Like many types of malignancies, further treatment of multiple myeloma after relapsed, progressive, or refractory disease usually yields a shorter duration and lower quality of response compared to the initial response. There is a high demand for agents that treat multiple myeloma that does not respond or that progresses after first- or subsequent-line therapy.
On November 16, 2015, the US Food and Drug Administration (FDA) granted approval of daratumumab (Darzalex), an intravenous (IV) monoclonal antibody, for the treatment of individuals with multiple myeloma who have received at least three prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent, or who are double-refractory to a PI and an immunomodulatory agent.
On May 1, 2020, the FDA granted approval of daratumumab and hyaluronidase-fihj (Darzalex Faspro), a subcutaneous (SC) formulation with almost the same indications as the IV formulation. It is available as a flat dose, administered by a professional provider over 3 to 5 minutes. Hyaluronidase increases the dispersion and absorption of the daratumumab when administered SC.
CD38 is a glycoprotein expressed on the surface of hematopoietic cells (including lymphoid and myeloid cells). When multiple myeloma is present, there is an overexpression of CD38 on malignant plasma cells. Daratumumab (Darzalex) works by binding to CD38 and inhibiting the growth of the malignant tumor cells through multiple mechanisms, including complement-dependent cytotoxicity (CDC) (causing tumor cell lysis and death), antibody-dependent cell-mediated cytotoxicity (ADCC) (causing tumor cell death by nonphagocytic processes via the activation of natural killer cells, macrophages, etc.), and antibody-dependent cellular phagocytosis (ADCP) by macrophages.
PEER-REVIEWED LITERATURE
SUMMARY OF LIGHT CHAIN AMYLOIDOSIS STUDIES
Daratumumab and Hyaluronidase-fihj (Darzalex Faspro) in Combination with Bortezomib, Cyclophosphamide, and Dexamathasone (VCd)
An open-label, randomized, active-controlled trial evaluated the efficacy of daratumumab and hyaluronidase-fihj (Darzalex Faspro) in 388 individuals with newly diagnosed light chain (AL) amyloidosis. One group received daratumumab and hyaluronidase-fihj (Darzalex Faspro) 1,800 mg/30,000 units SC weekly from weeks 1 to 8, once every 2 weeks from weeks 9 to 24, and once every 4 weeks starting with week 25 (until disease progression or unacceptable toxicity, or a maximum of 2 years) in combination with bortezomib, cyclophosphamide, and dexamathasone (D-VCd) (N=195), and the other group received VCd (N=193). Hematologic complete response was significantly improved in 42% of D-VCd compared to 13% in VCd group (P<0.0001).
SUMMARY OF MULTIPLE MYELOMA STUDIES
Newly Diagnosed Multiple Myeloma: Daratumumab (Darzalex) in Combination with Bortezomib, Melphalan, and Prednisone (VMP) or Lenalidomide and Dexamethasone in Individuals Ineligible for Autologous Stem Cell Transplant (ASCT)
The approval for daratumumab (Darzalex) in combination with bortezomib, melphalan, and prednisone (VMP) for the treatment of newly diagnosed multiple myeloma was based on an open-label, randomized, active-controlled, Phase 3 study of 706 individuals (ALCYONE study). Individuals were randomly assigned to treatment with either daratumumab (Darzalex) in combination with VMP (D-VMP group) or to treatment with VMP alone. The study showed an improvement in progression-free survival (PFS) in the D-VMP arm as compared to the VMP arm; the median PFS had not been reached in the D-VMP arm and was 18.1 months in the VMP arm (P<0.0001), representing 50 percent reduction in the risk of disease progression or death in individuals treated with D-VMP.
