A Phase II Study of Pegylated Liposomal Doxorubicin (PLD), Bortezomib, Dexamethasone and Lenalidomide (DVD-R) for Patients with Relapsed/Refractory (R/R) Multiple Myeloma (MM)

Despite the availability of many new therapeutic options showing efficacy for R/R MM patients, many of these treatments produce significant side effects and the disease remains incurable. The combination of PLD and bortezomib has shown significant anti-MM efficacy leading to FDA approval of that combination for patients who have received one prior therapy and are naïve to bortezomib. Moreover, the combination of lenalidomide and dexamethasone has also been approved for patients who have received one prior regimen. However, both regimens are associated with significant toxicity and produce response rates in only 40–60% of patients. Previous studies in our laboratory show the increased efficacy and improved tolerability of PLD given daily compared to weekly administration in severe combined immunodeficient mice bearing human MM. Based on these results and the frequent occurrence of peripheral neuropathy with bortezomib when given at 1.3 mg/m² dose on days 1, 4, 8, and 11 of a 3-week schedule, we modified the doses and schedules of both drugs and added intravenous (i.v) dexamethasone for MM patients. Using a modified lower dose (1.0 mg/m²) and longer cycle (4 weeks) of bortezomib administered on days 1, 4, 8, and 11 with lower dose PLD and intravenous (i.v.) dexamethasone administered on the same days for MM patients in both the frontline and R/R setting, we have shown the efficacy and marked reduction in AEs including neuropathy, hematologic, and hand-foot syndrome. A recent phase I/II trial investigating the combination of higher doses of lenalidomide, bortezomib, oral dexamethasone, and PLD on a 3-week schedule for newly diagnosed MM patients showed a high response rate but was associated with frequent AEs.

Thus, we conducted a single-arm multi-center phase II study for R/R MM patients to evaluate the combination of i.v. dexamethasone, bortezomib, PLD, and lenalidomide. The treatment consisted of 40 mg dexamethasone followed by 1.0 mg/m² bortezomib and then 4.0 mg/m² PLD on days 1, 4, 8, and 11 of a 28-day cycle. Lenalidomide was administered orally at a dose of 10 mg daily on days 1–14 of each cycle. Patients were treated to a maximum response plus two additional cycles or completed a maximum of eight cycles of therapy without disease progression.

Eighteen (of 40 planned) patients have been enrolled to date with a median age of 72 years (range, 34–82 years). Patients were heavily pretreated with a median of 4 (1-17) prior regimens. Sixteen (89%) patients received prior bortezomib and 11 (61%) were previously treated with either doxorubicin or PLD. Seven (39%) of these patients were exposed to both drugs. Fifteen (83%) had received prior glucocorticoids. Nine (50%) individuals had received immunomodulatory agents with 6 (33%) having been exposed to lenalidomide and all 9 to thalidomide. The majority of patients (72 %) showed International Staging System II or III disease. To date, 16 patients (89%) have shown objective responses to the DVD-R regimen, including 1 complete response (6%), 5 very good partial responses (28%), 4 partial responses (22%) and 6 minimal responses (33%). One of the nonresponding patients showed stable disease and the other progressed after one cycle of therapy. Thus, disease control was achieved in all but one patient (94%). To date, 6 patients have shown progressive disease after a median follow-up time of 6 months (1+ - 9+ months). The DVD-R regimen was well tolerated and only one patient discontinued treatment because of toxicity (peripheral neuropathy). Ten patients experienced grade 3 or 4 adverse events. The most common grade 3 adverse events were reversible neutropenia (n=3), pneumonia (n=3), reversible anemia (n=2), and thrombocytopenia (n=2). There were two patients with grade 4 thrombocytopenia that was reversible. To date, 5 patients (28%) have developed treatment-emergent peripheral neuropathy (four grade 1 and one grade 3). Notably, there have been no cases of stomatitis or hand-foot syndrome.

Thus, these results suggest that the DVD-R regimen using a modified schedule and doses of the combination of intravenous dexamethasone, bortezomib, PLD and lenalidomide is a well tolerated treatment that produces high response rates for heavily previously treated MM patients with R/R disease.

Berenson:Millennium: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau; Centocor OrthoBiotech: Consultancy. Vescio:Millennium: Speakers Bureau; Celgene: Speakers Bureau. Swift:Millennium: Consultancy.