| Coverage Policy Manual | |
| Policy #: | 2016012 |
| Category: | Pharmacy |
| Initiated: | May 2016 |
| Last Review: | May 2023 |
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| Daratumumab (e.g., Darzalex) / Daratumumab and Hyaluronidase-fihi (e.g., DARZALEX FASPRO) | |
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| Description: |
Daratumumab is a human IgG1κ monoclonal antibody that binds to the CD38 epitope indicated for the treatment of multiple myeloma individuals who have received at least three prior therapies, including a proteasome inhibitor (PI) and an immunomodulatory agent or who are double refractory to a PI and immunomodulatory agent. Daratumumab received FDA approval for this indication; continued approval for this indication may be contingent upon verification of clinical benefit in subsequent trials.
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 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 non-phagocytic processes via the activation of natural killer cells, macrophages, etc.) and antibody-dependent cellular phagocytosis (ADCP) by macrophages.
The FDA granted daratumumab breakthrough therapy designation, priority review and orphan product designation because the sponsor demonstrated through preliminary clinical evidence that the drug may offer a substantial improvement over available therapies; the drug had the potential, at the time the application was submitted, to be a significant improvement in safety or effectiveness in the treatment of a serious condition; and the drug is intended to treat a rare disease, respectively.
Regulatory Status
On May 1, 2020, the FDA approved Daratumumab and Hyaluronidase-fihi (e.g., DARZALEX FASPRO), a treatment for adult individuals with multiple myeloma:
Daratumumab and Hyaluronidase-fihi (e.g., DARZALEX FASPRO) is a subcutaneous formulation of daratumumab (e.g., Darzalex) which was previously available only as an intravenous infusion. The subcutaneous formulation can be given over 3–5 minutes, compared to hours required for the administration of the intravenous formulation.
On August 20, 2020, the Food and Drug Administration approved carfilzomib and daratumumab in combination with dexamethasone for adult individuals with relapsed or refractory multiple myeloma who have received one to three lines of therapy.
On January 15, 2021, the Food and Drug Administration granted accelerated approval to daratumumab plus hyaluronidase e.g., (Darzalex Faspro) in combination with bortezomib, cyclophosphamide and dexamethasone for newly diagnosed light chain (AL) amyloidosis.
On July 9, 2021, the Food and Drug Administration approved daratumumab plus hyaluronidase (e.g., Darzalex Faspro) in combination with pomalidomide and dexamethasone for the diagnosis of multiple myeloma in individuals who have received at least one prior line of therapy.
Coding
See CPT/HCPCS section for codes.
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Policy/ Coverage: |
Effective August 1, 2021, for members of plans that utilize an oncology benefits management program, Prior Approval is required for this service and is managed through the oncology benefits management program.
Effective May 18, 2022
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Daratumumab and daratumumab and hyaluronidase-fihj meet primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the treatment of multiple myeloma in individuals 18 years of age and older who meet ANY of the following criteria:
Primary/First Line of therapy Transplant Eligible
Primary/First Line of Therapy Transplant Ineligible
Relapsed Disease/Second and Subsequent Lines of Therapy
Systemic Light Chain Amyloidosis
Limitations of Use:
The use of this drug is covered if a FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
Dosing and Administration
Dosing per FDA Guidelines
Daratumumab should be administered by a healthcare provider, with immediate access to emergency equipment and appropriate medical support to manage infusion-related reactions if they occur.
Recommended FDA Dosage:
Monotherapy and in combination with Lenalidomide or Pomalidomide and Dexamethasone
The recommended dosing schedule for combination therapy (4-week cycle regimens) and monotherapy is as follows:
The recommended dose of Daratumumab is 16 mg/kg actual body weight administered as an IV infusion according to the following dosing schedule:
Weeks Schedule
Weeks 1 to 8 weekly (total of 8 doses)
Weeks 9-24* every two weeks (total of 8 doses)
Week 25 onwards until disease progression** every four weeks
* First dose ot the every-2-week dosing schedule is given at Week 9
** First dose of the every-4-week dosing schedule is given at Week 25
In Combination with Bortezomib, Melphalan and Prednisone
The dosing schedule for combination therapy with bortezomib, melphalan and prednisone (6-week cycle regimen) for individuals with newly diagnosed multiple myeloma ineligible for ASCT.
The recommended dose of Daratumumab is 16 mg/kg actual body weight administered as an IV infusion according to the following dosing schedule:
Weeks Schedule
Weeks 1 to 6 weekly (total of 6 doses)
Weeks 7 to 54* every three weeks (total of 16 doses)
Week 55 onwards until disease progression** every four weeks
* First dose of the every-3-week dosing schedule is given at Week 7
** First dose of the every-4-week dosing schedule is given at Week 55
In Combination with Bortezomib, Thalidomide and Dexamethasone
The dosing schedule for combination therapy with bortezomib, thalidomide, and dexamethasone (4-week cycle regimen) for individuals with newly diagnosed multiple myeloma eligible for ASCT.
The recommended dose of Daratumumab is 16 mg/kg actual body weight administered as an intravenous infusion according to the following dosing schedule:
Treatment Phase Weeks Schedule
Induction Weeks 1 to 8 weekly (total of 8 doses)
Weeks 9 to 16* every two weeks (total of 4 doses)
Stop for high dose chemotherapy and ASCT
Consolidation Weeks 1 to 8** every two weeks (total of 4 doses)
* First dose of the every-2-week dosing schedule is given at Week 9
** First dose ot the every-2-week dosing schedule is given at Week 1 upon re-initiation of treatment following ASCT
In Combination with Bortezomib and Dexamethasone
The dosing schedule for combination therapy with bortezomib and dexamethasone (3-week cycle) for individuals with relapsed/refractory multiple myeloma.
