942 Form

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Medical Policy
Engineered T-Cell Therapy for Multiple Myeloma
Table of Contents
• Policy: Commercial
• Description
•
Information Pertaining to All Policies • Authorization Information
• Policy History
•
References
• Coding Information

Policy Number: 942
BCBSA Reference Number: 8.01.66 (For Plan internal use only)
Related Policies
• Adoptive Immunotherapy #455
• Engineered T-Cell Therapy for Multiple Myeloma Prior Authorization Request Form #943
• Chimeric Antigen Receptor Therapy for Leukemia and Lymphoma #066
Policy
Commercial Members: Managed Care (HMO and POS), PPO, and Indemnity

Idecabtagene Vicleucel (ABECMA): Multiple Myeloma
Idecabtagene vicleucel may be considered MEDICALLY NECESSARY for patients with multiple
myeloma if they meet criteria 1 through 6:

1. Are adults (age ≥18) at the time of infusion
2. Have a documented diagnosis of multiple myeloma
3. Have relapsed or refractory disease after 2 or more prior lines of therapy *, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody
4. Have adequate organ and bone marrow function as determined by the treating oncologist/hematologist
5. Does not have active infection(s) or inflammatory disorders

6. Have not received prior FDA approved, BCMA-directed, chimeric antigen receptor T therapy.

   Ciltacabtagene autoleucel (Carvykti): Multiple Myeloma
   Ciltacabtagene autoleucel may be considered MEDICALLY NECESSARY for patients with multiple
   myeloma if they meet criteria 1 through 6:

7. Are adults (age ≥18) at the time of infusion
8. Have a documented diagnosis of multiple myeloma
9. Have relapsed or refractory disease after 1 or more prior lines of therapy*, including an immunomodulatory agent, a proteasome inhibitor, and are refractory to lenalidomide
10. Have adequate organ and bone marrow function as determined by the treating oncologist/hematologist
11. Does not have active infection(s) or inflammatory disorders
12. Have not received prior FDA approved, BCMA-directed, chimeric antigen receptor T therapy.

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*Relapsed Multiple Myeloma
Relapse requires 1 or more of the following direct indicators of increasing disease and/or end organ dysfunction that are considered related to the underlying plasma cell proliferative disorder.

1. Development of new soft tissue plasmacytomas or bone lesions
2. Definite increase in the size of existing plasmacytomas or bone lesions. A definite increase is defined as a 50% (and at least 1 cm) increase as measured serially by the sum of the products of the cross- diameters of the measurable lesion
3. Hypercalcemia (>11.5 mg/dL) [2.875 mmol/L]
4. Decrease in hemoglobin of >2 g/dL [1.25 mmol/L] or to <10 g/dL
5. Rise in serum creatinine by 2 mg/dL or more [177 μmol/L or more]

6. Hyperviscosity.
   Source: 2016 International Myeloma Working Group Uniform Response Criteria for Multiple Myeloma

   *Refractory Multiple Myeloma
   Refractory multiple myeloma is defined as documented progressive disease during or within 60 days (measured from the last dose) of completing treatment with the last anti-myeloma drug regimen.
   Source: The Protocol of the pivotal KarMMa study

   Progression is defined as an increase of ≥25% from the lowest response value in any 1 or more of the following:
   • Serum M-component (the absolute increase must be ≥0.5 g/dL) and/or
   • Urine M-component (the absolute increase must be ≥200 mg/24 hour) and/or
   • Only in subjects without measurable serum and urine M-protein levels: the difference between involved and uninvolved free light chains levels (the absolute increase must be >10 mg/dL)
   • Only in subjects without measurable serum and urine M-protein levels and without measurable disease by free light chains levels: bone marrow plasma cell percentage (the absolute percentage must be ≥10%)
   • Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas
   • Development of hypercalcemia (corrected serum calcium >11.5 mg/dL) that can be attributed solely to the plasma cell proliferative disorder.
   Source: 2016 International Myeloma Working Group Uniform Response Criteria for Multiple Myeloma

   *Prior Lines of Therapies for Multiple Myeloma
   Three common classes of antimyeloma medications include anti-CD38 monoclonal antibodies (such as daratumumab or isatuximab), immunomodulatory drugs (such as thalidomide, lenalidomide, or pomalidomide) and proteasome inhibitors (such as bortezomib, carfilzomib, or ixazomib).

   All CAR-T therapies are considered INVESTIGATIONAL for all other indications.

   Prior Authorization Information
   Inpatient
   •
   For services described in this policy, precertification/preauthorization IS REQUIRED for all products if the procedure is performed inpatient.
   Outpatient
   •
   For services described in this policy, see below for products where prior authorization might be required if the procedure is performed outpatient.

