A Phase 2 Study of Bortezomib in Relapsed, Refractory Myeloma

BACKGROUND Bortezomib, a boronic acid dipeptide, is a novel proteasome inhibitor that has been shown in preclinical and phase 1 studies to have antimyeloma activity. METHODS In this multicenter, open-label, nonrandomized, phase 2 trial, we enrolled 202 patients with relapsed myeloma that was refractory to the therapy they had received most recently. Patients received 1.3 mg of bortezomib per square meter of body-surface area twice weekly for 2 weeks, followed by 1 week without treatment, for up to eight cycles (24 weeks). In patients with a suboptimal response, oral dexamethasone (20 mg daily, on the day of and the day after bortezomib administration) was added to the regimen. The response was evaluated according to the criteria ofthe European Group for Blood and Marrow Transplantation and confirmed by an independent review committee. RESULTS Of 193 patients who could be evaluated, 92 percent had been treated with three or more ofthe major classes of agents for myeloma, and in 91 percent, the myeloma was refractory to the therapy received most recently. The rate of response to bortezomib was 35 percent, and those with a response included 7 patients in whom myeloma protein became undetectable and 12 in whom myeloma protein was detectable only by immuno-fixation. The median overall survival was 16 months, with a median duration of response of 12 months. Grade 3 adverse events included thrombocytopenia (in 28 percent of patients), fatigue (in 12 percent), peripheral neuropathy (in 12 percent), and neutropenia (in 11 percent). Grade 4 events occurred in 14 percent of patients. CONCLUSIONS Bortezomib, a member of a new class of anticancer drugs, is active in patients with relapsed multiple myeloma that is refractory to conventional chemotherapy

International evidence-based consensus diagnostic and treatment guidelines for unicentric Castleman disease.

Castleman disease (CD) includes a group of rare and heterogeneous disorders with characteristic lymph node histopathological abnormalities. CD can occur in a single lymph node station, which is referred to as unicentric CD (UCD). CD can also involve multicentric lymphadenopathy and inflammatory symptoms (multicentric CD [MCD]). MCD includes human herpesvirus-8 (HHV-8)-associated MCD, POEMS-associated MCD, and HHV-8-/idiopathic MCD (iMCD). The first-ever diagnostic and treatment guidelines were recently developed for iMCD by an international expert consortium convened by the Castleman Disease Collaborative Network (CDCN). The focus of this report is to establish similar guidelines for the management of UCD. To this purpose, an international working group of 42 experts from 10 countries was convened to establish consensus recommendations based on review of treatment in published cases of UCD, the CDCN ACCELERATE registry, and expert opinion. Complete surgical resection is often curative and is therefore the preferred first-line therapy, if possible. The management of unresectable UCD is more challenging. Existing evidence supports that asymptomatic unresectable UCD may be observed. The anti-interleukin-6 monoclonal antibody siltuximab should be considered for unresectable UCD patients with an inflammatory syndrome. Unresectable UCD that is symptomatic as a result of compression of vital neighboring structures may be rendered amenable to resection by medical therapy (eg, rituximab, steroids), radiotherapy, or embolization. Further research is needed in UCD patients with persisting constitutional symptoms despite complete excision and normal laboratory markers. We hope that these guidelines will improve outcomes in UCD and help treating physicians decide the best therapeutic approach for their patients

Immunomodulatory Compounds (Imids®) in the Treatment of Multiple Myeloma

The design of innovative, more effective, less toxic therapy of multiple myeloma (MM) is emerging in parallel to a better understanding of the underlying pathophysiology of this common hematologic malignancy. Thalidomide has changed the treatment paradigm of patients with MM. Its efficacy, however, has been compromised by significant side effects. IMiDs® (immunodulatory compounds) are structural and functional analogs of thalidomide that were specifically designed to create new agents with enhanced immunomodulatory and anticancer properties and better tolerability profiles. In this article, we review the clinical trial development of the second-generation IMiDs®, lenalidomide and pomalidomide. Both agents demonstrate potent activity and are highly effective and well tolerated treatment options for patients with MM

