With an increasing focus on sustainable technologies in the pharmaceutical industry, milling provides a solvent-free approach to improve drug dissolution. Milling of drugs with an excipient offers additional opportunities to achieve supersaturation kinetics. Therefore, this work aims to present insights of co-milling fenofibrate and apremilast, two good glass formers with low and high glass transition temperatures (Tgs) respectively. Drugs were co-milled with croscarmellose sodium for various process durations followed by thermal analysis, investigation of crystallinity, surface area and dissolution. The dissolution enhancement of the low-Tg glass former fenofibrate highly correlated with the process-induced increase in surface area of co-milled systems (R2 = 0.96). In contrast, the high-Tg glass former apremilast lost its crystalline order gradually after ≥ 10 min of co-milling, and favourable supersaturation kinetics during biorelevant dissolution testing were observed. Interestingly, the melting point of co-milled apremilast decreased and linearly correlated with the highest measured drug concentration (cmax) during in vitro dissolution (onset temperature R2 = 0.98; peak temperature R2 = 0.96). The melting point depression remained stable after 90 days for apremilast, whereas fenofibrate co-milled for 20 min or more showed an increase in melting point upon storage. This study demonstrated that co-milling with croscarmellose sodium is ideally suited to good glass formers with a high Tg. The melting point depression is thereby proposed as an easily accessible critical quality attribute to estimate likely dissolution performance of drugs in dry co-milled formulations.
- MeSH
- Aspirin chemistry analogs & derivatives MeSH
- Fenofibrate * chemistry MeSH
- Excipients chemistry MeSH
- Drug Compounding methods MeSH
- Solubility MeSH
- Glass * chemistry MeSH
- Thalidomide analogs & derivatives MeSH
- Transition Temperature MeSH
- Drug Liberation MeSH
- Publication type
- Journal Article MeSH
- Comparative Study MeSH
The International Staging System for multiple myeloma recently underwent a second revision (R2-ISS) to include gain/amplification of 1q21 and account for the additive prognostic significance of multiple high-risk features. The phase 3 ICARIA-MM (isatuximab-pomalidomide-dexamethasone vs. pomalidomide-dexamethasone) and IKEMA (isatuximab-carfilzomib-dexamethasone vs. carfilzomib-dexamethasone) studies provide large datasets for retrospectively validating the prognostic value of the R2-ISS in relapsed/refractory multiple myeloma. Of 609 pooled patients, 68 (11.2%) were reclassified as R2-ISS stage I, 136 (22.3%) as R2-ISS stage II, 204 (33.5%) as R2-ISS stage III, 55 (9.0%) as stage IV, and 146 (24.0%) "Not classified". Median progression-free survival was shorter among those reclassified as R2-ISS stage II (HR 1.52, 95% CI 0.979-2.358), stage III (HR 2.59, 95% CI 1.709-3.923), and stage IV (HR 3.51, 95% CI 2.124-5.784) versus stage I. Adding isatuximab led to longer progression-free survival versus doublet therapy (adjusted HR 0.544 [95% CI 0.436-0.680]), with a consistent treatment effect observed across all R2-ISS stages. This is the first study to validate the R2-ISS with novel agents, including anti-CD38 monoclonal antibodies, and to show that R2-ISS, as a prognostic scoring system, can be applied to patients with relapsed/refractory multiple myeloma.
