Less-fit patients with significant comorbidities or advanced age (aged ≥80 years)

A prospective randomized trial, reported in abstract form, included 395 patients with newly diagnosed myeloma who were aged 70 years or older or ineligible for autologous SCT with medical comorbidities. Patients received D-VRd or VRd.[69]

A prospective randomized trial, reported in abstract form, included 395 patients with newly diagnosed myeloma who were aged 70 years or older or ineligible for autologous SCT with medical comorbidities. Patients received D-VRd or VRd.[69]

With a median follow-up of 58.7 months, the 2-year MRD negativity (10-6) was 32.0% for patients who received D-VRd and 15.7% for patients who received VRd (HR, 0.40; 95% CI, 0.24–0.64; P = .001).[69][Level of evidence B3]

A prospective randomized trial (NCT03319667) was conducted in 446 patients with newly diagnosed myeloma who were ineligible for transplant. Patients were randomly assigned in a 3:2 ratio to receive either I-VRd or VRd alone.[14]

A prospective randomized trial (NCT03319667) was conducted in 446 patients with newly diagnosed myeloma who were ineligible for transplant. Patients were randomly assigned in a 3:2 ratio to receive either I-VRd or VRd alone.[14]

With a median follow-up of 59.7 months, the 5-year PFS rate was 63.2% for patients who received I-VRd versus 45.2% for patients who received VRd alone (HR, 0.60; 98.5% CI, 0.41–0.88; P < .001).[14][Level of evidence B1]

A prospective randomized trial (NCT03319667) was conducted in 446 patients with newly diagnosed myeloma who were ineligible for transplant. Patients were randomly assigned in a 3:2 ratio to receive either I-VRd or VRd alone.[14]

Isatuximab is given IV, unlike daratumumab, which is given subcutaneously (with significantly less side effects than the IV formulation).

A prospective randomized trial (NCT03319667) was conducted in 446 patients with newly diagnosed myeloma who were ineligible for transplant. Patients were randomly assigned in a 3:2 ratio to receive either I-VRd or VRd alone.[14]

Serious adverse events were similar in the two groups.

In a prospective randomized trial (NCT02252172) of 737 patients with newly diagnosed myeloma who were ineligible for transplant, daratumumab plus lenalidomide and dexamethasone was compared with Rd alone.[70]

In a prospective randomized trial (NCT02252172) of 737 patients with newly diagnosed myeloma who were ineligible for transplant, daratumumab plus lenalidomide and dexamethasone was compared with Rd alone.[70]

With a median follow-up of 56.2 months, the 60-month OS rate was 66.3% (95% CI, 60.8%–71.3%) for patients who received daratumumab and 53.1% (95% CI, 47.2%–58.6%) for patients who received Rd alone (HR, 0.68; 95% CI, 0.53–0.86; P = .0013).[70][Level of evidence A1]

In a prospective randomized trial (NCT02252172) of 737 patients with newly diagnosed myeloma who were ineligible for transplant, daratumumab plus lenalidomide and dexamethasone was compared with Rd alone.[70]

With a median follow-up of 56.2 months, the 60-month PFS rate was 52.5% for patients who received daratumumab (95% CI, 46.7%−58.0%) and 28.7% for patients who received Rd alone (95% CI, 23.1%−34.6%) (HR, 0.53; 95% CI, 0.43−0.66; P < .0001).[70]

In a prospective randomized trial (NCT02252172) of 737 patients with newly diagnosed myeloma who were ineligible for transplant, daratumumab plus lenalidomide and dexamethasone was compared with Rd alone.[70]

Results for the percentage of patients falling below the threshold for MRD (<1 tumor cell per 105 white cells) favored the daratumumab combination, 24.2% versus 7.3% (P < .001).

In a prospective randomized trial (NCT02252172) of 737 patients with newly diagnosed myeloma who were ineligible for transplant, daratumumab plus lenalidomide and dexamethasone was compared with Rd alone.[70]

The daratumumab combination resulted in significant and sustained reductions of pain scores and improved quality of life in the EuroQOL 5-dimensional descriptive visual system.[71][Level of evidence A3]

In a prospective randomized trial of 706 patients with newly diagnosed myeloma who were ineligible for transplant, daratumumab plus VMP was compared with VMP alone.[72]Immunological reaction to the initial dose of daratumumab can be modulated by splitting the first infusion over 2 days or using the subcutaneous version (this dosing schedule is not approved by the U.S. Food and Drug Administration).

In a prospective randomized trial of 706 patients with newly diagnosed myeloma who were ineligible for transplant, daratumumab plus VMP was compared with VMP alone.[72]Immunological reaction to the initial dose of daratumumab can be modulated by splitting the first infusion over 2 days or using the subcutaneous version (this dosing schedule is not approved by the U.S. Food and Drug Administration).