The recommended dose of Daratumumab is 16 mg/kg actual body weight administered as an intravenous infusion according to the following dosing schedule:
Weeks Schedule
Weeks 1 to 9 weekly (total of 9 doses)
Weeks 10 to 24* every three weeks (total of 5 doses)
Week 25 onwards until disease progression** every four weeks
* First dose of the every-3-week dosing schedule is given at Week 10
** First dose of the every-4-week dosing schedule is given at Week 25
In Combination with Carfilzomib and Dexamethasone
The recommended dosage of Daratumumab when administered in combination with carfilzomib and dexamethasone (4-week cycle) for individuals with relapsed/refractory multiple myeloma is as follows:
Weeks Daratumumab Dose*** Schedule
Week 1 8 mg/kg days 1 and 2 (total 2 doses)
Weeks 2 to 8 16 mg/kg weekly (total of 7 doses)
Weeks 9 to 24* 16 mg/kg every two weeks (total of 8 doses)
Week 25 onwards until disease progression** 16 mg/kg every four weeks
* First dose of the every-2-week dosing schedule is given at Week 9
** First dose of the every-4-week dosing schedule is given at Week 25
*** Based on actual body weight
See FDA label for additional information regarding dosing and administration.
The recommended dose of Daratumumab and Hyaluronidase-fihi is 1,800 mg/30,000 units (1,800 mg daratumumab and 30,000 units hyaluronidase) administered subcutaneously over approximately 3-5 minutes. Tables 1, 2, 3, and 4 provide the recommended dosing schedule when Daratumumab and Hyaluronidase-fihi is administered as monotherapy or as part of a combination therapy.
Monotherapy and In Combination with Lenalidomide and Dexamethasone, Pomalidomide and Dexamethasone or Carfilzomib and Dexamethasone
Use dosing schedule when Daratumumab and Hyaluronidase-fihi is administered:
Weeks Schedule
Weeks 1 to 8 weekly (total of 8 doses)
Weeks 9 to 24* every two weeks (total of 8 doses)
Week 25 onwards until disease progression* every four weeks
* First dose of the every-2-week dosing schedule is given at Week 9
** First dose of the ever-4-week dosing schedule is given at Week 25
In Combination with Bortezomib, Melphalan and Prednisone
Use the dosing schedule when Daratumumab and Hyaluronidase-fihi is administered in combination with bortezomib, melphalan and prednisone (6-week cycle).
Weeks Schedule
Weeks 1 to 6 weekly (total of 6 doses)
Weeks 7 to 54* every three weeks (total of 16 doses)
Week 55 onwards until disease progression** every four weeks
* First dose of the every-3-week dosing schedule is given at Week 7.
** First dose of the every-4-week dosing schedule is given at Week 55
In Combination with Bortezomib, Thalidomide, and Dexamethasone
Use the dosing schedule when Daratumumab and Hyaluronidase-fihi is administered in combination with bortezomib, thalidomide, and dexamethasone (4-week cycle).
Treatment Phase Weeks Schedule
Induction weeks 1 to 8 weekly (total of 8 doses)
weeks 9 to 16* every two weeks (total of 4 doses)
Stop for high dose chemotherapy and ASCT
Consolidation weeks 1 to 8** every two weeks (total of 4 doses)
* First dose of the every-2-wee dosing schedule is given at Week 9
** First dose of the every-2-week dosing schedule is given at Week 1 upon re-initiation of treatment following ASCT
In Combination with Bortezomib and Dexamethasone
Use the dosing schedule when Daratumumab and Hyaluronidase-fihi is administered in combination with bortezomib and dexamethasone (3-week cycle).
Weeks Schedule
Weeks 1 to 9 weekly (total of 9 doses)
Weeks 10 to 24* weekly three weeks (total of 5 doses)
Week 25 onwards until disease progression** every four weeks
* First dose of the every-3-week dosing schedule is given at Week 10
** First dose of the every-4-week dosing schedule is given at Week 25
Recommended Dosage for Light Chain Amyloidosis:
In Combination with Bortezomib, Cyclophosphamide and Dexamethasone
Use the dosing schedule provided when Daratumumab and Hyaluronidase-fihi is administered in combination with bortezomib, cyclophosphamide and dexamethasone (4-week cycle).
Weeks Schedule
Weeks 1 to 8 weekly (total of 8 doses)
Weeks 9 to 24* every two weeks (total of 8 doses)
Week 25 onwards until disease progression or a maximum of 2 years** every four weeks
* First dose of the every-2-week dosing schedule is given at Week 9
** First dose of the every-4-week dosing schedule is given at Week 25
See FDA label for additional information regarding dosing and administration.
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary
Coverage Criteria
The use of daratumumab and daratumumab and hyaluronidase-fihi does not meet member benefit certificate primary coverage criteria that there be scientific evidence in improving health outcomes for any indication or circumstance other than those outlined above.
For members with contracts without primary coverage criteria, the use of daratumumab and daratumumab and hyaluronidase-fihi for any indication or circumstance other than those outlined above is considered investigational.
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective January 1, 2022 to May 17, 2022
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Daratumumab (DarzalexTM) meets primary coverage criteria when used for multiple myeloma in adults when any of the following criteria are met (FDA,2021):
Off Label
The use of this drug is covered if a FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
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Dosing and Administration
Darzalex should be administered by a healthcare provider, with immediate access to emergency equipment and appropriate medical support to manage infusion-related reactions if they occur.