On June 27, 2019, the FDA approved daratumumab (Darzalex) in combination with lenalidomide and dexamethasone for the treatment of individuals with newly diagnosed multiple myeloma who are ineligible for ASCT. The approval is based on results from the phase 3 MAIA clinical trial, which showed that the addition of daratumumab to lenalidomide/dexamethasone (DRd) significantly reduced the risk of disease progression or death by 44 percent compared with treatment with lenalidomide/dexamethasone (Rd) alone. The randomized, open-label, multicenter phase III study included 737 newly diagnosed individuals with multiple myeloma who are ineligible for high-dose chemotherapy and ASCT between the ages of 45 and 90. Individuals were randomly assigned to receive either daratumumab plus lenalidomide/dexamethasone or lenalidomide/dexamethasone alone in 28-day cycles. At a median follow-up of 28.0 months, disease progression or death had occurred in 240 individuals (97 of 368 [26.4 percent] in the daratumumab group and 143 of 369 [38.8 percent] in the control group). The estimated percentage of individuals who were alive without disease progression at 30 months was 70.6 percent (95 percent confidence interval [CI], 65.0–75.4) in the daratumumab group and 55.6 percent (95 percent CI, 49.5–61.3) in the control group (hazard ratio [HR] for disease progression or death, 0.56; 95 percent CI, 0.43–0.73; P<0.001). The percentage of individuals with a complete response or better was 47.6 percent in the daratumumab group and 24.9 percent in the control group (P<0.001). A total of 24.2 percent of the individuals in the daratumumab group, as compared with 7.3 percent of the individuals in the control group, had results below the threshold for minimal residual disease (one tumor cell per 105 white cells) (P<0.001). After a median follow-up of 56 months, MAIA demonstrated an improvement in overall survival (OS) in the DRd arm as compared to the Rd arm (HR=0.68; 95% CI, 0.53–0.86; P=0.0013), representing a 32% reduction in the risk of death in individuals treated in the DRd arm. Median OS was not reached for either arm.
Newly Diagnosed Multiple Myeloma: Daratumumab and Hyaluronidase-fihj (Darzalex Faspro) in Combination with Bortezomib, Melphalan, and Prednisone (VMP) or Lenalidomide and Dexamethasone in Individuals Ineligible for ASCT
The approval for daratumumab and hyaluronidase-fihj (Darzalex Faspro) in combination with bortezomib, melphalan, and prednisone (VMP) for the treatment of newly diagnosed multiple myeloma in individuals who were ineligible for transplant was based on a single-arm, open-label, Phase 2 study of 67 individuals (PLEIADES study). Participants received bortezomib, melphalan, and daratumumab and hyaluronidase-fihj (Darzalex Faspro) at 1,800 mg/30,000 units SC once weekly from weeks 1 to 6, once every 3 weeks from weeks 7 to 54, and once every 4 weeks starting with week 55 until disease progression or unacceptable toxicity. The study showed an overall response rate (ORR) of 88%.
The approval for daratumumab and hyaluronidase-fihj (Darzalex Faspro) in combination with lenalidomide and dexamethasone for the treatment of newly diagnosed multiple myeloma in individuals who were ineligible for transplant was based on a single-arm, open-label, Phase 2 study of 65 individuals (PLEIADES study). Participants received lenalidomide, dexamethasone, and daratumumab and hyaluronidase-fihj (Darzalex Faspro) at 1,800 mg/30,000 units SC once weekly from weeks 1 to 8, once every 2 weeks from weeks 9 to 24, and once every 4 weeks starting with week 25 until disease progression or unacceptable toxicity. The study showed an overall response rate (ORR) of 91%.