   Outpatient
   Commercial Managed Care (HMO and POS)

   Prior authorization is required.
   Commercial PPO and Indemnity
   Prior authorization is required.

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Requesting Prior Authorization Using Authorization Manager
Providers will need to use Authorization Manager to submit initial authorization requests for services. Authorization Manager, available 24/7, is the quickest way to review authorization requirements, request authorizations, submit clinical documentation, check existing case status, and view/print the decision letter. For commercial members, the requests must meet medical policy guidelines.

To ensure the request is processed accurately and quickly:
• Enter the facility’s NPI or provider ID for where services are being performed.
• Enter the appropriate surgeon’s NPI or provider ID as the servicing provider, not the billing group.

Authorization Manager Resources
•
Refer to our Authorization Manager page for tips, guides, and video demonstrations.

Complete Prior Authorization Request Form for CAR T-Cell Therapy Services for Multiple Myeloma (Idecabtagene vicleucel) (943) using Authorization Manager.
For out of network providers: Requests should still be faxed to 888-973-0726.
CPT Codes / HCPCS Codes / ICD Codes
Inclusion or exclusion of a code does not constitute or imply member coverage or provider
reimbursement. Please refer to the member’s contract benefits in effect at the time of service to determine coverage or non-coverage as it applies to an individual member.

Providers should report all services using the most up-to-date industry-standard procedure, revenue, and diagnosis codes, including modifiers where applicable.
The following codes are included below for informational purposes only; this is not an all-inclusive list.

The above medical necessity criteria MUST be met for the following codes to be covered for Commercial Members: Managed Care (HMO and POS), PPO, Indemnity, Medicare HMO Blue and Medicare PPO Blue:

HCPCS Codes
HCPCS codes: Code Description
C9399
Unclassified drugs or biologicals
J3490
Unclassified drugs
J3590
Unclassified biologics
J9999
Not otherwise classified, antineoplastic drugs
Q2055
Idecabtagene vicleucel, up to 460 million autologous b-cell maturation antigen (bcma) directed car-positive t cells, including leukapheresis and dose preparation procedures, per therapeutic dose
Q2056
Ciltacabtagene autoleucel, up to 100 million autologous b-cell maturation antigen (bcma) directed car-positive t cells, including leukapheresis and dose preparation procedures, per therapeutic dose

ICD-10 Procedure Codes
ICD-10-PCS procedure codes:
Code Description

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XW033A7
Introduction of Ciltacabtagene Autoleucel into Peripheral Vein, Percutaneous Approach, New Technology Group 7
XW033K7
Introduction of Idecabtagene Vicleucel Immunotherapy into Peripheral Vein, Percutaneous Approach, New Technology Group 7
XW043A7
Introduction of Ciltacabtagene Autoleucel into Central Vein, Percutaneous Approach, New Technology Group 7
XW043K7
Introduction of Idecabtagene Vicleucel Immunotherapy into Central Vein, Percutaneous Approach, New Technology Group 7

Description
Relapsed/Refractory Multiple Myeloma
Multiple myeloma is a hematologic malignancy characterized by the abnormal growth of plasma cells with production of abnormal proteins instead of typical antibodies. Plasma cell proliferation in the marrow causes bone pain and fractures due to lytic lesions and displaces other marrow cellular elements. The majority of patients with myeloma present with symptoms related to organ involvement, including hypercalcemia, renal insufficiency, anemia, and bone lesions (known as calcium, renal failure, anemia, and bone lesions [CRAB] symptoms).1

Multiple myeloma is a relatively rare cancer with an annual incidence of approximately 7 in 100,000
Americans. It is estimated that 32,270 new cases of multiple myeloma were diagnosed in 2020 and 150,000 Americans are currently living with the disease.2 The American Cancer Society estimated that there will be approximately 34,920 new cases of multiple myeloma with 12,410 deaths in the United States in 2021.3

Multiple myeloma is primarily a disease of older adults, with a median age at diagnosis of 69. AfricanAmericans appear to be at approximately twice the risk of white Americans, while Asian-Americans appear to be at lower risk.2 The risk for developing multiple myeloma is unusually high in individuals with a history of monoclonal gammopathy of undetermined significance, a benign presence of abnormal monoclonal proteins in the blood. Such individuals are likely to develop multiple myeloma or a related malignancy at a rate of 1% per year.4

Diagnosis
Relapsed or refractory multiple myeloma is commonly identified through routine monitoring with laboratory studies using the standard 2016 International Myeloma Working Group response criteria for categorizing progression and relapse.5 Progression is usually identified by a rise in monoclonal (M) protein in the serum or urine or in the serum free light chain ratio. Not all patients with progression on laboratory testing need immediate treatment. Therapy is indicated if there is a clinical relapse, extramedullary disease, or a rapid rise in paraproteins.