- MeSH
- Dexamethasone therapeutic use administration & dosage MeSH
- Adult MeSH
- Antibodies, Monoclonal, Humanized * therapeutic use MeSH
- Middle Aged MeSH
- Humans MeSH
- Multiple Myeloma * pathology drug therapy mortality diagnosis MeSH
- Oligopeptides therapeutic use MeSH
- Prognosis MeSH
- Antineoplastic Combined Chemotherapy Protocols * therapeutic use MeSH
- Retrospective Studies MeSH
- Aged MeSH
- Neoplasm Staging * MeSH
- Thalidomide analogs & derivatives therapeutic use administration & dosage MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Clinical Trial, Phase III MeSH
- Randomized Controlled Trial MeSH
- Validation Study MeSH
- Keywords
- Contergan,
- MeSH
- World War II MeSH
- History, 20th Century MeSH
- Drug Industry history MeSH
- Physicians history MeSH
- Humans MeSH
- National Socialism history MeSH
- Thalidomide chemical synthesis history adverse effects MeSH
- Typhoid-Paratyphoid Vaccines chemical synthesis history MeSH
- Drug Development * history MeSH
- Crime history MeSH
- Criminals history MeSH
- Check Tag
- History, 20th Century MeSH
- Humans MeSH
- Geographicals
- Germany MeSH
The primary and prespecified updated analyses of ICARIA-MM (clinicaltrial gov. Identifier: NCT02990338) demonstrated improved progression-free survival (PFS) and a benefit in overall survival (OS) was reported with the addition of isatuximab, an anti-CD38 monoclonal antibody, to pomalidomide-dexamethasone (Pd) in patients with relapsed/refractory multiple myeloma. Here, we report the final OS analysis. This multicenter, randomized, open-label, phase III study included patients who had received and failed ≥2 previous therapies, including lenalidomide and a proteasome inhibitor. Between January 10, 2017, and February 2, 2018, 307 patients were randomized (1:1) to isatuximab-pomalidomide-dexamethasone (Isa-Pd; N=154) or Pd (N=153), stratified based on age (<75 vs. ≥75 years) and number of previous lines of therapy (2-3 vs. >3). At data cutoff for the final OS analysis after 220 OS events (January 27, 2022), median follow-up duration was 52.4 months. Median OS was 24.6 months (95% confidence interval [CI]: 20.3-31.3) with Isa-Pd and 17.7 months (95% CI: 14.4- 26.2) with Pd (hazard ratio=0.78; 95% CI: 0.59-1.02; 1-sided P=0.0319). Despite subsequent daratumumab use in the Pd group and its potential benefit on PFS in the first subsequent therapy line, median PFS2 was significantly longer with Isa-Pd versus Pd (17.5 vs. 12.9 months; log-rank 1-sided P=0.0091). In this analysis, Isa-Pd continued to be efficacious and well tolerated after follow-up of approximately 52 months, contributing to a clinically meaningful, 6.9-month improvement in median OS in patients with relapsed/refractory multiple myeloma.
- MeSH
- Survival Analysis MeSH
- Drug Resistance, Neoplasm MeSH
- Dexamethasone * administration & dosage MeSH
- Adult MeSH
- Antibodies, Monoclonal, Humanized * administration & dosage therapeutic use MeSH
- Middle Aged MeSH
- Humans MeSH
- Multiple Myeloma * drug therapy mortality pathology MeSH
- Antineoplastic Combined Chemotherapy Protocols * therapeutic use adverse effects MeSH
- Recurrence MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Thalidomide * analogs & derivatives administration & dosage MeSH
- Treatment Outcome MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Clinical Trial, Phase III MeSH
- Multicenter Study MeSH
- Research Support, Non-U.S. Gov't MeSH
- Randomized Controlled Trial MeSH
BACKGROUND: The thalidomide disaster resulted in tremendous congenital malformations in more than 10,000 children in the late 1950s and early 1960s. SUMMARY: Although numerous putative mechanisms were proposed to explain thalidomide teratogenicity, it was confirmed only recently that thalidomide, rather its derivative 5-hydroxythalidomide (5HT) in a complex with the cereblon protein, interferes with early embryonic transcriptional regulation. 5HT induces selective degradation of SALL4, a principal transcriptional factor of early embryogenesis. Genetic syndromes caused by pathogenic variants of the SALL4 gene phenocopy thalidomide embryopathy with congenital malformations ranging from phocomelia, reduced radial ray, to defects of the heart, kidneys, ear, eye, and possibly cerebral midline and pituitary. SALL4 interacts with TBX5 and a handful of other transcriptional regulators and downregulates the Sonic hedgehog signaling pathway. Cranial midline defects, microcephaly, and short stature due to growth hormone deficiency have been occasionally reported in children carrying SALL4 pathogenic variants associated with generalized stunting of growth rather than just the loss of height attributable to the shortening of leg bones in many children with thalidomide embryopathy. KEY MESSAGES: Thus, SALL4 joins the candidate gene list for monogenic syndromic pituitary insufficiency. In this review, we summarize the journey from the thalidomide disaster through the functions of the SALL4 gene to its link to the hormonal regulation of growth.
