Triplet induction, autologous HSCT, lenalidomide maintenance extend PFS in multiple myeloma
Click Here to Manage Email Alerts
CHICAGO — Lenalidomide, bortezomib and dexamethasone plus autologous stem cell transplantation and lenalidomide-based maintenance conferred a significant PFS benefit among patients with newly diagnosed multiple myeloma.
However, no OS benefit had been observed at the time of data cutoff, according to results of the phase 3 DETERMINATION trial presented during ASCO Annual Meeting and published simultaneously in The New England Journal of Medicine.
Rationale and methods
“We sought to explore the impact of a triplet therapy in a cohort of newly diagnosed, younger-aged patients and how to best use transplant in these patients,” Paul G. Richardson, MD, director of clinical research at Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute, and a HemOnc Today Editorial Board Member, told Healio.
Richardson and colleagues randomly assigned 357 patients with newly diagnosed multiple myeloma to three cycles of lenalidomide, bortezomib and dexamethasone (Rived) and stem cell mobilization, followed by five more cycles of RVd as induction/remission therapy (arm A), compared with 365 patients assigned IV melphalan dosed at 200 mg/m² plus autologous stem cell transplantation (ASCT) and two additional RVd cycles (arm B), followed by continuous lenalidomide maintenance in both arms until progression or intolerance.
Patients in arm A and arm B had similar baseline characteristics, including median age (57 years vs. 55 years), stage III disease according to the International Staging System (14% vs. 13%) and high-risk cytogenetics (18% in both groups).
PFS served as the primary endpoint.
Median follow-up was 76 months.
Key findings
Overall, 291 patients in arm A and 290 patients in arm B received lenalidomide maintenance for a median duration of 36 months and 41 months.
Researchers reported median PFS of 46.2 months in arm A compared with 67.5 months in arm B (HR = 1.53; 95% CI, 1.23-1.91).
They observed a complete response in 42% of patients in arm A compared with 47% in arm B; very good partial response in 80% vs. 83% and partial response in 95% vs. 97.5%.
Among all evaluable patients (n = 251), those in arm A had a minimal residual disease negativity rate of 40% compared with 54% in arm B within 1 year of lenalidomide maintenance, and 63% vs. 53% received subsequent treatment. Twenty-eight percent of patients in arm A underwent ASCT as first non-protocol therapy.
At the time of data cutoff Dec. 10, 2021, arm A had a 5-year OS rate of 79.2% (95% CI, 80-88) vs. 80.7% (95% CI, 81-88) for arm B (HR = 1.1; 95% CI, 0.73-1.65).
Researchers noted grade 3 or higher treatment-associated adverse events in 78% of patients in arm A vs. 94% in arm B, of which 61% and 90% were hematologic (P < .0001). Moreover, although 10% of patients in arm A and 11% in arm B experienced secondary malignancies overall, 10 patients in arm B developed AML/MDS vs. none in arm A (P = 0.002). Quality of life in patients undergoing ASCT early also declined significantly during transplant but recovered over time during maintenance.
“We were able to show a remarkable PFS benefit in favor of early transplant, with excellent PFS seen for both treatment arms and among the best reported so far,” Richardson said. “However, there was no OS difference observed for early use of ASCT, which we thought was important because the data are quite mature. OS with a median of over 6.5 years of follow-up was essentially the same, in fact, even though in the delayed or deferred transplant arm only 28% of patients underwent ASCT. This suggests that novel therapies being used as salvage are having a favorable impact on the one hand, and that there also are other factors influencing OS on the other. Additionally, continuous maintenance appears to really matter in this setting, with the best outcomes reported to date irrespective of treatment arm.”
Looking ahead
Ongoing research includes whole-genome sequencing, additional quality-of-life measures and correlative analyses, researchers noted.
“We showed high-quality responses in both groups of patients, and we saw encouraging rates of minimal residual disease for both arms, although higher with early transplant,” Richardson said. “We also saw better outcome for MRD-positive patients undergoing transplant early vs. not. Encouragingly, we now have four drug combinations with markedly higher minimal residual disease negativity overall, and we are evaluating next how much transplant adds in that setting and in the future, whether transplant can be kept further in reserve for a select group of patients. Conversely should it be used regardless in patients with certain types of high-risk disease? We are increasingly beginning to see a more tailored approach as a key new direction.” Additionally, researchers need to better understand why certain subgroups of patients demonstrated more pronounced benefits, he added.
“For example, we also saw that among the 18% of Black patients in the study — whose risk for myeloma is twofold higher than white individuals — the benefit of transplant was less obvious,” he said. “So for these patients, we may be able to conclude that should they and their families not want to pursue a transplant immediately, and prefer to keep it in reserve, this is a reasonable approach because our data indicate that they do not appear to lose a marked PFS benefit nor any OS gain from such a strategy. Importantly, with all of the new treatments in development and recently approved — such as CAR-T and specific small-molecule treatments, we have numerous exciting new options for all our patients and can further tailor treatment to each patient’s need.”
