Daratumumab vs. pomalidomide for the treatment of relapsed/refractory multiple myeloma: a cost‐effectiveness analysis
Authors: Cynthia L. Gong, Ann L. Studdert, Michaela Liedtke
Journal: American Journal of Hematology (2018)

The FDA has approved several options for relapsed/refractory multiple myeloma in the past decade, including carfilzomib, daratumumab, elotuzumab, pomalidomide, and ixazomib in various combinations with dexamethasone.1 Unfortunately, these drugs are costly, and while there is justified and increasing criticism of the high cost of cancer drugs, the price should not be judged in isolation but rather evaluated in the context of clinical benefit which can be assessed by cost-effectiveness analyses. The Institute of Clinical Effectiveness and Research previously conducted several cost-effectiveness analyses for these drugs, but did not include both daratumumab and pomalidomide in the same analysis, although they found that daratumumab-containing regimens are cost-effective compared to carfilzomib, elotuzumab, ixazomib, or panobinostat.2 A recent manufacturer-sponsored analysis compared the cost-effectiveness of pomalidomide relative to daratumumab and carfilzomib, and showed that pomalidomide was marginally dominant (ie, cheaper and more effective) compared to both drugs.3 Given that daratumumab and pomalidomide were not included in the same analysis in the reports published by the Institute of Clinical Effectiveness and Research, we sought to determine the cost-effectiveness of daratumumab relative to pomalidomide from a US public payer perspective. In contrast to the manufacturer-sponsored cost-effectiveness analysis, we used pomalidomide as the reference comparator as it was FDA-approved in 2013 prior to daratumumab's approval in 2015. Pomalidomide was also chosen as an indirect comparator because the patients in the clinical trial were most like those in the daratumumab trial; both groups of patients were heavily pre-treated with high rates of resistance to lenalidomide and bortezomib therapy.4, 5 We used a lifetime Markov model from the US payer perspective to simulate stable disease, progressed disease, and death for patients with relapsed/refractory multiple myeloma, with transition probabilities, costs, and utility values derived from clinical trial data and the literature. Costs were in 2017 USD and derived from government acquisition costs and reimbursement schedules for drugs, labs, imaging, and physician visits. Quality-of-life for each health state, adverse drug events, and response to drug treatment were based on multiple literature sources for multiple myeloma. The NMB is determined at each willingness-to-pay threshold. The treatment with higher NMB at a given threshold is considered the most cost-effective at that threshold. In addition, a one-way sensitivity analysis varying survival, cost, and quality-of-life was conducted to test the effect of individual parameters on the results of the model. A probabilistic sensitivity analysis was also conducted using 10 000 Monte Carlo simulations. We found that daratumumab was cost-effective relative to pomalidomide with an ICER of $156 385 per QALY. Results remained robust in one-way sensitivity analysis, with a relatively small deviation from the base-case result regardless of which parameters were varied (Figure 1). The ICER was most sensitive to overall survival and drug cost for both daratumumab and pomalidomide. Even at the lower end of the range for overall survival, daratumumab's ICER did not significantly exceed $160 000 per QALY if overall survival was assumed to be just 13.7 months. Only when daratumumab was assumed to be expensive did the ICER reach $224 736 per QALY; this was the maximum ICER calculated in one-way sensitivity analyses. The probabilistic sensitivity analysis showed that daratumumab is cost-effective relative to pomalidomide >50% of the time at a willingness-to-pay threshold of approximately $170 000 per QALY, whereas daratumumab was cost-effective only 34% of the time at a threshold of $160 000 per QALY. This was confirmed in NMBs analysis; daratumumab yielded higher benefits than pomalidomide at a willingness-to-pay threshold of $160 000 per QALY and greater. Based on our analysis, daratumumab is cost-effective for relapsed/refractory multiple myeloma compared to pomalidomide. We note that this contrasts with the findings by Pelligra et al, which determined pomalidomide to have higher QALYs gained and lower costs than daratumumab.3 While we similarly found that overall costs for pomalidomide were less than those for daratumumab, we found an overall worse quality-of-life associated with pomalidomide due to a more severe adverse drug reaction profile. This reflects our clinical experience as well; while patients on daratumumab may initially experience infusion reactions with the first few infusions, these subside over time with limited additional adverse effects, especially given the decreased frequency of administration over time. Overall tolerability is worse in patients on pomalidomide, who experience higher rates of central nervous system effects, diarrhea, cramping, rashes, and a more significant impact on blood counts. As the data were extrapolated from two different studies and the study populations were not identical, the analysis may be considered biased in favor of one drug or another. However, the two study populations were similar in their rates of bortezomib and lenalidomide-resistant myeloma. Pomalidomide was the most reasonable comparator for daratumumab in the absence of any comparator in daratumumab's phase 2 trial. We also note that daratumumab's improved overall survival despite lower progression-free survival relative to pomalidomide suggests that there is a lasting effect of the drug that persists even upon discontinuation. Our analysis contributes crucial information regarding the cost and value of these drugs. Our findings are highly relevant for payer and patient decision-making, enabling them to maximize health outcomes in relation to the available resources by identifying daratumumab as a high value intervention for the treatment of relapsed or refractory multiple myeloma. In addition to the clinical and financial benefits for the patient receiving daratumumab, the judicious use of high value interventions translates into improved societal health by allowing the allocation of limited resources to other areas of need. ML receives research funding for clinical trial research from Celgene and Janssen Pharmaceuticals, however, these funds go directly to Stanford University. CLG and ALS have no competing interests. CLG designed and performed the analysis and writing of the manuscript. ML and ALS edited it for clinical accuracy, relevance, and readability. ALS provided support for the analysis. Nothing to report.