-
Haematologica Apr 2016The approach to the patient with relapsed or relapsed/refractory multiple myeloma (RRMM) requires a careful evaluation of the results of previous treatments, the... (Review)
Review
The approach to the patient with relapsed or relapsed/refractory multiple myeloma (RRMM) requires a careful evaluation of the results of previous treatments, the toxicities associated with them and an assessment of prognostic factors. Since the majority of patients will have received prior therapy with drug combinations including a proteasome inhibitor and/or an immunomodulatory drug (IMiD), it is the physician's task to choose the right moment for the start of therapy and define with the patient which goals need to be achieved. The choice of regimen is usually based on prior responsiveness, drugs already received, prior adverse effects, the condition of the patient and expected effectiveness and tolerability. Many double and triple drug combinations are available. In addition, promising new drugs like pomalidomide, carfilzomib and monoclonal antibodies are, or will be, available shortly, while other options can be tried in clinical studies. Finally, supportive care and palliative options need to be considered in some patients. It is becoming increasingly more important to consider the therapeutic options for the whole duration of the disease rather than take a step by step approach, and to develop a systematic approach for each individual patient.
Topics: Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Drug Resistance, Neoplasm; Humans; Immunologic Factors; Multiple Myeloma; Oligopeptides; Palliative Care; Plasma Cells; Precision Medicine; Proteasome Inhibitors; Recurrence; Thalidomide
PubMed: 27033237
DOI: 10.3324/haematol.2015.129189 -
Blood Advances Dec 2019To gain insights into the characteristics of clinical resistance to lenalidomide, we evaluated the outcomes of 147 consecutive patients with multiple myeloma (MM)...
To gain insights into the characteristics of clinical resistance to lenalidomide, we evaluated the outcomes of 147 consecutive patients with multiple myeloma (MM) homogeneously treated with immunomodulatory imide drugs (IMiDs) pomalidomide and dexamethasone (Pd) for relapsed and/or refractory MM (median, 3 prior lines of treatment). We focused our analysis on the effect of the lenalidomide dose at which resistance was developed, the duration of lenalidomide exposure, and lenalidomide-free interval. On intent to treat, 33% of patients achieved ≥partial remission (PR) with Pd. When Pd was given immediately after lenalidomide, ≥PR was 32% (vs 37% after bortezomib). The response rates were similar for patients that received 5 to 15 mg vs 25 mg of lenalidomide (38.5% vs 30.5%, P = .329). Response rates were higher for patients that had received at least 12 months of lenalidomide (44% vs 27%) and for those with ≥18 months from last lenalidomide dose to pomalidomide dose (65% vs 23%). Median progression-free survival (PFS) and overall survival (OS) were 5 and 12.1 months, respectively, which was similar for patients who received lenalidomide, bortezomib or other regimens just before Pd and similar for patients who were receiving different doses of lenalidomide. IMiD-free interval ≥18 months was associated with longer PFS (10.3 vs 3.9 months, P = .003) and OS (27.1 vs 9.3, P = .008) as well as duration of last lenalidomide therapy ≥12 months (PFS: 7.8 vs 3.2, P = .023; OS: 16.5 vs 7.9, P = .005) even after adjustment for the number of prior therapies, duration of disease, and last lenalidomide dose.
Topics: Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Drug Dosage Calculations; Humans; Lenalidomide; Middle Aged; Multiple Myeloma; Progression-Free Survival; Thalidomide
PubMed: 31821457
DOI: 10.1182/bloodadvances.2019000539 -
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 -
Medicine Jan 2023Pomalidomide is an immunomodulatory imide drug used in multiple myeloma and in Kaposi sarcoma.
RATIONALE
Pomalidomide is an immunomodulatory imide drug used in multiple myeloma and in Kaposi sarcoma.
PATIENT CONCERNS
A 72-years-old male, treated for multiple myeloma with dexamethasone, pomalidomide and daratumumab, presented dyspnea, hypoxemia, biological inflammatory syndrome, ground glass opacities on computed tomography scan (CT-scan) and lymphocytic and eosinophilic alveolitis, with no specific cytologic or microbiological findings, 2 months after pomalidomide initiation.
INTERVENTION AND OUTCOME
Antibiotics were started after bronchoscopy. No improvement was noted in dyspnea and biological inflammatory syndrome after 5 days of treatment. Pomalidomide was then discontinued, with continuation of Daratumumab-Dexamethasone, resulting in a rapid recovery of symptoms and CT-scan anomalies. No recurrence of dyspnea was observed during the 15 months of follow-up.
DIAGNOSES
Pomalidomide-induced lung injury.
LESSONS
Pomalidomide-induced lung injury is a rare and serious adverse event that can occur early after Pomalidomide introduction. As pomalidomide use is increasing, the identification of drug toxicity as a possible cause of lung injury appears important. We report a rapid recovery of symptoms and CT-scan anomalies after pomalidomide discontinuation.
