Continuous Therapy Significantly Improves Outcomes compared to Fixed Duration of Therapy in Patients with Newly Diagnosed Multiple Myeloma

SUMMARY: Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, close to 27,000 new cases will be diagnosed in 2015 and 11,240 will die of the disease. Maintenance or Continuous Treatment in patients with newly diagnosed multiple myeloma following induction and consolidation, can result in significantly longer Progression Free Survival (PFS) and Overall Survival (OS), compared to those patients who receive therapy for a fixed duration of time. Not all studies however, have shown Overall Survival benefit. It has been hypothesized that Continuous Treatment could result in resistance to therapy which in turn could reduce the duration of subsequent remission after first relapse and negatively impact overall survival.To address this controversy, the authors conducted a pooled analysis of the outcomes of three randomized phase III trials, coordinated by the same principal investigator, designed to compare Continuous Treatment to Fixed Duration Therapy, in patients with newly diagnosed multiple myeloma.

In trial RV-MM-209, patients were randomized to either induction with Lenolidomide (REVLIMID®), followed by consolidation and subsequent maintenance with REVLIMID® (Continuous Treatment) or Fixed Duration Therapy which entailed REVLIMID® based induction followed by consolidation but no maintenance therapy. In the GIMEMA0305 trial, the randomization was between Bortezomib (VELCADE®) based induction followed by maintenance treatment (Continuous Treatment) and VELCADE® induction, with no maintenance treatment (Fixed Duration Therapy). In the CC-5013-MM-015 study, the comparison was between REVLIMID® in combination with Melphalan and Prednisone followed by REVLIMID® maintenance until disease progression and placebo given along with Melphalan and Prednisone.

The trial investigators assessed PFS1 as the time from diagnosis to the occurrence of 1st relapse, PFS2 as time from diagnosis to the occurrence of 2nd relapse and Overall Survival as time from diagnosis to death , incorporating the duration of both 1st and 2nd remission. They then evaluated PFS1, PFS2 and OS, in newly diagnosed multiple myeloma patients who received Continuous Therapy or Fixed Duration Therapy. In this pooled analysis of three trials, 604 patients were randomized to Continuous Treatment and 614 patients were randomized to Fixed Duration Therapy. Four hundred and seventeen (N=417) in the Continuous Therapy group and 410 patients in the Fixed Duration Therapy group were eligible for comparative analysis. The median follow up was 52 months.

Patients receiving Continuous Treatment had significantly prolonged PFS1 (median 32 months versus 16 months; HR=0.47; P<0.001), PFS2 (median 55 months versus 40 months; HR=0.61; P=0.001) and OS (4 year OS 69% versus 60%; HR=0.69; P=0.003), when compared with Fixed Dose Therapy. The authors evaluated the PFS and OS from first relapse to second relapse and from first relapse to death respectively, and they noted that the outcomes were similar among patients who received Continuous Treatment or Fixed Dose Therapy following initial diagnosis.

The authors concluded that Continuous Treatment significantly improved PFS1, PFS2, and OS and findings from this pooled analysis suggested that the clinical benefit observed during first remission was not negated by a shorter second remission and Continuous Treatment did not induce tumor resistance. Continuous Treatment may be essential, as patients with multiple myeloma will always have some residual disease. It should be noted that certain institutions including the Mayo Clinic cap Continuous/Maintenance treatment at approximately 2 years, due to the lack of randomized comparative data, on the value of prolonged maintenance beyond 2 years. Continuous Therapy Versus Fixed Duration of Therapy in Patients With Newly Diagnosed Multiple Myeloma. Palumbo A, Gay F, Cavallo F, et al. J Clin Oncol 2015;33:3459-3466