Recommended Dosage:
Monotherapy and in combination with Lenalidomide (D-Rd) or Pomalidomide (D-Pd) and Dexamehtasone
The recommended dosing schedule for combination therapy (4-week cycle regimens) and monotherapy is as follows:
The recommended dose of Daratumumab is 16 mg/kg actual body weight administered as an IV infusion according to the following dosing schedule:
Weeks Schedule
Weeks 1 to 8 weekly (total of 8 doses)
Weeks 9-24* every two weeks (total of 8 doses)
Week 25 onwards until disease progression** every four weeks
* First dose ot the every-2-week dosing schedule is given at Week 9
** First dose of the every-4-week dosing schedule is given at Week 25
In Combination with Bortezomib, Melphalan and Prednisone (D-VMP)
The dosing schedule for combination therapy with bortezomib, melphalan and prednisone (6-week cycle regimen) for patients with newly diagnosed multiple myeloma ineligible for ASCT.
The recommended dose of Daratumumab is 16 mg/kg actual body weight administered as an IV infusion according to the following dosing schedule:
Weeks Schedule
Weeks 1 to 6 weekly (total of 6 doses)
Weeks 7 to 54* every three weeks (total of 16 doses)
Week 55 onwards until disease progression** every four weeks
* First dose of the every-3-week dosing schedule is given at Week 7
** First dose of the every-4-week dosing schedule is given at Week 55
In Combination with Bortezomib, Thalidomide and Dexamethasone (D-VTd)
The dosing schedule for combination therapy with bortezomib, thalidomide, and dexamethasone (4-week cycle regimen) for patients with newly diagnosed multiple myeloma eligible for ASCT.
The recommended dose of Daratumumab is 16 mg/kg actual body weight administered as an intravenous infusion according to the following dosing schedule:
Treatment Phase Weeks Schedule
Induction Weeks 1 to 8 weekly (total of 8 doses)
Weeks 9 to 16* every two weeks (total of 4 doses)
Stop for high dose chemotherapy and ASCT
Consolidation Weeks 1 to 8** every two weeks (total of 4 doses)
* First dose of the every-2-week dosing schedule is given at Week 9
** First dose ot the every-2-week dosing schedule is given at Week 1 upon re-initiation of treatment following ASCT
In Combination with Bortezomib and Dexamethasone (D-Vd)
The dosing schedule for combination therapy with bortezomib and dexamethasone (3-week cycle) for patients with relapsed/refractory multiple myeloma.
The recommended dose of Daratumumab is 16 mg/kg actual body weight administered as an intravenous infusion according to the following dosing schedule:
Weeks Schedule
Weeks 1 to 9 weekly (total of 9 doses)
Weeks 10 to 24* every three weeks (total of 5 doses)
Week 25 onwards until disease progression** every four weeks
* First dose of the every-3-week dosing schedule is given at Week 10
** First dose of the every-4-week dosing schedule is given at Week 25
In Combination with Carfilzomib and Dexamethasone (DKd)
The recommended dosage of Daratumumab when administered in combination with carfilzomib and dexamethasone (4-week cycle) for patients with relapsed/refractory multiple myeloma is as follows:
Weeks Daratumumab Dose*** Schedule
Week 1 8 mg/kg days 1 and 2 (total 2 doses)
Weeks 2 to 8 16 mg/kg weekly (total of 7 doses)
Weeks 9 to 24* 16 mg/kg every two weeks (total of 8 doses)
Week 25 onwards until disease progression** 16 mg/kg every four weeks
* First dose of the every-2-week dosing schedule is given at Week 9
** First dose of the every-4-week dosing schedule is given at Week 25
*** Based on actual body weight
See FDA label for additional information regarding dosing and administration.
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
2. Daratumumab and Hyaluronidase-fihi (DARZALEX FASPROTM) meets primary coverage criteria that there be scientific evidence of effectiveness for:
Limitations of Use: Daratumumab and Hyaluronidase-fihi is not indicated and is not recommended for the treatment of patients with light chain (AL) amyloidosis who have NYHA Class IIIB or Class IV cardiac disease of Mayo Stage IIIB outside of controlled clinical trials.
Off Label
The use of this drug is covered if a FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).i
Dosing and Administration
Recommended Dosage for Multiple Myeloma:
The recommended dose of Daratumumab and Hyaluronidase-fihi is 1,800 mg/30,000 units (1,800 mg daratumumab and 30,000 units hyaluronidase) administered subcutaneously over approximately 3-5 minutes. Tables 1, 2, 3, and 4 provide the recommended dosing schedule when Daratumumab and Hyaluronidase-fihi is administered as monotherapy or as part of a combination therapy.
Monotherapy and In Combination with Lenalidomide or Pomalidomide and Dexamethasone (D-Rd)
Use dosing schedule when Daratumumab and Hyaluronidase-fihi is administered:
Weeks Schedule
Weeks 1 to 8 weekly (total of 8 doses)
Weeks 9 to 24* every two weeks (total of 8 doses)
Week 25 onwards until disease progression* every four weeks
* First dose of the every-2-week dosing schedule is given at Week 9
** First dose of the ever-4-week dosing schedule is given at Week 25
In Combination with Bortezomib, Melphalan and Prednisone (D-VMP)
Use the dosing schedule when Daratumumab and Hyaluronidase-fihi is administered in combination with bortezomib, melphalan and prednisone (6-week cycle).
Weeks Schedule
Weeks 1 to 6 weekly (total of 6 doses)
Weeks 7 to 54* every three weeks (total of 16 doses)
Week 55 onwards until disease progression** every four weeks
* First dose of the every-3-week dosing schedule is given at Week 7.
** First dose of the every-4-week dosing schedule is given at Week 55
In Combination with Bortezomib, Thalidomide, and Dexamethasone (D-VTd)
Use the dosing schedule when Daratumumab and Hyaluronidase-fihi is administered in combination with bortezomib, thalidomide, and dexamethasone (4-week cycle).
