Medical Policy Medical Policy
Policy Num: 05.002.001
Policy Name: Chimeric Antigen Receptor Therapy for Multiple Myeloma
Policy ID: [05.002.001] [Ac / B / M+ / P+] [8.01.66]
Last Review: January 15, 2025
Next Review: August 20, 2025
Related Policies:
08.001.053 - Chimeric Antigen Receptor Therapy for Leukemia and Lymphoma
| Population Reference No. | Populations | Interventions | Comparators | Outcomes |
| 1 | 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 anti-CD38 monoclonal antibody | Interventions of interest are: · Idecabtagene vicleucel | Comparators of interest are: · Standard of care (e.g., immunomodulatory agents, proteasome inhibitors, and anti-CD38 monoclonal antibodies) | Relevant outcomes include: · Overall survival · Disease-specific survival · Quality of life · Treatment-related mortality · Treatment-related morbidity |
| 2 | 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 anti-CD38 monoclonal antibody | Interventions of interest are: · Ciltacabtagene autoleucel | Comparators of interest are: · Standard of care (e.g., immunomodulatory agents, proteasome inhibitors, and anti-CD38 monoclonal antibodies) | Relevant outcomes include: · Overall survival · Disease-specific survival · Quality of life · Treatment-related mortality · Treatment-related morbidity |
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 and ciltacabtagene autoleucel are B-cell maturation antigen (BCMA) targeting chimeric antigen receptor (CAR) T-cell therapies for the treatment of individuals with relapsed and/or refractory multiple myeloma who have received at least 4 prior therapies.
For individuals who are adults with relapsed and/or refractory multiple myeloma previously treated with4 or more prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody who receive idecabtagene vicleucel, 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 endpoint 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 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.
For individuals who are adults with relapsed and/or refractory multiple myeloma previously treated with 4 or more prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody, who receive ciltacabtagene autoleucel, 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 1b/2 multicenter open-label study that enrolled adult patients with relapsed or refractory multiple myeloma who had received at least 3 different prior lines of therapy including proteasome inhibitors, immunomodulatory agents, and anti-CD38 monoclonal antibodies. The primary endpoint was overall response (partial response or better). After a median follow-up of 18 months, the primary efficacy analysis demonstrated an overall response rate of 98% (95 of 97) with a 78% rate of stringent complete response. In the absence of a randomized controlled trial, it is difficult to draw comparisons with currently available treatments. 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. Notable adverse events of grades 3-4 among 97 patients who received ciltacabtagene autoleucel included neutropenia (95%), anemia (68%), leukopenia (61%), thrombocytopenia (60%), and lymphopenia (50%). Any grade cytokine release syndrome and neurotoxicity were observed in 95% and 26% of patients, respectively. Grade 3 to 4 cytokine release syndrome and neurotoxicity were observed in 5% and 11% of patients, respectively. A notable limitation of the CARTITUDE-1 study included 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.
Not applicable.
The objective of this evidence review is to assess whether treatment with idecabtagene vicleucel and ciltacabtagene autoleucel improves the net health outcome in adult patients with relapsed and/or refractory multiple myeloma who have received 4 or more prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody.
Idecabtagene vicleucel may be considered medically necessary for individuals with multiple myeloma if they meet criteria 1 through 6:
Are adults (age ≥22) at the time of infusion.
Have a documented diagnosis of multiple myeloma.
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 (see Policy Guidelines).
Have adequate organ and bone marrow function as determined by the treating oncologist/hematologist.
Does not have active infection(s) or inflammatory disorders.
Have not received prior chimeric antigen receptor T therapy or any other gene therapy and are not being considered for treatment with any other cell or gene therapy.
Ciltacabtagene autoleucel may be considered medically necessary for individuals with multiple myeloma if they meet criteria 1 through 6:
Are adults (age ≥22) at the time of infusion.
Have a documented diagnosis of multiple myeloma.
Have relapsed or refractory disease and have received at least 1 prior line of therapy, including a proteasome inhibitor and an immunomodulatory agent, and are refractory to lenalidomide.
Does not have active infection(s) or inflammatory disorders.
Have not received prior chimeric antigen receptor T therapy or any other gene therapy and are not being considered for treatment with any other cell or gene therapy.
Idecabtagene vicleucel and ciltacabtagene autoleucel are considered investigational when the above criteria are not met.
Idecabtagene vicleucel and ciltacabtagene autoleucel are considered investigational for all other indications.
Idecabtagene vicleucel: Recommended dose range is 300 to 510 × 106 chimeric antigen receptor-positive viable T cells intravenously.
Ciltacabtagene autoleucel: Recommended dose range is 0.5 to 1.0 × 106 chimeric antigen receptor-positive viable T cells per kg of body weight with a maximum dose of 1 × 108 chimeric antigen receptor-positive viable T cells per single infusion.