TAFRO syndrome: New subtype of idiopathic multicentric Castleman disease

Castleman disease (CD) describes a group of three rare and poorly understood lymphoproliferative disorders that have heterogeneous clinical symptoms and common lymph node histopathological features. Unicentric CD (UCD) involves a single region of enlarged nodes. Multicentric CD (MCD) involves multiple regions of enlarged lymph nodes, constitutional symptoms, and organ dysfunction due to a cytokine storm often including interleukin 6. MCD is further divided into Human Herpes Virus-8 (HHV-8)-associated MCD, which occurs in immunocompromised individuals, and HHV-8-negative/idiopathic MCD (iMCD). Recently, iMCD has been further sub-divided into patients with TAFRO syndrome, which involves thrombocytopenia (T), anasarca (A), fevers (F), reticulin myelofibrosis (R), organomegaly (O), and normal or only slightly elevated immunoglobulin levels, and those who do not have TAFRO syndrome. Non-TAFRO iMCD patients typically have thrombocytosis, less severe fluid accumulation, and hypergammaglobulinemia. iMCD patients with TAFRO syndrome may have a worse prognosis, but more research is needed

Detection and partial characterization of receptors for [D-Trp6]-luteinizing hormone-releasing hormone and epidermal growth factor in human endometrial carcinoma.

In view of advancements in treatment of certain hormone-dependent cancers with analogues of luteinizing hormone-releasing hormone (LH-RH), this study was undertaken to establish the presence and characteristics of receptors for [D-Trp6]LH-RH on the membranes of human endometrial cancer. Specific binding of [125I,D-Trp6]LH-RH was demonstrated in membrane preparations from 24 of 31 (77%) endometrial carcinomas and from 3 of 13 (23.1%) nonmalignant human endometrial specimens. Ligand binding was dependent on temperature, time, and plasma membrane concentration in a fashion expected of a peptide hormone. Mathematical analysis of the binding data showed that interaction of [125I,D-Trp6]LH-RH with the binding sites was consistent with the presence of a single class of high affinity, noncooperative receptors (Kd 9.88 +/- 4.59 x 10(-9) M; Bmax 0.70 +/- 0.14 x 10(-12) mol/mg membrane protein). The rates of association and dissociation were calculated to be 6.5 x 10(6) M-1 min-1 and 0.021 min-1, respectively. [125I,D-Trp6]LH-RH binding was not displaced by either unlabeled somatostatin or epidermal growth factor, but was displaced completely by native LH-RH. Using 125I-epidermal growth factor, specific, high-affinity receptors were also detected in membranes from 22 of 26 (85%) endometrial cancers and in all of 6 nonmalignant endometrial specimens (Kd 0.42 +/- 0.12 x 10(-9) M; Bmax 0.30 +/- 0.15 x 10(-12) mol/mg membrane protein). The potential functional role of the receptors for [D-Trp6]LH-RH in human endometrial carcinoma is not clear, but this finding provides a rationale for the use of therapeutic approaches based on LH-RH analogues in this malignancy

Recovery of Pituitary-Gonadal Function in Male and Female Rats after Prolonged Administration of a Potent Antagonist of Luteinizing Hormone-Releasing Hormone (SB-75)

