenous (IV)) and low-dose dexamethasone (LoDEX) in...
This phase 1 dose-escalation study evaluated pomalidomide, bortezomib (subcutaneous (SC) or intravenous (IV)) and low-dose dexamethasone (LoDEX) in lenalidomide-refractory and proteasome inhibitor-exposed relapsed or relapsed and refractory multiple myeloma (RRMM). In 21-day cycles, patients received pomalidomide (1-4 mg days 1-14), bortezomib (1-1.3 mg/m days 1, 4, 8 and 11 for cycles 1-8; days 1 and 8 for cycle ⩾9) and LoDEX. Primary endpoint was to determine the maximum tolerated dose (MTD). Thirty-four patients enrolled: 12 during escalation, 10 in the MTD IV bortezomib cohort and 12 in the MTD SC bortezomib cohort. Patients received a median of 2 prior lines of therapy; 97% bortezomib exposed. With no dose-limiting toxicities, MTD was defined as the maximum planned dose: pomalidomide 4 mg, bortezomib 1.3 mg/m and LoDEX. All patients discontinued treatment by data cutoff (2 April 2015). The most common grade 3/4 treatment-emergent adverse events were neutropenia (44%) and thrombocytopenia (26%), which occurred more frequently with IV than SC bortezomib. No grade 3/4 peripheral neuropathy or deep vein thrombosis was reported. Overall response rate was 65%. Median duration of response was 7.4 months. Pomalidomide, bortezomib and LoDEX was well tolerated and effective in lenalidomide-refractory and bortezomib-exposed patients with RRMM.
Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Bortezomib; Dexamethasone; Drug Resistance, Neoplasm; Female; Humans; Lenalidomide; Male; Maximum Tolerated Dose; Middle Aged; Multiple Myeloma; Neoplasm Staging; Proteasome Inhibitors; Retreatment; Thalidomide; Treatment Outcome
PubMed: 28642620
DOI: 10.1038/leu.2017.173 -
Scientific Reports Dec 2023The design of cereblon-binding molecular glues (MGs) that selectively recruit a desired protein while excluding teratogenic SALL4 is an area of significant interest when...
The design of cereblon-binding molecular glues (MGs) that selectively recruit a desired protein while excluding teratogenic SALL4 is an area of significant interest when designing therapeutic agents. Previous studies show that SALL4 is degraded in the presence of IKZF1 degraders pomalidomide, and to a lesser extent by CC-220. To expand our understanding of the molecular basis for the interaction of SALL4 with cereblon, we performed biophysical and structural studies demonstrating that SALL4 zinc finger domains one and two (ZF1-2) interact with cereblon (CRBN) in a unique manner. ZF1 interacts with the N-terminal domain of cereblon and ZF2 binds as expected in the C-terminal IMiD-binding domain. Both ZF1 and ZF2 contribute to the potency of the interaction of ZF1-2 with CRBN:MG complexes and the affinities of SALL4 ZF1-2 for the cereblon:CC-220 complex are less potent than for the corresponding pomalidomide complex. Structural analysis provides a rationale for understanding the reduced affinity of SALL4 for cereblon in the presence of CC-220, which engages both ZF1 and ZF2. These studies further our understanding of the molecular glue-mediated interactions of zinc finger-based proteins with cereblon and may provide structural tools for the prospective design of compounds with reduced binding and degradation of SALL4.
Topics: Thalidomide; Zinc Fingers; Teratogens; Ubiquitin-Protein Ligases
PubMed: 38086859
DOI: 10.1038/s41598-023-48606-3 -
Haematologica Jan 2024In the ELOQUENT-3 trial, the combination of elotuzumab, pomalidomide and dexamethasone (EloPd) proved to have a superior clinical benefit over pomalidomide and...
Elotuzumab plus pomalidomide and dexamethasone in relapsed/refractory multiple myeloma: a multicenter, retrospective, real-world experience with 200 cases outside of controlled clinical trials.
In the ELOQUENT-3 trial, the combination of elotuzumab, pomalidomide and dexamethasone (EloPd) proved to have a superior clinical benefit over pomalidomide and dexamethasone with a manageable toxicity profile, leading to its approval for the treatment of patients with relapsed/refractory multiple myeloma (RRMM) who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor. We report here a real-world experience of 200 cases of RRMM treated with EloPd in 35 Italian centers outside of clinical trials. In our dataset, the median number of prior lines of therapy was two, with 51% of cases undergoing autologous stem cell transplant and 73% having been exposed to daratumumab. After a median follow-up of 9 months, 126 patients had stopped EloPd, most of them (88.9%) because of disease progression. The overall response rate was 55.4%, a finding in line with the pivotal trial results. Regarding adverse events, the toxicity profile in our cohort was similar to that in the ELOQUENT-3 trial, with no significant differences between younger (<70 years) and older patients. The median progression-free survival was 7 months, which was shorter than that observed in ELOQUENT-3, probably because of the different clinical characteristics of the two cohorts. Interestingly, International Staging System stage III disease was associated with worse progression-free survival (hazard ratio=2.55). Finally, the median overall survival of our series was shorter than that observed in the ELOQUENT-3 trial (17.5 vs. 29.8 months). In conclusion, our real-world study confirms that EloPd is a safe and possible therapeutic choice for patients with RRMM who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor.
Topics: Humans; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Lenalidomide; Multiple Myeloma; Proteasome Inhibitors; Retrospective Studies; Controlled Clinical Trials as Topic
PubMed: 37439329
DOI: 10.3324/haematol.2023.283251 -
Drug Design, Development and Therapy 2017Multiple myeloma is a very heterogeneous disease with variable survival. Despite recent progress and the widespread use of new agents, patients with relapsed and... (Review)
Review
Multiple myeloma is a very heterogeneous disease with variable survival. Despite recent progress and the widespread use of new agents, patients with relapsed and refractory disease have a poor outcome. Immunomodulatory drugs play a key role in both the front-line and the relapsed/refractory setting. The combination of pomalidomide (POM) and dexamethasone is safe and effective in relapsed and refractory patients, even in those with high-risk cytogenetic features. Furthermore, it can be used in most patients without the need to adjust according to the degree of renal failure. In order to further improve the results, POM-based triplet therapies are currently used. This article highlights the most relevant issues of POM and POM-based combinations in the relapsed/refractory multiple myeloma setting, from a pharmacological and clinical point of view.
Topics: Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Drug Design; Humans; Immunologic Factors; Multiple Myeloma; Survival Rate; Thalidomide
PubMed: 28860711
DOI: 10.2147/DDDT.S115456