Triplet Therapy Plus Transplantation Prolongs PFS in Multiple Myeloma

Induction treatment with the triplet of lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone (RVD) plus autologous stem cell transplantation (ASCT) was associated with longer progression-free survival (PFS) compared with RVD alone in patients with newly diagnosed multiple myeloma.

Findings showed that the median PFS was 46.2 months in the RVD-alone group and 67.5 months in the transplantation and RVD group. With a median follow-up of 76.0 months, 328 events of disease progression or death occurred with the risk 53% higher in the RVD-alone group than in the transplantation group (HR, 1.53; 95% CI, 1.23-1.91; P < .001).

Additionally, data published in the New England Journal of Medicine showed that the percentage of patients with a partial response (PR) or better was 95.0% in the RVD-alone group vs 97.5% in the transplantation group (P = .55). A total of 42.0% of patients in the RVD-alone group and 46.8% in the transplantation group had a complete response (CR) or better (P = .99).

“The phase 3 DETERMINATION trial [NCT01208662] showed the superiority of ASCT-based first-line therapy with respect to progression-free survival among eligible patients with newly diagnosed myeloma, findings that confirm those of the IFM 2009 trial.We found a significant 21.3-month benefit in median progression-free survival and a 35% lower risk of disease progression or death with RVD plus ASCT than with RVD alone,” wrote the study authors.

In this randomized, open-label phase 3 trial, adults aged 18 to 65 years of age with symptomatic myeloma received 1 cycle of RVD to examine it as the initial management strategy in this patient population.

Initially all patients received 1 cycle of RVD. Then, patients were randomly assigned in a 1:1 ratio to receive 2 additional RVD cycles plus stem cell mobilization. Randomization was stratified according to the International Staging System (ISS) disease stage and cytogenetic risk profile.

In both groups, patients received 2 additional cycles of RVD before stem cell collection. For those in the RVD-alone group, they received 5 additional RVD cycles vs those in the transplantation group who received high-dose melphalan at a dose of 200 mg/m2 plus ASCT. At approximately day 60, patients in the transplantation group received 2 additional RVD cycles.

The 21-day cycle of RVD therapy included oral lenalidomide at 25 mg on days 1 through 14; intravenous or subcutaneous bortezomib at 1.3 mg/m2 on days 1, 4, 8, and 11; and oral dexamethasone at 20 mg in cycles 1 to 3 and 10 mg starting in cycle 4 on days 1, 2, 4, 5, 8, 9, 11, and 12. For both groups, maintenance therapy was made up of daily lenalidomide at 0 mg, with a possible increase to 15 mg thereafter until disease progression, unacceptable toxic effects, or withdrawal from treatment or the trial.

For patients in the RVD-alone group at relapse, off-trial salvage transplantation was recommended but not required after completion of the protocol-specified treatment. Patients in the transplantation group could undergo a second transplantation with the selection of subsequent therapies made by patient and physician decision.

Enrollment was open to patients with symptomatic, measurable, newly diagnosed myeloma, and an ECOG performance status of 0 to 2, myeloma measurable by serum or urine evaluation of the monoclonal component or by assay of serum-free light chains, and a negative HIV blood test. Patients who had previously used systemic therapy for myeloma, central nervous system involvement, primary amyloidosis, and inadequate hematologic, hepatic, renal, or cardiac function were ineligible to be enrolled.

The primary end point was PFS. Secondary end points included response rates, the duration of response (DOR), the time to disease progression, overall survival (OS), quality of life, and adverse events (AEs).

Out of the 873 recruited patients, 357 were randomly assigned to the RVD-alone group and 365 to the transplantation group. Baseline patient and disease characteristics were balanced between the 2 groups with the median age as 57 years (interquartile range, 25-66) in the RVD-alone group and 55 years (interquartile range, 30-65) in the transplantation group. There were 122 patients (34.2%) and 102 patients (27.9%) aged 60 years or older, the ISS disease stage was II or III in 179 patients in the RVD-alone group (50.1%) and in 181 patients in the transplantation group (49.6%), a high-risk cytogenetic profile was identified in 66 of 334 patients (19.8%) and 66 of 340 patients (19.4%), respectively, with data that could be evaluated by means of fluorescence in situ hybridization.

