Medical Policy

 

Subject: Daratumumab (DARZALEX™)
Document #: DRUG.00082 Publish Date:    02/28/2018
Status: Revised Last Review Date:    01/25/2018

Description/Scope

 

This document addresses the use of daratumumab (DARZALEX, Janssen Biotech, Inc., Horsham, PA), a human anti-CD38 monoclonal antibody (mAb) used for the treatment of multiple myeloma (including plasma-cell leukemia) resistant to other therapies. Daratumumab is also being studied for the use in other indications.

 

Note: Please see the following related document for additional information:

Position Statement

Medically Necessary:

The use of daratumumab is considered medically necessary for the treatment of individuals with multiple myeloma, including plasma-cell leukemia, when treatment meets the following criteria (A, B, C or D, and E):

  1. Daratumumab used in combination with melphalan, prednisone and a proteasome inhibitor (PI) (for example, bortezomib) for newly diagnosed multiple myeloma for those who are ineligible for stem cell transplantation; or
  2. Daratumumab used as a single agent for individuals with relapsed or refractory disease following therapy with at least two prior lines of therapy including a PI (for example, bortezomib, carfilzomib, or ixazomib) and an immunomodulatory agent (for example, thalidomide, lenalidomide, or pomalidomide); or
  3. Daratumumab used as combination therapy for individuals with relapsed or refractory disease following therapy with at least one prior line of therapy including a PI or an immunomodulatory agent when used with one of following:
    1. Bortezomib and dexamethasone; or
    2. Lenalidomide and dexamethasone; or
  4. Daratumumab used in combination with pomalidomide and dexamethasone for individuals with relapsed or refractory disease following therapy with at least two prior lines of therapy including a PI and lenalidomide; and
  5. Has not received treatment with daratumumab or another anti-CD38 agent.

Investigational and Not Medically Necessary:

The use of daratumumab is considered investigational and not medically necessary when the above criteria are not met, and for all other conditions, including but not limited to any of the following:

  1. Presence of human immunodeficiency virus (HIV) infection or hepatitis B virus infection;
  2. The reason for treatment is other than for a diagnosis of multiple myeloma, including plasma-cell leukemia.
Rationale

On November 16, 2015 daratumumab was the first human mAb to achieve accelerated approval and breakthrough therapy status by the U.S. Food and Drug Administration (FDA), because it provided an option for individuals with multiple myeloma who have received at least three prior lines of therapy, including a PI and an immunomodulatory agent, or who are double-refractory to a PI and an immunomodulatory agent. The FDA approved daratumumab injection for intravenous infusion to be used as a single agent for the treatment of relapsed or refractory disease. In November 2016 the FDA approved the expanded use of daratumumab in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone in the treatment of individuals with refractory of relapsed multiple myeloma after failure of at least one prior line of therapy including a PI or an immunomodulatory agent. On June 16, 2017 Janssen Biotech Inc., received FDA approval for expanded use of daratumumab in combination with pomalidomide and dexamethasone for the treatment of individuals with multiple myeloma who have received at least two prior therapies including lenalidomide and a PI (Product Information, 2017).

The FDA approval of daratumumab was based on the safety and efficacy demonstrated in two open-label, non-comparative phase II studies. Lokhorst and colleagues (2015) reported results on a two-part study, part 1 dose-escalation and part 2 the dose-expansion phase. Part 2 randomly assigned 30 participants to receive daratumumab monotherapy (8 mg per kilogram) and 42 participants to receive daratumumab monotherapy (16 mg per kilogram) administered once weekly for eight doses, twice monthly for eight doses, then monthly for up to 24 months. The study enrolled participants with relapsed multiple myeloma, or disease that was refractory (79%) to two or more different therapies (for example, PI, immunomodulatory agents, chemotherapy, or autologous stem-cell transplantation); participants enrolled had received a median of four prior treatments. Subjects were at least 18 years of age, with a life expectancy greater than 3 months, ECOG performance status of 0-2, and a measurable level of M protein or free light chains. Pneumonia and thrombocytopenia were identified as the most common adverse events. Serious adverse events occurred in 40% of participants in the 8 mg per kilogram cohort and 33% in the 16 mg per kilogram cohort, with infection-related events the most common among both groups. Lokhorst and colleagues concluded:

