Multiple myeloma indication added to 'Darzalex'

DVRd quadruple combination therapy can be used regardless of the autologous stem cell transplantation history

Relapsed·refractory patients are also eligible for the triple-combination therapy…aligning with the global recommendations

Multiple myeloma treatment 'Darzalex'

The scope of use of 'Darzalex' has expanded in multiple myeloma treatments.

Following the expansion of combination therapy indications, from first-line treatment to relapsed·refractory settings, clinically validated Darzalex-based therapeutic strategies can now be utilized more broadly.

According to industry sources, the Ministry of Food and Drug Safety (MFDS) recently approved expanded indications for combination therapy containing Darzalex (daratumumab) subcutaneous (SC) Inj. Developed by Johnson & Johnson, Darzalex is a targeted monoclonal antibody that binds to the CD38 glycoprotein, highly expressed on the surface of multiple myeloma cells.

Following this regulatory approval, the DVRd quadruple combination therapy, which adds Darzalex SC into the conventional standard-of-care VRd triple combination therapy (bortezomib + lenalidomide + dexamethasone), has secured first-line therapeutic indications for both transplant-eligible (TE) and transplant-ineligible (TIE) patients.

Additionally, the DPd triple combination therapy, combining Darzalex with pomalidomide and dexamethasone, has been newly authorized for patients with relapsed or refractory multiple myeloma (RRMM) who have received prior therapies including a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD).

First-line DVRd quadruple combination therapy confirmed improved progression-free survival (PFS) 

The clinical efficacy of the DVRd therapy was validated through the pivotal Phase 3 PERSEUS clinical trial.

The PERSEUS trial evaluated and compared the efficacy and safety profiles of the DVRd therapy versus the standard VRd therapy in patients with newly diagnosed multiple myeloma (NDMM) aged 18 to 70 years.

The study was designed so that following DVRd induction and consolidation therapy, patients in the experimental group transitioned to a maintenance therapy combining lenalidomide and Darzalex SC. In contrast, the control group received lenalidomide monotherapy maintenance.

Trial results at 48-month analysis showed that the progression-free survival (PFS) rate was 84.3% in the DVRd group whereas 67.7% in the VRd control group. The data demonstrated a statistically significant reduction in the risk of disease progression or death with the DVRd therapy compared with the VRd group. 

The most prevalent Grade 3 or higher adverse events reported in the DVRd group were neutropenia (62.1%), followed by thrombocytopenia (29.1%), diarrhea (10.5%), pneumonia (10.5%), and febrile neutropenia (9.4%). Overall, the incidence of severe toxicities was higher in the DVRd group than in the baseline VRd control group.

In a PFS extrapolation analysis using data from the PERSEUS trial and another Phase 3 study, CEPHEUS, the best-fit model projected a median progression-free survival of approximately 17.1 years for the transplant-eligible group (PERSEUS) receiving the DVRd therapy. 

Currently, the National Comprehensive Cancer Network (NCCN) Guidelines designate the Darzalex SC-containing quadruple combination therapy (DVRd) as a preferred option for the first-line treatment of newly diagnosed, transplant-eligible (TE) multiple myeloma patients.

Effectiveness of first-line DVRd therapy in transplant-ineligible multiple myeloma

The therapeutic utility of the DVRd therapy in transplant-ineligible (TIE) patients, or those for whom first-line autologous stem cell transplantation is not planned, was robustly established in the Phase 3 CEPHEUS clinical trial.

This study evaluated multiple myeloma patients with no prior treatment history, as well as those who were either transplant-ineligible or did not intend to undergo upfront transplantation, and directly compared the long-term clinical benefits of DVRd therapy versus VRd therapy under a continuous treatment strategy.

At a median follow-up of 58 months, the DVRd group demonstrated a significantly reduced risk of disease progression or mortality compared to the VRd control group.

The primary endpoint of overall minimal residual disease (MRD) negativity rate (10⁻⁵) was significantly higher in the DVRd group (60.9%) than in the VRd group (39.4%).

Furthermore, the proportion of patients who achieved a sustained MRD-negative response lasting 12 months or longer was substantially higher in the DVRd group (48.7%) than in the VRd control group (26.3%).

The safety profile of the DVRd group reported in the CEPHEUS clinical trial was consistent with the established parameters previously documented for these individual agents.

The NCCN Guidelines recommend Darzalex-containing combination therapies, such as DVRd, as a preferred first-line treatment option for transplant-ineligible patient populations, contingent upon individual patient performance status.

Relapsed·refractory patients experiencing two or more incidences, expanded therapeutic options via the DPd Regimen

Additionally, regulatory approval was granted for a Darzalex SC-based triple combination therapy combining pomalidomide and dexamethasone (DPd). This therapy is designated for patients with relapsed or refractory multiple myeloma whose disease progressed following a first-line treatment and who have exposure to prior lines of therapy containing both a proteasome inhibitor and an immunomodulatory drug.

Consequently, treatment options have expanded to consider this Darzalex SC-containing combination therapy as a primary therapeutic alternative for relapsed or refractory multiple myeloma patients previously managed with PIs and IMiDs.

The clinical efficacy and safety of the DPd therapy were established through the Phase 3 APOLLO trial. This APOLLO trial is a Phase 3 clinical trial evaluating the therapeutic outcomes of the DPd therapy versus the Pd in patients with relapsed or refractory multiple myeloma who had received at least one prior line of therapy, ​including previous exposure to lenalidomide and a proteasome inhibitor.

Primary analysis at a median follow-up of 16.9 months demonstrated that the median progression-free survival in the DPd group was 12.4 months, compared with 6.9 months in the Pd control group, indicating a significantly lower risk of disease progression or mortality.

The current NCCN Guidelines recommend the DPd therapy as a preferred therapy for patients who have relapsed or become refractory following prior lines of therapy consisting of lenalidomide and a proteasome inhibitor.

As Darzalex SC-based combination therapies secure indications in first-line and second- or later-line settings, calls to broaden therapeutic access are intensifying within the medical community.

Professor Sung-Hoon Jung of the Department of Hematology at Chonnam National University Hwasun Hospital remarked, "The MFDS approval of these Darzalex-based combination therapies allows the domestic clinical community to align their multiple myeloma treatment strategies directly with established global guidelines. Given the high demand among clinicians for access to modern standards of care, it is imperative to initiate policy discussions to enhance patient access through national health insurance reimbursement or co-payment support frameworks."