Daratumumab-based regimen a ‘future standard’ for certain patients with multiple myeloma
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Key takeaways:
- The daratumumab-based regimen conferred significantly longer PFS than standard of care.
- Three-quarters of patients assigned the daratumumab-based regimen achieved MRD-negativity.
Daratumumab combined with bortezomib, lenalidomide and dexamethasone outperformed bortezomib, lenalidomide and dexamethasone alone in patients with newly diagnosed multiple myeloma, according to results of the phase 3 PERSEUS trial.
The findings — presented at ASH Annual Meeting and Exhibition and published simultaneously in The New England Journal of Medicine — also showed the overall safety profile of daratumumab (Darzalex, Janssen) plus bortezomib (Velcade, Millenium/Takeda), lenalidomide (Revlimid, Bristol Myers Squibb) and dexamethasone to be consistent with the known safety profiles for daratumumab and bortezomib, lenalidomide and dexamethasone alone.
“The progression-free survival that was achieved in transplant-eligible patients who were treated with the daratumumab-based induction, consolidation and maintenance therapy regimen is unprecedented in a phase 3 clinical study evaluating this patient population, but is not unexpected as these findings build on a number of studies that previously demonstrated clinical benefit with daratumumab-based regimens in this patient population,” Pieter Sonneveld, MD, PhD, professor of hematology at Erasmus University of Rotterdam and chair of the Erasmus MC Cancer Institute, said in a Johnson & Johnson press release. “The results we see across clinically relevant subgroups, including in patients who present with advanced disease or who are considered high risk, are promising for clinicians who are on the frontlines of treating patients who are newly diagnosed with this complex disease.”
Background and methods
Daratumumab, a monoclonal antibody targeting an overexpressed protein in multiple myeloma cells, is approved for use in patients ineligible for stem cell transplant or for cancers that relapse or do not respond to standard initial therapies, according to study background.
The PERSEUS trial included 709 patients (median age, 60 years) with newly diagnosed multiple myeloma across multiple European countries considered eligible for autologous stem cell transplantation.
Researchers randomly assigned patients to front-line therapy with either daratumumab plus bortezomib, lenalidomide and dexamethasone (n = 355) or the current standard of care backbone regiment of bortezomib, lenalidomide and dexamethasone (n = 354).
Patients assigned to the standard-of-care group received up to six cycles of induction therapy in 28-day cycles and went on to stem cell transplant if needed, followed by maintenance therapy with lenalidomide. Those assigned the daratumumab quadruplet regimen also received daratumumab via subcutaneous injections during both the induction and maintenance phases.
Researchers used a computerized algorithm based on International Myeloma Working Group response criteria to assess response and disease progression. They defined overall minimal residual disease (MRD)-negativity rate as the proportion of patients who achieved MRD negativity and complete response or greater at any time.
PFS served as the primary endpoint. Secondary endpoints included overall complete response or better rate, overall MRD-negativity rate and OS.
Findings
At median follow-up of 47.5 months, 613 patients completed the induction and consolidation phase of treatment.
Results showed significant improvements in PFS with the daratumumab-based regimen vs. standard of care (84.3% vs. 67.7%; HR = 0.42; 95% CI, 0.3-0.59) consistently across all groups, including those with more advanced and higher-risk disease, according to the researchers.
Study investigators additionally observed a complete response or better among 87.9% of patients assigned the daratumumab-based regimen compared with 70.1% with standard of care.
Results also showed 75.2% of patients achieved MRD-negativity with the daratumumab-based regimen vs. only 47.5% of those assigned standard of care.
“Two-thirds of patients receiving maintenance in the daratumumab group were able to discontinue daratumumab after achieving sustained MRD-negativity per protocol,” Sonneveld said during a press briefing. “These randomized phase 3 results support the daratumumab-based regimen followed by maintenance therapy as a new standard of care for transplant-eligible patients with newly-diagnosed multiple myeloma.”
Of note, researchers found a higher rate of serious treatment-associated adverse events in the daratumumab-based quadruplet group (57% vs. 49.3%). Yet, treatment discontinuation due to adverse events occurred less often in the quadruplet group and the majority of events were short-term and temporary.
Implications
“With these results, [I expect] this treatment schedule will be the future standard for these patients,” Sonneveld said in an ASH press release.
Researchers now have plans for a follow-up analysis to examine longer-term outcomes of stopping daratumumab after 2 years of maintenance therapy in patients who achieve MRD-negativity.
References:
- Daratumumab plus bortezomib, lenalidomide, and dexamethasone (VRd) outperforms VRd alone for multiple myeloma (press release). Available at: https://www.hematology.org/newsroom/press-releases/2023/lba1. Published Dec. 12, 2023. Accessed Dec. 12, 2023.
