Daratumumab (Darzalex SC): Therapeutic area: Multiple myeloma in patients ineligible for autologous stem cell transplant: Reimbursement Review

What is multiple myeloma?Multiple myeloma is a cancer of plasma cells (the white blood cells that make immunoglobulins) found in the bone marrow. In 2025, approximately 4,285 people in Canada were newly diagnosed with multiple myeloma (NDMM). Among them, 2,125 people were not suitable for treatment with autologous stem cell transplant (ASCT) or did not plan to receive ASCT initially. The prognosis for these patients is poorer than for those who receive ASCT (median overall survival [OS] is 4.5 years compared to 8 to 10 years).What are the treatment goals and current treatment options for ndmm?• Input from the patient group and the clinicians indicated that treatment goals for NDMM are to alleviate symptoms, achieve long-term remission, preserve health-related quality of life, minimize treatment side effects, prevent new complications from the treatment, and prolong survival. • Current treatments for patients with NDMM who are not undergoing ASCT include daratumumab in combination with lenalidomide and dexamethasone (DRd); the combination of bortezomib, lenalidomide, and dexamethasone (VRd); daratumumab in combination with cyclophosphamide, bortezomib, and dexamethasone; daratumumab in combination with bortezomib, melphalan, and prednisone (DVMp); and isatuximab in combination with VRd (Isa-VRd). Among these, DRd is the standard of care in Canada, according to the clinical experts consulted by Canada’s Drug Agency (CDA-AMC).What is darzalex sc and why did cda-amc conduct this review?• Darzalex SC is a monoclonal antibody targeting the CD38 protein, which is expressed on the surface of cells in a variety of blood cancers, including multiple myeloma. Health Canada has approved Darzalex SC (a subcutaneous formulation of daratumumab) in combination with other drugs (bortezomib, lenalidomide, and dexamethasone), referred to as D-VRd hereinafter, for the treatment of adult patients with NDMM who are not undergoing ASCT as initial therapy. • CDA-AMC reviewed Darzalex SC to inform a recommendation to the participating public drug programs on whether it should be reimbursed for the indication under review by Health Canada.How did cda-amc evaluate darzalex sc?• CDA-AMC reviewed evidence submitted by the sponsor, including clinical evidence on the beneficial and harmful effects, as well as economic evidence, of Darzalex SC versus other treatments used in Canada for adult patients with NDMM who are not undergoing ASCT as initial therapy. DRd, VRd, Isa-VRd, DVMp, and daratumumab in combination with cyclophosphamide, bortezomib, and dexamethasone were considered relevant treatments to compare with Darzalex SC when reviewing the evidence. • CDA-AMC identified equity and ethical considerations relevant to treatment with Darzalex SC in patients with NDMM for whom ASCT is not planned as the initial therapy. • The review was also informed by separate submissions from 1 patient group, 1 clinician group, and the participating public drug programs. The drug programs’ input covered issues that may impact their ability to implement a recommendation. • Two hematologists with representation from the Prairies (Manitoba and Alberta) were consulted as part of the review process.What were the findings?CLINICAL EVIDENCE: • CDA-AMC reviewed the following clinical evidence: o.. 1 randomized controlled phase III trial (the CEPHEUS study) comparing D-VRd with VRd in 395 patients with NDMM who are not undergoing ASCT as initial therapy; o.. 2 propensity score–based analyses and 1 anchored matching-adjusted indirect comparison of D-VRd versus DRd, DVMp, and Isa-VRd. • For the comparison of D-VRd versus VRd: o.. D-VRd demonstrated a clinically important increase in the probability of progression-free survival (PFS) compared to VRd at 54 months, with high certainty in the findings. o.. D-VRd demonstrated increases in the overall minimal residual disease (MRD) negativity rate and very good partial response or better rate compared to VRd at a median follow-up of 58.7 months, with high and moderate certainty in the findings, respectively. o.. There was no statistically significant difference between D-VRd and VRd in the OS at 54 months; the evidence was of moderate certainty. o.. D-VRd may not result in any clinically important difference in patients’ health-related quality of life compared to VRd; the evidence was of low certainty because of a large amount of missing data. o.. D-VRd likely results in an increase in the incidence of serious adverse events, infections and infestations, and cytopenia compared to VRd; the evidence was of moderate to high certainty. • For the comparison of D-VRd versus other active treatments (DRd, DVMp, and Isa-VRd): o.. Results from the propensity-based methods suggested that treatment with D-VRd may