With a median follow-up of 40.1 months, the 3-year OS rate favored the daratumumab combination group at 78% (95% CI, 73.2%−83.0%) versus 67.9% in the VMP-alone group (95% CI, 62.6%−72.6%) (HR, 0.60; 95% CI, 0.46−0.80; P = .003).[72][Level of evidence A1]

In a prospective randomized trial of 706 patients with newly diagnosed myeloma who were ineligible for transplant, daratumumab plus VMP was compared with VMP alone.[72]Immunological reaction to the initial dose of daratumumab can be modulated by splitting the first infusion over 2 days or using the subcutaneous version (this dosing schedule is not approved by the U.S. Food and Drug Administration).

With a median follow-up of 40.1 months, the 3-year PFS rate favored the daratumumab combination group at 50.7% (95% CI, 45.1%−55.9%) versus 18.5% in the VMP-alone group (95% CI, 14.4%−23.1%) (HR, 0.42; 95% CI, 0.34−0.51; P < .0001).[72][Level of evidence B1]

In a prospective randomized trial of 706 patients with newly diagnosed myeloma who were ineligible for transplant, daratumumab plus VMP was compared with VMP alone.[72]Immunological reaction to the initial dose of daratumumab can be modulated by splitting the first infusion over 2 days or using the subcutaneous version (this dosing schedule is not approved by the U.S. Food and Drug Administration).

In the daratumumab combination group, 22.3% of patients were MRD negative (at a threshold of one tumor cell per 105 white cells); in the VMP-alone group, 6.2% of patients were MRD negative (P < .001).

In a prospective randomized trial (NCT04751877), 270 patients with newly diagnosed myeloma who were transplant ineligible and aged 65 to 79 years received either I-VRd or isatuximab plus Rd.[73]

In a prospective randomized trial (NCT04751877), 270 patients with newly diagnosed myeloma who were transplant ineligible and aged 65 to 79 years received either I-VRd or isatuximab plus Rd.[73]

With a median follow-up of 23.5 months, the MRD negativity rates (at 10-5) at 18 months were 53% for the I-VRd group and 26% for the isatuximab-Rd group (OR, 3.16; 95% CI, 1.89–5.28; P < .0001).[73][Level of evidence B3]

In a prospective randomized trial (NCT04751877), 270 patients with newly diagnosed myeloma who were transplant ineligible and aged 65 to 79 years received either I-VRd or isatuximab plus Rd.[73]

Isatuximab is given IV, unlike daratumumab, which is given subcutaneously (with significantly less side effects than the IV formulation).

In a prospective randomized trial (NCT04751877), 270 patients with newly diagnosed myeloma who were transplant ineligible and aged 65 to 79 years received either I-VRd or isatuximab plus Rd.[73]

Serious adverse events were similar in the two groups.

In a prospective randomized trial, 955 patients with newly diagnosed multiple myeloma who were ineligible for transplant received either carfilzomib plus melphalan and prednisone or VMP.[74]

In a prospective randomized trial, 955 patients with newly diagnosed multiple myeloma who were ineligible for transplant received either carfilzomib plus melphalan and prednisone or VMP.[74]

With a median follow-up of 23 months, there was no difference in median PFS (22.3 vs. 22.1 months; HR, 0.91; 95% CI, 0.75−1.10; P = .159) or in median OS (HR, 1.1; 95% CI, 0.82−1.4).[74][Level of evidence A1]

In a prospective trial, 1,087 patients with standard-risk or intermediate-risk myeloma who deferred transplant for induction therapy were randomly assigned to receive carfilzomib plus lenalidomide and dexamethasone or bortezomib plus lenalidomide and dexamethasone.[75]

In a prospective trial, 1,087 patients with standard-risk or intermediate-risk myeloma who deferred transplant for induction therapy were randomly assigned to receive carfilzomib plus lenalidomide and dexamethasone or bortezomib plus lenalidomide and dexamethasone.[75]

With a median follow-up of 26 months, there was no difference in median PFS (34.6 vs. 34.4 months; HR, 1.04; 95% CI, 0.83−1.31; P = .742) or in median OS (HR, 0.98; 95% CI, 0.71−1.36; P = .923).[75][Level of evidence A1]

Many other phase II and phase III trials, published in preliminary abstract form, show results similar to the trial that combined daratumumab with melphalan and prednisone, and used daratumumab with other triplets and doublets in both previously untreated and previously treated patients.[76,77] Further follow-up is required to establish OS benefits. Mature OS data are required to better assess the cost-effectiveness of daratumumab in the first-line setting.[78]