1 injection per lifetime
Idecabtagene vicleucel (Abecma®) has a boxed warning because of the risks of cytokine release syndrome, neurologic toxicity, hemophagocytic lymphohistiocytosis/macrophage activation syndrome, prolonged cytopenia and T-cell malignancies. Idecabtagene vicleucel should not be administered to individuals with an active infection or inflammatory disorders. It is recommended that severe or life-threatening cytokine release syndrome be treated with tocilizumab or tocilizumab and corticosteroids. Individuals should be monitored for neurologic events after treatment.
Idecabtagene vicleucel is available only through a restricted program under a risk evaluation and mitigation strategy (REMS) called the Abecma REMS. The requirements for the REMS components are as follows:
Health care facilities that dispense and administer this CAR T therapy must be enrolled and comply with the REMS requirements.
Certified health care facilities must have onsite, immediate access to tocilizumab, and ensure that a minimum of 2 doses of tocilizumab are available for each individual for administration within 2 hours after infusion of this CAR T therapy, if needed for treatment of cytokine release syndrome.
Certified health care facilities must ensure that health care providers who prescribe, dispense, or administer these CAR T therapies are trained to manage cytokine release syndrome and neurologic toxicities.
Ciltacabtagene autoleucel (Carvykti®) has a boxed warning because of the risks of cytokine release syndrome, Immune Effector Cell-Associated Neurotoxicity Syndrome , parkinsonism/Guillain-Barré, hemophagocytic lymphohistiocytosis/macrophage activation syndrome, recurrent and prolonged cytopenia and secondary hematological malignancies. Ciltacabtagene autoleucel should not be administered to individuals with an active infection or inflammatory disorders. It is recommended that severe or life-threatening cytokine release syndrome be treated with tocilizumab or tocilizumab and corticosteroids. Individuals should be monitored for neurologic events after treatment.
Ciltacabtagene autoleucel is available only through a restricted program under a REMS called the Carvykti REMS. The requirements for the REMS components are similar to the Abecma REMS.
As per the 2016 International Myeloma Working Group Uniform Response Criteria for 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.
Development of new soft tissue plasmacytomas or bone lesions
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
Hypercalcemia (>11.5 mg/dL) [2.875 mmol/L]
Decrease in hemoglobin of >2 g/dL [1.25 mmol/L] or to <10 g/dL
Rise in serum creatinine by 2 mg/dL or more [177 μmol/L or more]
Hyperviscosity
In the protocol of the pivotal KarMMa and CARTITUDE-1 studies, refractory multiple myeloma was 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. As per the 2016 International Myeloma Working Group Uniform Response Criteria for Multiple Myeloma, 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
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).
See the Codes table for details.
BlueCard/National Account Issues
State or federal mandates (eg, Federal Employee Program) may dictate that certain U.S. Food and Drug Administration (FDA) approved devices, drugs, or biologics may not be considered investigational, and thus these devices may be assessed only by their medical necessity.
Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered. Benefit products or negotiated coverages may have all or some of the services discussed in this medical policy excluded from their coverage.
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. Most 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.
Multiple myeloma is primarily a disease of older adults, with a median age at diagnosis of 69. African Americans are at twice the risk of white Americans, while Asian-Americans are 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.3,
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.4, 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.
Most patients with multiple myeloma respond to initial therapies that consist of combination treatments and autologous stem cell transplants. However, conventional therapy is not curative and most of these patients will 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 many 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 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 National Comprehensive Cancer Network (NCCN) clinical practice guideline (version 2.2024), the triplet regimen including dexamethasone combined with a proteasome inhibitor, an immunomodulatory agent, or an anti-CD38 monoclonal antibody should be used as primary standard therapy for multiple myeloma (category 2A recommendation).5,
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.6,7, 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.7, Currently, belantamab mafodotin is the only U.S. Food and Drug Administration (FDA)-approved single-agent treatment for patients who have received at least 4 prior therapies including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent. Belantamab is an anti-B-cell maturation antigen (BCMA) humanized immunoglobulin G (IgG) antibody conjugated to an antineoplastic agent, monomethyl auristatin. This indication received accelerated approval based on response rate and continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. An overall response rate in the pivotal DREAMM-2 trial was achieved in 30 of 97 patients studied (31%, 95% confidence interval [CI]: 21 to 43%). The median time to first response was 1.4 months (95% CI: 1.0 to 1.6) and 73% of responders had a duration of response ≥6 months.8,
On March 26, 2021, idecabtagene vicleucel (Abecma) was approved by the FDA for the treatment of adult patients with relapsed or refractory multiple myeloma after 4 or more prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody.
On February 28, 2022, ciltacabtagene autoleucel (Carvykti) was approved by the FDA for the treatment of adult patients with relapsed or refractory multiple myeloma after 4 or more prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody.
This evidence review was created in April 2021 with searches of the PubMed database. The most recent literature update was performed through November 16, 2024.
Evidence reviews assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are length of life, quality of life, and ability to function including benefits and harms. Every clinical condition has specific outcomes that are important to patients and to managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.
To assess whether the evidence is sufficient to draw conclusions about the net health outcome of a technology, 2 domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent 1 or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. Randomized controlled trials are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.
Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., People of Color [African-American, Asian, Black, Latino and Native American]; LGBTQIA (Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, Asexual); Women; and People with Disabilities [Physical and Invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.
Population Reference No. 1
The purpose of the intervention is to provide a treatment option that is an alternative to or an improvement on existing therapies for patients with relapsed and/or refractory multiple myeloma who have received 4 or more prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody.
The following PICO was used to select literature to inform this review.
The relevant population of interest is individuals with relapsed and/or refractory multiple myeloma who have received 4 or more prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody.
The therapy being considered is idecabtagene vicleucel and ciltacabtagene autoleucel, B-cell maturation antigen (BCMA) CAR T-cell therapies. Manufacturing of CAR T-cells involves leukapheresis for harvesting T lymphocytes, modification of lymphocytes with a lentiviral vector containing an anti-BCMA antibody, and expansion of modified CAR T-cells. The final therapy is designed to recognize and bind to BCMA on the surface of multiple myeloma cells leading to apoptosis. Prior to the infusion, patients receive lymphodepletion therapy that includes fludarabine and cyclophosphamide.
The following practice is currently being used to treat relapsed/refractory multiple myeloma. 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 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.
The general outcomes of interest are overall survival, disease-specific survival, quality of life, treatment-related mortality, and treatment-related morbidity.
Historically, overall survival has been the standard endpoint for demonstrating clinical benefit for phase III RCTs in oncology. However, use of overall survival as the primary endpoint typically requires large sample sizes and prolonged follow-up. Further, use of multiple subsequent therapies in multiple myeloma after relapse can confound the interpretation of the overall survival results. Most recent FDA approvals for multiple myeloma have used time to progression or progression-free survival as a primary endpoint.10, Cartier et al (2015) published the findings of a meta-analysis of 21 myeloma RCTs (14 first-line, 4 maintenance, and 3 relapsed/refractory) using trial-level data and reported a moderate-to-strong positive correlation between hazard ratios for treatment effects for progression-free survival and overall survival and advocated that patient-level data be used to validate these findings.11,
The 2016 International Myeloma Working Group response criteria is the standard response criteria used for multiple myeloma and are summarized in Table 1.
| Response Category | Description |
| Stringent complete response | Complete response as defined below plus normal free light chain ratioa and absence of clonal cells in bone marrow biopsy by immunohistochemistry (κ/λ ratio ≤4:1 or ≥1:2 for κ and λ patients, respectively, after counting ≥100 plasma cells)b. |
| Complete response | Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and <5% plasma cells in bone marrow aspirates. |
| Very good partial response | Serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum M-protein plus urine M-protein level <100 mg per 24 hours. In patients in whom the only measurable disease is by serum free light chain levels: a >90% decrease in the difference between involved and uninvolved free light chain levels. |
| Partial response | ≥50% reduction of serum M-protein plus reduction in 24-hour urinary M-protein by ≥90% or to <200 mg per 24 hours. If the serum and urine M-protein are unmeasurable, a ≥50% decrease in the difference between involved and uninvolved free light chain levels is required in place of the M-protein criteria. If serum and urine M-protein are unmeasurable, and serum-free light assay is also unmeasurable, ≥50% reduction in plasma cells is required in place of M-protein, provided baseline bone marrow plasma-cell percentage was ≥30%. In addition to these criteria, if present at baseline, a ≥50% reduction in the size (SPD)c of soft tissue plasmacytomas is also required. |
| Minimal response | ≥25% but ≤49% reduction of serum M-protein and reduction in 24-hour urine M-protein by 50% to 89%. In addition to the above-listed criteria, if present at baseline, a ≥50% reduction in the size (SPD)c of soft tissue plasmacytomas is also required. |
| Stable disease | Not recommended for use as an indicator of response; stability of disease is best described by providing the time-to-progression estimates. Not meeting criteria for complete response, very good partial response, partial response, minimal response, or progressive disease. |
| Progressive Diseased | Increase of ≥25% from lowest response value in any 1 or more of the following:
|
| Relapse | Clinical 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.d
|
CR: complete response; FLC: free light chains; IMWG: International Myeloma Working Group; SPD: sum of the products of the maximal perpendicular diameters of measured lesions. a All recommendations regarding clinical uses relating to serum free light chain levels or free light chain ratio are based on results obtained with the validated Freelite test (Binding Site, Birmingham, UK). b Presence/absence of clonal cells on immunohistochemistry is based upon the κ/λ/L ratio. An abnormal κ/λ ratio by immunohistochemistry requires a minimum of 100 plasma cells for analysis. An abnormal ratio reflecting presence of an abnormal clone is κ/λ of >4:1 or <1:2. c Plasmacytoma measurements should be taken from the computed tomography portion of the positron emission tomography/computed tomography, or magnetic resonance imaging scans, or dedicated computed tomography scans where applicable. For patients with only skin involvement, skin lesions should be measured with a ruler. Measurement of tumor size will be determined by the SPD. d All response categories require 2 consecutive assessments made at any time before classification as relapse or disease progression and/or the institution of any new therapy. In the IMWG criteria, CR subjects must also meet the criteria for progressive disease shown here to be classified as progressive disease for the purposes of calculating time to progression and progression-free survival. The definitions of relapse, clinical relapse, and relapse from CR are not to be used in calculation of time to progression or progression-free survival. e For progressive disease, serum M-component increases of ≥1 gm/dL are sufficient to define relapse if starting M-component is ≥5 g/dL.