Newly Diagnosed Multiple Myeloma: Daratumumab (Darzalex) In Combination with Bortezomib, Thalidomide, and Dexamethasone in Individuals Eligible for ASCT
On September 26, 2019, the FDA approved daratumumab (Darzalex) for multiple myeloma in combination with bortezomib, thalidomide, and dexamethasone in newly diagnosed individuals who are eligible for ASCT. Efficacy was investigated in CASSIOPEIA, an open-label, randomized, active-controlled phase 3 study comparing induction and consolidation treatment with daratumumab 16 mg/kg in combination with bortezomib, thalidomide and dexamethasone (D-VTd) (n=543) to treatment with bortezomib, thalidomide and dexamethasone (VTd) (n=542) in individuals with newly diagnosed multiple myeloma eligible for ASCT. Approval is based on data from CASSIOPEIA, including progression-free survival (PFS), stringent complete response at 100 days post-ASCT, and complete response rate at day 100 post-ASCT. The trial demonstrated an improvement in PFS in the D-VTd arm as compared to the VTd arm; with a median follow up of 18.8 months, the median PFS had not been reached in either arm. Treatment with D-VTd resulted in a reduction in the risk of progression or death by 53 percent compared to VTd alone (HR=0.47; 95 percent CI, 0.33–0.67; P<0.0001). The sCR rate at Day 100 post-ASCT was 28.9 percent in the D-VTd arm and 20.3 percent in the VTd arm. There were no significant differences in the number or type of serious adverse events in the two treatment arms. D-VTd before and after ASCT improved depth of response and PFS with acceptable safety. CASSIOPEIA is the first study showing the clinical benefit of daratumumab (Darzalex) plus standard of care in transplant-eligible individuals with newly diagnosed multiple myeloma.
Monotherapy for Multiple Myeloma After Three Prior Lines of Therapy
Daratumumab (Darzalex)
The approval of daratumumab (Darzalex) was based on the results of a two-part, open-label, multicenter, Phase 2 study (SIRIUS). Enrolled in the trial were individuals who had responded to at least one previous treatment regimen, received an alkylating agent alone or in combination with other myeloma treatments, received at least three previous lines of treatment that included a PI and an immunomodulatory drug, or had disease double-refractory to the most recent PI and immunomodulatory drug they had received. (Refractory disease was defined as disease progression on or within 60 days of the last dose). All individuals had an Eastern Cooperative Oncology Group (ECOG) performance status score of 2 or lower.
Part 1 was a dose-defining study of 34 individuals randomly assigned (1:1) to either daratumumab (Darzalex) 8 mg/kg every 4 weeks or 16 mg/kg weekly for 8 weeks, then 16 mg/kg every 2 weeks for 16 weeks, then 16 mg/kg every 4 weeks. A first interim analysis was performed about 8 weeks after the last individual's enrollment; at that time, the individual could cross over to the more effective dose if appropriate. A second interim analysis was conducted after another 25 individuals were treated for at least 8 weeks.
Part 2 was an expansion cohort of 65 individuals, which brought the total number of individuals in the study to 106. All individuals were administered the optimal dose of 16 mg/kg weekly for 8 weeks, then 16 mg/kg every 2 weeks for 16 weeks, then 16 mg/kg every 4 weeks thereafter.
The primary efficacy endpoint was ORR, which is a measurement of a positive response to treatment. In this study the ORR was the sum of partial response, very good partial response, complete response, and stringent complete response. The results concluded that the ORR was 29.2 percent, and there was a median duration of response of 7.4 months.
Daratumumab and hyaluronidase-fihj (Darzalex Faspro)
The approval for daratumumab and hyaluronidase-fihj (Darzalex Faspro) as monotherapy in individuals who received at least three previous lines of treatment that included a PI and an immunomodulatory drug, or had disease double-refractory to the most recent PI and immunomodulatory drug they had received, was based on the COLUMBIA study, an open-label, randomized (1:1), noninferiority, Phase 3 study. Participants (N=522) were randomly assigned to receive either daratumumab and hyaluronidase-fihj (Darzalex Faspro) 1,800 mg/30,000 units SC or daratumumab (Darzalex) 16 mg/kg IV; each administered once weekly (cycles one and two), every 2 weeks (cycles three through six), and then every 4 weeks (28-day cycles) until progressive disease or toxicity. The primary efficacy endpoints were ORR and maximum Ctrough concentration at pre-dose cycle 3 day 1. The study resulted in noninferiority in terms of ORR (SC route 41%, IV route 37%) and maximum trough concentration. Median progression-free survival was 5.6 months in the SC arm and 6.1 months in the IV arm. Overall, 296 participants discontinued treatment, mainly due to progressive disease (112 [43%] of 260 in the subcutaneous group and 114 [44%] of 258 in the intravenous group.)
