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Continuous therapy improves PFS, OS in newly diagnosed multiple myeloma
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Patients with newly diagnosed multiple myeloma experienced prolonged OS and PFS at first and second progression when they received continuous therapy rather than fixed-duration treatment, according to the results of a pooled analysis of three phase 3 trials.
The improvement in second PFS (PFS2) — defined as time from random assignment until the second progression or death — suggested that the benefit reported during first remission (PFS1) is not voided by a shorter second remission, according to the researchers.
“Despite recent encouraging results, most patients with multiple myeloma eventually experience relapse,” Antonio Palumbo, MD, chief of the myeloma unit at University of Turin in Italy, and colleagues wrote. “Initial therapy may affect the tumor drug–resistance profile; there is some concern that patients who experience progression while on continuous therapy may become resistant to at least that therapy. In multiple myeloma, similarly to other cancers, the occurrence of resistant relapse may reduce the duration of subsequent remissions, with negative impact on OS.”
Palumbo and colleagues conducted a pooled analysis of three phase 3 clinical trials to evaluate the benefit of novel agent-based continuous therapy compared with fixed-duration therapy for patients with newly diagnosed multiple myeloma. Agents studied in these trials included lenalidomide (Revlimid, Celgene), thalidomide (Thalomid, Celgene) and bortezomib (Velcade, Millennium Pharmaceuticals).
The researchers restricted primary analyses to the intent-to-treat population eligible for continuous therapy, defined as progression-free patients alive at 1 year following random assignment.
PFS1, PFS2 and OS served as the primary endpoints.
Median follow-up was 52 months.
The intent-to-treat population included 417 patients assigned to continuous therapy and 410 patients assigned to fixed-duration therapy. In this population, patients who received continuous therapy experienced significantly prolonged PFS1 (median, 32 months vs. 16 months; HR = 0.47; 95% CI, 0.4-0.56) and PFS2 (median, 55 months vs. 40 months; HR = 0.61; 95% CI, 0.5-0.75). More patients assigned continuous therapy also achieved 4-year OS (69% vs. 60%; HR = 0.69; 95% CI, 0.54-0.88).
The researchers acknowledged limitations of their study, such as the inclusion of patients eligible and ineligible for stem-cell transplantation. Further, they noted that they lacked data on cytogenetics for approximately 30% of patients.
“Our results indicate that continuous therapy provides a clinically relevant improvement in median PFS1 and PFS2 of approximately 1 year and an OS improvement of approximately 10% in patients with newly diagnosed multiple myeloma,” Palumbo and colleagues wrote. “The improvement in PFS2 suggests that most of the benefit observed during the first remission is not affected by a short second remission. … PFS2 is a strong candidate endpoint to estimate long-term clinical benefit and should be included in future trials to evaluate the impact of chemotherapy resistance. Future individual patient data analyses on larger populations are needed to formally validate the role of PFS1 and PFS2 as surrogate endpoints for OS in multiple myeloma." – by Cameron Kelsall
Disclosure: Palumbo reports honoraria from and consultant roles with Celgene and Janssen-Cilag. Please see the full study for a list of all other researchers’ relevant financial disclosures.
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