Methodologically credible studies were selected using the following principles:
To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;
In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
Studies with duplicative or overlapping populations were excluded.
The clinical development program for idecabtagene vicleucel for relapsed/refractory multiple myeloma includes two open-label trials- KarMMa (a single-arm trial) and KarMMa-3 (an RCT). While KarMMa included patients after 3 or more prior lines of therapy, KarMMa-3 enrolled patients after 2 to 4 prior lines of therapy. Characteristics and results are summarized in Tables 2 and 3, respectively. In KarMMa, the primary endpoint was an overall response (partial response or better); a key secondary endpoint was a complete response or better (comprising complete and stringent complete responses). Responses were defined according to the 2016 International Myeloma Working Group uniform response criteria for multiple myeloma (See Table 1 for details). In KarMMa-3, the primary efficacy measure was progression free survival as determined by Independent Review Committee based on the 2016 International Myeloma Working Group uniform response criteria for multiple myeloma.
FDA analysis included data from 100 patients who received idecabtagene vicleucel in the dose range of 300 x 106 and 450 x 106. Patients were hospitalized for 14 days after infusion of idecabtagene vicleucel to monitor for potential cytokine release syndrome, hemophagocytic lymphohistiocytosis/macrophage activation syndrome, and neurotoxicity.11, After a median follow-up of 10.7 months, overall response was 72% (95% confidence interval [CI]: 62 to 81) with a 28% (95% CI: 19 to 38) rate of stringent complete response. Minimal residual disease (MRD)-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. Response durations were longer in patients who achieved a stringent complete response as compared to patients with a partial response or very good partial response. Of the 28 patients who achieved a stringent complete response, it is estimated that 65% (95% CI: 42%, 81%) had a remission lasting at least 12 months.11, Outcomes on health-related quality of life (HRQoL) using the European Organization for Research and Treatment of Cancer Quality of Life C30 Questionnaire and its supplementary 20-item multiple myeloma module, as well as the EuroQol 5-dimension 5-level instrument were reported.12, Mean changes from baseline that exceeded the predetermined threshold of minimally important difference were deemed clinically meaningful. A total of 126 (98%) of 128 patients treated with idecabtagene vicleucel were included. Statistically significant and clinically meaningful improvements from baseline were observed by month 1 for pain (-8.9) and disease symptoms (-10.2), and by month 2 for fatigue (-7.2), physical functioning (6.1), cognitive functioning (6.7), and global health status/QoL (8.0). Clinically meaningful improvements in fatigue, pain, and physical functioning were most prominent at months 9, 12, and 18, respectively, and were sustained through 15 to 18 months after idecabtagene vicleucel treatment.
In KarMMa-3, 386 individuals were randomized 2:1 to receive either idecabtagene vicleucel (n=254) or standard regimens (n= 132). The estimated median duration of follow-up reported in the FDA analysis was 15.9 months.11, The peer reviewed publications have reported data after a median follow-up of 18.6 months13, and 30.9 month.14, After a median follow-up of 15.9 months, the median progression-free survival was 13.3 months in the idecabtagene vicleucel group, as compared with 4.4 months in the standard-regimen group (hazard ratio for disease progression or death, 0.49. A response occurred in 71% of the patients in the idecabtagene vicleucel group and in 42% of those in the standard-regimen group (p<0.001); a complete response occurred in 39% and 5%, respectively. Data on overall survival were immature at the time of interim analysis. At final PFS analysis (median follow-up, 30.9 months), idecabtagene vicleucel further improved median PFS vs standard regimens (13.8 vs 4.4 months; HR=0.49; 95% CI, 0.38 to 0.63). PFS benefit was observed regardless of number of prior lines of therapy, with greatest benefit after 2 prior lines (16.2 vs 4.8 months, respectively).14, Patient-centric design allowed crossover from standard regimen (56%) to idecabtagene vicleucel upon progressive disease, confounding interpretation of overall survival.
