Efforts to position the blood cancer drugs Revlimid (lenalidomide, Celgene) and Velcade (bortezomib, Takeda/Johnson & Johnson) for earlier intervention and long-term maintenance therapy in multiple myeloma can take some sustenance from two Phase III trials presented at the 51st American Society of Hematology annual meeting in New Orleans, US.

Preclinical data from MM-0115, a randomised, double-blind study in older patients newly diagnosed with multiple myeloma (MM), showed marked survival benefits when one particular regimen of Revlimid was given early and as continuous therapy.

The trial involved 459 patients aged 65 years or over who received Revlimid in combination with the standard therapies melphalan and prednisone, followed by Revlimid alone (MPR-R, 152 patients); Revlimid in combination with melphalan/prednisone, followed by placebo (MPR, 153 patients); or placebo, melphalan and prednisone, followed by placebo (MP, 154 patients).

As Dr Maria-Victoria Mateos, lead investigator for the VISTA study of Velcade in multiple myeloma, pointed out, the preferred treatment for the disease in patients under the age of 65 is high-dose chemotherapy with haematopoietic stem-cell transplantation – although most newly diagnosed MM patients are over 65 years old.

The primary endpoint in the Revlimid study was to determine improvements in progression-free survival (PFS) on MPR-R versus MP. Two interim analyses were incorporated into the study and an independent adjudication committee confirmed responses to therapy as well as disease progression.

The preliminary data showed that patients treated with MPR-R had a 50% reduction in risk of disease progression compared with MP – “one of the highest reported risk reductions compared to MP of any Phase III study in newly diagnosed multiple myeloma to date”, Celgene said.

At the first interim analysis (median follow-up: 9.4 months), the median progression-free survival for MPR-R had not yet been reached, while the MP arm showed a median PFS of 13.0 months. However, analysts seized on the lack of difference in median PFS between the MP and the MPR arms - not mentioned in the press release issued by Celgene on the ASH results.

Reuters quoted investigators as suggesting this may have been due to the trial using a relatively low dose of Revlimid. Investigators were sceptical, though, and Celgene's shares dropped by nearly 3% on the study results.

Sanford Bernstein analyst Geoffrey Porges was quoted as saying that the lack of difference between the MPR and the MP arms "raises questions among investors about both the approvability of the MPR regimen in front-line use and the commercial viability of Revlimid front-line use generally".

A secondary comparison of MPR followed by continuous Revlimid (i.e., MPR-R) versus MPR of fixed duration (MPR) demonstrated the value of Celgene’s drug as maintenance therapy. Patients received Revlimid, melphalan and prednisone for nine cycles and were then randomised either to continuous Revlimid therapy or to placebo from cycle 10 onwards.

Those patients given continuous Revlimid therapy from the 10th cycle of treatment had a 75% reduction in the risk of disease progression compared with those on placebo after nine fixed cycles (MPR).

VISTA data

The VISTA (Velcade as Initial Standard Therapy in Multiple Myeloma: Assessment with Melphalan and Prednisone) study is the largest to date of long-term overall survival in multiple myeloma patients, noted its sponsor, Janssen-Cilag.

Running to September 2007, VISTA was a randomised, open-label Phase III trial conducted at 151 centres in Europe, Asia and North and South America.

Patients with newly diagnosed, untreated, symptomatic and measurable myeloma who were not eligible for high-dose chemotherapy plus stem-cell transplantation, due to co-existing conditions or age (65 years or over). were given the standard nine six-week cycles of MP therapy alone or in combination with Velcade.

The primary endpoint was time to disease progression and secondary endpoints included duration of response, time to subsequent myeloma therapy and overall survival. The data presented by Dr Mateos in New Orleans were an updated survival analysis of VISTA after a median follow-up of 36.7 months, with the majority of patients receiving subsequent therapy.

Notably, the findings showed that at the end of the follow-up period, the combination of MP (melphalan/prednisone) and Velcade (VMP) continued to provide a survival benefit, with a 35% reduction in risk of death versus MP alone, Janssen-Cilag said.

Three-year overall survival rates were 68.5% and 54.0% in the VMP and MP groups respectively, and these were consistent across patient subgroups pre-defined by baseline characteristics (e.g., age greater or less than 75 years).

As of the data cut-off point of 16 March 2009, 178 (52%) and 233 (69%) of the VMP and MP patients respectively were given subsequent therapy. In this case, VMP scored better on median time to subsequent therapy (28.1 months versus 19.2 months for MP) and median treatment-free interval (17.6 months versus 8.4 months).

Moreover, 43% of VMP patients had a treatment-free interval of up to two years, compared with only 18% of the MP group, Janssen-Cilag noted.

The new findings confirm those previously reported from the VISTA trial, which showed that adding Velcade to MP extended time to disease progression (24 months versus 16.6 months on MP alone), it added.