Daratumumab‐lenalidomide‐dexamethasone vs standard‐of‐care regimens: Efficacy in transplant‐ineligible untreated myeloma

Abstract

Daratumumab in combination with lenalidomide-dexamethasone (D-Rd) recently received FDA approval for the treatment of transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM). The present PEGASUS study compared progression-free survival (PFS) in patients treated with D-Rd in the MAIA trial and patients treated with common standard-of-care regimens from the Flatiron Health electronic health record-derived deidentified database, which has data from patients treated primarily at community-based oncology practices in the United States. Individual-level patient data from both data sources were used to perform an anchored indirect treatment comparison (ITC) of D-Rd to bortezomib-lenalidomide-dexamethasone (VRd) and bortezomib-dexamethasone (Vd); lenalidomide-dexamethasone (Rd) was the common anchor for the ITC. Hazard ratios (HRs) reflecting direct comparisons of PFS within MAIA (D-Rd vs Rd) and Flatiron Health (VRd vs Rd; Vd vs Rd) were used to make ITCs for D-Rd vs VRd and Vd, respectively. After application of MAIA inclusion/exclusion criteria and propensity-score weighting, the Flatiron Health patients resembled the MAIA trial population on measured baseline characteristics. Based on the direct comparison within MAIA, treatment with D-Rd was associated with a significantly lower risk of progression or death compared to Rd (HR 0.54; 95% CI 0.42, 0.71). Based on the ITCs, D-Rd was associated with a significantly lower risk of progression or death compared to VRd (HR 0.68; 95% CI 0.48, 0.98) and Vd (HR 0.48; 95% CI 0.33, 0.69). In the absence of head-to-head trials comparing D-Rd to VRd or Vd, the present ITC may help inform treatment selection in transplant-ineligible patients with NDMM. 1 | INTRODUCTION Daratumumab in combination with lenalidomide-dexamethasone (D-Rd) received approval from the US Food and Drug Administration (FDA) in June 2019 for the treatment of patients with newly diagnosed multiple myeloma (NDMM) who were ineligible for autologous stem cell transplant (ASCT). 1 FDA approval was based on results from a prespecified interim analysis of data from the MAIA phase III clinical trial, which showed that D-Rd was associated with a significantly lower risk of disease progression or death relative to lenalidomide-dexamethasone

Treatment Pattern and Outcomes in Newly Diagnosed Multiple Myeloma Patients Who Did Not Receive Autologous Stem Cell Transplantation: A Real-World Observational Study

“…Except for SWOG s0777, there are no other head-to-head phase 3 studies comparing VRd with other frontline regimens in patients who are not eligible for ASCT. However, our result is consistent with a study [ 18 ] based on the US Flatiron Health EHR which reported the OS HR for VRd versus Rd as 0.88 (95% CI 0.69, 1.11).…”

Daratumumab for the Management of Newly Diagnosed and Relapsed/Refractory Multiple Myeloma: Current and Emerging Treatments

“…Recently, the PEGASUS study ( 28 ) made an anchored indirect treatment comparison (ITC) in terms of PFS among patients treated with D-Rd in the MAIA trial and those receiving VRd or Vd in real life. This analysis demonstrated that D-Rd reduced the risk of progression or death compared to either VRd (HR 0.68; p = 0.04) or Vd (HR 0.48; p < 0.001) in transplant-ineligible patients.…”

Immunotherapy of Multiple Myeloma: Promise and Challenges

“…However, daratumumab-dexamethasone in combination with proteasome inhibitors and/or immunomodulators has since assumed a key role in even earlier courses of anti-myeloma therapy as data from additional phase III trials demonstrated more sustained responses and good tolerability from such combinations, including use in newly diagnosed patients whether ASCT-eligible 23 or -ineligible. 24 …”

“…However, daratumumab-dexamethasone in combination with proteasome inhibitors and/or immunomodulators has since assumed a key role in even earlier courses of antimyeloma therapy as data from additional phase III trials demonstrated more sustained responses and good tolerability from such combinations, including use in newly diagnosed patients whether ASCT-eligible 23 or -ineligible. 24 Current NCCN treatment guidelines for MM, based on most favorable response and safety data, include one triplet protocol (daratumumab-lenalidomidedexamethasone); and a number of quartet regimens which include, in addition to daratumumab-bortezomibcorticosteroid (dexamethasone or prednisone), either an alkylating agent (cyclophosphamide or melphalan) or an immunomodulator (lenalidomide or thalidomide). 7 Moreover, combinations with pomalidomide 25 and more recently carfilzomib 26,27 also have received FDA approval for use in relapsed and/or refractory MM (RRMM).…”