Findings showed that in the RVD-alone group, the median duration of treatment was 28.2 months (95% CI, 21.1-36.3) vs 36.1 months (95% CI, 28.5-41.5) in the transplantation group. Of the 365 patients in the transplantation group, 310 (84.9%) underwent ASCT. There were 289 patients (81.5%) in the RVD-alone group and 289 patients (79.2%) in the transplantation group who received lenalidomide maintenance therapy with the median duration being 36.4 months (95% CI, 25.7-40.8) and 41.5 months (95% CI, 34.0-47.1). At the time of data cutoff, 78 (26.8%) and 89 patients (30.8%) were still receiving maintenance therapy, respectively.

Additionally, the median percentage of maintenance cycles was 87.0% in the RVD-alone group and 60.0% in the transplantation group when the average lenalidomide dose was at least 10 mg. Then, 259 patients (89.0%) in the RVD-alone group and 264 patients (91.3%) in the transplantation group who received lenalidomide maintenance therapy had at least 1 dose modification, with 9854 dose modifications reported during maintenance therapy after RVD alone and 13,695 dose modifications after RVD plus ASCT. Dose modifications were due to AEs or illness in 50.5% of the RVD-alone group and 51.6% in the transplantation group.

Of the 328 patients with events of disease progression or death, there were 189 in the RVD-alone group (52.9%) and 139 in the transplantation group (38.1%). The duration of PFS among patients with a high-risk cytogenetic profile was 17.1 months in the RVD-alone group vs 55.5 months in the transplantation group. For disease progression, a secondary end point of the trial, the percentage of patients who were alive without progression at 5 years was 41.6% and 58.4%, respectively (HR, 1.66; 95% CI, 1.21-2.27).

Additionally, the median DOR was 38.9 months in the RVD-alone group vs 56.4 months in the transplantation group (HR, 1.45; 95% CI, 1.09-1.93), and the percentage of patients with a CR or better at 5 years was 52.9% and 60.6%, respectively.

In regard to safety, hematologic treatment-related AEs (TRAEs) that occurred were neutropenia (42.6% with RVD alone vs 86.3% with transplantation), thrombocytopenia (19.9% vs 82.7%, respectively), leukopenia (19.6% vs 39.7%), anemia (18.2% vs 29.6%), lymphopenia (9.0% vs 10.1%), and febrile neutropenia (4.2% vs 9.0%). Other TRAEs included diarrhea (3.9% in the RVD-alone group vs 4.9% in the transplantation group), nausea (0.6% vs 6.6%, respectively), fatigue (2.8% vs 6.0%), fever (2.0% vs 5.2%), pneumonia (5.0% vs 9.0%), hypophosphatemia (9.5% vs 8.2%), hyperglycemia (2.5% vs 4.1%), hypokalemia (3.4% vs 1.9%), neuropathy (5.6% vs 7.1%) syncope (2.2% vs 1.9%), and maculopapular rash (2.8% vs 3.6%).

Overall, grade 3 of higher TRAE occurred in 279 patients (78.2%) in the RVD-alone group and 344 patients (94.2%) in the transplantation group. Serious RVD-related AEs were observed in 144 patients in the RVD-alone group (40.3%) and 172 patients in the transplantation group (47.1%). Further, treatment-related serious infections were reported during maintenance therapy in 33 patients (11.3%) and 48 (16.6%), respectively.

“Our results also highlight the value of long-term lenalidomide maintenance therapy until disease progression in both groups. In our trial, the median progression-free survival among patients who received RVD alone was 11.2 months longer than that in the IFM 2009 trial [46.2 vs. 35.0 months]; in the latter trial, patients received the same treatment as in the current trial except with only 1 year of maintenance therapy,” wrote the study authors. “The median progression-free survival among patients who received RVD plus ASCT was 20.2 months longer in our trial than in the IFM 2009 trial [67.5 vs 47.3 months]. These findings confirm previous observations of increased progression-free survival with a greater duration of lenalidomide maintenance therapy.”

Reference:

Richardson PG, Jacobus SJ, Weller EA, et al; DETERMINATION Investigators. Triplet therapy, transplantation, and maintenance until progression in myeloma. N Engl J Med. 2022;387(2):132-147. doi:10.1056/NEJMoa2204925