be related to longer PFS and a higher MRD negativity rate when compared to DRd and DVMp, although the magnitude of benefit is uncertain. This uncertainty was likely related to the cross-trial heterogeneity (e.g., different patients’ characteristics at baseline). Additionally, it is possible that the comparisons were not adjusted for all effect modifiers. There was no statistically significant difference in OS between D-VRd and DRd or DVMp. o.. Results from a matching-adjusted indirect comparison analysis suggested that evidence is insufficient to conclude whether D-VRd or Isa-VRd is favoured for prolonging PFS or OS, or improving the MRD negativity rate, in patients with NDMM who are not undergoing ASCT as initial therapy. The estimates were affected by serious imprecision (i.e., wide 95% confidence intervals) that included the null, suggesting that either treatment could be favoured. ECONOMIC EVIDENCE: • Darzalex SC is available as single-dose vials (1,800 mg per 15 mL). At the submitted price of $8,028.00 per 1,800 mg vial, the 21-day cycle cost of Darzalex SC is expected to be $24,084 per patient in cycles 1 and 2, $8,028 per patient in cycles 3 to 8, and the 28-day cycle cost of Darzalex SC is expected to be $8,028 per patient in cycle 9 and onwards, based on the Health Canada–recommended dosage. The regimen cost of D-VRd is expected to be $28,210 per patient in cycles 1 and 2 (21 days), $12,154 per patient in cycles 3 to 8 (21 days), and $10,278 per patient in cycles 9 and beyond (28 days). • Key clinical efficacy outcomes in the economic analysis for D-VRd versus VRd were derived from the CEPHEUS trial. Evidence submitted by the sponsor indicates that D-VRd is likely to improve PFS compared with VRd among patients 18 years and older with NDMM who are not undergoing ASCT as initial therapy. However, treatment benefit in OS was uncertain because median OS was not reached in either treatment group at the latest data cut-off for analyses, and the between-group difference in the 54-month OS rate was not statistically significant. For D-VRd versus all other comparators, clinical efficacy was informed by sponsor-submitted indirect treatment comparisons, which suggest that D-VRd may improve PFS when compared to DRd and DVMp, although the magnitude of benefit is uncertain because of study limitations. There was no statistically significant difference in OS between D-VRd and DRd or DVMp., When compared to Isa-VRd, there was insufficient evidence to conclude whether D-VRd or Isa-VRd is favoured for prolonging PFS or OS. There remain several critical limitations to these analyses, including heterogeneity in the included trials and some patients’ characteristics at baseline, and the possibility that not all confounding factors were adjusted for. Consequently, the estimates of PFS and OS used in the model are associated with uncertainty. • The results of the CDA-AMC base case suggest: o.. D-VRd is predicted to be associated with higher costs to the health care system than VRd (incremental costs = $1,072,043) and DRd (incremental costs = $311,182). These cost increases are driven by drug acquisition costs associated with D‑VRd. o.. D-VRd is predicted to result in no additional life-years compared to VRd and DRd. D-VRd may result in a gain of 0.10 quality-adjusted life-years (QALYs) compared to VRd, and 0.04 QALYs gained compared to DRd. o.. The incremental cost-effectiveness ratio of D-VRd compared to VRd was $10,623,156 per QALY gained and $7,029,398 per QALY gained compared to DRd in the CDA-AMC base case. o.. The estimated incremental cost-effectiveness ratio was highly sensitive to the predicted OS benefit and the drug acquisition costs of Darzalex SC. Approximately 82% and 89% of the incremental benefit relative to VRd and DRd, respectively, was gained in the extrapolated period (i.e., after 5.3 years). In the absence of comparative evidence beyond this time point and uncertainty in the comparative clinical evidence, the QALYs gained remain highly uncertain and may be overestimated. Higher price reductions than those presented in this report may therefore be required to achieve cost-effectiveness at a given willingness-to-pay threshold. • CDA-AMC estimates that the budget impact of reimbursing D-VRd for the indicated population will result in savings of approximately $39 million over the first 3 years of reimbursement compared to the amount currently spent on comparators, with an estimated expenditure of $369 million on D-VRd over this period. The actual budget impact of reimbursing D-VRd will depend on the market uptake of D-VRd, the negotiated prices of reimbursed comparators, and the distribution of therapies that are likely to be displaced by D-VRd. The magnitude of uncertainty in the budget impact must be addressed to ensure the feasibility of adoption given the difference between the sponsor’s estimate and the CDA-AMC estimate.