Daratumumab-Based Combination Effective in Relapsed/Refractory Multiple Myeloma, Short PFS in Heavily Pretreated Patients

Surabhi Dangi-Garimella, PhD

MANAGING HEAVILY PRETREATED, often less fit, patients with relapsed/refractory multiple myeloma (RRMM) is a challenge in routine practice, as illustrated by the fact progression-free survival (PFS) remains short, particularly in quadruple-refractory patients, although daratumumab-based combination therapies are proven effective. This conclusion, based on results of a single-center study, was presented during a poster session at the 2017 American Society of Clinical Oncology Annual Meeting.1 

Daratumumab-based combination therapies with bortezomib/lenalidomide/pomalidomide, and dexamethasone have shown exceptional activity in patients with RRMM in clinical trials. However, since the approval of daratumumab in 2015, experience outside of trials is limited.

Patients with RRMM who were seen at Mayo Clinic, Rochester, Minnesota, from 2015 to 2016, were reviewed. Those who received at least 1 cycle of daratumumab-based combination therapies were included. Time-to-event analyses were performed from the date of starting daratumumab-based combination therapy, and common terminology criteria for adverse events v4.0 were used to grade toxicities. Of 130 patients, 59% were male, the median age at daratumumab-based combination therapy initiation was 67 years (range, 43-93), and the Eastern Cooperative Oncology Group performance score was ≥2 in 29% of patients.

Patients were classified as melanoma Stratification for Multiple and Risk-adapted Therapy (mSMART) high (22%), intermediate (22%), or standard (56%) risk. The median time from diagnosis to initiation of daratumumab-based combination therapy was 51.3 months (range, 5-156), and the median number of prior therapies was 4 (range, 1-14).

Fourteen percent of patients were refractory to prior daratumumab monotherapy. Fifty-three (41%), 34 (26%), and 25 (19%) received daratumumab/ pomalidomide/dexamethasone, daratumumab/lenalidomide/ dexamethasone, and daratumumab/ bortezomib/dexamethasone, respectively. Eighteen (14%) patients received “other” daratumumab-based combination therapies, according to the abstract.

Median time to first response (at least a partial response) was 3.1 months (95% CI, 2.1-4.6), with an overall response rate of 46% (complete response, 2%; very good partial response, 18%; and partial response, 26%). Seventeen percent of enrollees experienced a minimal response, with a clinical benefit rate of 62%.

The median estimated follow-up from initiation of daratumumab-based combination therapy was 5.5 months (95% CI, 4.2-6.1), the median duration of response was 6.1 months (95% CI, 5.1-not reached), median PFS was 5.5 (95% CI, 4.1-7.8) months, and the median time to next therapy was 5.9 months (95% CI, 4.6-9.4).

The median PFS durations for daratumumab/pomalidomide/dexamethasone, daratumumab/lenalidomide/dexamethasone, daratumumab/bortezomib/ dexamethasone, and other daratumumab-based combination therapy was 4.6 (95% CI, 2.7-not reached), 7.8 (95% CI, 5-not reached), 3.9 (95% CI, 2.1-not reached), and 3.9 (95% CI, 2.8-8.2) months, respectively (P = .3).

Median PFS for quadruple-refractory (n = 28) multiple myeloma (MM) was 2.8 (95% CI, 2.2-5.3) versus 5.9 (95% CI, 4.9-not reached) months (<.01). Median overall survival from the start of daratumumab-based combination therapy was not reached (95% CI, 11.4 months-not reached). Grade 3 or higher hematological toxicities were seen in 42% of patients. Other toxicities included infections (37%), fatigue (31%), infusion reactions (16%), and diarrhea (10%).

The investigators concluded that daratumumab-based combination therapies are effective in RRMM, but PFS remains short, particularly in quadruple-refractory patients. These suboptimal outcomes illustrate the challenges encountered in managing heavily pretreated, and often less fit, patients in routine practice.

Daratumumab (Darzalex) is the first CD38-directed cytolytic antibody indicated2,3: Daratumumab was designated as a breakthrough therapy for the second and third indications above. The antibody is believed to induce tumor cell death through multiple immune-mediated mechanisms of action, including complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, and antibody-dependent cellular phagocytosis, as well as through apoptosis, in which a series of molecular steps in a cell lead to its death. A subset of myeloid-derived suppressor cells, CD38+ regulatory T cells, and CD38+ B cells were decreased by daratumumab.2,3
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