Patients with newly diagnosed multiple myeloma (MM) who received daratumumab (Darzalex®; Janssen Oncology/Janssen Pharmaceuticals) along with the standard care regimen of bortezomib (Velcade®; Takeda), lenalidomide (Revlimid®; Celgene Corporation, a Bristol Myers Squibb company), and dexamethasone (VRd) showed significantly higher rates of survival without disease progression compared with those who received standard care alone.[1]

This conclusion is based on the outcomes of a phase 3 clinical study, funded by the European Myeloma Network with support from Janssen Pharmaceuticals, presented at the 65th American Society of Hematology (ASH) Annual Meeting and Exposition, held December 9 – 12, 2023 in San Diego, CA.

At a median follow-up of 47.5 months the estimated rate of progression-free survival (PFS), the trial’s primary endpoint, was significantly improved with D-VRd versus VRd. Patients who received daratumumab plus VRd (D-VRd) had an estimated four-year PFS rate of 84.3% compared with 67.7% among those receiving VRd alone, a difference of about 17%.

Cancer
Multiple myeloma is a blood cancer that forms in a type of white blood cell called plasma cells and affects the bone marrow. In patients diagnosed with the disease plasma cells are transformed into cancerous or malignant cells that grow out of control and crowd out the normal, healthy cells that help fight infection. In turn, these malignant plasma cells produce an abnormal antibody called M-protein. High levels of this protein in the blood and urine are a characteristic hallmark of multiple myeloma and can damage the kidneys and other organs.

Myeloma cells may also activate other cells in the marrow that can damage your bones.  This may cause bone pain and weakened spots on bones known as osteolytic lesions. This, in turn, may increase the risk of fractures and lead to hypercalcemia or increased levels of calcium in the blood.

Advertisement #3

The disease may also lead to thrombocytopenia, a condition in which the thrombocytes, needed for blood clotting and wound healing, are low in number (generally a platelet count below the lower limit of normal, i.e., 150,000/microliter for adults.[2]

Multiple myeloma is most common in older adults. According to the National Cancer Institute (NCI), the 5-Year Relative Survival of myeloma patients diagnosed between 2013 and 2019 was 59.8% [3]

Relapses are common after initial treatment, underscoring the need for improved therapies.

Pieter Sonneveld, MD, Ph.D., is a world-leading expert in multiple myeloma. He is a current Professor of Hematology at the Erasmus University of Rotterdam and Erasmus Medical Center, Rotterdam, the Netherlands. Sonneveld helped to found the European Myeloma Network (EMN). Within EMN, he coordinates a cooperative network for independent clinical trials in Europe and initiates efforts to create international standards for diagnostics and patient care. Sonneveld has also been a Board member (2011- ) and President (2017-2019) of the European Hematology Association (EHA), and is the organization’s Scientific Working Group Committee.

Adding daratumumab
“We were not surprised to see the difference with the addition of daratumumab, but we were very surprised by the magnitude of the difference between the two arms,” noted Pieter Sonneveld, MD, Ph.D., professor of hematology at Erasmus MC Cancer Institute in Rotterdam, the Netherlands, the study’s lead author.

“This difference is of major clinical significance to the patient in terms of their well-being and [remaining] disease-free.”

Daratumumab is a CD38-directed cytolytic monoclonal antibody targeting a protein that is overexpressed in multiple myeloma cells.* It has previously been approved for use in patients who are ineligible for stem cell transplants or for cancers that relapse or do not respond to standard initial therapies.

The new phase 3 trial is the first to test its use as part of frontline therapy for newly diagnosed multiple myeloma in a head-to-head comparison with the current standard of care.

For the trial, researchers enrolled 709 patients newly diagnosed with multiple myeloma across multiple European countries who were considered eligible for autologous stem cell transplantation, which is part of the standard treatment for MM. Patients received up to six cycles of VRd induction therapy in 28-day cycles, proceeded to a stem cell transplant if possible, and continued taking lenalidomide afterward as maintenance therapy.

Participating patients who were randomized to receive D-VRd also received daratumumab via subcutaneous injections during both the induction and maintenance phases. Researchers noted that elements of the trial design, including the use of subcutaneous injections rather than daratumumab infusions and the administration of treatment in 28-day cycles rather than 21-day cycles, were intended to make the regimen gentler on patients and reduce the likelihood of adverse effects.

At the time of data cutoff, 613 participants had completed the induction/consolidation phase of treatment and patients had been followed for a median of just under four years. PFS was significantly higher in the D-VRd arm and subgroup analyses showed that this was consistent across all groups including those with more advanced and higher-risk forms of multiple myeloma.