Treatment Phase Weeks Schedule
Induction weeks 1 to 8 weekly (total of 8 doses)
weeks 9 to 16* every two weeks (total of 4 doses)
Stop for high dose chemotherapy and ASCT
Consolidation weeks 1 to 8** every two weeks (total of 4 doses)
* First dose of the every-2-wee dosing schedule is given at Week 9
** First dose of the every-2-week dosing schedule is given at Week 1 upon re-initiation of treatment following ASCT
In Combination with Bortezomib and Dexamethasone (D-Vd)
Use the dosing schedule when Daratumumab and Hyaluronidase-fihi is administered in combination with bortezomib and dexamethasone (3-week cycle).
Weeks Schedule
Weeks 1 to 9 weekly (total of 9 doses)
Weeks 10 to 24* weekly three weeks (total of 5 doses)
Week 25 onwards until disease progression** every four weeks
* First dose of the every-3-week dosing schedule is given at Week 10
** First dose of the every-4-week dosing schedule is given at Week 25
Recommended Dosage for Light Chain Amyloidosis:
In Combination with Bortezomib, Cyclophosphamide and Dexamethasone (D-VCd)
Use the dosing schedule provided when Daratumumab and Hyaluronidase-fihi is administered in combination with bortezomib, cyclophosphamide and dexamethasone (4-week cycle).
Weeks Schedule
Weeks 1 to 8 weekly (total of 8 doses)
Weeks 9 to 24* every two weeks (total of 8 doses)
Week 25 onwards until disease progression or a maximum of 2 years** every four weeks
* First dose of the every-2-week dosing schedule is given at Week 9
** First dose of the every-4-week dosing schedule is given at Week 25
See FDA label for additional information regarding dosing and administration.
Off Label
The use of this drug is covered if a FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary
Coverage Criteria
The use of daratumumab and daratumumab and hyaluronidase-fihi does not meet member benefit certificate primary coverage criteria that there be scientific evidence for any other indication than those outlined above.
For members with contracts without primary coverage criteria, the use of daratumumab and daratumumab and hyaluronidase-fihi for any other indication is considered investigational.
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Due to the detail of the policy statement, the document containing the coverage statements for dates prior to January 1, 2022 are not online. If you would like a hardcopy print, please email: codespecificinquiry@arkbluecross.com
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| Rationale: |
FDA accelerated approval of daratumumab was based on a two-part, phase 1–2, open-label, multicenter trial and data from another open label trial. Eligible patients had multiple myeloma requiring systemic therapy and had had a relapse after, or had disease that was refractory to, two or more different prior therapies, including immunomodulatory agents, proteasome inhibitors, chemotherapy, and autologous stem-cell transplantation. Patients were 18 years of age or older, had a life expectancy of at least 3 months, an ECOG performance-status score of ≤ 2 a measurable level of M protein or free light chains (or both) according to the International Myeloma Working Group (IMWG) guidelines. Other pertinent exclusion criteria were an <1000 per m3, a PLT count < 75×109 per liter, a serum creatinine level greater than 2 times the UNL, ALT and alkaline phosphatase levels greater than 3.5 times the UNL range, a bilirubin level greater than 2.5 times the UNL, a hemoglobin level of less than 7.5 g per deciliter, other malignant conditions, uncontrolled infections, clinically significant cardiovascular and respiratory conditions, and meningeal involvement of myeloma. In part 1, the dose escalation portion, patients received daratumumab at doses of 0.005 to 24 mg/kg body weight.
In in part 2, the open-label portion, 30 patients received daratumumab at 8 mg/kg and 42 patients received daratumumab at 16mg/kg. Treatment continued until unacceptable toxicity or disease progression. Patients had received a median of 5 prior lines of therapy. Patients in the study had received a median of 4 prior lines of therapy. Overall response rate was 36% (95% CI: 21.6, 52.0%) with 1 CR and 3 VGPR and PFS was 5.6 months (95 % CI: 4.2 to 8.1) in patients who received 16mg/kg.
In another open-label trial, evaluated daratumumab at 8mg/kg and 16mg/kg in multiple myeloma patients who have received at least three prior therapies, including a proteasome inhibitor (PI) and an immunomodulatory agent or who are double refractory to a PI and immunomodulatory agent. Patients had received a median of 5 prior lines of therapy. ORR (IRC assessed) was in 106 patients within the 16mg/kg dosing group and was 29.2%, with 3 sCR, 10 VGPR, and 18 PR with a 7.4 month median duration of response. After a median follow up of 9.4 months 14/31 (45.2%) of responders remain on therapy.
Daratumumab is dosed 16 mg/kg body weight administered as an intravenous infusion given weekly for weeks 1 to 8, every two weeks for weeks 9 to 24, and every four weeks from week 25 onward until progression.
The most frequent serious adverse reactions were pneumonia (6%), general physical health deterioration (3%), and pyrexia (3%) in safety data from 156 patients treated in three open-label clinical trials.
2017 Update
A literature search conducted using the MEDLINE database through October 2017 did not reveal any new information that would prompt a change in the coverage statement.
2019 Update
A literature search conducted through April 2019 did not reveal any new information that would prompt a change in the coverage statement.
2020 Update
An open-label, randomized, active-controlled Phase 3 study (MAIA), compared treatment with DARZALEX 16 mg/kg in combination with lenalidomide and low-dose dexamethasone (DRd) to treatment with lenalidomide and low-dose dexamethasone (Rd) in patients with newly diagnosed multiple myeloma ineligible for autologous stem cell transplant. Lenalidomide (25 mg once daily orally on Days 1-21 of repeated 28-day [4-week] cycles) was given with low dose oral or intravenous dexamethasone 40 mg/week (or a reduced dose of 20 mg/week for patients >75 years or body mass index [BMI] <18.5). On DARZALEX infusion days, the dexamethasone dose was given as a pre-infusion medication. Dose adjustments for lenalidomide and dexamethasone were applied according to manufacturer’s prescribing information. Treatment was continued in both arms until disease progression or unacceptable toxicity.