- Sonneveld P, et al. LBA-1. Presented at: ASH Annual Meeting and Exposition; Dec. 9-12, 2023; San Diego.
- Sonneveld P, et al. N Eng J Med. 2023;doi:10.1056/NEJMoa2312054.
Perspective
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Mansi R. Shah, MD
The PERSEUS trial's findings align with the current practices embraced by myeloma specialists, specifically the implementation of upfront quadruplet induction therapy. This trial substantiates the effectiveness of a quadruplet treatment approach for patients with newly diagnosed multiple myeloma (NDMM) eligible for transplantation. The study underscores the potency of daratumumab (DARA) when combined with bortezomib, lenalidomide and dexamethasone (VRd), notably showcasing a significant improvement in PFS compared with VRd alone. Impressively, the 48-month PFS rate of 84.3% with DARA-VRd stands out against the 67.7% observed with VRd alone.
An essential aspect of these findings is the consistent efficacy observed across diverse patient subgroups, including those with higher cytogenetic risk or advanced disease stages. This underscores the broad applicability and potential transformative impact of this therapy. The augmented depth of response, reflected in increased rates of achieving complete response ( CR) and MRD negativity, bolsters the case for considering this combination regimen as the standard of care for NDMM.
It's imperative to acknowledge the safety profile. Adverse events such as neutropenia, thrombocytopenia and diarrhea were notable and, in some instances, prompted treatment discontinuation. However, these occurrences did not significantly differ from those observed in the VRd-only arm.
The cumulative evidence from the PERSEUS trial, coupled with the earlier GRIFFIN study results, presents a compelling case for adopting DARA-VRd as a potential new standard in managing transplant-eligible NDMM patients.
RWJBarnabas Health
Perspective
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Chakra P. Chaulagain, MD, FACP
The addition of DARA to the RVd triplet has shown a remarkable improvement in the CR, MRD negativity and PFS both in a large phase 2 GRIFFIN trial and now in a large phase 3 PERSEUS trial without added toxicity. These findings do set the stage for DARA-VRd as the new standard of care, but some questions remain unanswered.
The cytogenetic abnormalities in chromosome 1 (1q+ or 1p-) have been recognized as an adverse cytogenetic subgroup in multiple myeloma and are associated with inferior survival, independent of other high-risk chromosomal abnormalities, despite therapy with novel agents. Based on the preliminary data presented, the PERSEUS study did not include this subgroup in the cytogenetic high-risk category. A subgroup analysis of this group, if it can be added at this point in the study, will be very helpful to clarify this question. Furthermore, the durability of response in high cytogenetic risk groups will be of most interest to patients and physicians because of the urgent unmet need to improve outcomes in this subgroup of highly aggressive multiple myeloma. This group is known for good early response to therapy with unfortunate early relapse. In the PERSEUS study, it is also unclear what percentage of patients had more than one high risk cytogenetic abnormality. For example, those with two or more high-risk cytogenetics were not found to benefit from quadruplet therapy of DARA-KRd (daratumumab, carfilzomib, lenalidome and dexamethasone) in the phase 2 MASTER trial. The future will tell us if the DARA-VRd combination can fulfill this unmet need and ameliorate the negative prognostic effects of patients who have more than one high risk cytogenetic abnormality. Therefore, longer term follow-up data are needed.
Even a practice-changing approval does not automatically and immediately translate into widespread adoption in the real-world setting, and it could be several years before the quadruplet therapy is fully adopted by oncologists/hematologists as a mainstream therapy. In addition, the D-R maintenance can be considered a burden compared with the convenience of oral R maintenance, both by patients and providers, due to the long-term nature of the therapy.
One can also question whether both D and R are needed for maintenance in all patients or whether the therapy should be personalized based on MRD negativity (MRD-adapted therapy) and cytogenetic risk of the patients. The cost of quadruplet therapy can also be a concern, particularly in a resource-poor setting.
Finally, the alarmingly high dose of dexamethasone (160 mg per week) used in PERSEUS trial is noteworthy. As patients with myeloma live longer, excessive exposure to very high-dose steroids during induction therapy can have long-term effects in their cardiovascular and endocrine health. It would be interesting to know how many patients had prediabetes or impaired fasting glucose and if there was an increased risk for conversion to frank diabetes requiring antidiabetic therapy during treatment. This is another area of disconnect between the clinical trial and real-world practice, as in clinical practice we barely use more than 40 mg of dexamethasone per week. In clinical practice, since most of the side effects experienced by the patients are due to dexamethasone, future clinical trials in multiple myeloma should consider a steroid-free triplet and quadruplet regimens.
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Sonneveld P, et al. LBA-1. Presented at: ASH Annual Meeting and Exposition; Dec. 9-12, 2023; San Diego.
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