The overall response rate was 36% in the cohort that received 16 mg per kilogram (15 patients had a partial response or better, including 2 with a complete response and 2 with a very good partial response) and 10% in the cohort that received 8 mg per kilogram (3 had a partial response). In the cohort that received 16 mg per kilogram, the median progression-free survival was 5.6 months (95% confidence interval [CI], 4.2 to 8.1), and 65% (95% CI, 28 to 86) of the patients who had a response did not have progression at 12 months.

Lonial and colleagues (2016) reported preliminary results of an ongoing phase II open-label, multicenter study of 106 participants (18 years or older) that received daratumumab 16 mg per kilogram in parts 1 and 2; 80% (n=85) of participants had previously undergone autologous stem cell transplantation, 95% of participants (n=101) were refractory to most recent treatment (PI and immunomodulatory agent used), and 97% of participants (n=103) were refractory to last lines of therapy. Final results reported an overall response rate of 29% among participants (n=31) that experienced a complete or partial reduction in tumor burden, which lasted for an average of 7.4 months “(95% CI, 5.5- not estimable) and progression-free survival was 3.7 months (95% CI, 2.8-4.6). The 12-month overall survival was 64.8% (95% CI, 51.2-75.5) and, at a subsequent cutoff, median overall survival was 17.5 months (95% CI, 13.7- not estimable).” The most common adverse reactions (any grade) for daratumumab were fatigue (n=42; 40%) and anemia (n=35; 33%). Daratumumab was well tolerated, with no drug-related adverse events that led to discontinuation of treatment. Authors found daratumumab monotherapy an effective option for individuals with relapsed or refractory multiple myeloma for whom available treatments have been exhausted.

The updated National Comprehensive Cancer Network® (NCCN) Drugs and Biologics Compendium™ and the NCCN CPG for multiple myeloma (2017) included recommendations for off-label use of daratumumab for previously treated myeloma for disease relapse or for progressive or refractory disease. The panel offers a category 2A recommendation for use as a single agent in individuals that have received at least three prior therapies, including a PI and an immunomodulatory agent or who are double refractory to a PI and immunomodulatory agent. Another category 2 A recommendation is for use of daratumumab in combination with pomalidomide and dexamethasone for the treatment of individuals who have received at least two prior therapies including an immunomodulatory agent and a PI and who have demonstrated disease progression on or within 60 days of completion of the last therapy. The panel included a category 1 recommendation for use of daratumumab when used in combination with bortezomib and dexamethasone or lenalidomide and dexamethasone. The NCCN off-label recommendations are based on interim analysis from a phase II study (Lonial, 2016) and two phase III studies (Dimopoulos, 2016; Palumbo, 2016) that evaluated the use of daratumumab in the treatment of multiple myeloma.

Palumbo and colleagues (2016) reported an interim analysis from the CASTOR study, a phase III randomized controlled study that enrolled 498 participants with relapsed or refractory multiple myeloma (RRMM). Subjects were randomly assigned to receive daratumumab in combination with standard of care bortezomib, and dexamethasone (DVd) (n=259) versus the control group that received bortezomib and dexamethasone (Vd) (n=247), after receiving a partial response from one or more prior therapies (median of two previous lines of therapy). “The primary endpoint was progression-free survival, defined as the time from the date of randomization to the date of disease progression or death, whichever occurred first”. Data from the clinical trial showed that daratumumab in combination with standard of care therapy demonstrated a 60.7% reduction in the risk of disease progression or death (PFS) at 12 months compared to 26.9% in the control group population with RRMM. The authors reported additional interim findings:

After a median follow-up period of 7.4 months, the median progression-free survival was not reached in the daratumumab group and was 7.2 months in the control group (hazard ratio for progression or death with daratumumab vs. control, 0.39; 95% confidence interval, 0.28 to 0.53; P<0.001). The rate of overall response was higher in the daratumumab group than in the control group (82.9% vs. 63.2%, P<0.001), as were the rates of very good partial response or better (59.2% vs. 29.1%, P<0.001), as were the rates of very good partial response or better (59.2% vs. 29.1%, P<0.001) and complete response or better (19.2% vs. 9.0%, P=0.001).