Current Treatment
The majority of patients with multiple myeloma respond to initial therapies that consist of combination treatments and autologous stem cell transplant. However, conventional therapy is not curative and most of these patients will ultimately progress. A small proportion of patients do not respond to initial treatment (i.e., refractory disease).

There is no single standard treatment for patients with relapsed/refractory multiple myeloma and multiple treatment options are used. Most patients experience serial relapse and are treated with the majority of available agents at some point during their disease course. The main pharmacological medications used are monoclonal antibodies (daratumumab, elotuzumab, isatuximab), proteasome inhibitors (bortezomib, carfilzomib, ixazomib), immunomodulatory drugs (lenalidomide, pomalidomide, thalidomide), alkylators, anthracyclines, panobinostat, selinexor, and corticosteroids. A preferred order for their use has not been established. The choice of therapy at each relapse is informed by prior therapies used, response to these

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treatments, comorbidities, risk stratification, and the location of disease (e.g., extramedullary disease). Three-drug regimens are preferred over 2-drug regimens. However, 2-drug regimens are acceptable alternatives for frail patients who may not be able to tolerate 3-drug regimens. According to the most recent NCCN clinical practice guideline (version 5, 2021), the triplet regimen including dexamethasone combined with a proteasome inhibitor, an immunomodulatory agent, or an anti-CD38 monoclonal antibody should be used as a primary standard therapy for multiple myeloma (category 2A recommendation).6

Patients with myeloma who have been treated with the 3 main backbones of interventional therapy
(proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies) have poor outcomes to subsequent treatment. Patients with heavily pretreated multiple myeloma that are daratumumab refractory have an expected median overall survival ranging from 6.6 to 9.3 months. Reported median progression- free survival for this population is 2.3 to 3.4 months.7,8 In the observational MAMMOTH study, among participants with triple-class refractory multiple myeloma on current therapies, the overall response rate was 31% with a median progression-free survival of 3.4 months.8

A summary of side-by-side comparisons of pivotal studies of 3 new treatments targeting the BCMA pathway for heavily pre-treated patients with relapsed refractory multiple myeloma patients who have cycled through numerous previous lines of therapy is provided in Table 1.

Table 1. Summary of Treatments Targeting BCMA Pathway for Relapsed Refractory Multiple Myeloma

Idecabtagene vicleucel 10,11,12
Ciltacabtagene autoleucel13
FDA status
Approved March 26, 2021
Approved February 28th 2022

Proposed/Approv ed Indication
Treatment of adult individuals with relapsed and/or refractory multiple myeloma who have received at least 3 prior therapies.
Treatment of adult individuals with relapsed and/or refractory multiple myeloma who have received at least 3 prior therapies.
Limitation of use
Black box warning due to the risk of cytokine release syndrome, neurologic toxicity,
hemophagocytic lymphohistiocytosis/macroph age activation syndrome, and prolonged cytopenia
Black box warning due to the risk of cytokine release syndrome, neurologic toxicity,
hemophagocytic lymphohistiocytosis/macroph age activation syndrome, and prolonged cytopenia
Pivotal Trials
KarMMa (NCT03361748)
CARTITUDE (NCT03548207)
Design
Single-arm, open-label
Single-arm, open-label
Key eligibility criteria Received at least 2 cycles of ≥3 prior treatment regimens (incl. PI, IMiD, anti- CD38 antibody) and refractory to the last regimen
Received ≥3 prior treatment regimens (incl. PI, IMiD, antiCD38 antibody) or are double
refractory to a PI and IMiD

Population
Mostly triple-class refractory
Mostly triple-class refractory

N
128
126
Follow-up
Duration
13.3 months
12.4 months

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Efficacy %

OR (as treated)
OR (ITT)

72%
63%
97%
75%
Median PFS or OS As-treated PFS = 8.9 months
As treated KM estimated OS = 19.4 months
As-treated PFS >12.4 months
Toxicity
51% CRS Grade 2+
44% CRS Grade 2+
6% Treatment-related deaths

Summary
Multiple myeloma is a hematologic malignancy characterized by abnormal growth of plasma cells with production of abnormal proteins instead of typical antibodies. Plasma cell proliferation in the marrow causes bone pain and fractures due to lytic lesions and displaces other marrow cellular elements. An increase in total or monoclonal proteins can have direct toxic effects on the kidney, resulting in worsening renal function, hypercalcemia, and anemia. Treatment of multiple myeloma includes immunomodulatory agents (thalidomide, lenalidomide, or pomalidomide), proteasome inhibitors (bortezomib, carfilzomib, or ixazomib) and anti-CD38 monoclonal antibodies (daratumumab or isatuximab). While multiple combinations of these agents can lead to remission, most patients eventually relapse. Idecabtagene vicleucel is a B-cell maturation antigen (BCMA) targeting chimeric antigen receptor (CAR) T-cell therapy for the treatment of individuals with relapsed and/or refractory multiple myeloma who have received at least 4 prior therapies.

