Daratumumab as first line
Newly diagnosed multiple myeloma [NDMM] (Transplant Ineligible)
|Regimen||Approval based on Trial||Benefit documented|
|Dara-Rd||Phase 3 MAIA||PFS and Deeper Responses (No OS benefit documented)#|
|Dara-VMP||Phase 3 ALCYONE||PFS and Deeper Responses (No OS benefit documented)*|
At a median follow-up of 28 months, Phase 3 MAIA showed (Dara Rd VS Rd)
|Disease progression/Death||Daratumumab with Rd significantly reduced the risk of disease progression or death by 44 percent in patients with NDMM who are transplant ineligible, compared to treatment with Rd alone (HR = 0.56; 95 percent confidence interval [CI]: 0.43-0.73; p<0.0001).|
|PFS benefit||The median PFS for Dara-Rd has not yet been reached, compared to 31.9 months for patients who received Rd alone.|
|CR/VGPR rates||The addition of Daratumumab resulted in deeper responses compared to Rd alone, including increased rates of complete response (CR) or better (48 percent vs. 25 percent), very good partial response (VGPR) or better (79 percent vs. 53 percent) and overall response (93 percent vs. 81 percent).|
|MRD negativity||Daratumumab-Rd induced a >3-fold higher rate of minimal residual disease (MRD) negativity compared to Rd alone (24 percent vs. 7 percent).|
#Update: EHA2021 and ASH 2020 MAIA Trial Update showed that the estimated 5-year overall survival rates were 66.3% and 53.1% with and without daratumumab, respectively.
Issue with Phase 3 MAIA study: Comparator/Control Rd is not a standard of Care
At a median follow-up of 16.5 months Phase 3 ALCYONE (Dara VMP vs VMP) showed
|Disease progression/Death||Daratumumab with VMP reduced the risk of disease progression or death by 50 percent, compared to treatment with VMP alone (HR = 0.50; 95 percent CI [0.38-0.65], p<0.0001).|
|PFS benefit||The median PFS for Daratumumab -VMP had not yet been reached, compared to a median PFS of 18.1 months for patients who received VMP alone.|
|CR/VGPR rates||Daratumumab in combination with VMP significantly improved overall response rates (91 vs. 74 percent) compared to VMP alone. Additionally, measures of stringent complete response (18 vs. 7 percent), complete response or better (43 vs. 24 percent) and very good partial response or better (71 vs. 50 percent) all showed marked improvement.|
|MRD negativity||Patients receiving Daratumumab in combination with VMP achieved a more than three-fold increase in the minimal residual disease (MRD) negativity rate (22 vs. 6 percent) compared to those who received VMP alone.|
*Updated efficacy and safety results from a prespecified, interim, overall survival analysis of ALCYONE with more than 36 months of follow-up. At a median follow-up of 40·1 months (IQR 37·4–43·1), 83 (24%) of 350 patients in the D-VMP group and 126 (35%) of 356 patients in the VMP group had died. The Kaplan-Meier estimate of the 36-month rate of overall survival was 78·0% (95% CI 73·2–82·0) in the D-VMP group and 67·9% (62·6–72·6) in the VMP group.
Newly diagnosed multiple myeloma (Transplant eligible)
|Regimen||Approval based on Trial||Benefit documented|
|Dara-VTd||Phase 3 CASSIOPEIA||PFS and Deeper Responses (No OS benefit documented)|
At a median follow-up of 18.8 months, Phase 3 CASSIOPEIA (Dara VTd vs VTd) showed
|Disease progression/Death||Daratumumab-VTd at a median follow-up of 18.8 months resulted in a 53 % reduction in the risk of disease progression or death compared to VTd alone (HR = 0.47; 95 percent CI, 0.33–0.67; P<0.0001).|
|PFS benefit||Median PFS from first randomization was not reached in either group (HR = 0·47, 95% CI 0·33–0·67, p<0·0001).|
|CR/VGPR rates||The primary endpoint of sCR rate post consolidation was significantly higher in the Daratumumab-VTd arm compared to VTd alone (29 percent vs. 20 percent) (Odds Ratio [OR] = 1.60; 95 percent confidence interval [CI], P=0.0010).
After consolidation, Daratumumab -VTd also increased the rate of complete response or better (39 percent vs. 26 percent) (OR = 1.82; 95 percent CI, 1.40-2.36) and very good partial response or better (83 percent vs. 78 percent) (OR = 1.41; 95 percent CI, 1.04-1.92) compared to VTd alone, respectively.
|MRD Negativity||Patients in the D-VTd group versus VTd group achieved 64% versus 44% minimal residual disease-negativity (10−5 sensitivity threshold, assessed by multiparametric flow cytometry; both p<0·0001).|
Schedule for Dara 1st line regimens
|Dara-Rd||Weeks 1-8 Weekly (total of 8 doses)||Weeks 9-24: every 2 weeks (total of 8 doses)||Week 25 onwards until disease progression: every 4 weeks|
|Dara-VMP||Weeks 1-6 Weekly (total 6 doses)||Weeks 7-54: every 3 weeks (total of 16 doses)||Week 55 onwards until disease progression: every 4 weeks|
|Dara-VTd||Induction phase (Weeks 1-8) weekly (total of 8 doses)||Induction phase (Weeks 9-16): every 2 weeks (total of 4 doses)||Consolidation post ASCT (Week 1-8): 16 mg/kg IV infusion every 2 weeks (total of 4 doses)|
 Facon T et al. Daratumumab, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone alone in newly diagnosed multiple myeloma (MAIA): overall survival results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2021 Oct 13:S1470-2045(21)00466-6. doi: 10.1016/S1470-2045(21)00466-6. Epub ahead of print. PMID: 34655533.
 Mateos MV et al. Daratumumab plus Bortezomib, Melphalan, and Prednisone for Untreated Myeloma. N Engl J Med. 2018 Feb 8;378(6):518-528. doi: 10.1056/NEJMoa1714678. Epub 2017 Dec 12. PMID: 29231133.
 Moreau P et al. Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): a randomised, open-label, phase 3 study. Lancet. 2019 Jul 6;394(10192):29-38. doi: 10.1016/S0140-6736(19)31240-1. Epub 2019 Jun 3. Erratum in: Lancet. 2019 Jun 14;: PMID: 31171419.