BACKGROUND: Triplet or quadruplet therapies incorporating proteasome inhibitors, immunomodulators, and anti-CD38 antibodies have led to prolonged survival among patients with newly diagnosed multiple myeloma; however, most patients have a relapse. Frontline lenalidomide therapy has increased the number of patients with lenalidomide-refractory disease at the time of the first relapse. METHODS: In this phase 3, randomized, open-label trial, we evaluated belantamab mafodotin, pomalidomide, and dexamethasone (BPd), as compared with pomalidomide, bortezomib, and dexamethasone (PVd), in lenalidomide-exposed patients who had relapsed or refractory myeloma after at least one line of therapy. The primary end point was progression-free survival. Disease response and safety were also assessed. RESULTS: A total of 302 patients underwent randomization; 155 were assigned to the BPd group, and 147 to the PVd group. At a median follow-up of 21.8 months (range, <0.1 to 39.2), the 12-month estimated progression-free survival with BPd was 71% (95% confidence interval [CI], 63 to 78), as compared with 51% (95% CI, 42 to 60) with PVd (hazard ratio for disease progression or death, 0.52; 95% CI, 0.37 to 0.73; P<0.001). Data on overall survival were immature. The percentage of patients with a response to treatment (partial response or better) was 77% (95% CI, 70 to 84) in the BPd group and 72% (95% CI, 64 to 79) in the PVd group; 40% (95% CI, 32 to 48) and 16% (95% CI, 11 to 23), respectively, had a complete response or better. Grade 3 or higher adverse events occurred in 94% of the patients in the BPd group and 76% of those in the PVd group. Ocular events occurred in 89% of the patients who received BPd (grade 3 or 4 in 43%) and 30% of those who received PVd (grade 3 or 4 in 2%); ocular events in the BPd group were managed with belantamab mafodotin dose modification. Ocular events led to treatment discontinuation in 9% of the patients in the BPd group and in no patients in the PVd group. CONCLUSIONS: Among lenalidomide-exposed patients with relapsed or refractory myeloma, BPd conferred a significantly greater benefit than PVd with respect to progression-free survival, as well as deeper, more durable responses. Ocular events were common but were controllable by belantamab mafodotin dose modification. (Funded by GSK; DREAMM-8 ClinicalTrials.gov number, NCT04484623; EudraCT number, 2018-004354-21.).
- MeSH
- Bortezomib administration & dosage adverse effects MeSH
- Drug Resistance, Neoplasm MeSH
- Dexamethasone * administration & dosage adverse effects MeSH
- Progression-Free Survival * MeSH
- Adult MeSH
- Antibodies, Monoclonal, Humanized * administration & dosage adverse effects MeSH
- Kaplan-Meier Estimate MeSH
- Lenalidomide administration & dosage adverse effects MeSH
- Middle Aged MeSH
- Humans MeSH
- Neoplasm Recurrence, Local diagnosis drug therapy mortality MeSH
- Multiple Myeloma * diagnosis drug therapy mortality MeSH
- Eye Diseases chemically induced epidemiology MeSH
- Disease Progression MeSH
- Antineoplastic Combined Chemotherapy Protocols * administration & dosage adverse effects MeSH
- Recurrence MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Thalidomide * administration & dosage adverse effects analogs & derivatives MeSH
- Treatment Outcome MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Clinical Trial, Phase III MeSH
- Multicenter Study MeSH
- Randomized Controlled Trial MeSH
- Comparative Study MeSH