Of patients who received the D-VRd regimen, 87.9% saw a complete response or better, meaning that cancer was not detectable after the treatment, compared with 70.1% among those who received standard care. Patients in the D-VRd arm also had a significantly higher rate of minimal residual disease (MRD) negativity, another marker indicating the cancer has been eradicated, which was achieved in 75.2% of patients receiving D-VRd and 47.5% of those receiving VRd alone. The amount of follow-up time is not yet sufficient to compare trends in overall survival rates.

The rate of serious treatment-related adverse events was higher in the D-VRd arm with 57% of patients who received daratumumab experiencing such events compared with 49.3% among those receiving VRd alone. However, researchers noted that adverse events led to treatment discontinuation significantly less often in the D-VRd arm, and most adverse events were short-term and temporary. The most common adverse events of grade three or higher were low white blood cell counts, low platelet counts, diarrhea, pneumonia, and fever.

Taken together, Sonneveld said that the results suggest that D-VRd outperforms VRd alone for frontline multiple myeloma treatment with a manageable safety profile.

“With these results, [I expect] this treatment schedule will be the future standard for these patients,” he concluded.

A follow-on analysis will examine the longer-term outcomes of stopping daratumumab after two years of maintenance therapy in patients who achieve MRD negativity.

__

Note: * CD38 is a transmembrane glycoprotein (48 kDa) expressed on the surface of hematopoietic cells, including multiple myeloma and other cell types and tissues, and has multiple functions, such as receptor-mediated adhesion, signaling, and modulation of cyclase and hydrolase activity. Daratumumab is an IgG1κ human monoclonal antibody (mAb) that binds to CD38 and inhibits the growth of CD38-expressing tumor cells by inducing apoptosis directly through Fc-mediated cross-linking as well as by immune-mediated tumor cell lysis through complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). A subset of myeloid-derived suppressor cells (CD38+MDSCs), regulatory T-cells (CD38+Tregs) and B cells (CD38+Bregs) are decreased by daratumumab.

Clinical trial
Daratumumab, VELCADE (Bortezomib), Lenalidomide and Dexamethasone Compared to VELCADE, Lenalidomide and Dexamethasone in Subjects With Previously Untreated Multiple Myeloma (Perseus) – ClinicalTrials.gov ID NCT03710603

Highlights of Prescribing Information
Daratumumab (Darzalex®; Janssen Oncology/Janssen Pharmaceuticals)[Prescribing Information]
Bortezomib (Velcade®; Takeda) [Prescribing Information]
Lenalidomide (Revlimid®; Celgene Corporation, a Bristol Myers Squibb company)[Prescribing Information]

ASH Presentation
[1] Sonneveld P, Dimopoulos MA, Boccadoro M, Quach H, Joy Ho P, Beksac M, Hulin C, Antonioli E, Leleu X, Mangiacavalli S, Perrot A, Cavo M, Belotti A, Broijl A, Gay F, Mina R, Nijhof IS, Van de Donk NWCJ, Katodritou E, Schjesvold F, Sureda Balari A, Rosiñol L, Delforge M, Roeloffzen W, Silzle T, Vangsted A, Einsele H, Spencer A, Hajek R, Jurczyszyn A, Lonergan S, Ahmadi T, Liu Y, Wang J, Vieyra D, Van Brummelen EMJ, Vanquickelberghe V, Sitthi-Amorn A, De Boer CJ, Carson R, Rodríguez Otero P, Bladé J,  and Moreau P. LBA 1: Phase 3 Randomized Study of Daratumumab (DARA) + Bortezomib, Lenalidomide, and Dexamethasone (VRd) Versus Vrd Alone in Patients (Pts) with Newly Diagnosed Multiple Myeloma (NDMM) Who Are Eligible for Autologous Stem Cell Transplantation (ASCT): Primary Results of the Perseus Trial. Presented on Tuesday, December 12, 2023, 9:00 AM-10:30 AM during the annual meeting of the 65th annual meeting of the American Society of Hematology, held December 9 – 12, 2023 in San Diego, CA. [Abstract]

Reference
[2] Jinna S, Khandhar PB. Thrombocytopenia. [Updated 2023 Jul 4]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Online. Last accessed on December 8, 2023.
[3] Cancer Stat Facts: Myeloma. National Cancer Institute Surveillance, Epidemiology, and End Results Program (SEER) database. [Online] Last accessed on December 8, 2023.

Featured image courtesy © 2019 – 2024 American Society of Hematology ASH/Matt Herp. Used with permission.

Advertisement #5