Daratumumab-Containing Regimens Display PFS Benefit Across Myeloma Subgroups

María-Victoria Mateos, MD, PhD

Daratumumab (Darzalex) combinations elicited significant progression-free survival (PFS), overall survival (OS), overall response rate (ORR), and minimal residual disease (MRD)–negativity benefits vs control in pretreated patients with relapsed or refractory multiple myeloma across clinically relevant subgroups.

The post hoc subgroup analysis was conducted using data from the phase 3 CASTOR (NCT02136134) and POLLUX (NCT02076009) trials. Findings were presented at the 19th International Myeloma Society Annual Meeting.

“Our post-hoc analyses of CASTOR and POLLUX, both individually and pooled, showed that adding daratumumab to standard-of-care [SOC] regimens prolonged the PFS across many relapsed and refractory myeloma subgroups after a median follow-up of more than 6 years,” lead study author, María-Victoria Mateos, MD, PhD, a hematologist at the University Hospital of Salamanca in Salamanca, Spain, said in a presentation of the data. 

In the CASTOR trial, daratumumab plus bortezomib (Velcade) and dexamethasone improved was compared with bortezomib and dexamethasone alone. In the POLLUX trial, daratumumab plus lenalidomide (Revlimid) and dexamethasone was compared with lenalidomide and dexamethasone alone. Subgroups included in the analysis were: age, high cytogenetic risk defined as translocations (t) in (11;14) or (14;16), having received only 1 prior line of therapy, and renal impairment, International Staging System (ISS) stage, prior autologous stem cell transplant, prior bortezomib (CASTOR), prior lenalidomide (POLLUX), and refractory status to either lenalidomide (CASTOR) or bortezomib (POLLUX). The median follow-up was 72.6 months for CASTOR and 79.7 months for POLLUX.

Daratumumab, a human IgGx monoclonal antibody, targets CD38 through direct-on-tumor and immunomodulatory mechanisms of action. The agent is approved in combination with SOC regimens in patients with newly diagnosed multiple myeloma, or as monotherapy and in combination with SOC regimens in patients with relapsed or refractory multiple myeloma.

Daratumumab has demonstrated a greater cytotoxicity of multiple myeloma cells ex vivo vs analogs of other CD38 antibodies. When compared with other CD38 antibodies, daratumumab induces higher levels of complement-dependent cytotoxicity, similar levels of antibody-dependent cellular phagocytosis and antibody-dependent cell-mediated toxicity, and similar levels of cell death in the presence of Fc receptor cross-linking, which occurs naturally in vivo.

The primary end point of both trials was PFS. Patients were excluded from CASTOR if they were refractory or intolerant to bortezomib or another proteasome inhibitor. Patients were excluded from POLLUX if they were refractory or intolerant to lenalidomide.

Post-hoc analyses of CASTOR and POLLUX compared PFS and OS between study treatments in subgroups based on a log-rank test. Hazard ratios and confidence intervals were estimated using a Cox proportional hazards model, with treatment as the sole explanatory variable.

Response and disease progression were assessed using a validated computer algorithm per International Myeloma Working Group recommendations. Treatment-group responses were compared using a Mantel-Haenszel estimate of the common odds ratio.

MRD status was assessed using bone marrow aspirate samples and evaluated with next-generation sequencing at a 10-5 sensitivity threshold. MRD was compared between treatment groups using Fisher’s exact test and a Mantel-Haenszel estimate of the common odds ratio.

PFS Outcomes

CASTOR

Daratumumab plus bortezomib and dexamethasone improved PFS vs bortezomib and dexamethasone alone across intention-to-treat (ITT) subgroups. In patients aged at least 75 years, the median PFS was 17.9 months with the investigative combination vs 8.1 months with control (HR, 0.22; 95% CI, 0.10-0.47). In patients with stage III disease, the median PFS was 8.3 months vs 5.3 months, respectively (HR, 0.43; 95% CI, 0.27-0.69). In patients with high cytogenetic risk, the median PFS was 12.6 months with the investigative combination vs 6.2 months with control (HR, 0.37; 95% CI, 0.21-0.64). In patients with renal impairment, the median PFS was 13.1 months vs 6.2 months, respectively (HR, 0.32; 95% CI, 0.20-0.50).

In terms of prior treatment, patients who received 1 prior line of therapy, the median PFS was 27.0 months with the investigative combination vs 7.9 months with control (HR, 0.25; 95% CI, 0.18-0.35). Among those who received ASCT, the median PFS was 14.7 months vs 6.8 months, respectively (HR, 0.39; 95% CI, 0.30-0.51). Patients who received prior bortezomib had a median PFS of 12.1 months with the daratumumab combination vs 6.7 months with control (HR, 0.35; 95% CI, 0.27-0.46). In patients who were refractory to lenalidomide, the median PFS was 7.8 months vs 4.9 months, respectively (HR, 0.42; 95% CI, 0.28-0.61).