The majority of participants in both groups reported at least one adverse event, with grade 3 or 4 adverse events observed in 76.1% of the daratumumab population and 62.4% of the control population. Commonly reported grade 3 or 4 adverse events among the daratumumab group and the control group were thrombocytopenia (45.3% vs/ 32.9%), anemia (14.4% vs. 16.0%), and neutropenia (12.8% vs. 4.2%). In the daratumumab group, 45.3% of subjects reported infusion-related reactions (majority grade 1 or 2), with 98.2% of infusion-related reactions occurring during the first daratumumab infusion. In conclusion, the authors reported that:

Among patients with relapsed or relapsed and refractory multiple myeloma, daratumumab in combination with bortezomib and dexamethasone resulted in significantly longer progression-free survival than bortezomib and dexamethasone alone.

Dimopoulos and colleagues (2016) reported interim results from a randomized, open-label, multicenter phase III trial that enrolled 569 participants with relapsed or refractory multiple myeloma with one or more prior lines of therapy to receive lenalidomide and dexamethasone alone (control group) (n=283) or in combination with daratumumab (n=286). “The primary endpoint was progression-free survival, with progression determined with the use of a validated computer algorithm that combined laboratory results (e.g., M-protein level) and applicable imaging and generated the outcome according to IMWG criteria.” Interim analysis was reported at 13.5 months (median follow-up); “169 events of disease progression or death were observed (in 53 of 286 patients [18.5%] in the daratumumab group vs. 116 of 283 [41.0%] in the control group; hazard ratio, 0.34; 95% confidence interval [CI], 0.27 to 0.52; p<0.001 by stratified log-rank test).” At 12 months the rate of progression-free survival was “83.2% (95% CI, 78.3 to 87.2) in the daratumumab group, as compared with 60.1% (95% CI, 54.0 to 65.7) in the control group”. The overall response rate observed in the daratumumab group was 92.9% compared to 76.4% among the control group; the complete response was also higher in the daratumumab group, 43.1% versus a rate of 19.2% in the control group. Grade 3 or 4 adverse events commonly reported among the daratumumab group and the control group included neutropenia (51.9% vs 37.0%), thrombocytopenia (12.7% vs 13.5%) and anemia (12.4% vs. 19.6%). Infusion-related reactions occurred in 47.7% of participants in the daratumumab group; the majority reported as grade 1 or 2 adverse events. The authors concluded that “the addition of daratumumab to lenalidomide and dexamethasone significantly lengthened progression-free survival among patients with relapsed or refractory multiple myeloma.”

The FDA approval for expanded use of daratumumab in combination with pomalidomide and dexamethasone was based on unpublished data from a cohort of a phase 1 (MMY1001, EQUULEUS) study that investigated the safety and tolerability of daratumumab in combination with pomalidomide and dexamethasone in relapsed or refractory multiple myeloma. The phase 1, open-label study included 103 participants with multiple myeloma who received prior treatment with PI and an immunomodulatory agent. The overall response rate observed in the study was 59% (95% CI, 49.1%-68.8%) and partial response achieved in 28% of participants. The median duration of response reported was 13.6 months. Among participants that received treatment, grade 3 or 4 serious adverse events were reported in 5% of participants, including pneumonia, neutropenia, thrombocytopenia and anemia.