BACKGROUND: Preclinical studies suggest that combining nivolumab, a programmed death-1 (PD-1) immune checkpoint inhibitor, with pomalidomide/dexamethasone (Pd) with or without elotuzumab, an antisignaling lymphocytic activation molecule F7 monoclonal antibody, may improve multiple myeloma (MM) treatment efficacy. PATIENTS AND METHODS: The phase 3 CheckMate 602 study (NCT02726581) assessed the efficacy and safety of nivolumab plus pomalidomide/dexamethasone (NPd) and NPd plus elotuzumab (NE-Pd). Eligible patients (aged ≥ 18 years) had measurable MM after ≥ 2 prior lines of therapy, that included an immunomodulatory drug (IMiD) and proteasome inhibitor (PI), each for ≥ 2 consecutive cycles, alone or combined, and were refractory to their last line of therapy. Patients were randomized 3:3:1 to receive NPd, Pd, or NE-Pd. The primary endpoint was progression-free survival (PFS); overall response rate (ORR) was a key secondary endpoint. RESULTS: At a median follow-up of 16.8 months, PFS was similar between treatment arms (Pd, 7.3 months [95% CI, 6.5-8.4]; NPd, 8.4 months [95% CI, 5.8-12.1]; NE-Pd, 6.3 months [95% CI, 2.4-11.1]). ORR was similar in the Pd (55%), NPd (48%), and NE-Pd (42%) arms. Nivolumab-containing arms were associated with a less favorable safety profile versus Pd, including a higher rate of thrombocytopenia (NPd, 25.0%; NE-Pd, 16.7%; Pd, 15.7%), any-grade immune-mediated adverse events (NPd, 13.9%; NE-Pd, 16.7%; Pd, 2.9%), and adverse events leading to discontinuation (NPd, 25.0%; NE-Pd, 33.3%; Pd, 18.6%). No new safety signals were identified. CONCLUSION: CheckMate 602 did not demonstrate clinical benefit of nivolumab (+/- elotuzumab) plus Pd versus Pd for patients with relapsed/refractory MM (RRMM).
- MeSH
- Adult MeSH
- Antibodies, Monoclonal, Humanized * therapeutic use administration & dosage pharmacology MeSH
- Middle Aged MeSH
- Humans MeSH
- Neoplasm Recurrence, Local drug therapy MeSH
- Multiple Myeloma * drug therapy mortality MeSH
- Nivolumab * therapeutic use pharmacology administration & dosage MeSH
- Antineoplastic Combined Chemotherapy Protocols * therapeutic use pharmacology MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Thalidomide * analogs & derivatives therapeutic use pharmacology administration & dosage MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Clinical Trial, Phase III MeSH
- Randomized Controlled Trial MeSH
- Keywords
- isatuximab, pomalidomid,
- MeSH
- Dexamethasone pharmacology therapeutic use MeSH
- Antibodies, Monoclonal, Humanized pharmacology therapeutic use MeSH
- Humans MeSH
- Multiple Myeloma * drug therapy MeSH
- Antineoplastic Combined Chemotherapy Protocols MeSH
- Aged MeSH
- Thalidomide analogs & derivatives pharmacology therapeutic use MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Aged MeSH
- Publication type
- Case Reports MeSH
- Keywords
- isatuximab, pomalidomid,
- MeSH
- ADP-ribosyl Cyclase 1 pharmacology therapeutic use MeSH
- Transplantation, Autologous MeSH
- Dexamethasone pharmacology therapeutic use MeSH
- Adult MeSH
- Antibodies, Monoclonal, Humanized pharmacology therapeutic use MeSH
- Humans MeSH
- Multiple Myeloma * drug therapy MeSH
- Antineoplastic Combined Chemotherapy Protocols MeSH
- Thalidomide analogs & derivatives pharmacology therapeutic use MeSH
- Bone Marrow Transplantation MeSH
- Check Tag
- Adult MeSH
- Humans MeSH
- Female MeSH
- Publication type
- Case Reports MeSH
- Keywords
- isatuximab, pomalidomid,
- MeSH
- Liver Diseases, Alcoholic MeSH
- Alcoholism therapy MeSH
- Dexamethasone pharmacology therapeutic use MeSH
- Antibodies, Monoclonal, Humanized pharmacology therapeutic use MeSH
- Humans MeSH
- Multiple Myeloma * drug therapy MeSH
- Antineoplastic Combined Chemotherapy Protocols MeSH
- Recurrence MeSH
- Aged MeSH
- Thalidomide analogs & derivatives pharmacology therapeutic use MeSH
- Check Tag
- Humans MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Case Reports MeSH
