|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Originally published as JCO Early Release 10.1200/JCO.2004.05.984 on July 12 2004 © 2004 American Society of Clinical Oncology.
Immunomodulatory Analogs of Thalidomide: An Emerging New Therapy in Myeloma
1 Jerome Lipper Multiple Myeloma Center, Harvard Medical School, and Dana-Farber Cancer Institute, Boston, MA In this issue of the Journal of Clinical Oncology (JCO), Schey et al1 present the results of a phase I study of the immunomodulatory thalidomide analog CC-4047 in relapsed, and relapsed refractory multiple myeloma (MM). This important work represents a next step in a series of studies for the development of new agents in the treatment of relapsed MM, which remains incurable, despite advances such as high-dose therapy and stem-cell transplantation (SCT). Since the encouraging results of the thalidomide trial led by Singhal et al in advanced relapsed and refractory MM, thalidomide has been established as an effective therapy for the treatment of MM in the relapsed and upfront settings.2-4 However, the efficacy of thalidomide has been significantly limited by adverse effects, which include sedation, neuropathy, constipation, and deep vein thrombosis. This toxicity profile seems both dose-related and duration-related, especially post-SCT,5 spurring the development of thalidomide-derived immunomodulatory analogs known as immunomodulatory drugs (IMiDs), which have the potential of improved potency and reduced toxicity. CC-4047 is one of two small-molecule 4-amino derivatives currently under study in patients with MM.
Studies demonstrate that both thalidomide and IMiDs not only act to inhibit angiogenesis, but also act directly to induce both apoptosis and growth arrest in resistant myeloma cells. They also block both the adhesion of myeloma cells to bone marrow stromal cells and the related protection against apoptosis, and block the increased secretion of myeloma cell growth, survival, and migratory factors such as interleukin-6, tumor necrosis factor alpha (TNF-
On the basis of this promising preclinical data, the first phase I study of the thalidomide analog CC-5013 was carried out in 2001, when a dose range of 5 to 50 mg/d was tested in 25 patients with relapsed and refractory MM. Patients in this study had received a median of three prior regimens, including autologous SCT and prior thalidomide in approximately two-thirds of the patients. Importantly, no dose-limiting toxicity was observed at any dose level within the first 28 days, but grade 3 myelosuppression developed after 28 days in all 13 patients treated at the highest dose level of 50 mg/d. In 12 of these patients, dose reduction to 25 mg/d was well tolerated and was considered the maximum-tolerated dose. No significant constipation or neuropathy was seen in any cohort, and encouragingly, responses were seen in 17 (71%) of 24 assessable patients, including 11 patients (46%) who had received prior thalidomide.13 A second study by Zangari et al14 in 15 patients with advanced MM confirmed a maximum-tolerated dose of 25 mg/d. These studies provided the basis for the further evaluation of CC-5013, either alone or in combination with dexamethasone, to treat patients with MM at first relapse, or for relapsed refractory MM. Results of these studies have been encouraging, with impressive response rates and acceptable tolerability.15 A series of phase II trials with CC-5013 have been completed, and a multicenter, parallel group, controlled phase III randomized double-blind study of CC-5013 plus dexamethasone compared with dexamethasone alone in previously treated patients with MM has just completed accrual. CC-4047 is the second IMiD to enter clinical trials. In the dose-escalation study reported in this issue of the JCO and conducted in 24 patients with relapsed, and relapsed refractory MM, patients had received at least one previous line of therapy. The treatment consisted of daily oral CC-4047 administered at doses of 1, 2, 5, or 10 mg for 4 weeks in a dose-escalated fashion. The maximum-tolerated dose was identified as 2 mg daily. Neutropenia was the major dose-limiting toxicity, seen in 58% of the patients. Grade 3 deep vein thrombosis was seen in four (16%) of 24 patients. Other side effects were mild and included rash, neuropathy, constipation, edema, and hypotension. Importantly, treatment resulted in minor response (> 25% reduction in paraprotein) or better in two-thirds of patients, with four (16%) of 24 assessable patients achieving complete remission. An exciting aspect of this study was a comprehensive analysis of immune modulation. The authors report T-cell activation, with increased RO expression on CD-4–positive and CD-8–positive cells, and a concomitant fall in resting CD-45 RO-positive cells seen. Moreover, there were significant increases in serum levels of serum interleukin-2 receptor and interleukin-12, consistent with activation of T cells. These data are consistent with those described in the in vitro setting,9 and is the first clinical report supporting the potential for the CC-4047 as an immunostimulatory agent. In comparing this experience with that of CC-5013, it is important to note that 19 of 24 of the patients in this trial relapsed, and five (20%) of 24 were relapsed and refractory, compared with 70% of the patients in the first CC-5013 phase I study who were both relapsed and refractory.13 Moreover, while the median number of prior therapies in both trials was similar, only 20% had had prior SCT, and a third had received prior thalidomide, which is significantly less than that seen in the CC-5013 study. An important difference in toxicities is the apparent higher incidence in DVT seen with CC-4047 (16% v 4%, respectively).15 However, similar to the CC-5013 experience, neutropenia was manageable with dose reduction and growth factor support. Encouragingly, with CC-4047, the incidence of significant thrombocytopenia may be less (12% v 22%),15 pointing to possible important differences in the adverse effect profile, as well as response rate. Importantly, like CC-5013, no significant constipation, neuropathy, or sedation was seen. However, unlike CC-5013, CC-4047 is a known teratogen,12 which may lead to limitations in its use. MM has been a paradigm for translational research in the last several years, with important advances made in the translation of novel biologically derived therapies from bench to bedside.16 The article published in this issue of the JCO represents another example of this encouraging progress. Intriguingly, CC-4047 shows potent activity with manageable toxicities and offers yet another potential therapeutic opportunity for patients with advanced MM. The results of this study show an important proof of principle in the mechanism of action of CC-4047 and IMiDs as a drug class. Further studies of this orally bioavailable agent in patients with MM and in the treatment of other tumors, are warranted, with phase I/II trials in prostate cancer already underway. Authors' Disclosures of Potential Conflicts of Interest The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Consultant/Advisory Role: Paul Richardson, Celgene; Kenneth Anderson, Celgene. Honoraria: Paul Richardson, Celgene; Kenneth Anderson, Celgene. For a detailed description of these categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration form and the "Disclosures of Potential Conflicts of Interest" section of Information for Contributors found in the front of every issue.