Mateos and colleagues (2017) reported interim analysis from a multicenter, randomized, open-label, phase 3 trial (NCT02195479) that enrolled participants with newly diagnosed multiple myeloma, ineligible for high-dose chemotherapy with stem-cell transplantation due to age greater than or equal to 65 years, or in participants less than 65 years of age with presence of comorbid conditions likely to have a negative impact on tolerability of high-dose chemotherapy with stem cell transplantation. A total of 700 participants received the assigned intervention, 346 participants in the daratumumab group (daratumumab in combination with bortezomib, melphalan, and prednisone) and 354 participants in the control group (bortezomib, melphalan, and prednisone alone). The primary endpoint was PFS, “defined as the time from randomization to either disease progression or death.” The authors reported interim findings:

The 18-month progression-free survival rate was 71.6% (95% confidence interval [CI], 65.5 to 76.8) in the daratumumab group and 50.2% (95% CI, 43.2 to 56.7) in the control group (hazard ratio for disease progression or death, 0.50; 95% CI, 0.38 to 0.65; P<0.001). The overall response rate was 90.9% in the daratumumab group, compared with 73.9% in the control group (P<0.001), and the rate of complete response or better (including stringent complete response) was 42.6%, versus 24.4% (P<0.001).

The most common grade 3 or 4 adverse events reported among the daratumumab group and the control group included neutropenia (39.9% vs 38.7%), thrombocytopenia (34.4% vs 37.6%) and anemia (15.9% vs. 19.8%). Infusion-related reactions occurred in 47.7% of participants in the daratumumab group; the majority reported as grade 1 or 2 adverse events. The authors concluded that daratumumab combined with bortezomib, melphalan, and prednisone in individuals newly diagnosed with multiple myeloma who were ineligible for stem cell transplantation resulted in a lower risk of disease progression or death than treatment with bortezomib, melphalan and prednisone.

Daratumumab is also currently being studied in clinical trials for other uses including, but not limited to the treatment of acute myeloid leukemia (AML), relapsed/refractory mantle cell lymphoma, diffuse large B-cell lymphoma, and follicular lymphoma. However, there is insufficient published evidence to support the use of daratumumab for such conditions.

Background/Overview

Multiple myeloma is a systemic malignancy of plasma cells that accumulate in the bone marrow, leading to destruction of bone and failure of the bone marrow. Multiple myeloma is highly treatable but rarely curable. However, when it presents as a solitary plasmacytoma of bone or as an extramedullary plasmacytoma, it is potentially curable. Multiple myeloma accounts for approximately 10% of all hematologic cancers. The American Cancer Society (ACS) has estimated 30,280 new cases of multiple myeloma will be diagnosed in the United States in 2017, with an estimated 12,590 deaths (ACS, 2017). The stage of the disease at presentation is a strong determinant of survival, but has little influence on the choice of therapy since almost all individuals (except for those with solitary bone tumors or extramedullary plasmacytomas) have generalized disease. Multiple myeloma affects mostly older individuals around 62 years of age. The age and general health of the individual, prior therapy and the presence of complications of the disease influence treatment selection. The median survival in the pre-chemotherapy era was about 7 months. Multiple myeloma has demonstrated chemosensitivity to initial treatment or treatment for relapsed disease. Improvements in newer treatments have resulted in an increase in 5-year survival which is currently around 50%.

Daratumumab (DARZALEX) 2017 FDA Product Information label includes the following contraindications, warnings, precautions and adverse events:

Contraindications

Warnings and Precautions
Warning: Immune-Mediated Adverse Reactions:

Adverse Reactions

The most frequently reported adverse reactions (incidence ≥20%) were: Infusion reactions, neutropenia, thrombocytopenia, fatigue, nausea, diarrhea, constipation, vomiting, muscle spasms, arthralgia, back pain, pyrexia, chills, dizziness, insomnia, cough, dyspnea, peripheral edema, peripheral sensory neuropathy and upper respiratory tract infection.

