Daratumumab Improves Depth of Response and Progression-free Survival in Transplant-ineligible, High-risk, Newly Diagnosed Multiple Myeloma

Abstract

Background Patients with high-risk, newly diagnosed multiple myeloma (HR-NDMM) who are ineligible for autologous stem cell transplant (ASCT) have limited first-line treatment options. Recent meta-analyses evaluating the impact of incorporating daratumumab in the backbone regimen on progression-free survival (PFS) have found mixed results in these patients. Materials and Methods A pooled analysis of patient-level data for ASCT-ineligible patients with HR-NDMM [ie, del(17p), t(4;14), t(14;16)] from the MAIA and ALCYONE trials; stratified by study identifier and adjusting for cytogenetic abnormality subtype, baseline performance status, International Staging System stage, myeloma type, and renal impairment; was conducted. Impact of daratumumab on PFS and rates of complete response or better (≥CR), minimal residual disease (MRD)-negative CR, very good partial response or better (≥VGPR), and overall response (ORR) was compared to control. Results Among 101 patients in the daratumumab and 89 patients in the control cohort, median follow-up was 43.7 months. Daratumumab reduced the risk of progression or death by 41% (adjusted hazard ratio for PFS [95% confidence interval (CI)] = 0.59 [0.41-0.85]) versus control. At 36 months, the estimated proportion of patients who did not progress and were still alive was 41.3% in the daratumumab and 19.9% in the control cohort. Rates of ≥CR (41.6% vs. 22.5%), MRD-negative CR (24.8% vs. 5.6%), ≥VGPR (75.2% vs. 46.1%), and ORR (92.1% vs. 74.2%) were higher for daratumumab versus control. Conclusion These findings demonstrate that incorporation of daratumumab in frontline treatment regimens reduced the risk of progression or death and improved response rates among ASCT-ineligible HR-NDMM patients.

Isatuximab, Carfilzomib, Lenalidomide, and Dexamethasone for the Treatment of High-Risk Newly Diagnosed Multiple Myeloma

“…19 Albeit from a small cohort of TNE patients, the 69.2% MRD negativity rate and mPFS that was not reached after 33 months in CONCEPT compare favorably with the KRdonly arm in the FORTE trial, reporting a 29-month mPFS, 20 despite the older age and reduced fitness in CONCEPT. The same holds true for MAIA (ClinicalTrials.gov identifier: NCT02252172) and ALCYONE (ClinicalTrials.gov identifier: NCT02195479) subgroup analyses, with a 41.3% 3-year PFS rate for HRNDMM TNE patients with daratumumab-based regimens (daratumumab-lenalidomide-dexamethasone or daratumumab-bortezomib-melphalan-prednisone) 25 compared with a 58.4% 3-year PFS rate in CONCEPT.…”

“…The primary end point is the proportion of patients reaching MRD negativity (<10 25 , NGF) at the end of consolidation. Secondary end point is PFS, defined as the time from enrollment to progression or death, whichever occurs first.…”

“…The phase II GMMG-CONCEPT trial (ClinicalTrials.gov identifier: NCT03104842) was designed to study patients with newly diagnosed (ND) HRMM (TE and TNE) treated with the quadruplet combination of isatuximab, carfilzomib, lenalidomide, and dexamethasone (Isa-KRd) in induction/consolidation, followed by triplet maintenance (Isa-KR). The primary objective was to evaluate MRD negativity (<10 25 , next-generation flow [NGF]) after consolidation. The secondary objective was to assess PFS.…”

“…95% CIs refer to the one-sided binomial test result of the primary end point, testing the observed MRD negativity rate against 50% and 30%, respectively. (D and E) Swimmer plots showing achievement and sustainment of MRD negativity (next-generation flow; MRD <1025 ) for (D) TE and (E) TNE patients. (F) Sustained MRD negativity for ≥6 months or ≥12 months in both study arms.…”

A Journey through the Inter-Cellular Interactions in the Bone Marrow in Multiple Myeloma: Implications for the Next Generation of Treatments

“…The relevance of MDSCs has been translated to patients. Thus, dual targeting of MM cells and MDSCs with biotherapeutic agents, such as Daratumumab [ 147 ], has emerged as a promising new therapeutic option with high potential, as recently reviewed by Uckun [ 218 ]. On the other hand, the α-chain of the IL3 receptor, known as CD123, is highly expressed on MDSCs [ 219 ].…”