Initial clinical results from Pivotal Phase III Special Protocol Assessment ( SPA ) trials using Revlimid ( Lenalidomide ) as a new approach in the treatment of heavily pretreated patients with relapsed or refractory multiple myeloma have been presented at the10th International Multiple Myeloma Workshop, in Sidney ( Australia ).

The studies reported an overwhelming statistically significant difference ( p < 0.00001 ) in time-to-progression ( TTP ) rate -- the primary endpoint of the two trials -- had not yet been reached for the combination therapy arms.
At the time of the interim analysis, the median TTP for the U.S. trial ( MM-009 ) was at least fifteen months ( MM-009 ) and for the international trial ( MM-010 ) more than eleven months. This is in contrast to the TTP for the Dexamethasone only treated arms of both trials in which the median TTP was five months.

Multiple myeloma is the second most common cancer of the blood, representing approximately one percent of all cancers and two percent of all cancer deaths with a worldwide prevalence of approximately 200,000 cases.
In the year 2004, there were an estimated 74,000 new cases of multiple myeloma worldwide.
The estimated number of deaths from multiple myeloma in 2005 was about 60,000 worldwide.

" The North American and International Multiple Myeloma Phase III trials confirm a significant clinical benefit for patients treated with Revlimid plus Dexamethasone.
In multiple myeloma patients with resistant disease, Revlimid plus Dexamethasone more than doubled the response rate compared with Dexamethasone alone confirming that Revlimid has the potential to be an important new agent for multiple myeloma, " explained Donna Weber, of The University of Texas MD Anderson Cancer Center.

Weber led the U.S. Phase III trial ( MM-009 ), a randomized, double-blinded, placebo-controlled trial, using Revlimid plus Dexamethasone, versus Dexamethasone alone in heavily pretreated relapsed or refractory multiple myeloma patients.
This study enrolled 354 patients from 47 clinical sites throughout the U.S. with data available from 170 patients randomized to Revlimid plus Dexamethasone and 170 patients randomized to Dexamethasone alone.
The median patient age was 63 years.
An Independent Data Monitoring Committee ( IDMC ) reviewed the planned interim analysis and determined that the U.S. Phase III trial overwhelmingly exceeded the pre-established efficacy stopping rule of p < 0.0015 for the primary endpoint, time-to- disease progression.
The response data in MM-009 were available on 340 of the 354 eligible patients that confirmed the findings of the interim analysis, with responses occurring in 51.3% of patients treated with Revlimid plus Dexamethasone, compared to 22.9% of patients treated with Dexamethasone alone ( p = 0.001; one-sided Fisher's exact test ).

" Multiple myeloma is an illness with a discouraging outcome, but, today, with advances such as Revlimid, there is a prospect for myeloma to become a chronic illness for the majority of patients worldwide," explained Meletios Dimopoulos, of The University of Athens School of Medicine, Greece.

Dimopoulos led the International Phase III trial ( MM-010 ), a randomized, double-blinded, placebo-controlled trial, using Revlimid plus Dexamethasone, versus Dexamethasone alone in heavily pretreated relapsed or refractory multiple myeloma patients.
This study enrolled 351 patients from 50 clinical sites internationally with data available from 176 patients randomized to Revlimid plus Dexamethasone and 176 patients randomized to Dexamethasone alone.
The median patient age was 62.5 years.
An Independent Data Monitoring Committee ( IDMC ) reviewed the planned interim analysis and determined that this International Phase III trial overwhelmingly exceeded the pre-established efficacy stopping rule of p < 0.0015 for the primary endpoint, time-to-disease progression.
Response data in MM-010 were available on all 351 eligible patients that confirmed the findings of the interim analysis, with responses occurring in 47.5% of patients treated with Revlimid plus Dexamethasone, compared to 18.4% of patients treated with Dexamethasone alone ( p = 0.001; one-sided Fisher's exact test ).

In both trials, patients treated with Revlimid and Dexamethasone had an increase in side effects as compared to those patients only treated with Dexamethasone.
These adverse drug events were generally manageable and included anemia, thrombocytopenia, neutropenia, fatigue, neuropathy and constipation.
Deep vein thrombosis ( DVT ) occurred in 11.2 and 4.7% of patients treated with Revlimid plus Dexamethasone in MM-009 and MM-010 respectively, compared to 2.9% of patients treated with Dexamethasone alone in both trials.
Pulmonary embolism ( PE ) occurred in 2.4 and 3.5% of patients treated with Revlimid plus Dexamethasone, compared to 0.6 and 1.2% of patients treated with Dexamethasone alone in MM-009 and MM-010 respectively.

About the U.S. ( MM-009 ) and International ( MM-010 ) Phase III SPA Trials These Phase III SPA trials are designed to investigate the effectiveness and safety of syncopated dosing of Revlimid ( Lenalidomide ) at 25 mg combined with high-dose Dexamethasone compared with placebo and HDD in previously treated patients with multiple myeloma.

These trials enrolled 705 patients and are being conducted in 97 sites internationally.
Revlimid ( Lenalidomide ) and high-dose Dexamethasone are given in 28-day cycles : Lenalidomide 25 mg once daily on Days 1-21 every 28 days, and high-dose Dexamethasone 40 mg on Days 1-4, 9-12 and 17-20 every 28 days.
After four cycles the high-dose Dexamethasone schedule is reduced to 40 mg on Days 1-4 every 28 days).

The primary endpoint of the study is time-to-tumor progression ( TTP ) calculated as the time from randomization to the first documentation of progressive disease based on Blade myeloma response criteria.
The secondary endpoints are response and overall survival.

Source: Celgene, 2005


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