Idecabtagene vicleucel carries a boxed warning due to the risk of cytokine release syndrome, neurologic toxicity, hemophagocytic lymphohistiocytosis/macrophage activation syndrome, prolonged cytopenia and T cell malignancies. In the two pivotal trials (n=349), CRS occurred in 89% (310/349), including ≥Grade 3 CRS (Lee grading system) in 7% (23/349) of patients and Grade 5 CRS in 0.9% (3/349) of patients. The median time-to-onset of CRS, any grade, was 1 day (range: 1 to 27 days), and the median duration of CRS was 5 days (range: 1 to 63 days). Neurologic toxicities, including immune-effector cell-associated neurotoxicity, which may be severe or life-threatening, occurred concurrently with CRS, after CRS resolution, or in the absence of CRS following treatment with Idecabtagene vicleucel. In the two pivotal trials (n=349), CAR T cell associated neurotoxicity occurred in 40% (139/349), including Grade 3 in 4% (14/349) and Grade 4 in 0.6% (2/349) of patients. The median time to onset of neurotoxicity was 2 days (range: 1 to 148 days). The median duration was 8 days (range: 1 to 720 days). Hemophagocytic lymphohistiocytosis/macrophage activation syndrome occurred in 2.9% (10/349) of patients. All events had onset within 10 days of receiving Idecabtagene vicleucel, with a median onset of 6.5 days (range: 4 to 10 days) and occurred in the setting of ongoing or worsening CRS. Patients may develop secondary malignancies. In KarMMa-3, myeloid neoplasms (four cases of myelodysplastic syndrome and one case of acute myeloid leukemia) occurred in 2.2% (5/222).11,
| Study | Study Type | Country | Dates | Participants | Treatment | Follow-Up |
| KarMMa (NCT03361748)11, | Open-label, Single-arm | Global (24 sites) | 2017-2018 | Adults with a diagnosis of RRMM and at least 3 prior lines of therapy including PI, IMiD, and an anti-CD38 antibody (≥2 consecutive cycles of treatment for each regimen)
| Patient disposition
| 10.7 months |
| KarMMa-3 (NCT03651128)11, | Open-label RCT | Global (49 sites) | 2019-2022 | Adults with a diagnosis of RRMM and who have received two to four prior therapies including an immunomodulatory agent, a proteasome inhibitor and daratumumab
| 386 individuals were randomized 2:1 to receive either idecabtagene vicleucel (N = 254) or standard regimensj (N = 132). Randomization was stratified by age, number of prior antimyeloma regimens, and presence of high-risk cytogenetics abnormalities. Patient disposition
| 15.9 months |
CAR: chimeric antigen receptor; CNS: central nervous system; ECOG: Eastern Cooperative Oncology Group; IMiD: immunomodulatory agents (e.g., lenalidomide or pomalidomide); ISS: International Staging System; PI: proteasome inhibitors (e.g., bortezomib or carfilzomib); RRMM: relapsed/refractory multiple myeloma. a 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 before study entry. b At least 1 of the following: serum M-protein ≥1.0 g/dL or urine M-protein ≥200 mg/24 h or serum free light chain level ≥10 mg/dL (100 mg/L) provided serum free light chain ratio is abnormal. c Selective exclusion criteria included known CNS involvement with myeloma disease, presence of plasma cell leukemia, those with solitary plasmacytomas without other evidence of measurable disease, creatinine clearance of less than or equal to 45 mL/minute, alanine aminotransferase >2.5 times upper limit of normal, left ventricular ejection fraction <45%, absolute neutrophil count <1000 cells/mm3 and platelet count <50,000/mm3. d Cytogenetic abnormality defined as presence of t(4:14), t(14:16), and 17p13 del. e Refractory to a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody. f Refractory to 2 proteasome inhibitors, 2 immunomodulatory drugs, and an anti-CD38 monoclonal antibody. g For 300 x 106 and 450 x 106 CAR-positive T cell dose cohorts. h Due to death (n=2), adverse event (n=1), disease progression (n=1), consent withdrawal (n=3), physician decision (n=3), or manufacturing failure (n=1). i Serum creatinine clearance <45 mL/min, serum aspartate aminotransferase or alanine aminotransferase >2.5 times upper limit of normal, left ventricular ejection fraction <45%, absolute neutrophil count <1000/μL and platelet count <75,000/μL in patients in whom <50% of bone marrow nucleated cells are plasma cells and platelet count <50,000/μL in patients in whom ≥50% of bone marrow nucleated cells are plasma cells. j The standard regimens consisted of daratumumab, pomalidomide, dexamethasone [DPd], daratumumab, bortezomib, dexamethasone [DVd], ixazomib, lenalidomide, dexamethasone [IRd], carfilzomib, dexamethasone [Kd], or elotuzumab, pomalidomide, dexamethasone [EPd]), selected by Investigator prior to randomization contingent upon the patient’s most recent antimyeloma treatment.
