A Phase 1 Trial of Lenalidomide (REVLIMID®) with Bortezomib (VELCADE®) in Relapsed and Refractory Multiple Myeloma.

Abstract

Introduction: Bortezomib and lenalidomide are active agents in multiple myeloma (MM), and preclinical data showing additive activity in MM in vitro suggest that enhanced clinical benefit may be derived from combining the two drugs. Bortezomib is approved in MM patients (pts) who have received at least one prior therapy in both the US and EU. Lenalidomide has produced durable responses in the relapsed and refractory MM setting, including in those who received prior bortezomib. Toxicities of bortezomib and lenalidomide do not overlap unfavorably. These observations suggest that this regimen, compared with either agent alone, may provide better clinical anti-MM activity. In phase 1 trials, the maximum tolerated doses (MTD) of single-agent bortezomib and lenalidomide were 1.3 mg/m2 (IV bolus twice weekly) and 25 mg/d (PO days 1–21 of a 28–day cycle), respectively. The objective of this phase 1 dose-escalation trial was to determine the MTD and activity of this combination in pts with relapsed and/or refractory MM. Methods: Eight 3-pt cohorts were planned with bortezomib 1.0 or 1.3 mg/m2 and lenalidomide 5, 10, 15, or 20 mg/day. Pts received bortezomib on days 1, 4, 8, and 11 and lenalidomide on days 1–14 of a 21-day cycle. Dexamethasone 20 mg orally could be added on days 1, 2, 4, 5, 8, 9 and 11, 12 in the event of PD. Toxicity was assessed using NCI-CTC, version 3.0. Dose-limiting toxicity (DLT) was defined as grade ≥ 3 nonhematologic toxicity, grade 4 neutropenia lasting ≥ 5 days and/or neutropenic fever, or a platelet count ≤ 10,000 on > 1 occasion despite transfusion. Modified EBMT criteria were used to assess response. Results: Nineteen pts with MM have been enrolled to date to cohorts 1–5, including 8 with relapsed and 11 with relapsed and refractory disease. Median number of prior therapies was 4 (range, 1–9). Twelve pts had prior SCT; 17 had received thalidomide, 9 bortezomib, 2 lenalidomide. With a median of 7 cycles completed (range, 2–16), pts have received bortezomib 1.0–1.3 mg/m2 and lenalidomide 5–15 mg/d. Two pts with rapid disease progression were not evaluable and were removed from study within the first cycle. One DLT was observed (cohort 4, grade 3 hyponatremia). To date, doses of study drugs were reduced in 6 pts beyond cycle 3. Bortezomib was reduced for thrombocytopenia [n = 3] and hypotension [n = 1] and lenalidomide was reduced for neutropenia [n = 1] and fatigue [n = 1]. No significant treatment-emergent PN has been seen. Responses by cohort are shown in the table, and of 17 evaluable pts, 10 (59%) achieved CR + PR. Conclusions: In heavily treated pts with relapsed and/or refractory MM, the combination of bortezomib and lenalidomide has been well tolerated and has demonstrated very promising activity, even in pts who had previously received either agent alone. Dose escalation is continuing until MTD is reached. Phase II evaluation of this regimen is planned both in relapsed and/or refractory and in newly diagnosed MM. Cohort Bortezomib, mg/m2 Lenalidomide, mg Best Response NE = not evaluable. 1 1.0 5 2 PR, 1 MR 2 1.3 5 1 CR, 2 PR 3 1.0 10 1 nCR, 2 PR, 1 NE 4 1.3 10 2 PR, 2 MR, 1 SD, 1 PD 5 1.0 15 2 SD, 1 NE

Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma

“…61 The combination of lenalidomide-bortezomib did not increase the risk of VTE in relapsed/refractory patients. 62 The incidence of VTE according to different agents and regimens is summarized in Table 2. Risk factors associated with an increased risk of VTE were the dexamethasone dose and erythropoietin administration.…”

The Emerging Role of Novel Therapies for the Treatment of Relapsed Myeloma

“…24 VATD has been shown to produce a 63% response rate, with 25% complete or near complete responses (M-protein reduction), 22 and recently reported data show that the addition of liposomal doxorubicin to the VTD regimen can increase the response rate to 74%, with 33% complete or near complete responses. 23 Other combinations that have produced high response rates (up to 73%) 25 and complete or near complete response rates (up to 36%) 25 in the relapsed setting include bortezomib plus liposomal doxorubicin alone 37 or with thalidomide, 27 lenalidomide, 26 and melphalan plus thalidomide, with or without steroids. 28,29 The safety profile in these combination studies has been as expected, with no additive toxicities reported, and, in fact, better tolerability described.…”

Long‐term results of thalidomide in refractory and relapsed multiple myeloma with emphasis on response duration

“…A response rate of about 40% has been consistently reported when using thalidomide as a single agent in myeloma patients with refractory or relapsed disease (11)(12)(13)(14)(15)(16)(17). When thalidomide is combined with other anti-myeloma agents the response rate increases to 50-63% (25)(26)(27)(28)(29)(30)(31)(32). However, there is limited information on the duration of such responses.…”