In Combination with Carfilzomib (Kyprolis) and Dexamethasone for Multiple Myeloma After at Least One to Three Prior Lines of Therapy
Daratumumab (Darzalex)
The safety and efficacy of daratumumab (Darzalex) in combination with twice-weekly carfilzomib (Kyprolis) and dexamethasone was established in CANDOR, a Phase 3, randomized, multicenter, open-label study of 466 participants that evaluated daratumumab (Darzalex) in combination with twice-weekly carfilzomib (Kyprolis) (DKd) and dexamethasone compared to carfilzomib (Kyprolis) and dexamethasone (Kd) in those with relapsed/refractory multiple myeloma who had received at least one to three prior treatments. Participants had received a median of two prior teatments, and 58% of participants had received prior ASCT. DKd demonstrated a statistically significant improvement in PFS compared to the Kd arm; the median PFS had not been reached in the DKd arm and was 15.8 months in the Kd arm (P=0.0014), which represented a 37% reduction in the risk of disease progression or death or those treated with DKd compared to Kd.
The safety and efficacy of daratumumab (Darzalex) in combination with once-weekly carfilzomib (Kyprolis) and dexamethasone was established in EQUULEUS, an open-label, multicohort trial of 85 participants that evaluated daratumumab (Darzalex) in combination with once-weekly carfilzomib (Kyprolis) (DKd) and dexamethasone in those with relapsed/refractory multiple myeloma who had received at least one to three prior treatments. Participants had received a median of two prior teatments and 73% of participants had received prior ASCT. DKd demonstrated an overall response rate in 69 participants (81%).
Daratumumab and hyaluronidase-fihj (Darzalex Faspro)
The efficacy of daratumumab and hyaluronidase-fihj (Darzalex Faspro) in combination with carfilzomib and dexamethasone was evaluated in PLEIADES, an open-label, multicohort trial of 66 participants that evaluated daratumumab and hyaluronidase-fihj (Darzalex Faspro) in combination with once-weekly carfilzomib (Kyprolis) (DKd) and dexamethasone in those with relapsed/refractory multiple myeloma who had received at least one prior treatment. This regimen demonstrated an ORR in 56 participants (84.8%).
In Combination with Lenalidomide (Revlimid) or Bortezomib (Velcade) and Dexamethasone for Multiple Myeloma After at Least One Prior Line of Therapy
Daratumumab (Darzalex)
The approval of daratumumab (Darzalex) in combination with lenalidomide (Revlimid) and dexamethasone for the treatment of multiple myeloma after one prior therapy was based on a Phase 3, randomized, open-label trial (POLLUX) in 569 individuals. These individuals had relapsed or refractory multiple myeloma and received one or more previous lines of therapy. They were assigned to receive either daratumumab, lenalidomide, and dexamethasone [DRd (daratumumab group, n=286)], or lenalidomide and dexamethasone [Rd (control group, n=283)]. The primary endpoint of this study was PFS. At a median follow-up of 13.5 months, there was a total of 169 events of disease progression or death; 53 (18.5 percent) in the daratumumab group and 116 (41 percent) in the control group. The median PFS was not reached in the daratumumab group, as compared to 18.4 months in the control group; however, the rate of PFS at 12 months was 85.7 percent in the daratumumab group versus 63.2 percent in the control group. In conclusion, the group treated with daratumumab experienced a significant PFS and higher rates of overall response in individuals with relapsed or refractory multiple myeloma. The daratumumab group did have higher rates of adverse reactions (including neutropenia and infusion-related reactions), but this did not result in increased treatment discontinuation or death. After a median follow-up of 80 months, POLLUX demonstrated an improvement in OS in the DRd arm as compared to the Rd arm (HR=0.73; 95% CI, 0.58–0.91; P=0.0044), representing a 27% reduction in the risk of death in individuals treated in the DRd arm. The median OS was 67.6 months in the DRd arm and 51.8 months in the Rd arm.
