DaraVCD Elicits Responses in Multiple Myeloma With Extramedullary Disease

Meral Beksac, MD, PhD

The combination of daratumumab (Darzalex) plus bortezomib (Velcade), cyclophosphamide, and dexamethasone (DaraVCD), elicited a complete response (CR) rate of 40% and a CR or better (≥CR) rate of 43% in patients with multiple myeloma presenting with extramedullary disease (EMD), according to data from an interim analysis of the phase 2 EMN19 study (NCT04166565) presented at the 2023 EHA Congress.

At a median follow-up of 18.8 months (range, 2.0-35.0), the overall response rate (ORR) with the regimen was 80.0% in the overall population (n = 40), with 75% of patients experiencing a very good partial response (VGPR) or better. The time to response 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 of 4.1 weeks (range, 4-10). In the group of patients with newly diagnosed disease (n = 29), the CR or better rate was 51.7% and the VGPR or better rate was 82.8%, with an ORR of 89.7%. In this group, the median time to first response was 4.1 weeks (range, 4.1-17.4).

Of 17 patients evaluated for minimal residual disease, 13 patients achieved negativity; 11 of these patients had newly diagnosed disease and 2 patients had first relapsed disease.

The median progression-free survival (PFS) in those with first relapsed disease was 15.3 months (95% CI, 0.95-not reached [NR]) and it was NR (95% CI, 7.2-NR) in those with newly diagnosed disease. Moreover, the median PFS in those with 1 to 2 plasmacytomas was NR (95% CI, 10.2-NR) and 15.3 months (95% CI, 2.2-NR) in those with 3 or more plasmacytomas.

“Newly diagnosed multiple myeloma and a lower number of plasmacytomas were associated with higher rates of ≥VGPR responses and better PFS,” lead study author Meral Beksac, MD, PhD, of Ankara University Faculty of Medicine Cebeci Hospital, in Ankara, Turkey, and colleagues, wrote in a poster of the data. “DaraVCD was effective in terms of significant rates of MRD [negativity] and complete metabolic response.”

Currently, no standard treatment exists for patients with EMD beyond radiotherapy. Preclinical findings have indicated that pairing CD38-targeted monoclonal antibodies with VCD can be effective in this population. Morover, other studies evaluating daratumumab plus bortezomib or lenalidomide have shown that these combinations possess 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 who had EMD. Patients were required to have measurable disease that was not refractory to bortezomib-based regimens. Patients could not have hypersensitivity to bortezomib, nor could they have undergone autologous stem cell transplantation within 12 weeks of treatment initiation. If patients had prior allogeneic stem cell transplantation, they were excluded.

Patients initially received daratumumab at 16 mg/mL intravenously (IV); from July 2020, they received the agent subcutaneously (SC), at a dose of 1800 mg. Daratumumab was given weekly during cycles 1 and 2, every 2 weeks for cycles 3 through 6, and every 4 weeks in cycle 7 and beyond. SC bortezomib was administered at a weekly dose of 1.5 mg/m2, cyclophosphamide was given orally or IV at a weekly dose of 300 mg/m2, and oral or IV dexamethasone was given at a dose of 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 DaraVCD. Important secondary end points included ORR, duration of response, PFS, overall survival (OS), and safety.

In the overall population, the median age was 58 years (range, 37-77). More than half of patients (72.5%) had newly diagnosed disease and 27.5% had first relapsed disease. More than half (55.0%) of patients were male and 47.5% had stage I disease by International Staging System (ISS) criteria. Sixty-five percent of patients had 1 or more extramedullary plasmacytoma, 45.0% had at least 1 paraosseous plasmacytoma, and 10% had both. The median number of plasmacytomas was 2, with a range of 1 to 16. Of the 25 FISH-evaluable patients, 24% had high-risk cytogenetics at baseline.

Treatment is ongoing in 19 patients at sites in Turkey, Greece, and Italy. At the time of data cutoff, 21 patients discontinued treatment. Reasons for discontinuation included disease progression (61.9%), death (14.3%), inadequate response following 3 cycles (14.3%), patient withdrawal (4.8%), and physician decision (4.8%). Twenty-five percent of patients received transplant during the study treatment period; this occurred at a median of 8.2 months (range, 5.9-10.2) following study treatment initiation.

An assessment of extramedullaryresponses by PET and Impetus criteria showed that 3 of the patients with first relapsed disease achieved a CMR; 1 of the CMRs occurred before hematologic CR, the second occurred during the first response assessment following CR, and the third hematologic CR had not been achieved yet. Of the 15 evaluable patietns with newly diagnosed disease, 11 had CMR, 2 had partial metabolic response, 1 had stable disease, and 1 had progressive disease per Deauville score. Of the 11 patients with CMR, 4 experienced their CMR before hematologic CR; 1 hematologic CR has not been achieved yet. For 6 patients, the first assessment of extramedullary responses was post-CR.

Investigators quantified circulating tumor cells (CTCs) in the blood at baseline by leveraging EuroFlow Next Generation flow cytometry. Following red blood cell lysis, peripheral blood was stained with CD38, CD138, CD45, CD19, CD27, CD56, CD81, CD117, CylgK, and CylgL markers.

Of the 40 patients, 38 were noted to be evaluable for CTC. In 68.4% of cases, CRCs were detected at the time of study entry; 8 cases were paraosseous only, 16 were extramedullary only, and 2 were both. Data indicated that the VGPR or better rates in those with detectable vs non-detectable CTCs were comparable, at 80.8% (n = 21/26) and 66.7% (n = 8/12), respectively (P = .423).

“To our knowledge this is the first report of CTC in extramedullary disease and CTCs were found to be positively correlated with ISS, both in percentage of patients presenting with CTC and quantitative CTC percentage,” the study authors wrote.

Invesigators also performed a PFS comparison 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; the 24-month PFS rate in the EMN19 study was 53.3%. The 36-month PFS rates were 69.3%, 72.6%, and 53.3%, respectively.

“Based on the level of current responses approaching the results of the LYRA study which includes a similar DaraVCD protocol among newly diagnosed [patients with] multiple myeloma, this protocol may be considered as an alternative for this high-risk population of unmet need,” the study investigators concluded.

Reference

Efficacy of daratumumab plus bortezomib, cyclophosphamide and dexamethasone in patients with multiple myeloma presenting with extramedullary disease: A European Myeloma Network study (EMN19). Presented at: EHA 2023 Hybrid Congress; June 8-11, 2023; Frankfurt, Germany. Abstract P872.