| Study | Responsea, % | Median Duration of Response, months (95% CI) | Progression-free Survival, months (95% CI) | Overall Survival, months (95% CI) |
| KarMMa, FDA Prescribing Label11, | ||||
| 300 to 460 x 106 CAR T-cells (n=100) | OR=72% (95% CI: 62 to 81) sCR=28% (95% CI: 19 to 38) VGPR=25% (95% CI: 17 to 35) PR=19% (95% CI: 12 to 28) | OR: 11 (10.3 to 11.4) sCR: 19 (11.4 to NE) VGPR: 11.1 (8.7 to 11.3) PR: 4 (2.7 to 7.2) | Not reported | Not reported |
| MRD-negativity rate (n=100) | 21% (95% CI: 13 to 30) | - | - | - |
| MRD-negativity rate in those with CR or sCR (n=28) | 75% (95% CI: 55 to 89) | - | - | - |
| KarMMa, Munshi et al (2021) 15,; | ||||
| All doses (N=128) | OR=73% CR/sCR=33% VGPR=20% PR=21% | 10.7 (9.0 to 11.3) | 8.8 (5.6 to 11.6) | 19.4 (18.2 to NE) |
| 450 x 106 CAR T-cells (n=54) | OR=81% CR/sCR=39% VGPR=26% PR=17% | 11.3 (10.3 to 11.4) | 12.1 (8.8 to 12.3) | - |
| 300 x 106 CAR T-cells (n=70) | OR=69% CR/sCR=29% VGPR=14% PR=26% | 9.9 (5.4 to 11.0) | 5.8 (4.2 to 8.9) | - |
| 150 x 106 CAR T-cells (n=4) | OR=50% CR/sCR=25% VGPR=25% PR=None | NR (2.8 to NE) | 2.8 (1.0 to NE) | - |
| KarMMa-3, FDA Prescribing Label11, | Idecabtagene vicleucel treated (n=254) | Standard regimen treated (n=132) | ||
| Progression free survival | ||||
| Number of events, n (%) | 149 (59) | 93 (70) | ||
| Median, months [95% CI]b | 13.3 [11.8, 16.1] | 4.4 [3.4, 5.39] | ||
| Hazard Ratio [95% CI]c | 0.49 [0.38, 0.64] | |||
| One-sided p-valued | <0.0001 | |||
| Overall Response Rate (ORR), n (%) | ||||
| n (%) | 181 (71) | 55 (42) | ||
| 95% CI (%)e | (66,77) | (33,50) | ||
| One-sided p-valuef | <0.0001 | |||
| CR or better (sCR+CR) | 98 (39) | 7 (5) | ||
| sCR | 90 (35) | 6 (4.5) | ||
| CR | 8 (3.1) | 1 (0.8) | ||
| VGPR | 55 (22) | 13 (10) | ||
| PR | 28 (11) | 35 (27) | ||
CAR: chimeric antigen receptor; CI: confidence interval; CR: complete response; FDA: US Food and Drug Administration; MRD: minimal residual disease; NE: could not be estimated; NR: not reached; OR: overall response; PR: partial response; sCR: stringent clinical response; VGPR: very good partial response. a Defined according to International Myeloma Working Group uniform response criteria for multiple myeloma as assessed by an independent review committee. b Kaplan-Meier estimate. c Based on stratified univariate Cox proportional hazards model. d One-sided p-value is based on stratified log-rank test. e Two-sided Wald confidence interval. f One-sided p-value from Cochran-Mantel-Haenszel (CMH) test stratified by stratification factors
The purpose of the limitations tables (Tables 4 and 5) is to display notable limitations in the evidence. No limitations were noted for the KarMaa-3 trial. The main limitation in KarMaa was lack of an intention-to-treat analysis. Nine percent of the patients who underwent leukapheresis did not receive treatment and were not included in the efficacy estimates. Reasons cited by 12 participants for not receiving idecabtagene vicleucel subsequent to leukapheresis included withdrawal by patient (n=4), physician decision (n=3), death (n=2), disease progression (n=1), adverse event (n=1), and manufacturing failure (n=1). Thus, it is likely that sicker patients who were less likely to respond were excluded from receiving therapy and therefore excluded from the efficacy analysis.
| Study | Populationa | Interventionb | Comparatorc | Outcomesd | Follow-Upe |
| KarMMa15,11, | 1. Not sufficient duration for benefit 2. Not sufficient duration for harms | ||||
| KarMMa-311, |
The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment. a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use. b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4. Not the intervention of interest. c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively. d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported. e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.
| Study | Allocationa | Blindingb | Selective Reportingc | Data Completenessd | Powere | Statisticalf |
| KarMMa15,11, | 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias | 1. Not blinded to treatment assignment | 6. Not intent to treat analysis | |||
| KarMMa-313,14,11, |
The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment. a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias. b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician. c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication. d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials). e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference. f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated.
The evidence for use of idecabtagene vicleucel for relapsed and/or refractory multiple myeloma in adults after two or more prior lines of therapy includes results from the single-arm, phase II, KarMMa trial and open-label RCT, KarMaa-3. While KarMMa included patients after 3 or more prior lines of therapy, KarMMa-3 enrolled patients after 2 to 4 prior lines of therapy. KarMaa enrolled 127 patients with relapsed/refractory myeloma, 100 of whom were evaluated for response. The 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. 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. KarMaa-3 randomized 386 individuals to idecabtagene vicleucel (n=254) or standard regimens (n= 132). After a median follow-up 15.9 months, the median PFS was 13.3 versus 4.4 months (HR= 0.49) in the idecabtagene vicleucel and standard-regimen group respectively. Overall response rate was 71% and 42% respectively. At final PFS analysis (median follow-up, 30.9 months), median PFS vs standard regimens was 13.8 vs 4.4 months; HR=0.49. Patient-centric design allowed crossover from standard regimen (56%) to idecabtagene vicleucel upon progressive disease, confounding interpretation of overall survival. With idecabtagene vicleucel, any grade cytokine release syndrome occurred in 89% of patients, and grade ≥3 cytokine release syndrome occurred in 7% of patients. Neurotoxicity occurred in 40% of patients, reaching grade ≥3 severity in 4% of patients.