Summary of Evidence
For individuals who are adults with relapsed and/or refractory multiple myeloma and have received 4 or more prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an antiCD38 monoclonal antibody, the evidence includes 1 single-arm prospective trial. Relevant outcomes are overall survival, disease-specific survival, quality of life, and treatment-related mortality and morbidity. The KarMMa study was a Phase 2, multicenter, open label study that enrolled adult patients with relapsed or refractory multiple myeloma who received at least 3 different prior lines of therapy including proteasome inhibitors, immunomodulatory agents, and anti-CD38 monoclonal antibodies. A Food and Drug
Administration analysis included data from 100 patients who received idecabtagene vicleucel in the dose range of 300 x 106 and 450 x 106. The primary end point was an overall response (partial response or better). After a median follow-up of 10.7 months, results showed an overall response rate of 72% and stringent complete responses in 28% of patients. The median time to response was 30 days, and the median duration of response was 11 months, increasing to 19 months for patients who achieved stringent complete responses. Minimal residual disease-negative status (<10−5 nucleated cells) was achieved in 21% of all treated patients and 75% of all patients with a complete response or stringent complete response. In the absence of a randomized controlled trial, it is difficult to draw comparisons with currently available salvage treatment. Historically, in patients with relapsed/refractory multiple myeloma who have disease progression despite receiving the 3 main classes of myeloma therapy, outcomes are poor. Complete responses are infrequent with reported median progression-free survival ranging from 3 to 4 months, and a median overall survival of 8 to 9 months. With idecabtagene vicleucel, any grade cytokine release syndrome occurred in 85% of patients, and grade ≥3 cytokine release syndrome occurred in 9%
of patients. Neurotoxicity occurred in 28% of patients, reaching grade ≥3 severity in 4% of patients. Notable limitations of the KarMMa study included lack of an intention-to-treat analysis and a relatively short follow-up period to assess safety and efficacy. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

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For individuals who are adults with relapsed and/or refractory multiple myeloma and have received 4 or more prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an antiCD38 monoclonal antibody, the evidence includes 1 single-arm prospective trial. Relevant outcomes are overall survival, disease-specific survival, quality of life, and treatment-related mortality and morbidity. The CARTITUDE 1 study was a Phase 2, multicenter, open label study that enrolled adult patients with relapsed or refractory multiple myeloma who received at least 3 different prior lines of therapy including proteasome inhibitors, immunomodulatory agents, and anti-CD38 monoclonal antibodies. A Food and Drug Administration analysis included data from 97 patients who received ciltacabtagene autoleucel in the dose range of 0.5-1.0x106 and 1 x 108. The primary end point was an overall response (partial response or better). After a median follow-up of 18 months, results showed an overall response rate of 97% and stringent complete responses in 78% of patients. The median time to response was 30 days, and the median duration of response was 18 months, increasing to 21.8 months for patients who achieved stringent complete responses. In the absence of a randomized controlled trial, it is difficult to draw comparisons with currently available salvage treatment. Historically, in patients with relapsed/refractory multiple myeloma who have disease progression despite receiving the 3 main classes of myeloma therapy, outcomes are poor. Complete responses are infrequent with reported median progression-free survival ranging from 3 to 4 months, and a median overall survival of 8 to 9 months. With ciltacabtagene autoleucel, any grade cytokine release syndrome occurred in 95% of patients.
Neurotoxicity occurred in 26% of patients. Notable limitations of the CARTITUDE 1 study included lack of an intention-to-treat analysis and a relatively short follow-up period to assess safety and efficacy. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Policy History
Date
Action
6/2025 Updated policy name to streamline all CAR-T MP titles. Updated Idecabtagene criteria, removed belantamab due to removal of FDA indication. 1/2025
Ciltacabtagene autoleucel (Carvykti) criteria #3 clarified.
3/2024
Clarified coding information.
9/2023
Policy clarified to include prior authorization requests using Authorization Manager.
10/2022
New medically necessary indications added for Ciltacabtagene autoleucel. FDA approved February 28th 2022. Clarified coding information. 10/1/2022.
7/2022
Clarified coding information.
1/2022
Clarified coding information.
10/2021
Clarified coding information.
6/2021
New medical policy describing medically necessary indications. Effective 6/4/2021.
Information Pertaining to All Blue Cross Blue Shield Medical Policies
Click on any of the following terms to access the relevant information:
Medical Policy Terms of Use
Managed Care Guidelines
Indemnity/PPO Guidelines
Clinical Exception Process
Medical Technology Assessment Guidelines