Definitions

ECOG Performance Status: A scale used to determine the individual's level of functioning. This scale may also be referred to as the WHO (World Health Organization) or Zubrod score which is based on the following scale:

0 = Fully active, able to carry on all pre-disease performance without restriction
1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work
2 = Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about more than 50% of waking hours
3 = Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours
4 = Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair
5 = Dead

Line of therapy:

Monoclonal antibody: A type of protein made in the laboratory that can bind to substances in the body, including cancer cells. There are many kinds of monoclonal antibodies. A monoclonal antibody is made so that it binds to only one substance. Monoclonal antibodies are being used to treat some types of cancer. They can be used alone or to carry drugs, toxins, or radioactive substances directly to cancer cells. (NCI, 2017)

Multiple myeloma: A type of cancer that begins in plasma cells (white blood cells that produce antibodies).

Off-label: Utilization of an FDA approved drug for uses other than those listed in the FDA approved label.

Refractory disease: Illness or disease that does not respond to treatment.

Relapse: After a period of improvement, the return of signs and symptoms of cancer.

Coding

The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services may be Medically Necessary when criteria are met:

HCPCS

 

J9145

Injection, daratumumab, 10 mg [DARZALEX]

 

 

ICD-10 Diagnosis

 

 

C90.00-C90.32

Multiple myeloma and malignant plasma cell neoplasms

 

Z85.79

Personal history of other malignant neoplasms of lymphoid, hematopoietic and related tissues

 

When services are Investigational and Not Medically Necessary:
For the procedure codes listed above when criteria are not met or for all other diagnoses not listed; or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

References

Peer Reviewed Publications:

  1. Chari A, Suvannasankha A, Fay JW, et al. Daratumumab plus pomalidomide and dexamethasone in relapsed and/or refractory multiple myeloma. Blood. 2017; 130(8):974-981.
  2. de Weers M, Tai YT, van der Veer MS, et al. Daratumumab, a novel therapeutic human CD38 monoclonal antibody, induces killing of multiple myeloma and other hematological tumors. J Immunol. 2011;186(3):1840-1848.
  3. Dimopoulos MA, Oriol A, Nahi H, et al. Daratumumab , lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016; 375:1319-1331.
  4. Lokhorst HM, Plesner T, Laubach JP, et al. Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma. N Engl J Med. 2015;373(13):1207-1219.
  5. Lonial S, Weiss BM, Usmani SZ, et al. Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): an open-label, randomized, phase 2 trial. Lancet. 2016; 387(10027):1551-1560.
  6. Mateos MV, Dimopoulos MA, Cavo M, et al. Daratumumab plus bortezomib, melphalan, and prednisone for untreated myeloma. N Engl J Med. 2017. DOI: 10.1056/NEJMoa1714678. [Epub ahead of print]
  7. Palumbo A, Chanan-Khan A, Weisel K, et al. Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med. 2016; 375:754-766.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. American Cancer Society. Cancer facts & figures 2017. Atlanta: American Cancer Society; 2017.
  2. Daratumumab Monograph. Lexicomp® Online, American Hospital Formulary Services® (AHFS®) Online, Hudson, Ohio, Lexi-Comp., Inc. Last revised October 21, 2016. Accessed on December 14, 2017.
  3. Daratumumab (systemic). In: DrugPoints® System (electronic version). Truven Health Analytics, Greenwood Village, CO. Updated August 28, 2017. Available at: http://www.micromedexsolutions.com. Accessed on December 14, 2017.
  4. DARZALEX [Product Information], Horsham, PA. Janssen Biotech, Inc; June 16, 2017. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761036s005lbl.pdf. Accessed on December 14, 2017.
  5. Janssen Research & Development, LLC. Addition of daratumumab to combination of bortezomib and dexamethasone in participants with relapsed or refractory multiple myeloma. NLM Identifier: NCT02136134. Last updated on December 13, 2017. Available at: https://clinicaltrials.gov/show/NCT02136134. Accessed on December 15, 2017.
  6. Janssen Research & Development, LLC. An efficacy and safety study of daratumumab in patients with multiple myeloma who have received at least 3 prior lines of therapy (including a proteasome inhibitor [PI] and immunomodulatory drug [IMiD] or are double refractory to a PI and an IMiD. NLM Identifier: NCT01985126. Last updated on September 8, 2017. Available at: https://clinicaltrials.gov/ct2/show/NCT01985126. Accessed on December 14, 2017.
  7. Janssen Research & Development, LLC. A study of combination of daratumumab and velcade (bortezomib) melphalan-prednisone (DVMP) compared to velcade melphalan- prednisone (VMP) in participants with previously untreated multiple myeloma. NLM Identifier: NCT02195479. Last updated November 24, 2017. Available at: https://clinicaltrials.gov/ct2/show/NCT02195479. Accessed on December 14, 2017.
  8. Janssen Research & Development, LLC. A study comparing daratumumab, lenalidomide, and dexamethasone with lenalidomide and dexamethasone in relapsed or refractory multiple myeloma. NLM Identifier: NCT02076009. Last updated July 28, 2017. Available at: https://clinicaltrials.gov/ct2/show/NCT02076009. Accessed on December 14, 2017.
  9. Janssen Research & Development, LLC. Daratumumab (HuMAX®-CD38) safety study in multiple myeloma. NLM Identifier: NCT00574288. Last updated on July 12, 2017. Available at: https://clinicaltrials.gov/ct2/show/NCT00574288?term=NCT00574288&rank=1. Accessed on December 14, 2017.
  10. National Comprehensive Cancer Network®. NCCN Drugs & Biologic Compendium (electronic version). For additional information visit the NCCN website: http://www.nccn.org. Accessed on December 14, 2017.
  11. NCCN Clinical Practice Guidelines in Oncology®. © 2017 National Comprehensive Cancer Network, Inc. Multiple myeloma (V.3.2018). Revised November 22, 2017. For additional information visit the NCCN website: http://www.nccn.org/index.asp. Accessed on December 14, 2017.
Websites for Additional Information
  1. American Cancer Society. Multiple myeloma. Available at: http://www.cancer.org/cancer/multiplemyeloma/index. Accessed on December 14, 2017.
  2. National Cancer Institute. Plasma cell neoplasms (including multiple myeloma treatment (PDQ®). Last modified October 20, 2017. Available at: http://www.cancer.gov/cancertopics/types/alphalist. Accessed on December 14, 2017.
Index