POLLUX

Similar to CASTOR, the addition of daratumumab to lenalidomide and dexamethasone improved PFS vs lenalidomide and dexamethasone alone across subgroups. When stratified by baseline characteristics, patients who were aged 75 years or older had a median PFS of 36.4 months in the investigative arm vs 11.4 months in the control (HR, 0.48; 95% CI, 0.27-0.85). In patients with stage III disease, the median PFS was 26.7 months vs 8.8 months, respectively (HR, 0.49; 95% CI, 0.32-0.77). In patients with high cytogenetic risk, the median PFS was 26.8 months with the investigative combination vs 8.3 months with control (HR, 0.47; 95% CI, 0.28-0.79 and was 33.6 months vs 11.3 months (HR, 0.42; 95% CI, 0.28-0.62) among those with renal impairment.

In patients who received 1 prior line of therapy, the median PFS was 52.1 months vs 19.6 (HR, 0.50; 95% CI, 0.38-0.67) with daratumumab combination and the control treatment, respectively. In patients with prior ASCT, the median PFS was 45.0 months vs 19.6 months, respectively (HR, 0.54; 95% CI, 0.42-0.70). In patients with prior lenalidomide treatment, the median PFS was 35.2 months with the investigative combination vs 18.6 months with control (HR, 0.40; 95% CI, 0.25-0.65). In patients who were refractory to bortezomib, the median PFS was 34.3 months vs 11.3 months, respectively (HR, 0.47; 95% CI, 0.30-0.72).

CASTOR AND POLLUX: Pooled Analysis

In the pooled ITT population of both studies, the median PFS for patients treated with investigative combinations vs control regimens stratified by subgroup were as follows:

1. Age at least 75 years: 28.9 months vs 9.4 months (HR, 0.41; 95% CI, 0.27-0.63)
2. Stage III disease: 17.9 months vs 6.1 months (HR, 0.53; 95% CI, 0.39-0.72)
3. High cytogenetic risk: 20.3 months vs 7.3 months (HR, 0.45; 95% CI, 0.31-0.65)
4. One prior line of therapy: 36.4 months vs 11.4 months (HR, 0.43; 95% CI, 0.35-0.53)
5. Renal impairment: 24.2 months vs 7.5 months (HR, 0.39; 95% CI, 0.29-0.52)
6. Prior ASCT: 23.3 months vs 10.8 months (HR, 0.54; 95% CI, 0.45-0.65)

For OS, outcomes with investigative combinations vs standard-of-care arms were as follows:

• Age at least 75 years: 52.7 months vs 35.1 months (HR, 0.87; 95% CI, 0.57-1.33)
• Stage III disease: 27.6 months vs 17.1 months (HR, 0.70; 95% CI, 0.52-0.96)
• High cytogenetic risk: 40.0 months vs 23.6 months (HR, 0.68; 95% CI, 0.47-1.00)
• One prior line of therapy: 77.8 months vs 51.2 months (HR, 0.66; 95% CI, 0.52-0.83)
• Renal impairment: 50.8 months vs 28.8 months (HR of 0.65; 95% CI, 0.49-0.86)
• Prior ASCT: 55.8 months vs 50.4 months (HR, 0.81; 95% CI, 0.67-0.99)

ORR Outcomes

CASTOR

Regarding ORR, in CASTOR, patients at least 75 years of age had an ORR of 95.0% with the investigative combination (n = 20) vs 78.8% with control (n = 33), with an odds ratio (OR) of 5.12 (95% CI, 0.58-45.13; P = .1134).

Those with stage III disease had an ORR of 70.6% vs 44.7% with the investigative combination (n = 51) and SOC (n = 47), respectively (OR, 2.97; ­­­95% CI, 1.29-6.83; P = .0098). Patients with high cytogenetic risk had an ORR of 84.6% with the investigative combination (n = 39) vs 55.9% with control (n = 34; OR, 4.34; 95% CI, 1.44-13.07; P = .0072). Among patients who received 1 prior line of therapy, the ORR was 91.6% in the experimental arm (n = 119) vs 74.3% in the control arm (n = 109), with an odds ratio of 3.77 (95% CI, 1.73-8.20; P = .0005).