References

1. Mikhael J, Ismaila N, Cheung MC, et al. Treatment of Multiple Myeloma: ASCO and CCO Joint Clinical Practice Guideline. J Clin Oncol. May 10 2019; 37(14): 1228-1263. PMID 30932732
2. National Cancer Institute. Cancer Stat Facts: Myeloma..
   https://seer.cancer.gov/statfacts/html/mulmy.html. Accessed April 5, 2021.
3. Key Statistics About Multiple Myeloma. https://www.cancer.org/cancer/multiple- myeloma/about/keystatistics.html. Accessed April 5, 2021.

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4. Manier S, Salem KZ, Liu D, et al. Future Directions in the Evaluation and Treatment of Precursor Plasma Cell Disorders. Am Soc Clin Oncol Educ Book. 2016; 35: e400-6. PMID 27249747
5. Kumar S, Paiva B, Anderson KC, et al. International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol. Aug 2016; 17(8): e328-e346. PMID 27511158
6. NCCN Clinical Practice Guidelines in Oncology- Multiple Myeloma Version 5.2021- March 15, 2021. https://www.nccn.org/professionals/physician_gls/pdf/myeloma.pdf. Accessed April 5, 2021.
7. Pick M, Vainstein V, Goldschmidt N, et al. Daratumumab resistance is frequent in advanced-stage multiple myeloma patients irrespective of CD38 expression and is related to dismal prognosis. Eur J Haematol. May 2018; 100(5): 494-501. PMID 29453884
8. Gandhi UH, Cornell RF, Lakshman A, et al. Outcomes of patients with multiple myeloma refractory to CD38-targeted monoclonal antibody therapy. Leukemia. Sep 2019; 33(9): 2266-2275. PMID 30858549
9. Prescribing Label: Abecma (idecabtagene vicleucel), suspension for intravenous infusion. Available at https://packageinserts.bms.com/pi/pi_abecma.pdf. Accessed on April 6, 2021
10. Munshi NC, Anderson LD, Shah N, et al. Idecabtagene Vicleucel in Relapsed and Refractory Multiple Myeloma. N Engl J Med. Feb 25 2021; 384(8): 705-716. PMID 33626253
11. Institute for Clinical and Economic Review. Evidence Report: Anti B-Cell Maturation Antigen CAR Tcell and Antibody Drug Conjugate Therapy for Heavily Pre-Treated Relapsed and Refractory Multiple Myeloma. April 5, 2021 https://34eyj51jerf417itp82ufdoe-wpengine.netdna- ssl.com/wpcontent/uploads/2020/10/ICERMultiple-MyelomaEvidence-Report_040521.pdf. Accessed April 5, 2021.
12. Janssen Press Release, Dec 5, 2020. Early, Deep, Durable Responses of Ciltacabtagene Autoleucel
    (cilta-cel) Observed in Phase 1b/2 CARTITUDE-1 Study Show Potential of BCMA CAR-T in Treatment of Heavily Pretreated Patients with Multiple Myeloma. https://www.janssen.com/earlydeep- durable-responses-ciltacabtagene-autoleucel-cilta-cel-observed-phase-1b2-cartitude-1. Accessed April 7, 2021.
13. Madduri, D., Berdeja, M.D, Usmani, S., et al. CARTITUDE-1: Phase 1b/2 Study of Ciltacabtagene Autoleucel, a B-Cell Maturation Antigen-Directed Chimeric Antigen Receptor T Cell Therapy, in Relapsed/Refractory. American Society of Hematology. 136(1). August 3, 2021.
14. Holstein SA, Suman VJ, McCarthy PL. Should Overall Survival Remain an Endpoint for Multiple Myeloma Trials?. Curr Hematol Malig Rep. Feb 2019; 14(1): 31-38. PMID 30661162
15. Cartier S, Zhang B, Rosen VM, et al. Relationship between treatment effects on progression-free survival and overall survival in multiple myeloma: a systematic review and meta-analysis of published clinical trial data. Oncol Res Treat. 2015; 38(3): 88-94. PMID 25792079
16. Lee DW, Gardner R, Porter DL, et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood. Jul 10 2014; 124(2): 188-95. PMID 24876563