A total of 737 patients were randomized: 368 to the DRd arm and 369 to the Rd arm. The baseline demographic and disease characteristics were similar between the two treatment groups. The median age was 73 (range: 45-90) years, with 44% of the patients ≥75 years of age. The majority were white (92%), male (52%), 34% had an Eastern Cooperative Oncology Group (ECOG) performance score of 0, 50% had an ECOG performance score of 1 and 17% had an ECOG performance score of ≥2. Twenty-seven percent had International Staging System (ISS) Stage I, 43% had ISS Stage II and 29% had ISS Stage III disease. Efficacy was evaluated by progression free survival (PFS) based on International Myeloma Working Group (IMWG) criteria.
MAIA demonstrated an improvement in Progression Free Survival (PFS) in the DRd arm as compared to the Rd arm; the median PFS had not been reached in the DRd arm and was 31.9 months in the Rd arm (hazard ratio [HR]=0.56; 95% CI: 0.43, 0.73; p<0.0001), representing 44% reduction in the risk of disease progression or death in patients treated with DRd.
In responders, the median time to response was 1.05 months (range: 0.2 to 12.1 months) in the DRd group and 1.05 months (range: 0.3 to 15.3 months) in the Rd group. The median duration of response had not been reached in the DRd group and was 34.7 months (95% CI: 30.8, not estimable) in the Rd group. (Facon T, Kumar S, Plesner T, et al., 2019)
POLLUX (NCT02076009), an open-label, randomized, active-controlled Phase 3 trial, compared treatment with DARZALEX 16 mg/kg in combination with lenalidomide and low-dose dexamethasone (DRd) to treatment with lenalidomide and low-dose dexamethasone (Rd) in patients with multiple myeloma who had received at least one prior therapy. Lenalidomide (25 mg once daily orally on Days 1-21 of repeated 28-day [4-week] cycles) was given with low dose oral or intravenous dexamethasone 40 mg/week (or a reduced dose of 20 mg/week for patients >75 years or BMI <18.5). On DARZALEX infusion days, 20 mg of the dexamethasone dose was given as a pre-infusion medication and the remainder given the day after the infusion. For patients on a reduced dexamethasone dose, the entire 20 mg dose was given as a DARZALEX pre-infusion medication. Dose adjustments for lenalidomide and dexamethasone were applied according to manufacturer’s prescribing information. Treatment was continued in both arms until disease progression or unacceptable toxicity.
A total of 569 patients were randomized; 286 to the DRd arm and 283 to the Rd arm. The baseline demographic and disease characteristics were similar between the DARZALEX and the control arm. The median patient age was 65 years (range 34 to 89 years), 11% were ≥75 years, 59% were male; 69% Caucasian, 18% Asian, and 3% African American. Patients had received a median of 1 prior line of therapy. Sixty-three percent (63%) of patients had received prior autologous stem cell transplantation (ASCT). The majority of patients (86%) received a prior PI, 55% of patients had received a prior immunomodulatory agent, including 18% of patients who had received prior lenalidomide; and 44% of patients had received both a prior PI and immunomodulatory agent. At baseline, 27% of patients were refractory to the last line of treatment. Eighteen percent (18%) of patients were refractory to a PI only, and 21% were refractory to bortezomib. Efficacy was evaluated by PFS based on IMWG criteria.
POLLUX demonstrated an improvement in PFS in the DRd arm as compared to the Rd arm; the median PFS had not been reached in the DRd arm and was 18.4 months in the Rd arm (HR=0.37; 95% CI: 0.27, 0.52; p<0.0001), representing 63% reduction in the risk of disease progression or death in patients treated with DRd. With a median follow-up of 13.5 months, 75 deaths were observed; 30 in the DRd group and 45 in the Rd group. (Bahlis NJ, Dimopoulos MA, White DJ, et al., 2020)
CASSIOPEIA (NCT02541383), an open-label, randomized, active-controlled Phase 3 study compared induction and consolidation treatment with DARZALEX 16 mg/kg in combination with bortezomib, thalidomide and dexamethasone (DVTd) to treatment with bortezomib, thalidomide and dexamethasone (VTd) in patients with newly diagnosed multiple myeloma eligible for ASCT. The consolidation phase of treatment began a minimum of 30 days post-ASCT, when the patient had recovered sufficiently, and engraftment was complete. The trial was limited to patients 65 years of age and younger.
Bortezomib was administered by subcutaneous (SC) injection or intravenous (IV) injection at a dose of 1.3 mg/m2 body surface area twice weekly for two weeks (Days 1, 4, 8, and 11) of repeated 28-day (4-week) induction treatment cycles (Cycles 1-4) and two consolidation cycles (Cycles 5 and 6) following ASCT after Cycle 4. Thalidomide was administered orally at 100 mg daily during the six bortezomib cycles. Dexamethasone (oral or intravenous) was administered at 40 mg on Days 1, 2, 8, 9, 15, 16, 22 and 23 of Cycles 1 and 2, and at 40 mg on Days 1-2 and 20 mg on subsequent dosing days (Days 8, 9, 15, 16) of Cycles 3-4. Dexamethasone 20 mg was administered on Days 1, 2, 8, 9, 15, 16 in Cycles 5 and 6. On the days of DARZALEX infusion, the dexamethasone dose was administered intravenously as a pre-infusion medication. Dose adjustments for bortezomib, thalidomide and dexamethasone were applied according to manufacturer’s prescribing information.