Topics: Male; Humans; Aged; Multiple Myeloma; Lung Injury; Dexamethasone; Dyspnea; Antineoplastic Combined Chemotherapy Protocols
PubMed: 36637962
DOI: 10.1097/MD.0000000000032473 -
Journal of the Advanced Practitioner in... May 2014Multiple myeloma (MM) remains an incurable cancer of the bone marrow plasma cells. However, the overall survival of patients with MM has increased dramatically within... (Review)
Review
Multiple myeloma (MM) remains an incurable cancer of the bone marrow plasma cells. However, the overall survival of patients with MM has increased dramatically within the past decade. This is due, in part, to newer agents such as immunomodulatory drugs (lenalidomide, thalidomide, and pomalidomide) and proteasome inhibitors (bortezomib, carfilzomib, MLN9708). These and several other new classes of drugs have arisen from an improved understanding of the complex environment in which genetic changes occur. Improved understanding of genetic events will enable clinicians to better stratify risk before and during therapy, tailor treatment, and test the value of personalized interventions. The ultimate goal in this incurable disease setting is to reduce the impact of cancer- or chemotherapy-related side effects. Nurses and advanced practitioners are integral to the treatment team. Thus, each should be aware of changes to the current drug landscape. Targeted drugs with sophisticated mechanisms of action are currently under investigation. Patients gain access to newer drugs within the context of clinical trials. Awareness of such trials will help accrual and determine if therapeutic benefit exists. In this article, we will describe new agents with unique and targeted mechanisms of action that have activity in patients with relapsed and/or refractory multiple myeloma.
PubMed: 25089218
DOI: No ID Found -
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 -
Journal of Clinical Pharmacology May 2015A population pharmacokinetic (PPK) model of pomalidomide was developed and the influence of demographic and disease-related covariates on PPK parameters was assessed...
A population pharmacokinetic (PPK) model of pomalidomide was developed and the influence of demographic and disease-related covariates on PPK parameters was assessed based on data from 6 clinical trials of pomalidomide (dose range, 0.5-10 mg) in healthy participants (n = 96) and patients with multiple myeloma (MM; n = 144). PPK data described herein suggest that systemic clearance of pomalidomide is comparable between healthy study participants and patients with MM. However, apparent peripheral volume of distribution and apparent intercompartmental clearance between central and peripheral compartments were 8- and 3.7-fold higher in patients with MM vs. healthy subjects, suggesting drug exposure is higher in peripheral compartments of patients with MM vs. healthy subjects. Covariate analysis suggested pomalidomide clearance is not affected by demographic factors except for gender, and it is unlikely this factor is clinically relevant. In addition, renal function as measured by creatinine clearance or renal impairment (RI) does not significantly affect clearance of pomalidomide. In conclusion, pomalidomide has robust pharmacokinetic exposure, not affected by demographic factors or renal impairment. Pomalidomide is preferentially taken up by tumors over healthy tissues in patients with MM.
Topics: Adult; Age Factors; Aged; Aged, 80 and over; Clinical Trials as Topic; Female; Humans; Immunologic Factors; Male; Metabolic Clearance Rate; Middle Aged; Models, Biological; Multiple Myeloma; Renal Insufficiency; Sex Factors; Thalidomide
PubMed: 25556560
DOI: 10.1002/jcph.455 -
Hematology. American Society of... Dec 2017The approach to the patient with relapsed or relapsed/refractory multiple myeloma requires a careful evaluation of the results of previous treatments, the toxicities... (Review)
Review
The approach to the patient with relapsed or relapsed/refractory multiple myeloma requires a careful evaluation of the results of previous treatments, the toxicities associated with it, and an assessment of prognostic factors. The majority of patients will have received prior therapy with drug combinations, including a proteasome inhibitor and an immune-modulatory agent. It is the physician's task to choose the right moment for the start of therapy and decide with the patient which goals need to be achieved. The choice of regimen is usually based on prior response, drugs already received, adverse effects, comorbidities of the patient, and expected efficacy and tolerability. Many double and triple drug combinations are available. In addition, promising new drugs such as pomalidomide, carfilzomib, and monoclonal antibodies are or will be available shortly, and other options can be explored in clinical trials. Finally, supportive care and palliative options need to be considered in later relapsed disease. Increasingly, it becomes important to consider the therapeutic options for the whole duration of the disease and integrate a systematic approach for the patient.
Topics: Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Humans; Immunologic Factors; Multiple Myeloma; Oligopeptides; Proteasome Inhibitors; Recurrence; Thalidomide
PubMed: 29222299
DOI: 10.1182/asheducation-2017.1.508 -
Proceedings of the National Academy of... Jul 2013Thalidomide and its analog, Lenalidomide, are in current use clinically for treatment of multiple myeloma, complications of leprosy and cancers. An additional analog,...
Thalidomide and its analog, Lenalidomide, are in current use clinically for treatment of multiple myeloma, complications of leprosy and cancers. An additional analog, Pomalidomide, has recently been licensed for treatment of multiple myeloma, and is purported to be clinically more potent than either Thalidomide or Lenalidomide. Using a combination of zebrafish and chicken embryos together with in vitro assays we have determined the relative anti-inflammatory activity of each compound. We demonstrate that in vivo embryonic assays Pomalidomide is a significantly more potent anti-inflammatory agent than either Thalidomide or Lenalidomide. We tested the effect of Pomalidomide and Lenalidomide on angiogenesis, teratogenesis, and neurite outgrowth, known detrimental effects of Thalidomide. We found that Pomalidomide, displays a high degree of cell specificity, and has no detectable teratogenic, antiangiogenic or neurotoxic effects at potent anti-inflammatory concentrations. This is in marked contrast to Thalidomide and Lenalidomide, which had detrimental effects on blood vessels, nerves, and embryonic development at anti-inflammatory concentrations. This work has implications for Pomalidomide as a treatment for conditions Thalidomide and Lenalidomide treat currently.
Topics: Angiogenesis Inhibitors; Animals; Chick Embryo; Chickens; Lenalidomide; Neovascularization, Physiologic; Neurites; Neurotoxins; Species Specificity; Teratogens; Thalidomide; Zebrafish
PubMed: 23858438
DOI: 10.1073/pnas.1307684110