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Immunomodulatory Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
After the renewed marketing of thalidomide by Celgene for use in various cancer treatments following identification of its antiangiogenic and immunomodulatory activities, research led to several other analogs. For example, lenalidomide was found to have a significantly enhanced potency with fewer side effects but with greater myelosuppression. Celgene received FDA approval for lenalidomide (RevlimidTM) in 2005, as the first commercially useful thalidomide derivative. However, it is available only in a tightly controlled restricted distribution scenario to prevent its use in pregnancy. Further studies led to the analog pomalidomide which was approved by the FDA in 2013 as a treatment for relapsed and refractory multiple myeloma.
New Drugs in Myeloproliferative Disorders
Published in Richard T. Silver, Ayalew Tefferi, Myeloproliferative Disorders, 2007
Srdan Verstovsek, Ruben A. Mesa
Another promising IMID, pomalidomide, is 20,000-fold more potent than thalidomide in inhibiting TNF-a, although cross-resistance with the latter does not appear to occur (43). Due to its excellent oral absorption and adequate pharmacokinetics, pomalidomide is suitable for once-daily administration. In phase I trials in patients with multiple myeloma, the main side effects associated with pomalidomide therapy were related to myelosuppression and deep vein thrombosis (44). Given the promising results obtained with lenalidomide, a randomized, placebo-controlled, international clinical study to determine the activity of pomalidomide (with or without a prednisone taper) in PMF and post-ET/PV MF is currently underway.
Case 1
Published in Atul B. Mehta, Keith Gomez, Clinical Haematology, 2017
Chemotherapy should be commenced once he is stabilised. Bortezomib is a proteosome inhibitor which is administered subcutaneously alongside dexamethazone. Addition of an anthracycline drug, for example, Adriamycin should be considered; it can be given as an infusional regime with the bortezomib and dexamethazone. There is evidence that intensive early treatment aimed at reducing the tumour burden and the serum level of free light chains may help to restore renal function. Cyclophosphamide may be added as a weekly bolus; it is preferred in renal failure, as it is metabolised by the liver. Thalidomide is an immunomodulatory agent which also has direct anti-myeloma effects; side effects include drowsiness, constipation, neuropathy and a critical need to avoid pregnancy (self or partner). A stable (‘plateau’) phase of the disease is typically achieved after four to six cycles of chemotherapy. Long-term bisphosphonate therapy (e.g. sodium clodronate) may slow progress of skeletal disease in myeloma. The typical course of myeloma is that patients relapse but will respond to reinstitution of chemotherapy. Thalidomide derivatives include lenalidomide, which has an increasing role as a first-line agent as it has greater activity than thalidomide and less neurotoxicity and it is also less likely to provoke thrombosis. Pomalidomide is a derivative that has activity in subjects who are resistant to lenalidomide. Other options include melphalan and (intermittent oral) prednisolone (+/− thalidomide); further courses of bortezomib or its newer derivatives (e.g. carfilzomib, a newly licensed proteosome inhibitor with less neurotoxicity than bortezomib; or ixazomib, which can be given orally) with dexamethazone. Bendamustine and dexamethazone may be considered. Older regimes which may have a role in relapsed patients include vincristine, adriamycin, both by IV infusion, and dexamethasone (VAD), and the combination of idarubicin and dexamethazone.
Application of new targeted drugs in relapsed/refractory primary central nervous system lymphoma
Published in Hematology, 2022
Preclinical data show that the penetration rate of pomalidomide (a third-generation immunomodulator) in the CNS is nearly 39%. Pomalidomide has significant anti-tumor activity and the ability to regulate the tumor microenvironment in CNS lymphoma [34]. Its effect on the tumor microenvironment may help overcome the immune evasion that characterizes PCNSL [8]. Tun et al. reported the results of a phase I study of pomalidomide in the treatment of r/r PCNSL and ocular lymphoma [35]. At 16.5 months (median follow-up), the median PFS and remission times were 5.3 and 9 months, respectively. The ORR of 25 patients was 48%, of which eight and four were CR and PR, respectively. The median duration of remission was 4.7 months. CNS pharmacokinetic analysis was performed on a patient in the 3 mg group. The CSF/plasma ratio of pomalidomide was comparable to lenalidomide with 19% and 17% on days 1 and 14 of the first cycle, respectively.
Pomalidomide-based therapy for extramedullary multiple myeloma
Published in Hematology, 2022
Yating Li, Jiamei Ji, Hua Lu, Jianyong Li, Xiaoyan Qu
A total of six patients (two females and four males) were treated with pomalidomide regimens. The median age at the time of diagnosis was 55 (range: 47–70) years. Two patients had IgA and four had IgG. There are two patients in Durie–Salmon (D-S) stage ⅢB, two in stage ⅡA, and two in stage ⅢA. For the International Staging System (ISS), one was in stage Ⅰ, one in stage Ⅱ, and four in stage Ⅲ. Four patients had EM-B, one had malignant pleural effusion and one had parenchymal organ involvement (liver and spleen). Four patients had needle biopsy: ascites flow cytometry in patient 1 analyzed 182696 cells; of these, 18.6% were abnormal plasma cells with CD38, CD56, cKAPPA expression and CD45, CD19, CD27, LAMBDA non-expression. Pleural effusion flow cytometry in patient 4 showed a marked number of plasmablasts, indicating EMD. Ultrasound-guided needle biopsy of soft tissue in patients 3 and 5 also revealed EMD because of the presence of monoclonal plasma cells. PET/CT of patient 6 showed a soft tissue mass in the left anterior chest wall with increased FDG metabolism and extramedullary infiltration was considered (Figure 1). Patients’ characteristics are summarized in Table 1.
A safety review of drug treatments for patients with systemic immunoglobulin light chain (AL) amyloidosis
Published in Expert Opinion on Drug Safety, 2021
Mario Nuvolone, Marco Basset, Giovanni Palladini
Pomalidomide is a second-generation immunomodulatory drug. It is a thalidomide analog, with an amino substituent at the fourth position of the phthalimide ring [65]. Analogously to lenalidomide, pomalidomide has increased potency and reduced toxicity with respect to the parental drug thalidomide [63]. Pomalidomide has label indication, in association with dexamethasone, for the treatment of patients with MM who have received at least two prior therapies (including lenalidomide and a proteasome inhibitor) and have demonstrated disease progression on or within 60 days of completion of the last therapy. Pomalidomide has a toxicity profile similar to lenalidomide. However, it is mainly catabolized through the liver and does not require dose adjustments unless for patients with hemodialysis.