A total of 1,085 patients were randomized: 543 to the DVTd arm and 542 to the VTd arm. The baseline demographic and disease characteristics were similar between the two treatment groups. The median age was 58 years (range: 22 to 65 years). The majority were male (59%), 48% had an ECOG performance score of 0, 42% had an ECOG performance score of 1 and 10% had an ECOG performance score of 2. Forty percent had ISS Stage I, 45% had ISS Stage II and 15% had ISS Stage III disease. Efficacy was evaluated by stringent Complete Response (sCR) rate at Day 100 post-transplant, Complete Response Rate (CR) at Day 100 post-transplant, and Progression-Free Survival (PFS).
CASSIOPEIA demonstrated an improvement in PFS in the DVTd 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 DVTd resulted in a reduction in the risk of progression or death by 53% compared to VTd alone (HR=0.47; 95% CI: 0.33, 0.67; p<0.0001). (Moreau P, Attal M, Hulin C, et al., 2019)
June 2020 Update
In an ongoing, multicentre (147 sites in 18 countries), open-label, non-inferiority, randomized, phase 3 trial, adult patients (age ≥18 years) recruited if they had confirmed relapsed or refractory multiple myeloma according to International Myeloma Working Group criteria; received at least three previous lines of therapy, including a proteasome inhibitor and immunomodulatory drug, or were double refractory to both a proteasome inhibitor and immunomodulatory drug; and had an Eastern Cooperative Oncology Group performance status score of 2 or lower. Patients were randomly assigned (1:1) by a computer-generated randomisation schedule and balanced using randomly permuted blocks to receive daratumumab subcutaneously (subcutaneous group) or intravenously (intravenous group). Randomisation was stratified on the basis of baseline bodyweight (≤65 kg, 66-85 kg, >85 kg), previous therapy lines (≤four vs >four), and myeloma type (IgG vs non-IgG). Patients received 1800 mg of subcutaneous daratumumab co-formulated with 2000 U/mL recombinant human hyaluronidase PH20 or 16 mg/kg of intravenous daratumumab once weekly (cycles 1-2), every 2 weeks (cycles 3-6), and every 4 weeks thereafter (28-day cycles) until progressive disease or toxicity. The co-primary endpoints were overall response and maximum trough concentration. The non-inferiority margin for overall response was defined using a 60% retention of the lower bound (20·8%) of the 95% CI of the SIRIUS trial. Efficacy analyses were done by intention-to-treat population. The pharmacokinetic-evaluable population included all patients who received all eight weekly daratumumab doses in cycles 1 and 2 and provided a pre-dose pharmacokinetics blood sample on day 1 of cycle 3. The safety population included all patients who received at least one daratumumab dose.
Between Oct 31, 2017, and Dec 27, 2018, 655 patients were screened, of whom 522 were recruited and randomly assigned (subcutaneous group n=263; intravenous group n=259). Three patients in the subcutaneous group and one in the intravenous group did not receive treatment and were not evaluable for safety. At a median follow-up of 7·5 months (IQR 6·5-9·3), overall response and Ctrough met the predefined non-inferiority criteria. An overall response was seen in 108 (41%) of 263 patients in the subcutaneous group and 96 (37%) of 259 in the intravenous group (relative risk 1·11, 95% CI 0·89-1·37). The geometric means ratio for Ctrough was 107·93% (90% CI 95·74-121·67), and the maximum Ctrough was 593 μg/mL (SD 306) in the subcutaneous group and 522 μg/mL (226) in the intravenous group. The most common grade 3 and 4 adverse events were anaemia (34 [13%] of 260 patients evaluable for safety in the subcutaneous group and 36 [14%] of 258 patients in the intravenous group), neutropenia (34 [13%] and 20 [8%]), and thrombocytopenia (36 [14%] and 35 [14%]). Pneumonia was the only serious adverse event in more than 2% of patients (seven [3%] in the subcutaneous group and 11 [4%] in the intravenous group). There was one death resulting from a treatment-related adverse event in the subcutaneous daratumumab group (febrile neutropenia) and four in the intravenous group (sepsis [n=2], hepatitis B reactivation [n=1], and Pneumocystis jirovecii pneumonia [n=1]).
Subcutaneous daratumumab was non-inferior to intravenous daratumumab in terms of efficacy and pharmacokinetics and had an improved safety profile in patients with relapsed or refractory multiple myeloma. (Mateos MV, Nahi H, Legiec W, et al., 2020).
A non-randomized, open-label, parallel assignment Phase 2 PLEIADES study (MMY2040) included more than 240 adults with multiple myeloma, including 67 patients with newly diagnosed multiple myeloma who were treated with 1,800 mg of Darzalex Faspro™ in combination with bortezomib, melphalan, and prednisone (D-VMP) and 65 patients with relapsed or refractory disease who were treated with 1,800 mg of Darzalex Faspro™ plus lenalidomide and dexamethasone (D-Rd). The primary endpoint for the D-VMP and D-Rd cohorts was overall response rate.
2021 Update
CANDOR (NCT03158688) was a randomized, open-label, multicenter trial which evaluated the combination of DARZALEX with twice-weekly carfilzomib and dexamethasone (DKd) versus twice-weekly carfilzomib and dexamethasone (Kd) in patients with relapsed or refractory multiple myeloma who had received at least 1 to 3 prior lines of therapy. Patients who had the following were excluded from the trial: known moderate or severe persistent asthma within the past 2 years, known chronic obstructive pulmonary disease (COPD) with a FEV1 <50% of predicted normal, and active congestive heart failure. Randomization was stratified by the ISS (stage 1 or 2 vs stage 3) at screening, prior proteasome inhibitor exposure (yes vs no), number of prior lines of therapy (1 vs ≥2), or prior cluster differentiation antigen 38 (CD38) antibody therapy (yes vs no).
