Originally published as JCO Early Release 10.1200/JCO.2009.22.2679 on September 28 2009

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Multicenter, Phase I, Dose-Escalation Trial of Lenalidomide Plus Bortezomib for Relapsed and Relapsed/Refractory Multiple Myeloma

From the Department of Medical Oncology, Dana-Farber Cancer Institute; and Beth Israel Deaconess Medical Center, Boston; and Millennium Pharmaceuticals, Cambridge, MA; St Vincent's Comprehensive Cancer Center, New York, NY; H. Lee Moffitt Cancer Center, Tampa, FL; and Celgene, Summit, NJ.

Corresponding author: Paul G. Richardson, MD, Dana-Farber Cancer Institute, 44 Binney St, Dana 1B02, Boston, MA 02115; e-mail: paul_richardson{at}dfci.harvard.edu.

Purpose Lenalidomide and bortezomib are active in relapsed and relapsed/refractory multiple myeloma (MM). In preclinical studies, lenalidomide sensitized MM cells to bortezomib and dexamethasone. This phase I, dose-escalation study (ie, NCT00153933 [ClinicalTrials.gov] ) evaluated safety and determined the maximum-tolerated dose (MTD) of lenalidomide plus bortezomib in patients with relapsed or with relapsed and refractory MM.

Patients and Methods Patients received lenalidomide 5, 10, or 15 mg/d on days 1 through 14 and received bortezomib 1.0 or 1.3 mg/m² on days 1, 4, 8, and 11 of 21-day cycles. Dexamethasone (20mg or 40 mg on days 1, 2, 4, 5, 8, 9, 11, and 12) was added for progressive disease after two cycles. Primary end points were safety and MTD determination.

Results Thirty-eight patients were enrolled across six dose cohorts. The MTD was lenalidomide 15 mg/d plus bortezomib 1.0 mg/m². Dose-limiting toxicities (n = 1 for each) were grade 3 hyponatremia and herpes zoster reactivation and grade 4 neutropenia. The most common treatment-related, grades 3 to 4 toxicities included reversible neutropenia, thrombocytopenia, anemia, and leukopenia. Among 36 response-evaluable patients, 61% (90% CI, 46% to 75%) achieved minimal response or better. Among 18 patients who had dexamethasone added, 83% (90% CI, 62% to 95%) achieved stable disease or better. Median overall survival was 37 months.

Conclusion Lenalidomide plus bortezomib was well tolerated and showed promising activity with durable responses in patients with relapsed and relapsed/refractory MM, including patients previously treated with lenalidomide, bortezomib, and/or thalidomide. The combination of lenalidomide, bortezomib, and dexamethasone is being investigated in a phase II study in this setting and in newly diagnosed MM.

See accompanying editorial on page 5676

Supported in part by Millennium Pharmaceuticals; Johnson & Johnson Pharmaceuticals Research and Development; Celgene; National Institutes of Health/Specialized Project of Research Excellence Grants No. P50 CA100707, P01 CA78378, and R01 CA50947; and the Rick Corman Multiple Myeloma Research Fund.

Presented in part at the 48th Annual Meeting of the American Society of Hematology, December 9-12, 2006, Orlando, FL.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Clinical trial information can be found for the following: NCT00153933 [ClinicalTrials.gov] .

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