Patients with renal impairment had an ORR of 78.6% with the investigative combination (n = 56) vs 57.4% with the SOC (n = 68; OR, 2.73; 95% CI, 1.23-6.06; P = .128). Among the 151 patients who received the daratumumab combination with prior ASCT, the ORR was 83.4% vs 65.7% among the 140 patients who received SOC (OR, 2.63; 95% CI, 1.51-4.57; P = .0005). Patients with prior bortezomib exposure had an ORR of 81.2% vs 59.5% in the investigative (n = 154) and control arms (n = 153), respectively (OR, 2.94; 95% CI, 1.75-4.93; P < .0001). Patients who were refractory to lenalidomide had an ORR of 76.8% with the investigative combination (n = 56) vs 48.7% with control (n = 78), with an odds ratio of 3.48 (95% CI, 1.62-7.47; P = .0011).

POLLUX

Patients aged at least 75 years had an ORR of 93.1% with the daratumumab-based combination (n = 29) vs 76.5% with SOC (n = 34), with an odds ratio of 4.15 (95% CI, 0.81-21.42; P = .0740). Patients with stage III disease had an ORR of 88.7% vs 73.1% in the investigative (n = 53) and control arms (n = 52), respectively (OR, 2.89; 95% CI, 1.01-8.23; P = .0428). Patients with high cytogenetic risk had an ORR of 88.6% with the investigative combination (n = 35) vs 67.6% with control (n = 34; OR, 3.71; 95% CI, 1.05-13.13; P = .0365). Those who received 1 line of prior line in the daratumumab arm (n = 147) had an ORR of 93.2% compared with 80.3% among 142 patients who received SOC (OR, 3.36; 95% CI, 1.57-7.22; P = .0012).

Patients with renal impairment had an ORR of 91.3% with the investigative combination (n = 80) vs 68.3% with control (n = 63), with an odds ratio of 4.85 (95% CI, 1.90-12.41; P = .0005). Patients with prior ASCT had an ORR of 91.6% vs 78.5% in the investigative (n = 178) and control arms (n = 177), respectively (OR, 2.97; 95% CI, 1.57-5.63; P = .0006). Patients with prior lenalidomide exposure had an ORR of 84.0% with the daratumumab-based combination (n = 50) vs 68.1% with control (n = 47; OR, 2.46; 95% CI, 0.93-6.51; P = .0669). Patients who were refractory to bortezomib had an ORR of 87.7% vs 67.9% in the investigative combination (n = 57) and control arms (n = 56), respectively (OR, 3.38; 95% CI, 1.28-8.92; P = .0113).

MRD Negativity

CASTOR

Daratumumab plus bortezomib and dexamethasone improved MRD-negativity rates vs bortezomib and dexamethasone alone across subgroups as follows:

1. Age 75 years of age: OR, not evaluable(NE; 95% CI, NE-NE; P = .3966)
2. Stage III disease: OR, NE (95% CI, NE-NE; P = .0294)
3. High cytogenetic risk: OR, NE (95% CI, NE-NE; P = .0271)
4. One prior line of therapy: OR, 9.45 (95% CI, 2.77-32.28; P < .0001)
5. Renal impairment: OR, NE (95% CI, NE-NE; P = .0878)
6. Prior ASCT: OR, 7.51 (95% CI, 2.19-25.76; P = .0002)
7. Prior bortezomib exposure: OR, NE (95% CI, NE-NE; P < .0001)
8. Refractory to lenalidomide: OR, NE (95% CI, NE-NE; P = .0051)

POLLUX

Daratumumab plus lenalidomide and dexamethasone improved MRD-negativity rates vs lenalidomide and dexamethasone alone in POLLUX subgroups as follows:

• Age at least 75 years of age: OR, 12.95 (95% CI, 1.51-111.07; P = .0084)
• Stage III disease: OR, 4.03 (95% CI, 1.46-11.11; P = .0059)
• High cytogenetic risk: OR, 13.60 (95% CI, 1.63-113.25; P = .0063)
• One prior line of therapy: OR, 4.28 (95% CI, 2.27-8.07; P < .0001)
• Renal impairment: OR, 6.54 (95% CI, 2.13-20.01; P = .0003)
• Prior ASCT: OR, 7.88 (95% CI, 3.98-15.60; P < .001)
• Refractory to lenalidomide: OR, 6.82 (95% CI, 1.87-24.93; P = .0020)

“Our results support the use of daratumumab-containing regimens in patients with relapsed/refractory multiple myeloma across clinically relevant subgroups,” the study authors concluded.

Reference

1. Mateos M, Richardson PG, Weisel K, et al. Daratumumab (DARA) plus bortezomib and dexamethasone (D-Vd) or lenalidomide and dexamethasone (D-Rd) in relapsed or refractory multiple myeloma (RRMM): subgroup analyses of CASTOR and POLLUX. Presented at: 19th International Myeloma Society Annual Meeting. August 25-27, 2022. Los Angeles, CA. P-260