The reversibility of the antifertility effects induced by long-term administration of the LH-RH antagonistic analog [Ac-D-Nal(2)’, D-Phe(4Cl)2, D-Pal(3)3, D-Cit6, D-Ala10]-LH-RH (SB-75) was investigated in male and female rats. Male rats were implanted with osmotic minipumps releasing 50 µg of SB-75/day for 60 days. The control rats were implanted with minipumps containing only vehicle. The treatment with the antagonist caused a significant decrease in the weights of the testes, seminal vesicles and ventral prostates (p < 0.01) and reduced serum LH and testosterone levels (p < 0.01). The histology of the testes from the treated rats showed that spermatogenesis was totally depressed. No mature elongated or round spermatids were found in the seminiferous tubules, spermatocytes being the most advanced germ cell form in 100% of the testicular tubules. These changes indicate that a total spermatogenetic arrest occurred in the treated animals. Ninety days after cessation of treatment with the LH-RH antagonist, there was a complete recovery of the weights of the testes, seminal vesicles and ventral prostates and LH and testosterone returned to control levels. Histological studies revealed a complete recovery of spermatogenesis, with 99.2% of seminiferous tubules containing mature elongated spermatids. Immediately after the discontinuation of treatment with SB-75, a significant down-regulation of the pituitary LH-RH receptors was found, but 90 days later, this phenomenon was completely reversed. Female rats were injected every 3 weeks for 6 weeks with SB-75 microcapsules, at a dose calculated to release 27 µg/day of the antagonist. The treatment with SB-75 disrupted the normal estrous cycle. Body weights were not affected, but ovarian and uterine weights were significantly decreased (p < 0.01 and p < 0.05, respectively) in the animals treated with the antagonist. Treated rats had significantly lower LH (p < 0.05) and estradiol (p < 0.01) levels than controls. The histology of the ovaries from the SB-75-treated group showed that the ratio of small to large maturing follicles increased significantly (p < 0.01) and corpora lutea were absent. Two months after the cessation of treatment, a complete recovery in the organ weights and in hormonal levels was observed and no histological differences were found between the ovaries in treated and untreated rats. These collective results indicate that the suppression of gonadal function induced by the treatment with LH-RH antagonist SB-75 is completely reversible both in male and female animals. These findings should facilitate the use of modern LH-RH antagonists, free of side effects, for the treatment of hormone-sensitive cancers, gynecologic conditions and other disorders where inhibition of the pituitary-gonadal axis is desirable

Inhibitory effects of analogs of luteinizing hormone‐releasing hormone and somatostatin on pancreatic cancers in hamsters events that accompany tumor regression

Syrian golden hamsters bearing N‐nitrosobis(2‐oxopropyl)amine (BOP)‐induced pancreatic carcinomas were treated for 2 months with the delayed delivery systems of the agonist D‐Trp‐6‐LH‐RH (microcapsules releasing 25 μg/day for 30 days), the somatostatin analog RC‐160 (the microcapsules liberating 48.2 μg/day for 30 days), or with the combination of these two analogues. The increase in the dose of RC‐160 was possible in view of the lack of toxicity of this analog. This higher dose of RC‐160 exerted a greater suppressive effect on pancreatic cancers than the regimens previously used (5‐25 μg/day). RC‐160, D‐Trp‐6‐LH‐RH, and their combination reduced the number of pancreatic carcinomas and significantly inhibited tumor growth as compared with the controls. The combination had the strongest tumor‐inhibitory effect and reduced tumor weight by 85% as compared with controls. Both the light and electron microscopic analysis of the tumors showed that the inhibitory effect was due to the enhancement of apoptosis (programmed cell death) of tumor cells. Insulin‐like growth factor (IGF‐I) receptors were detected immunohistochemically in the untreated tumors and their number decreased after the treatment with the analogues. Binding of D‐Trp‐6‐LH‐RH and RC‐160 to tumor cells was shown immunohistochemically and receptors to these analogues and IGF‐I were also determined biochemically by radioligand titration. Treatment with D‐Trp‐6‐LH‐RH and RC‐160 decreased the binding capacity of receptors for D‐Trp‐6‐LH‐RH and IGF‐I, producing down‐regulation of these receptors. This suggests that pancreatic tumor cells with receptors to these peptides are sensitive to the treatment. This work reinforces the view that the combination of high doses of somatostatin analog RC‐160 with LH‐RH agonists or antagonists should be considered for the development of a new hormonal therapy for ductal pancreatic cancers