References:
Richardson PG, et al. Abstract LBA4. Presented at: ASCO Annual Meeting; June 3-7, 2022; Chicago.
Richardson PG, et al. N Engl J Med. 2022;doi:10.1056/NEJMoa2204925.
For more information:
Paul G. Richardson, MD, can be reached at paul_richardson@dfci.haravrd.edu.
Perspective
Back to Top
Nitya Nathwani, MD
Multiple myeloma is the second most common hematologic malignancy and although there have been tremendous advances in treatment, it is not currently thought to be curable.
Historically, high-dose melphalan with autologous stem cell transplant (ASCT) has been offered to eligible patients as consolidation therapy following front-line induction. This is typically followed by lenalidomide maintenance until progression. Unfortunately, a significant proportion of patients ultimately relapse.
The DETERMINATION trial is a parallel trial to another phase 3 study conducted by the French myeloma group. Both trials utilized RVd induction therapy alone or with high-dose melphalan-ASCT, followed by lenalidomide maintenance in transplant-eligible patients with newly diagnosed multiple myeloma. In the French trial, lenalidomide maintenance was administered for 1 year, and in this U.S. trial, it was administered until progressive disease.
Both trials demonstrated an improvement in PFS with use of ASCT, and in the DETERMINATION trial, with the longer duration of lenalidomide maintenance, it was not surprising that the improvement in PFS was also greater. In this trial, ASCT lead to deeper responses with improvement in the rate of measurable residual disease (MRD) negativity, and there is a growing body of evidence demonstrating the prognostic value of achieving MRD negativity.
These long-awaited results from the DETERMINATION trial confirmed that there was no improvement in OS in either trial, and a notable difference between the French and U.S. trials is that in the latter, only a minority of patients underwent ASCT at relapse. This may be due to the multiple available effective options at relapse. Additionally, although the PFS among both ASCT and RVd arms in the U.S. trial was encouraging, this was a relatively young cohort, with a lower proportion of patients having higher-stage disease.
Although ASCT has traditionally been considered the standard of care for transplant-eligible patients, there are ongoing trials that may ultimately question its role. With novel approaches such as quadruplet induction with incorporation of CD38 monoclonal antibodies, and exploring potentially moving highly effective CAR T-cell therapy and bispecific antibodies to earlier lines of therapy, we anticipate a greater percentage of patients achieving MRD negativity. The higher number of second primary hematologic malignancies (in particular AML and myelodysplastic syndrome in the HDM-ASCT group from the DETERMINATION trial, combined with tolerability concerns with ongoing lenalidomide use, and the unfortunate reality that the majority of myeloma patients ultimately relapse raises important questions: Can the duration of maintenance be adapted to response, particularly among patients with standard risk disease who achieve sustained MRD negativity (ie, could this subgroup of patients potentially stop therapy)?
What is the optimal treatment of high-risk patients, and should they receive augmented therapy with novel approaches? Observations from the DETERMINATION trial and other advances in the field suggest the use of personalized medicine with individualized treatment based on disease risk status, and depth of response, among other factors.
Reference:
Attal M, et al. N Engl J Med. 2017;doi:10.1056/NEJMoa1611750.
Perspective
Back to Top
Samer Al-Homsi, MD, MBA
The study results further support an already established role of autologous hematopoietic stem cell transplantation in the management of patients with multiple myeloma. The treatment regimen is applicable to patients determined by an expert in transplantation fit to receive autologous hematopoietic transplantation.
Although this study — like many others — establish hematopoietic stem cell transplantation as part of the standard of care in multiple myeloma, only a fraction of patients actually are offered this important modality of treatment for a variety of reasons, including provider bias. In fact, although improvement in supportive care have enhanced the safety of the procedure, many patients are denied this therapy.
The lack of difference in OS might be due to the fact that many patients in arm A ended up receiving transplantation at the time of progression. Also, longer follow-up might reveal a difference in OS.
The toxicities are manageable. The incidence of secondary malignancies was not statistically different between the two groups. However, lenalidomide has been associated in other studies with increased incidence of secondary malignancies, and it must be noted that this study used extended administration of lenalidomide until progression.
Perspective
Back to Top
Julie R. Gralow, MD, FACP, FASCO
The prognosis for multiple myeloma has improved substantially during the past 10 years. Very striking here is the improved PFS of years and not just months as we see for many disease types. [The fact that] this trial started in 2009 shows that it takes this long to achieve results. We need to invest in this, but standard of care does change.
This trial gives very important information related to the benefits and toxicity of treatment so that we can have better informed discussions with our patients. Duration of response matters to many patients who would prefer to hold off on toxic treatment like a transplant until they may need it later.
Locking in the benefit of lenalidomide-based maintenance is an important concept here, as well. We want to give our patients the best quality of life for as long as possible.
Collapse
Richardson PG, et al. Abstract LBA4. Presented at: ASCO Annual Meeting; June 3-7, 2022; Chicago.
Click Here to Manage Email Alerts