A phase 3, open-label, randomized clinical trial has provided extended follow-up data on the efficacy and safety of subcutaneous daratumumab in combination with pomalidomide and dexamethasone for patients with relapsed or refractory multiple myeloma. The APOLLO study, conducted across 48 academic centers and hospitals in 12 European countries, was funded by the European Myeloma Network and Janssen Research & Development. Results from this extended analysis were published in October 2023 in The Lancet Haematology.
The primary purpose of the APOLLO trial was to evaluate the addition of subcutaneous daratumumab to standard pomalidomide and dexamethasone therapy in patients with relapsed or refractory multiple myeloma. While the primary endpoint of progression-free survival was previously reported, this latest publication provides final overall survival data and updated safety results after approximately 3 years of follow-up.
A total of 304 adult patients were enrolled in the study between June 2017 and June 2019. Key inclusion criteria were: age 18 years or older, relapsed or refractory multiple myeloma with measurable disease, Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, prior treatment including both a proteasome inhibitor and lenalidomide, and at least a partial response to one or more previous lines of therapy. Patients who had received only one previous line of therapy were required to be refractory to lenalidomide. Those with previous exposure to anti-CD38 monoclonal antibodies or pomalidomide were excluded.
Participants were randomized 1:1 to receive either daratumumab plus pomalidomide and dexamethasone (151 patients) or pomalidomide and dexamethasone alone (153 patients). Randomization was stratified by number of prior lines of therapy and International Staging System disease stage. The median age of patients was 67 years, with 47% female and 53% male. The vast majority (89%) were White. Patients had received a median of 2 prior lines of therapy, and approximately 80% were refractory to lenalidomide.
In the daratumumab arm, patients received subcutaneous daratumumab 1800 mg in combination with oral pomalidomide 4 mg (days 1-21) and oral dexamethasone 40 mg (days 1, 8, 15, 22) in 28-day cycles. The control arm received pomalidomide and dexamethasone at the same doses. Treatment continued until disease progression or unacceptable toxicity.
At a median follow-up of 39.6 months, the median overall survival was 34.4 months in the daratumumab combination group compared to 23.7 months in the control group. While this represents a 10.7 month improvement, the difference did not reach statistical significance (hazard ratio 0.82, 95% CI 0.61-1.11, p=0.20). The lack of statistical significance may be partly attributed to the higher rate of subsequent anti-CD38 therapy use in the control arm (69% vs 10%).
Progression-free survival on next line of therapy, a pre-planned exploratory endpoint, was significantly improved with daratumumab, with a median of 24.4 months vs 17.6 months (HR 0.73, 95% CI 0.55-0.98, p=0.034). At 36 months, 41.4% of daratumumab-treated patients remained progression-free on next therapy compared to 27.0% in the control group.
The safety profile remained consistent with previous reports, with no new concerns identified. The most common grade 3-4 adverse events in the daratumumab arm were neutropenia (69%), anemia (18%), and thrombocytopenia (18%). Serious adverse events occurred in 54% of daratumumab-treated patients vs 40% in the control arm, with pneumonia being most frequent (15% vs 9%). Treatment-emergent adverse events leading to death occurred in 9% of patients in both groups.
Key limitations of the study include its open-label design and the fact that it was not powered for overall survival analysis. Additionally, the small sample size and relatively short study duration may have impacted the ability to detect statistically significant differences in overall survival.
The study authors concluded that while the overall survival difference was not statistically significant, the safety profile and other efficacy results continue to support the use of daratumumab in combination with pomalidomide and dexamethasone for patients with relapsed or refractory multiple myeloma. They note that the favorable attributes of subcutaneous administration, including shorter infusion times and lower rates of infusion-related reactions, make this a beneficial and convenient treatment option.
These findings have potential clinical implications for the management of relapsed/refractory multiple myeloma. The extended follow-up data provide further evidence for the efficacy and long-term safety of daratumumab-containing regimens. The significant improvement in progression-free survival on next line of therapy suggests a durable benefit that extends beyond initial treatment.
However, the lack of statistically significant overall survival benefit highlights the challenges in demonstrating survival advantages in a setting where effective subsequent therapies are available. The high rate of anti-CD38 therapy use in the control arm after progression likely contributed to this. This underscores the importance of considering the entire treatment journey when interpreting clinical trial results in multiple myeloma.
The safety profile, with no new concerns identified after extended follow-up, provides reassurance for the long-term use of this regimen. The higher rates of cytopenias with daratumumab combination therapy emphasize the need for appropriate monitoring and management strategies in clinical practice.
These results should be interpreted in the context of other recent studies evaluating anti-CD38 monoclonal antibodies in combination with pomalidomide and dexamethasone. The phase 3 ICARIA-MM trial of isatuximab plus pomalidomide and dexamethasone showed similar trends, with a non-significant overall survival benefit but significant improvements in progression-free survival. The consistency across studies supports the clinical value of adding anti-CD38 therapy to pomalidomide-based regimens.
An important consideration raised by this and other recent studies is the optimal sequencing of therapies in multiple myeloma. The authors note that real-world data show high attrition rates across lines of therapy, with many patients not receiving third-line treatment. This supports the argument for using the most effective therapies earlier in the disease course to maximize the chance of durable response.
The subcutaneous formulation of daratumumab used in this study offers practical advantages over intravenous administration. The shorter infusion time (3-5 minutes) and lower rates of infusion-related reactions may improve treatment adherence and patient quality of life. This could be particularly beneficial for older or frail patients who may struggle with lengthy infusions.
From a health economics perspective, the lack of significant overall survival benefit may impact cost-effectiveness evaluations of this regimen. However, the improved progression-free survival and potential for reduced healthcare utilization due to the subcutaneous formulation should also be considered in comprehensive economic analyses.
For clinicians, these results provide further evidence to support the use of daratumumab-containing regimens in relapsed/refractory multiple myeloma. The choice between different anti-CD38 antibodies (daratumumab vs isatuximab) may depend on factors such as dosing schedule, route of administration, and institutional familiarity. The subcutaneous option may be particularly attractive in settings where minimizing patient time in the clinic is a priority.
In conclusion, this extended follow-up of the APOLLO trial provides valuable long-term efficacy and safety data on the combination of subcutaneous daratumumab with pomalidomide and dexamethasone in relapsed/refractory multiple myeloma. While the overall survival benefit did not reach statistical significance, the significant improvements in other efficacy endpoints and the manageable safety profile support the continued use of this regimen. As the multiple myeloma treatment landscape continues to evolve, these findings contribute to the growing body of evidence guiding optimal therapeutic strategies for this challenging disease.
References
Dimopoulos MA, Terpos E, Boccadoro M, et al. Subcutaneous daratumumab plus pomalidomide and dexamethasone versus pomalidomide and dexamethasone in patients with relapsed or refractory multiple myeloma (APOLLO): extended follow up of an open-label, randomised, multicentre, phase 3 trial. Lancet Haematol. 2023;10(10):e813-e824. doi:10.1016/S2352-3026(23)00218-1