DARZALEX was administered intravenously at a dose of 8 mg/kg in Cycle 1 on Days 1 and 2. Thereafter, DARZALEX was administered intravenously at a dose of 16 mg/kg on Days 8, 15 and 22 of Cycle 1; Days 1, 8 and 15 and 22 of Cycle 2; Days 1 and 15 of Cycles 3 to 6; and Day 1 of each 28-day cycle until disease progression. Carfilzomib was administered intravenously at a dose of 20 mg/m2 in Cycle 1 on Days 1 and 2; at a dose of 56 mg/m2 in Cycle 1 on Days 8, 9, 15, and 16 ; and at a dose 56 mg/m2 on Days 1, 2, 8, 9, 15, and 16 of each 28-day cycle thereafter. Dexamethasone 20 mg was administered orally or intravenously on Days 1, 2, 8, 9, 15 and 16 and then 40 mg orally or intravenously on Day 22 of each 28-day cycle. For patients >75 years on a reduced dexamethasone dose of 20 mg, the entire 20 mg dose was given as a DARZALEX pre-infusion medication on days when DARZALEX was administered. Dosing of dexamethasone was otherwise split across days when carfilzomib was administered in both study arms. Treatment was continued in both arms until disease progression or unacceptable toxicity.
A total of 466 patients were randomized; 312 to the DKd arm and 154 to the Kd arm. The baseline demographic and disease characteristics were similar between arms. The median age was 64 years (range 29 to 84 years), 9% were ≥75 years, 58% were male; 79% White, 14% Asian, and 2% Black. Patients had received a median of 2 prior lines of therapy and 58% of patients had received prior autologous stem cell transplantation (ASCT). The majority of patients (92%) received a prior PI and of those 34% were refractory to PI including regimen. Fourty-two percent (42%) of patients had received prior lenalidomide and of those, 33% were refractory to a lenalidomide containing regimen.
Efficacy was evaluated by IRC evaluation of PFS based on the IMWG response criteria. CANDOR demonstrated an improvement in PFS in the DKd arm as 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 (hazard ratio [HR]=0.63; 95% CI: 0.46, 0.85; p=0.0014), representing 37% reduction in the risk of disease progression or death for patients treated with DKd versus Kd. The median time to response was 1 month (range: 1 to 14 months) in the DKd group and 1 month (range: 1 to 10 months) in the Kd group. The median duration of response had not been reached in the DKd group and was 16.6 months (95% CI: 13.9, not estimable) in the Kd group. (Dimopoulos M, Quach H, Mateos MV, et. al., 2020)
EQUULEUS (NCT01998971) was an open-label, multi-cohort trial which evaluated the combination of DARZALEX with one-weekly carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma who had received at least 1 to 3 prior lines of therapy. Patients who had the following were excluded from the trial: known moderate or severe persistent asthma within the past 2 years, known chronic obstructive pulmonary disease (COPD) with a FEV1 <50% of predicted normal, or active congestive heart failure (defined as New York Heart Association Class III-IV).
Ten patients were administered DARZALEX at a dose of 16 mg/kg intravenously on Cycle 1, Day 1 and the remaining patients were administered DARZALEX at a dose of 8 mg/kg intravenously on Cycle 1, Days 1 and 2. Thereafter, DARZALEX was administered intravenously at a dose of 16 mg/kg on Days 8, 15 and 22 of Cycle 1; Days 1, 8, 15 and 22 of Cycle 2; Days 1 and 15 of Cycles 3 to 6; and then Day 1 for the remaining cycles of each 28 day cycle. Carfilzomib was administered intravenously once weekly at a dose of 20 mg/m2 on Cycle 1 Day 1 and escalated to dose of 70 mg/m2 on Cycle 1 Days 8 and 15, and Days 1, 8, and 15 of each subsequent 28-day cycle. In Cycles 1 and 2, dexamethasone 20 mg was administered orally or intravenously on Days 1, 2, 8, 9, 15, 16, 22 and 23; in cycles 3 to 6, dexamethasone 20 mg was administered orally or intravenously on Days 1, 2, 15 and 16 and at a dose of 40 mg on Day 8 and 22; and in cycles 7 and thereafter, dexamethasone 20 mg was administered orally or intravenously on Days 1 and 2 and at a dose of 40 mg on Days 8, 15, and 22. For patients >75 years of age, dexamethasone 20 mg was administered orally or intravenously weekly after the first week. Treatment continued until disease progression or unacceptable toxicity.
The EQUULEUS trial enrolled 85 patients. The median patient age was 66 years (range: 38 to 85 years) with 9% of patients ≥75 years of age; 54% were male; 80% were White, 3.5% were Black and 3.5% were Asian. Patients in the study had received a median of 2 prior lines of therapy. Seventy-three percent (73%) of patients had received prior ASCT. All patients received prior bortezomib, and 95% of patients received prior lenalidomide. Fifty-nine percent (59%) of patients were refractory to lenalidomide and 29% of patients were refractory to both a PI an IMiD.
Efficacy results were based on overall response rate using IMWG criteria. The median time to response was 0.95 months (range: 0.9, 14.3). The median duration of response was 28 months (95% CI: 20.5, not estimable). (Leleu X, Beksac M, Chou T, et. al., 2021).