For individuals who are adults with relapsed and/or refractory multiple myeloma previously treated with4 or more prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody who receive idecabtagene vicleucel, 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 FDA analysis included data from 100 patients who received idecabtagene vicleucel in the dose range of 300 x 106 and 450 x 106. The primary endpoint 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 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.
| Population Reference No. 1 Policy Statement | [X] MedicallyNecessary | [ ] Investigational |
The clinical development program for ciltacabtagene autoleucel for relapsed/refractory multiple myeloma includes two open-label trials- CARTITUDE-1 (a single arm trial) and CARTITUDE-4 (an RCT). While CARTITUDE-1 included patients who previously received at least 3 prior lines of therapy, CARTITUDE-4 enrolled patients who previously received at least 1 prior line of therapy including a proteasome inhibitor and an immunomodulatory agent. Characteristics and results are summarized in Tables 6 and 7, respectively. In CARTITUDE-1, the primary endpoint was an overall response (partial response or better); a key secondary endpoint was a complete response or better (comprising complete and stringent complete responses). Responses were defined according to the 2016 International Myeloma Working Group uniform response criteria for multiple myeloma (See Table 1 for details). In CARTITUDE-4, the primary efficacy measure was progression free survival as determined by Independent Review Committee based on the 2016 International Myeloma Working Group uniform response criteria for multiple myeloma.
Trial results after a median follow-up of 12.4 months (data cut-off September 1, 2020) were published by Berdeja et al (2021).16, Results with a median follow-up of 18 months (data cut-off February 11, 2021) were reported in the FDA-approved prescribing label17, and are summarized in Table 7. Primary efficacy analysis demonstrated an overall response of 98% (95 of 97) with a 78% (76 of 97) rate of stringent complete response. The median time to first response was 1 month (range: 0.9 to 10.7 months). The overall response in the 113 patients that underwent leukapheresis was 84% (95% CI: 76 to 90) with a stringent complete response rate of 67% (95% CI: 58 to 76), very good partial response rate of 14% (95% CI: 8 to 22), and partial response rate of 3% (95% CI: 1 to 8).
Long term results with a median follow-up of 27.7 months have also been published. Overall response was 97.9% (95 of 97) with a 82.5% rate of stringent complete response.18, Outcomes on HRQoL using the European Organization for Research and Treatment of Cancer Quality of Life C30 Questionnaire and its supplementary 20-item multiple myeloma module, as well as the EuroQol 5-dimension 5-level instrument were reported.19, Clinically meaningful changes in patient-reported outcomes were defined by anchor-based minimally important differences. Mean change from baseline to day 464 in global health status (+8.0±20.9), physical (+4.6±21.1) and emotional functional scales (+1.9±23.7), and declines for symptom-based scores (-14.1±31.5 for pain and -15.4± 29.5 for fatigue) indicate improved patient HRQOL outcomes.
In CARTITUDE-4, 419 individuals were randomized 1:1 to receive either ciltacabtagene autoleucel (n=208) or standard regimens (n= 211). The median duration of follow-up reported in the FDA analysis was 15.9 months (data cut-off November 1, 2022).17, The median progression-free survival was not reached in the ciltacabtagene autoleucel group, as compared with 12 months in the standard-regimen group (hazard ratio for disease progression or death, 0.41). A response occurred in 74% of the patients in the ciltacabtagene autoleucel group and in 22% of those in the standard-regimen group (p<.001); a complete response occurred in 66% and 18%, respectively. Data on overall survival were immature at the time of interim analysis.
Similar to idecabtagene vicleucel, ciltacabtagene autoleucel also carries a boxed warning due to the risk of cytokine release syndrome, neurologic toxicity, hemophagocytic lymphohistiocytosis/macrophage activation syndrome, prolonged cytopenia and T cell malignancies. In the two pivotal trials (n=285), CRS occurred in 84% (238/285), including ≥Grade 3 CRS (ASTCT 2019 criteria) in 4% (11/285) of patients. The median time-to-onset of CRS, any grade, was 7 days (range: 1 to 23 days), and the median duration of CRS was 4 days (range: 1 to 23 days). Neurologic toxicities, including immune-effector cell-associated neurotoxicity, which may be severe or life-threatening, occurred concurrently with CRS, after CRS resolution, or in the absence of CRS following treatment with Idecabtagene vicleucel. In the two pivotal trials (n=285), CAR T cell associated neurotoxicity occurred in 24% (69/285), including ≥ Grade 3 in 7% (19/285) patients. The median time to onset of neurotoxicity was 10 days (range: 1 to 101 days). The median duration was 23 days (range: 1 to 544 days). Hemophagocytic lymphohistiocytosis/macrophage activation syndrome occurred in 1% (3/285) of patients. All events had onset within 99 days of receiving ciltacabtagene autoleucel, with a median onset of 10 days (range: 8 to 99 days) and all occurred in the setting of ongoing or worsening CRS. Patients may develop secondary malignancies. In the pivotal studies, myeloid neoplasms occurred in 5% (13/285) of patients (9 cases of myelodysplastic syndrome, 3 cases of acute myeloid leukemia, and 1 case of myelodysplastic syndrome followed by acute myeloid leukemia).17,
The purpose of the limitations table (Table 8 ) is to display notable limitations in the pivotal trials. Significant limitations in the study design and conduct or study relevance were not noted in either of the studies.