REFERENCES
1. Schey SA, Fields P, Marriott JB, et al: Phase I study of an immunomodulatory thalidomide analog (CC 4047) in relapsed/ refractory multiple myeloma. J Clin Oncol 22:3269-3276, 2004
2. Singhal S, Mehta J, Desikan R, et al: Anti-tumor activity of thalidomide in refractory multiple myeloma. N Engl J Med 341:1565-1571, 1999
3. Rajkumar V, Hayman S, Gertz M, et al: Combination therapy with thalidomide plus dexamethasone for newly diagnosed myeloma. J Clin Oncol 20:4319-4323, 2002
4. Weber D, Rankin K, Gavino M, et al: Thalidomide alone or with dexamethasone for previously untreated multiple myeloma. J Clin Oncol 21:16-19, 2003
5. Richardson P, Schlossman R, Jagannath S, et al: A multicenter phase 2 dose escalation study of thalidomide in patients with relapsing multiple myeloma post-SCT. Mayo Clin Proc 79:875-882, 2004 6. Anderson KC: Multiple Myeloma: Advances in disease biology—Therapeutic implications. Semin Hematol 38:6-10, 2001[Medline]
7. Hideshima T, Chauhan D, Shima Y, et al: Thalidomide and its analogs overcome drug resistance of human multiple myeloma cells to conventional therapy. Blood 96:2943-2950, 2000 8. Gupta D, Treon SP, Shima Y, et al: Adherence of multiple myeloma cells to bone marrow stromal cells upregulates vascular endothelial growth factor secretion: Therapeutic applications. Leukemia 15:1950-1961, 2001[Medline]
9. Davies FE, Raje N, Hideshima T, et al: Thalidomide and immunomodulatory derivatives augment natural killer cell cytotoxicity in multiple myeloma. Blood 98:210-216, 2001 10. Treon SP, Mitsiades C, Mitsiades N, et al: Tumor cell expression of CD59 is associated with resistance to CD20 serotherapy in B-cell malignancies. J Immunother 24:236-271, 2001 11. Lentzsch S, LeBlanc R, Podar K, et al: Immunomodulatory derivatives of thalidomide inhibit growth of B-cell hematologic malignancies and angiogenesis in vivo. Leukemia 17:41-44, 2003[CrossRef][Medline] 12. Bartlett J, Dredge K, Dalgleish AG, et al: The evolution of thalidomide and its IMiD derivatives as anticancer agents. Nat Rev Cancer 4:314-322, 2004[CrossRef][Medline]
13. Richardson P, Schlossman R, Hideshima T, et al: A phase I trial of oral CC-5013 an immunomodulatory thalidomide derivative, in patients with relapsed and refractory multiple myeloma. Blood 100:3063-3067, 2002 14. Zangari M, Tricot G, Zeldis J, et al: Results of a phase I study of CC-5013 for the treatment of multiple myeloma (MM) patients who relapse after high dose chemotherapy (HDCT). Blood 98:3226a, 2001 (abstr) 15. Richardson P, Jagannath S, Schlossman R, et al: A multicenter, randomized phase 2 study to evaluate the efficacy and safety of 2 CDC-5013 dose regimens when used alone or in combination with Dexamethasone (Dex) for the treatment of relapsed or relapsed refractory multiple myeloma (MM). Blood 102:825a, 2003 (abstr) 16. Hideshima T, Anderson KC: Molecular mechanisms of novel therapeutic approaches for multiple myeloma. Nat Rev Cancer 2:927-937, 2002[CrossRef][Medline]
Related Article
This article has been cited by other articles:
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
), and vascular endothelial growth factor, triggered by the binding of myeloma cells to bone marrow stromal cells. In addition, they expand natural killer cell and T-cell numbers, and improve function against human myeloma cells and enhance their susceptibility to antibody-dependent cell-mediated cytotoxicity in vivo (
, represents inhibition; 
, represents stimulation; BFGF, basic fibroblast growth factor; VEGF, vascular endothelial growth factor; IL-2, interleukin-2; IL-6, interleukin-6; IFN