Daratumumab
DARZALEX

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

Document History

Status

Date

Action

Revised

01/25/2018

Medical Policy & Technology Assessment Committee (MPTAC) review.

Revised

01/17/2018

Hematology/Oncology Subcommittee review. Added MN criteria for use of daratumumab in combination with melphalan, prednisone and a proteasome inhibitor (PI) (for example, bortezomib) for newly diagnosed multiple myeloma when criteria met. Revised I/NMN statement, removing the indication for treatment used as first-line therapy. Updated Rationale, Background, References and Websites sections.

Reviewed

11/02/2017

MPTAC review.

Reviewed

11/01/2017

Hematology/Oncology Subcommittee review. The document header wording updated from “Current Effective Date” to “Publish Date”. Updated Rationale, Definitions, References and Websites sections.

Revised

08/03/2017

MPTAC review.

Revised

07/24/2017

Hematology/Oncology Subcommittee review. Added MN statement to address use of daratumumab in combination with pomalidomide and dexamethasone when criteria met. Updated Rationale, Background, References and Websites Sections. Updated Coding section to remove HCPCS C9476 deleted 12/31/2016.

Revised

11/03/2016

MPTAC review.

Revised

11/02/2016

Hematology/Oncology Subcommittee review. Reformatted MN clinical criteria section. Clarified MN criteria for daratumumab used in the treatment of individuals with multiple myeloma, including plasma-cell leukemia when criteria met. Daratumumab used as combination therapy after one prior line of therapy was added as MN when criteria met. Updated Rationale, References and Websites sections. Updated Coding section with 01/01/2017 HCPCS changes.

New

05/05/2016

MPTAC review.

New

05/04/2016

Hematology/Oncology Subcommittee review. Initial document development.

 

 

 

 

 

 

 

 

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