The combination of daratumumab (Darzalex) and bortezomib (Velcade), cyclophosphamide, and dexamethasone (DaraVCD) resulted in a complete response (CR) rate of 40% and a CR or better (≥CR) rate of 43% in patients with multiple myeloma. Data from an interim analysis of the phase 2 EMN19 study (NCT04166565) presented at the 2023 EHA Congress suggest that it is associated with endometrial disease (EMD).
At a median follow-up of 18.8 months (range, 2.0-35.0), the overall response rate (ORR) was 80.0% in the total population (n = 40), 75% of patients experienced an excellent partial response. Response (VGPR) or better. The response time was 4.1 weeks (range, 4.0-17.4).
In the subset of patients with first relapsed disease (n = 11), the CR or better rate was 18.2% and the VGPR or better rate was 54.5%, with an ORR of 54.5%. The median time to first response was 4.1 weeks (range, 4-10). In the group of patients with newly diagnosed disease (n = 29), CR or better rate was 51.7% and VGPR or better rate was 82.8%, ORR was 89.7%. In this group, the median time to first response was 4.1 weeks (range, 4.1-17.4).
Of the 17 patients evaluated for minimal residual disease, 13 patients achieved negativity; Among these patients, 11 had newly diagnosed disease and 2 patients had first relapsed disease.
Median progression-free survival (PFS) in those with first relapsed disease was 15.3 months (95% CI, 0.95–not reached). [NR]) and was NR (95% CI, 7.2-NR) in newly diagnosed individuals. Moreover, the median PFS in 1 to 2 plasmacytomas was NR (95% CI, 10.2-NR) and 15.3 months (95% CI, 2.2-NR) in 3 or more plasmacytomas.
“Newly diagnosed multiple myelomas and lower numbers of plasmacytomas were associated with ≥VGPR responses and better PFS,” lead study author Meral Beksak, MD, PhD, of Ankara University Medical Faculty Sebesi Hospital in Ankara, Turkey, and colleagues, wrote in the data poster. “DaraviCD was effective in terms of significant rates of MRD. [negativity] and a complete metabolic response.
Currently, there is no standard treatment for patients with EMD other than radiotherapy. Preclinical findings have indicated that the combination of CD38-targeted monoclonal antibodies with VCD may be effective in this population. Additionally, other studies evaluating daratumumab plus bortezomib or lenalidomide have shown that these combinations have the potential to overcome high-risk cytogenetics.
The multinational, open-label, phase 2 EMN19 study enrolled 40 patients with newly diagnosed or first relapsed multiple myeloma. Patients have measurable disease that does not interfere with bortezomib-based drugs. Patients may not have hypersensitivity to bortezomib, or autologous stem cell transplantation within 12 weeks of starting treatment. Patients were excluded if they had undergone allogeneic stem cell transplantation before.
Patients were initially treated with daratumumab at 16 mg/mL intravenously (IV); From July 2020 at 1800 mg. Received by subcutaneous agent (SC). Daratumab was administered weekly in cycles 1 and 2, every 2 weeks in cycles 3 to 6, and every 4 weeks in cycles 7 and above. SC bortezomib at 1.5 mg/m2 weekly, oral or IV cyclophosphamide at 300 mg/m2 weekly, and oral or IV dexamethasone at 20 mg on days 1, 2, 8. , 9, 15, 16, 22 and 23.
The primary objective of the study was to evaluate the CR rate achieved with DaraviCD. Important secondary endpoints included ORR, duration of response, PFS, overall survival (OS), and safety.
In the entire population, the mean age was 58 years (range, 37-77). More than half of patients (72.5%) had newly diagnosed diseases and 27.5% had first relapses. More than half (55.0%) of the patients were men and 47.5% had stage I disease according to the criteria of the International Classification System (ISS). Sixty-five percent of patients had 1 or more medullary plasmacytomas, 45.0% had at least 1 parasocious plasmacytoma, and 10% had both. The median number of plasmacytomas is 2, ranging from 1 to 16. Of the 25 patients with FISH values, 24% had high-risk cytogenetics at baseline.
Treatment continues in 19 patients at sites in Turkey, Greece and Italy. At the time of data cutoff, 21 patients discontinued treatment. Reasons for discontinuation were disease progression (61.9%), death (14.3%), inadequate response after 3 cycles (14.3%), patient withdrawal (4.8%), and physician’s decision (4.8%). During the study treatment period, 25 percent of patients received a transplant; This occurred at a median of 8.2 months (range 5.9-10.2) following initiation of study treatment.
Evaluation of non-medical responses by PET and EMPETUS criteria showed that 3 patients with first relapse achieved CMR. Of the CMRs, 1 occurred before hematologic CR, the second occurred in the first response evaluation following CR, and the third was a hematologic CR not yet detected. Of the 15 newly diagnosed patients, 11 had CMR, 2 had a partial metabolic response, 1 had mild disease, and 1 had progressive disease by Devil’s score. Of the 11 patients with CMR, 4 experienced CMR before hematological CR. 1 Hematological CR has not yet been achieved. For 6 patients, after initial assessment of medical responses – post-CR.
Investigators quantified circulating tumor cells (CTCs) at baseline using EuroFlow next-generation flow cytometry. After red blood cell lysis, the peripheral blood was stained for CD38, CD138, CD45, CD19, CD27, CD56, CD81, CD117, CylgK, and CylgL markers.
Of the 40 patients, 38 were evaluable for CTC. In 68.4% of cases, CRCs were detected at study entry; 8 cases were parasympathetic only, 16 were extramedullary only, and 2 were both. The data indicated that the VGPR or better rates were 80.8% (n = 21/26) and 66.7% (n = 8/12) compared to detectable and non-detectable CTCs, respectively.P = .423).
“To our knowledge, this is the first report of CTCs in extramedullary disease and CTCs were found to be positively associated with ISS, both as a percentage of CTCs and as a percentage of patients presenting,” the study authors wrote.
Investigators also compared PFS with the LYRA study. In that study, the 24-month PFS rates in the newly diagnosed non-transplant and newly diagnosed transplant groups were 72.6% and 89.0%, respectively; In the EMN19 study, the 24-month PFS rate was 53.3%. The 36-month PFS rates were 69.3%, 72.6%, and 53.3%, respectively.
“The results of the LYRA study included a DravCD protocol similar to that of the newly investigated based on the current response rate. [patients with] multiple myeloma, this protocol may be considered as an alternative for this high-risk unmet need,” the study investigators concluded.
Ref
Efficacy of daratumumab and bortezomib, cyclophosphamide, and dexamethasone in patients with metastatic multiple myeloma: a European Myeloma Network study (EMN19). Presented at: EHA 2023 Hybrid Congress; June 8-11, 2023; Frankfurt, Germany. Abstract P872.
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