Photo by Chad McNeeley
HSCT preparation
The use of autologous transplant after a 3-drug induction regimen for multiple myeloma (MM) prolongs progression-free survival (PFS) but not overall survival (OS), according to new research.
In a phase 3 trial, newly diagnosed MM patients who received lenalidomide, bortezomib, and dexamethasone (RVD) followed by an autologous hematopoietic stem cell transplant (HSCT) had significantly better PFS but similar OS when compared to patients who only received RVD.
In addition, HSCT recipients had significantly higher rates of high-grade blood and lymphatic system disorders, gastrointestinal events, and infections.
The study also showed that OS outcomes were similar for patients who received HSCT after completing treatment with RVD and patients who were in the RVD-only treatment arm but underwent HSCT later, as salvage therapy.
Researchers believe this suggests MM patients can potentially choose when to undergo a transplant.
The team reported their findings in NEJM. The study was supported by grants from Celgene and Janssen and by funds from the French Ministry of Health Programme Hospitalier de Recherche Clinique and from the French National Research Agency.
“Over the past decade, drugs that modulate the immune system and agents known as proteasome inhibitors have shown a great deal of promise in patients with multiple myeloma, when used in combination with chemotherapy,” said study author Paul Richardson, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts.
“This led us to propose that these combinations could be used selectively with established modalities such as transplant for patients with newly diagnosed myeloma, and this, in turn, raised questions about where and how transplant should be fit into the therapeutic paradigm. Our trial sought to comprehensively address these issues in a prospective fashion, and provide a foundation for future studies as the next generation of agents, such as monoclonal antibodies, impact the field.”
The study enrolled 700 adult patients under the age of 65 who were newly diagnosed with MM. They were treated at 69 centers in France, Belgium, and Switzerland.
The patients were randomized to 2 treatment arms. Both groups received 3 initial cycles of RVD.
One group then received 5 more cycles of RVD. The other received high-dose chemotherapy (melphalan) followed by an autologous HSCT and 2 additional cycles of RVD.
Patients in both groups then received lenalidomide as maintenance therapy for 1 year or until they progressed, experienced unacceptable adverse events (AEs), or withdrew consent.
Response and survival
The complete response rate was significantly higher in the HSCT arm than the RVD-alone arm—59% and 48%, respectively (P=0.03).
And there was a significantly higher percentage of patients who were negative for minimal residual disease in the HSCT arm than in the RVD arm—79% and 65%, respectively (P<0.001).
The median PFS was significantly longer in the HSCT arm than the RVD arm—50 months and 36 months, respectively (P<0.001). The researchers said this benefit was observed across all patient subgroups, including those stratified according to International Staging System stage and cytogenetic risk.
There was no significant between-group difference in the rate of OS at 4 years, which was 81% in the HSCT arm and 82% in the RVD arm.
Subsequent therapy
In the RVD arm, 207 patients progressed, and 172 received second-line therapy, which was followed by salvage HSCT in 136 patients (79%).
In the HSCT arm, 149 patients progressed, and 123 received second-line therapy, which was followed by a second HSCT in 21 patients (17%).
Safety
Nine percent of patients in the RVD arm and 11% in the HSCT arm discontinued treatment due to AEs. There were 2 treatment-related deaths in the RVD arm and 6 in the HSCT arm.
Grade 3/4 AEs with a significantly higher incidence in the HSCT arm than the RVD arm were blood and lymphatic system disorders (95% and 64%, respectively, P<0.001), gastrointestinal disorders (28% and 7%, respectively, P<0.001), and infections (20% and 9%, respectively, P<0.001).
Thirteen patients in the RVD arm and 17 in the HSCT arm had at least 1 invasive second primary malignancy (P=0.36). Acute myeloid leukemia occurred in 1 patient in the RVD arm and 4 in the HSCT arm (P=0.21).
The researchers said these results suggest the benefits of HSCT plus RVD must be weighed against the increased risk of toxicity associated with high-dose chemotherapy plus HSCT, particularly since HSCT after progression might be as effective as early HSCT for ensuring long-term OS.
