SUMMARY: Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 35,730new cases will be diagnosed in 2023 and 12,590 patients are expected to die of the disease. Multiple Myeloma is a disease of the elderly, with a median age at diagnosis of 69 years and characterized by intrinsic clonal heterogeneity. Almost all patients eventually will relapse, and patients with a high-risk cytogenetic profile, extramedullary disease or refractory disease have the worst outcomes. The introduction of Proteasome Inhibitors, Immunomodulatory agents and CD38 targeted therapies has resulted in higher Response Rates, as well as longer Progression Free Survival (PFS) and Overall Survival (OS), with the median survival for patients with myeloma approaching 10 years or more. Nonetheless, multiple myeloma in 2023 remains an incurable disease.
Transplantation-eligible patients with newly diagnosed multiple myeloma are often treated with Bortezomib, Lenalidomide, and Dexamethasone (VRd) induction therapy followed by Autologous Stem-Cell Transplantation, consolidation therapy with VRd, and maintenance therapy with Lenalidomide. With the introduction of CD38 targeted therapies, new treatment combinations are being explored to increase the depth of response and attain long-term disease control.
Daratumumab (DARZALEX®) is a human IgG1 antibody that targets CD38, a transmembrane glycoprotein abundantly expressed on malignant plasma cells and with low levels of expression on normal lymphoid and myeloid cells. Daratumumab exerts its cytotoxic effect on myeloma cells by multiple mechanisms, including Antibody Dependent Cellular Cytotoxicity (ADCC), Complement Mediated Cytotoxicity and direct apoptosis. Additionally, Daratumumab may have a role in immunomodulation by depleting CD38-positive regulator immune suppressor cells, and thereby expanding T cells, in patients responding to therapy.
PERSEUS trial is an open-label, multicenter, randomized Phase III study, conducted to evaluate the efficacy and safety of subcutaneous Daratumumab combined with VRd induction and consolidation therapy and with Lenalidomide maintenance therapy (D-VRd group), as compared with VRd induction and consolidation therapy and Lenalidomide maintenance therapy alone (VRd group), for the treatment of transplantation-eligible patients with newly diagnosed multiple myeloma. The subcutaneous formulation of Daratumumab was chosen as it has been found to be noninferior to intravenous Daratumumab, as it is associated with a lower incidence of infusion-related reactions, can be administered in a single dose for all patients, and has a shorter duration of administration of 3-5 minutes.
In this study, 709 eligible patients were randomly assigned in a 1:1 ratio to receive either subcutaneous Daratumumab combined with VRd induction therapy before transplantation, with VRd consolidation therapy after transplantation, and with Lenalidomide maintenance therapy (D-VRd group) or VRd induction and consolidation therapy and Lenalidomide maintenance therapy alone (VRd group). All patients received VRd in six 28-day cycles (four induction cycles and two consolidation cycles) and VRd consisted of Bortezomib 1.3 mg/m2 subcutaneous on days 1, 4, 8, and 11 of each cycle, Lenalidomide 25 mg orally on days 1 through 21 of each cycle, and Dexamethasone 40 mg oral or IV given on days 1-4 and days 9-12 of each cycle. Patients in the D-VRd group also received Daratumumab 1800 mg given subcutaneous weekly during cycles 1 and 2, 1800 mg subcutaneous every 2 weeks cycles 3-6. Patients underwent Autologous Stem-Cell Transplantation after the completion of induction therapy (cycle 4) and consolidation therapy began 30-60 days after transplantation. After completion of consolidation therapy (cycle 6), all the patients received Lenalidomide 10 mg orally in 28-day maintenance cycles until disease progression or unacceptable toxicities. Patients in the D-VRd group also received maintenance therapy with subcutaneous Daratumumab 1800 mg subcutaneous every 4 weeks for at least 24 months and Daratumumab therapy was discontinued in patients who had a Complete Response or better and had sustained Minimal Residual Disease (MRD)–negative status (defined as absence of malignant cells at a sensitivity threshold of 10−5 or lower) for at least 12 months. The median age was 60 years and randomization was stratified according to the Stage (I, II, or III) and cytogenetic risk (standard risk or high risk, defined as the absence or presence, respectively, of a del[17p], t[4;14], or t[14;16] cytogenetic abnormality). The Primary end point was Progression Free Survival. Secondary end points included a Complete Response or better and Minimal Residual Disease negative status.
At a median follow-up of 47.5 months, at the first interim analysis, the risk of disease progression or death in the D-VRd group was significantly lower than the risk in the VRd group. The 4-year PFS was 84.3% in the D-VRd group and 67.7% in the VRd group (HR for disease progression or death=0.42; P<0.001). The percentage of patients with a Complete Response or better was higher in the D-VRd group than in the VRd group (87.9% versus 70.1%; P<0.001). The same was true with MRD-negative status (75.2% versus 47.5% respectively, P<0.001). Serious adverse events occurred in 57% of the patients in the D-VRd group and 49.3% of those in the VRd group. Treatment discontinuation due to adverse events however occurred less often in the quadruplet group.
The researchers concluded that the addition of subcutaneous Daratumumab to VRd induction and consolidation therapy and to Lenalidomide maintenance therapy conferred a significant and clinically meaningful benefit with respect to Progression Free Survival, Complete Response rate and MRD-negative status, with a favorable benefit–risk profile, among transplantation-eligible patients with newly diagnosed multiple myeloma.
Daratumumab, Bortezomib, Lenalidomide, and Dexamethasone for Multiple Myeloma. Sonneveld P, Dimopoulos MA, Boccadoro M, et al. for the PERSEUS Trial Investigators. Published on December 12, 2023, at NEJM.org. DOI: 10.1056/NEJMoa2312054.