The efficacy of DARZALEX FASPRO with VCd was evaluated in ANDROMEDA (NCT03201965), an open-label, randomized, active-controlled trial. Eligible patients were required to have newly diagnosed light chain (AL) amyloidosis with at least one affected organ, measurable hematologic disease, Cardiac Stage I-IIIA (based on European Modification of Mayo 2004 Cardiac Stage), and NYHA Class I-IIIA. Patients with NYHA Class IIIB and IV were excluded. Patients were randomized to receive bortezomib 1.3 mg/m2 administered subcutaneously, cyclophosphamide 300 mg/m2 (max dose 500 mg) administered orally or intravenously, and dexamethasone 40 mg (or a reduced dose of 20 mg for patients >70 years or body mass index <18.5 or who have hypervolemia, poorly controlled diabetes mellitus or prior intolerance to steroid therapy) administered orally or intravenously on Days 1, 8, 15, and 22 of each 28-day cycle with or without DARZALEX FASPRO 1,800 mg/30,000 units subcutaneously 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 a maximum of two years. When DARZALEX FASPRO and dexamethasone were administered on the same day, dexamethasone 20 mg was administered before DARZALEX FASPRO with the remaining dose of dexamethasone administered after DARZALEX FASPRO if applicable. The major efficacy outcome measure was confirmed hematologic complete response (HemCR) rate based on Consensus Criteria as determined by the Independent Review Committee (negative serum and urine immunofixation, involved free light chain level decrease to less than the upper limit of normal, and normal free light chain ratio). Randomization was stratified by Cardiac Stage (European Modification of Mayo 2004 Cardiac Stage) countries that typically offer autologous stem cell transplant (ASCT) for patients with light chain (AL) amyloidosis, and renal function.
A total of 388 patients were randomized: 195 to D-VCd and 193 to VCd. The median patient age was 64 years (range: 34 to 87 years); 58% were male; 76% White, 17% Asian, and 3% Black or African American; 23% had light chain (AL) amyloidosis Cardiac Stage I, 40% had Stage II, and 37% had Stage IIIA. The median number of organs involved was 2 (range: 1-6) and 66% of patients had 2 or more organs involved. Vital organ involvement was: cardiac 71%, renal 59% and hepatic 8%. The majority (79%) of patients had lambda free light chain disease.
The median time to HemCR was 59 days (range: 8 to 299 days) in the D-VCd arm and 59 days (range: 16 to 340 days) in the VCd arm. The median time to VGPR or better was 17 days (range: 5 to 336 days) in the D-VCd arm and 25 days (range: 8 to 171 days) in the VCd arm. The median duration of HemCR had not been reached in either arm.
The median follow-up for the study is 11.4 months. Overall survival (OS) data were not mature. A total of 56 deaths were observed [N=27 (13.8%) D-VCd vs. N=29 (15%) VCd group]. (Palladini G, Kastritis E, Maurer MS, et. al., 2020)
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through May 2022. No new literature was identified that would prompt a change in the coverage statement.
2023 Update
CASTOR was a multicenter, randomized, open-label, phase III study during which eligible patients with ≥ 1 line of prior therapy were randomly assigned to Vd (up to eight cycles) with or without daratumumab (until disease progression). After positive primary analysis and protocol amendment, patients receiving Vd were offered daratumumab monotherapy after disease progression.
At a median (range) follow-up of 72.6 months (0.0-79.8), significant OS benefit was observed with D-Vd (hazard ratio, 0.74; 95% CI, 0.59 to 0.92; P = .0075). Median OS was 49.6 months with D-Vd versus 38.5 months with Vd. Prespecified subgroup analyses demonstrated an OS advantage with D-Vd versus Vd for most subgroups, including patients age ≥ 65 years and patients with one or two prior lines of therapy, International Staging System stage III disease, high-risk cytogenetic abnormalities, and prior bortezomib treatment. The most common (≥ 10%) grade 3/4 treatment-emergent adverse events with D-Vd versus Vd were thrombocytopenia (46.1% v 32.9%), anemia (16.0% v 16.0%), neutropenia (13.6% v 4.6%), lymphopenia (10.3% v 2.5%), and pneumonia (10.7% v 10.1%).
D-Vd significantly prolonged OS in patients with RRMM, with the greatest OS benefit observed in patients with one prior line of therapy. (Sonneveld P, Chanan-Khan A, Weisel K, 2023)
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Chari A, Martinez-Lopez J, Mateos M, et al.(2018) Daratumumab in combination with carfilzomib and dexamethasone in lenalidomiderefractory patients with relapsed multiple myeloma: Subgroup analysis of MMY1001. J Clin Oncol. 2018; 36(15):8002-8002 Food and Drug Administration (FDA).(2021) Darzalex Faspro Highlights of Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761145s007lbl.pdf . Accessed September 10, 2021 Food and Drug Administration (FDA).(2021) Darzalex Highlights of Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761036s035lbl.pdf. Accessed September 10, 2021 Jakubowiak A, Chari A, Lonial S, et al.(2017) Daratumumab in combination with carfilzomib, lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma (MMY1001) J Clin Oncol. 2017; 35(15):8000-8000. Kimmich CR, Terzer T, Benner A, et al:(2020) Daratumumab for systemic AL amyloidosis: prognostic factors and adverse outcome with nephrotic-range albuminuria. Blood 2020; 135(18):1517-1530. NCCN Clinical Practice Guidelines in Oncology™. © 2022 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website: http://www.nccn.org/index.asp. Accessed May 4, 2022. Roussel M, Merlini G, Chevret S, et al.(2020) A prospective phase II of daratumumab in previously treated systemic light chain amyloidosis (AL) patients. Blood. 2020; 135: 1531-1540. Sonneveld P, Chanan-Khan A, Weisel K, Nooka AK, Masszi T, Beksac M, Spicka I, Hungria V, Munder M, Mateos MV, Mark TM, Levin MD, Ahmadi T, Qin X, Garvin Mayo W, Gai X, Carey J, Carson R, Spencer A.(2023) Overall Survival With Daratumumab, Bortezomib, and Dexamethasone in Previously Treated Multiple Myeloma (CASTOR): A Randomized, Open-Label, Phase III Trial. J Clin Oncol. 2023 Mar 10;41(8):1600-1609. doi: 10.1200/JCO.21.02734. Epub 2022 Nov 22. PMID: 36413710; PMCID: PMC10022857. |
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Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
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