Evaluation of Re-Intensification of Daratumumab to Weekly or Biweekly Dosing Schedule

Introduction:

Multiple Myeloma (MM) is a hematologic cancer caused by malignant plasma cells. Daratumumab is an immunoglobin G1 kappa human monoclonal antibody that targets CD38 antigen which is a cell surface glycoprotein highly expressed on myeloma cells. Daratumumab is FDA approved as monotherapy and in combination with dexamethasone and lenalidomide, bortezomib or pomalidomide in relapsed/refractory MM. Daratumumab is typically dosed: 16mg/kg weekly (Weeks 1-8), then 16mg/kg biweekly (Weeks 9-24), then 16mg/kg monthly (Weeks 25 and beyond until disease progression).

At Dana-Farber Cancer Institute (DFCI), some patients receiving a daratumumab-containing regimen were "re-intensified" upon progression of disease. "Re-intensification" could include (1) re-escalation to weekly dosing from biweekly or monthly dosing or (2) re-escalation to biweekly dosing from monthly dosing or (3) continuation of biweekly or monthly dosing. However, there is a lack of evidence to support the safety and efficacy of daratumumab dose "re-intensification" (Dara-RI) during treatment. We aimed to assess the efficacy and safety of Dara-RI, with or without the addition of other myeloma-agents, in 13 patients with disease progression while on a daratumumab-containing regimen.

Method/Results:

This is an institutional review board approved, descriptive, retrospective medical chart review of 13 adult patients with MM who received Dara-RI at DFCI from November 2015 to October 2017. The median age was 68 years (range, 53-88). Most patients (8) had IgG Kappa MM (62%) followed by 2 patients (15%) with Lambda Light Chain, 2 patients (15%) with IgA Kappa, and 1 patient (8%) with IgG Lambda.

Of the 13 patients, 1 patient continued weekly dosing, 4 patients continued biweekly dosing; 5 patients re-intensified from monthly to biweekly dosing; 1 patient re-intensified from biweekly to weekly; and 2 patients re-intensified from monthly to weekly. Patients were re-intensified at a median of 14 months after starting a daratumumab-containing regimen (range, 4-26). Of the 13 patients, there were 5 patients who had another drug adjustment at the time of Dara-RI. Of note, there were 3 patients who were on a non-FDA approved daratumumab-containing regimen at the time of Dara-RI.

At the time of our final analysis, there were 7 patients (54%) who remained on a daratumumab-based regimen. Of these 7 patients, 6 patients continued Dara-RI and 1 patient transitioned from biweekly to monthly daratumumab due to stable disease. Notably, 3 patients had another drug adjustment at the time of Dara-RI. The median length of Dara-RI is 8 months and ongoing (range, 4-12). There were 5 patients (38%) who discontinued their daratumumab-based regimen after Dara-RI. Of these 5 patients, 2 patients had another drug adjustment at the time of Dara-RI. All 5 patients had at least stable disease or partial response to Dara-RI, with exception of one individual who had progressive disease. In addition, all 5 patients who discontinued Dara-RI was within 4 months of starting Dara-RI. Uniquely, one patient had panobinostat added to their Dara-RI regimen after 1 month of re-intensification, but continued with Dara-RI.

No patients experienced a dose delay due to adverse effects or were hospitalized after initiation of Dara-RI. Only one patient was prescribed antibiotics for treatment of a cold sore. There were no new hypersensitivity, cardiovascular, hematologic, gastrointestinal, or central nervous system toxicities noted after initiation of Dara-RI.

Conclusion:

Limitations of this study include other myeloma drug-related adjustments at the time of Dara-RI and the heterogeneous population as well as the retrospective nature of the study. In our experience with 13 patients, Dara-RI appears to be a safe and tolerable alternative regimen for patients who have disease progression on a daratumumab-containing regimen.