As FDA Weighs Use of MRD, Negativity Rates in PERSEUS Linked to Improved PFS in Newly Diagnosed Transplant-Eligible Multiple Myeloma

An in-depth analysis presented Monday at the 2024 annual meeting of the American Society of Clinical Oncology (ASCO) highlighted links between rates of minimal residual disease (MRD) negativity and progression-free survival (PFS) seen among transplant-eligible patients treated with subcutaneous daratumumab (Darzalex Faspro, Janssen) and a standard backbone triplet in the phase 3 PERSEUS trial.^1,2

Primary results for PERSEUS (NCT03710603), presented in December 2023 at the American Society of Hematology meeting in San Diego, showed PFS was 84.3% at 4 years for patients treated with daratumumab and a triplet of bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone, known as VRd, vs 67.7% for VRd (HR, 0.42).²

In PERSEUS, 709 patients were randomized 1:1 to receive the daratumumab combination or VRd only. Patients in both arms received up to 6 cycles (28 days) of VRd, with 4 prior to autologous stem cell transplant (ASCT) and 2 post-ASCT consolidation. Subcutaneous (SC) daratumumab and placebo were administered on a separate schedule from VRd, with daratumumab SC and lenalidomide given as maintenance in the investigational arm; patients in the placebo arm received lenalidomide maintenance. Those in the investigational arm who achieved MRD negativity could stop daratumumab SC, with the chance to restart the therapy if there was a loss of CR or MRD negativity.²

Measures of MRD negativity could soon become even more important, as the FDA must weigh whether they can be used as surrogate end points following a unanimous endorsement from the Oncologic Drugs Advisory Committee. As the number of therapies for multiple myeloma increases—along with the length of time needed to demonstrate overall survival—experts in both the United States and Europe have voiced support for this change.

Paula Rodriguez-Otero, MD, PhD | Image credit: CUN

Monday’s presentation by Paula Rodriguez-Otero, MD, PhD, of the Department of Hematology, Cancer Center Clinica Universidad de Navarra in Pamplona, Spain, reviewed data on MRD negativity at sensitivity of both 10^-5 and 10^-6. According to the Multiple Myeloma Research Foundation, this difference refers to MRD tests that can detect at least 1 myeloma cell in 100,000 healthy bone marrow cells (for a threshold of 1 x 10^-5) vs tests that can detect 1 myeloma cell in 1 million (1 x 10^-6).

“In newly diagnosed multiple myeloma, minimal residual disease negativity has been associated with prolonged survival,” Rodrigues-Otero said during the oral abstract session at ASCO. “Moreover, deeper responses with a sensitivity level of 10^-6 have been associated with superior outcomes compared to 10^-5 and 10^-4 current [MRD] testing. This sensitivity level of 10^-6 and sustained for over 5 years translates into very good survival and a potential for cure for patients with newly diagnosed multiple myeloma.”

Data showed that 88% of transplant-eligible patients achieved a complete response (CR) or better, and 47% of patients treated with daratumumab-based induction, consolidation, and maintenance therapy remained MRD negative after 12 months. The MRD negativity rate, as measured by the clonoSEQ test, deepened over time, Rodriguez-Otero reported. The rate was defined as the share of intent-to-treat patients who achieved both a CR or better and MRD negativity.

Results. According to the ASCO abstract,¹ at the end of consolidation, MRD negativity rates were 44.5% for the daratumumab SC arm vs 34.7% for the VRd-only arm (P = .0078). Data from the abstract report overall MRD negativity rates were 87.9% for the daratumumab SC arm vs 70.1% for the VRd-only arm (P < .0001).

“Importantly, the rates of conversion from patients that were MRD-positive at the end of consolidation and converted to MRD negativity during maintenance was also higher with D-R treatment as compared to lenalidomide alone,” Rodriguez-Otero noted.

Rates of MRD negativity deepened over time as follows, all favoring the daratumumab SC-VRd arm (daratumumab SC) at both levels of sensitivity (all P < .0001). First, to a 10^-5 sensitivity:

• At 12 months, rates were 65.1% for daratumumab SC vs 38.7% for VRd-only
• At 24 months, rates were 72.1% for daratumumab SC vs 44.9% for VRd-only
• At 36 months, rates were 74.6% for daratumumab SC vs 46.9% for VRd-only

Second, to a 10^-6 sensitivity:

• At 12 months, rates were 43.9% for daratumumab SC vs 20.9% for VRd-only
• At 24 months, rates were 57.7% for daratumumab SC vs 27.4% for VRd-only
• At 36 months, rates were 63.9% for daratumumab SC vs 30.8% for VRd-only

During her presentation, Rodriguez-Otero focused on MRD negativity rates for patients with high-risk cytogenetic abnormalities; she noted that the rates of sustained MRD negativity at least 12 months out from the start of treatment were higher in the daratumumab arm: 30% for daratumumab vs 14% in the VRd-only arm. “This translates into a prolonged progression-free survival for high-receptor genetic abnormality patients when treated with D-VRd followed by D-R maintenance.”

Will the MRD negativity rate take on greater meaning going forward? An official with Adaptive Biotechnologies, which makes the clonoSEQ test used in PERSEUS, weighed in with this statement to AJMC:

"In recent years, the significance of MRD as a prognostic biomarker has become increasingly clear. The unanimous recommendation by the FDA’s Oncologic Drugs Advisory Committee to accept MRD as a primary endpoint for accelerated approvals in multiple myeloma trials, based on its strong correlation with progression-free survival and overall survival, underscores the clinical benefit of specific and sensitive MRD testing with clonoSEQ, as highlighted by the data presented at the ASCO annual meeting,” said Adaptive Biotechnologies’ Susan Bobulsky, chief commercial officer, MRD.

The test, she continued, is “well-positioned” to continue as the preferred testing option in clinical trials. “We are proud to contribute to this paradigm shift in clinical trial end point consideration, which may help bring us closer to a cure for people living with multiple myeloma.”

"MRD-negativity is an important measure in predicting long-term progression-free survival for patients with multiple myeloma," said Rodriguez-Otero in a statement. The higher rates of deep and sustained MRD negativity with a subcutaneous daratumumab-based regimen show the potential of this quadruplet and daratumumab-based maintenance “to shift the treatment paradigm for transplant-eligible patients with newly diagnosed multiple myeloma and bring us closer to the potential for a functional cure.”

References

1. Rodriguez-Otero P, Moreau P, Dimopoulos MA, et al. Daratumumab (DARA) + bortezomib/lenalidomide/dexamethasone (VRd) in transplant-eligible (TE) patients (pts) with newly diagnosed multiple myeloma (NDMM): analysis of minimal residual disease (MRD) in the PERSEUS trial. J Clin Oncol 2024;42(suppl 16); Abstract 7502. doi:10.1200/JCO.2024.42.16_suppl.7502
2. Sonneveld P, Dimopoulos MA, Boccadoro M, et al. Daratumumab, bortezomib, lenalidomide, and dexamethasone for multiple myeloma. 2024;390(4):301-313. doi:10.1056/NEJMoa2312054