The use of daratumumab (Darzalex) in combination with bortezomib (Velcade) and dexamethasone for multiple myeloma was approved based on a Phase 3, open-label, randomized, multicenter trial (CASTOR). A total of 498 individuals with relapsed or refractory multiple myeloma were randomly assigned bortezomib and dexamethasone [Vd (control group)] or daratumumab, bortezomib, and dexamethasone [DVd (dartumumab group)]. The primary endpoint was PFS, which was defined as the time from the date of randomization to date of disease progression or death. At a median follow-up period of 7.4 months, a total of 189 events of disease progression or death had occurred; 67 in the daratumumab group and 122 in the control group. The 12-month PFS was 60.7 percent in the daratumumab group versus 26.9 percent in the control group. The overall response rate, which was a secondary endpoint of the study, was 82.9 percent in the daratumumab group and 63.2 percent in the control group. In conclusion, this study determined that, for individuals with relapsed or refractory multiple myeloma, the combination of daratumumab, bortezomib, and dexamethasone resulted in significantly longer PFS than bortezomib and dexamethasone alone. Additionally, the daratumumab group did experience infusion-related reactions (i.e., dyspnea, bronchospasm, and cough) and higher rates of thrombocytopenia and neutropenia. After a median follow-up of 73 months, CASTOR demonstrated an improvement in OS in the DVd arm as compared to the Vd arm (HR=0.74; 95% CI, 0.59–0.92; P=0.0075), representing a 26% reduction in the risk of death in individuals treated in the DVd arm. The median OS was 49.6 months in the DVd arm and 38.5 months in the Vd arm.
Daratumumab and hyaluronidase-fihj (Darzalex Faspro)
The approval for daratumumab and hyaluronidase-fihj (Darzalex Faspro) in combination with lenalidomide (Revlimid) and dexamethasone for the treatment of relapsed/refractory multiple myeloma was based on a single-arm cohort of PLEIADES, a multicohort, open-label trial in 65 participants who received daratumumab and hyaluronidase-fihj (Darzalex Faspro) 1,800 mg/30,000 units SC weekly from weeks 1 to 8, once every 2 weeks from weeks 9 to 24, and once every 4 weeks starting with week 25 until disease progression or unacceptable toxicity, in combination with lenalidomide and dexamethasone. The ORR was achieved in 59 participants (91%).
In Combination with Pomalidomide (Pomalyst) and Dexamethasone for Multiple Myeloma After at Least One Prior Line of Therapy Including Lenalidomide and a Proteasome Inhibitor
Daratumumab (Darzalex)
Approval for daratumumab (Darzalex) in combination with pomalidomide and dexamethasone for the treatment of multiple myeloma was based on EQUULEUS, an open-label trial including 103 individuals who had received prior PI and an immunomodulatory agent. The ORR was 60 percent with a median PFS of 8.8 months, 12-month PFS of 42 percent, and median time to progression of 10.4 months.
Daratumumab and hyaluronidase-fihj (Darzalex Faspro)
The approval for daratumumab and hyaluronidase-fihj (Darzalex Faspro) in combination with pomalidomide and dexamethasone for the treatment of multiple myeloma was based on APOLLO, an open-label, randomized, active-controlled trial including 304 individuals who had received prior PI and an lenalidomide. One arm of the trial received daratumumab and hyaluronidase-fihj (Darzalex Faspro) with pomalidomide and dexamethasone (Darzalex Faspro-Pd), while the other arm received pomalidomide and dexamethasone (Pd) alone until disease progression or unacceptable toxicity. The PFS showed a statistically significant improvement in the Darzalex Faspro-Pd arm (12.4 months) compared to the Pd arm (6.9 months) (P=0.0018).
OFF-LABEL INDICATIONS
There may be additional indications contained in the Policy section of this document due to evaluation of criteria highlighted in the Company’s off-label policy, and/or review of clinical guidelines issued by leading professional organizations and government entities.
