DETERMINATION Results In Extended PFS For Newly Diagnosed Multiple Myeloma

Author: By Lynda Williams, medwireNews Reporter 

medwireNews: The DETERMINATION investigators have demonstrated a significant progression-free survival (PFS) benefit with the addition of autologous stem-cell transplantation (ASCT) to lenalidomide, bortezomib and dexamethasone (RVD) plus lenalidomide maintenance for patients with newly diagnosed multiple myeloma. 

The phase III trial findings were presented at the 2022 ASCO Annual Meeting in Chicago, Illinois, USA, by Paul Richardson, from the Dana–Farber Cancer Institute in Boston, Massachusetts, USA, and simultaneously published in The New England Journal of Medicine. 

However, the trial did not show a significant overall survival (OS) benefit with early ASCT, prompting the authors to write that “in the context of considerations regarding real-world factors such as treatment burden, acute and long-term toxic effects, patient preference and quality of life, these findings may be taken into account when making treatment decisions.” 

The trial recruited 722 patients with symptomatic myeloma, all of whom received a first 21-day cycle of RVD consisting of lenalidomide 25 mg on days 1–14; bortezomib 1.3 mg/m2 on days 1, 4, 8 and 11; and dexamethasone 20 mg in cycles 1–3 on days 1, 2, 4, 5, 8, 9, 11 and 12 (increasing to 10 mg for later cycles).  

The patients were then randomly assigned to receive a further two RVD cycles, followed by stem cell collection, high-dose melphalan plus ASCT and an additional two cycles of RVD on recovery (n=365) or to receive two RVD cycles, stem cell collection and a further five RVD cycles (n=357). 

Overall, 84.9% of patients in the transplantation arm underwent ASCT, say the researchers. 

The majority of patients in both the ASCT (79.2%) and control (81.5%) arms went onto receive lenalidomide 10 mg/day maintenance therapy until disease progression and/or unacceptable toxicity, for a median of 41.5 and 36.4 months, respectively. 

After a median of 76.0 months, the rate of disease progression or death was a significant 53% higher for the patients given only RVD versus those who received ASCT, with median PFS of 67.5 and 46.2 months, respectively. 

Analysis by cytogenetic risk showed that patients with a high-risk profile had a median PFS of 55.5 months after ASCT versus 17.1 months after RVD only (HR=1.99), with corresponding durations for standard-risk patients of 82.3 and 53.2 months (HR=1.38). 

And further investigation indicated that “broadly, early transplant did very well across all prespecified subgroups”, Paul Richardson told delegates. But he noted that patients with International Staging System (ISS) stage III appeared to derive less benefit from early ASCT than those with ISS I or II disease, and that among high-risk cytogenetic patients, those with t(4;14) cytogenetics benefited from ASCT but there was less evidence for those with del(17p). In addition, there was only a “marginal” benefit with early ASCT among African American participants, he said. 

The transplantation and control arms had a similar likelihood of achieving a partial response or better outcome (97.5 vs 95.0%) or complete response or better (46.8 vs 42.0%), and the 5-year rates of OS were also comparable, at 80.7% versus 79.2%. For patients with high-risk disease, the 5-year OS rates were 63.4% and 54.3%, respectively. 

Response lasted for a median of 56.4 months after transplantation and 38.9 months after RVD alone, giving a significant hazard ratio of 1.45 in favour of ASCT. Among patients who achieved a complete response, a comparable 60.6% of ASCT-treated patients and 52.9% of controls remained in response for 5 years.  

The researchers also reported preliminary analysis regarding the impact of minimal residual disease (MRD) at time of lenalidomide maintenance initiation, as determined by next-generation sequencing.  

Overall, 54% of 90 patients who underwent ASCT and 40% of 108 patients given only RVD had no MRD when beginning maintenance and for these participants, 5-year PFS rates were similar at 53.5% versus 59.2%.  

Safety profile analysis indicated that patients who underwent early ASCT were more likely than controls to experience treatment-related adverse events (TRAEs) at grade 3 or more (94.2 vs 78.2%), as well as haematological TRAEs at this grade (89.9 vs 60.5%). 

Serious AEs related to RVD occurred in 47.1% of the transplantation arm and 40.3% of the control group, while treatment-related serious infections were reported for a corresponding 16.6% and 11.3%. The 5-year cumulative incidence of second primary cancers was a comparable 10.8% and 9.7%, respectively, although the researchers note that 10 patients who underwent ASCT developed acute myeloid leukaemia or myelodysplastic syndrome compared with none of the controls. 

EORTC QLQ-C30 global health status scores were comparable for the treatment groups, except that patients given ASCT had a “meaningful dip” after transplantation that subsequently recovered, Paul Richardson said. 

The authors emphasize that the DETERMINATION study shows the benefit of maintenance lenalidomide, with a median 11.2-month longer PFS compared with the earlier IFM 2009 trial, participants in which received only 1 year of maintenance therapy. 

They suggest that “[t]he lack of an overall survival benefit of RVD plus ASCT is probably associated with the multiple, highly efficacious options available after first-line therapy that have emerged over the past 10 years”, noting that just 28.0% of patients given only RVD went onto receive ASCT after trial drug discontinuation versus 76.7% of those in the RVD-only arm of IFM 2009, although “this proportion may increase with longer follow-up”.

Session discussant Joseph Mikhael, from City of Hope Cancer Center in Phoenix, Arizona, USA, commended the DETERMINATION trial for achieving an African American participation rate of approximately 19%, noting that this patient population has a lower age at time of diagnosis, less access to key treatments and poorer outcomes than White individuals. 

He said that the take-home messages from the presentation were that ASCT “remains a viable and valuable component of therapy”, and that maintenance treatment should continue until disease progression, but that the OS findings mean that treatment should be individualised based on factors such as age, risk status, patient preference, treatment availability, and the likely feasibility of ASCT in the future. 

Joseph Mikhael concluded that use of quadruplet therapy and immunotherapy may mean that use of ASCT in the future is based on depth of response and residual disease, rather than transplant eligibility. 

Reference  

Richardson PG, Jacobus SJ, Weller EA, et al. Triplet therapy, transplantation, and maintenance until progression in myeloma. N Engl J Med; Advance online publication 5 June 2022. DOI: 10.1056/NEJMoa2204925