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Tandem transplant, RVD consolidation after upfront HSCT do not improve outcomes in myeloma
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SAN DIEGO — Two alternative and more intensive interventions after upfront hematopoietic stem cell transplant failed to extend survival among patients with multiple myeloma compared with the standard approach, according to results of the STAMINA trial presented at the ASH Annual Meeting and Exposition.
Patients who underwent tandem autologous hematopoietic stem cell transplant and those who underwent upfront transplant followed by triple-therapy consolidation derived no PFS or OS benefit compared with those who underwent upfront transplant followed by maintenance with lenalidomide (Revlimid, Celgene).
“There are many important future evaluations needed to fully understand the impact of these results,” Edward A. Stadtmauer, MD, chief of hematologic malignancies at Abramson Cancer Center at University of Pennsylvania, said during a presentation. “Long-term follow-up is essential for survival, toxicity, and correlations of initial therapy and outcomes.”
Lenalidomide maintenance after autologous hematopoietic cell transplant improves PFS and OS in patients with multiple myeloma.
However, the potential benefits of additional interventions — such as second transplant or consolidation with combinations of thalidomide (Thalomid, Celgene) analogues, proteasome inhibitors and corticosteroids — had not been established.
The randomized, prospective, phase 3 STAMINA trial — the largest randomized comparison of posttransplant approaches in myeloma in the United States — included 758 transplant-eligible patients aged 70 years or younger with symptomatic myeloma.
All patients had Karnofsky performance status of at least 70, had received at least two cycles of systemic therapy, and were enrolled within 2 to 12 months of initial therapy initiation.
All patients underwent autologous hematopoietic cell transplant with melphalan 200 mg/m2. Prior to transplant, more than 50% received the RVD regimen, which consisted of bortezomib (Velcade, Takeda), lenalidomide and dexamethasone; about 15% received cyclophosphamide, bortezomib and dexamethasone; approximately 10% received lenalidomide and dexamethasone; about 12% received bortezomib and dexamethasone; and less than 10% received other regimens.
Patients then underwent one of three regimens, to which they were randomly assigned prior to initial transplant:
- 257 patients received lenalidomide maintenance, starting at 10 mg daily for three cycles, followed by 15 mg/day. The maintenance regimen initially was offered for 3 years, but an amendment in 2014 based on results of the CALGB 100104 trial changed the duration to the time of disease progression or unacceptable toxicity.
- 254 patients received RVD consolidation followed by lenalidomide maintenance. The RVD regimen, administered in 21-day cycles for four cycles, consisted of bortezomib 1.3 mg/m2 on days 1, 4, 8 and 11; lenalidomide 15 mg on days 1-15; and dexamethasone 40 mg on days 1, 8 and 15.
- 247 patients underwent a second autologous hematopoietic cell transplant with melphalan 200 mg/m2, followed by lenalidomide maintenance.
Demographics — including disease risk status, sex, Karnofsky performance status — were balanced between groups.
A comparison of PFS at 38 months from randomization served as the primary objective. This allowed 2 months for patients to obtain first transplant and an additional 3 years of follow-up.
Secondary endpoints included comparisons of OS, response rates, rate of complete remission conversion, toxicity, infection incidence, protocol therapy noncompliance, treatment-related mortality and quality of life.
Median follow-up was 37.8 months (range, 28.2-47.4).
Compliance with the assigned posttransplant regimen was 94.6% among patients assigned lenalidomide maintenance alone, 88.2% among patients assigned RVD consolidation plus lenalidomide maintenance, and 68% among those assigned a second transplant.
Results showed no statistically significant difference in estimated 38-month PFS between those assigned lenalidomide maintenance alone (52.2%), RVD consolidation plus lenalidomide maintenance (56.7%) or second transplant (56.5%).
Researchers observed no significant difference in estimated 38-month OS between those assigned lenalidomide maintenance alone (83.4%), RVD consolidation plus lenalidomide maintenance (85.7%) or second transplant (82%).
Analyses stratified by disease risk continued to show no significant differences in 38-month PFS (range for standard-risk patients, 55.9% to 60.9%; range for high-risk patients, 40.2% to 48.3%) or 38-month OS (range for standard-risk patients, 82.9% to 88.3%; range for high-risk patients, 77.5% to 79.6%).
“I think it’s an impressive result that about 77% to 79% of high-risk patients at 38 months were alive,” Stadtmauer said.
Researchers reported no differences in treatment-related mortality. One patient assigned lenalidomide maintenance alone died, compared with three assigned RVD consolidation and four assigned tandem transplant.
Thirty-nine patients (5.1%) developed second primary malignancies. This included 10 (4%) assigned lenalidomide maintenance alone, 15 (6%) assigned RVD consolidation and 14 (5.9%) assigned second transplant.
Stadtmauer and colleagues are conducting further response assessments. They also are analyzing the conversion rates to complete remission, exploring the reasons why patients did not proceed to their assigned posttransplant regimen, and performing minimal residual disease analyses.
“We also need to compare and contrast these results with those of other large prospective randomized trials,” he said. – by Mark Leiser
Reference: Stadtmauer EA, et al. Abstract LBA-1. Presented at: ASH Annual Meeting and Exposition; Dec. 3-6, 2016; San Diego.
Disclosure: Stadtmauer reports consultant roles with Amgen, Celgene, Janssen, Novartis and Takeda. Please see the abstract for a list of all other researchers’ relevant financial disclosures.
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Saad Z. Usmani, MD, FACP
It is interesting to note in this trial — unlike previous European studies that have shown superiority of tandem transplants to single autologous transplants — is that there was heterogeneity in the kinds of regimens patients received before enrolling on the study. Some may have received doublets and some may have received triplets. Even within the triplets there was heterogeneity. Nevertheless, the trial — at least at this point — does not show any statistical differences between the survival curves for PFS or OS. In most transplant trials that compare one modality to another, the curves don’t start separating until about the 5-year or 6-year mark. So, even though the data show no differences, we still have to wait a little while and see how the data really play out.
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