| Study | Study Type | Country | Dates | Participants | Treatment | Follow-Up |
| Berdeja et al (2021)15,; CARTITUDE-1 (NCT03548207) | Open-label, Single-arm | United States (16 centers) | 2018-2019 |
| Dose levelsf
| 18 months (median) |
ASCT: autologous stem cell transplantation;CAR: chimeric antigen receptor; ECOG: Eastern Cooperative Oncology Group; IMiD: immunomodulatory agents (e.g., lenalidomide or pomalidomide); IQR: interquartile range; PI: proteasome inhibitors (e.g., bortezomib or carfilzomib); RRMM: relapsed/refractory multiple myeloma. a Defined as documented disease progression based on investigator’s determination of response by the International Myeloma Working Group (IMWG) criteria on or within 12 months after the last line of therapy. b At least one of the following: serum M-protein ≥1.0 g/dL or urine M-protein ≥200 mg/24 h; or light chain multiple myeloma without measurable disease in the serum or the urine (serum immunoglobulin free light chain ≥10 mg/dL and abnormal serum immunoglobulin kappa lambda free light chain ratio). c Selective exclusion criteria included previous treatment with a CAR T-cell-targeted or BCMA-targeted therapy, known active or prior history of significant CNS disease, including CNS multiple myeloma, plasma cell leukemia, allogeneic stem cell transplant within 6 months before apheresis or ongoing treatment with immunosuppressants, creatinine clearance <40 mL/min, absolute lymphocyte concentration <300/μL, absolute neutrophil count <750 cells/mm3, platelet count <50,000/mm3, hepatic transaminases >3 times the upper limit of normal, cardiac ejection fraction <45%, or with active serious infection. d At screening according to the International Staging System. e Cytogenetic abnormality defined as t(4:14), (14:16), and 17p13 del]. f Dose selection in phase 2 of the CARTITUDE-1 trial was based on the results of the LEGEND-2 trial (first-in-human clinical trial of ciltacabtagene autoleucel), and then confirmed in the 29 patients enrolled in phase 1b of the CARTITUDE-1 trial. g The 97 patients who received ciltacabtagene autoleucel include 17 patients (18%) with manufacturing failures either because they received ciltacabtagene autoleucel that did not meet product release specifications or received ciltacabtagene autoleucel for which there were insufficient data to confirm product release specifications. h Patients with known active or prior history of central nervous system involvement, patients who exhibit clinical signs of meningeal involvement of multiple myeloma and patients with a history of Parkinson’s disease or other neurodegenerative disorder, were excluded from the trial i Standard therapy which included daratumumab, pomalidomide and dexamethasone (DPd) or bortezomib, pomalidomide and dexamethasone (PVd) selected by physician prior to randomization based on patient’s prior antimyeloma therapy.| Study | Responsea, % (95% CI) | Duration of Response, months (95% CI) | Overall survival, % (95% CI) |
| CARTITUDE-1 | N=97 | N=97 | N=97 |
| Berdeja et al (2021)16,; CARTITUDE-1 (data cutoff Sep 1, 2020) | OR=97% (91.2 to 99.4) sCR=67% VGPR=26% PR=4% | NE (15.9 to NE) | At 12 months: 89% (80.2 to 93.5) |
| Prescribing Labe17,l; CARTITUDE-1 (data cutoff Feb 11, 2021) | OR=98% sCR=78% VGPR=17% PR=3% | 21.8 (21.8 to NE) | Not reported |
| Martin et al (2023)18,; CARTITUDE-1 (data cutoff Jan 11, 2022) | OR=97.9% (92.7 to 99.7) sCR=82.5% (73.4 to 89.4) VGPR=12.4% (6.6 to 20.6) PR=3.1% (0.6 to 8.8) | NE (23.3 to NE) | At 27 months: 70.4% |
| CARTITUDE-4 | Ciltacabtagene autoleucel (n=208) | Standard Therapy (N=211) | |
| Progression-Free Survivala | |||
| Number of events, n (%) | 65 (31.3) | 119 (56.4) | |
| Median, months [95% CI]b | Not estimable [22.8 to not estimable] | 12 [9.8 to 14.0] | |
| Hazard ratio [95% CI]c | 0.41 [0.30 to 0.56] | - | |
| p valued | <.0001 | - | |
| Complete Response or Better Rateb, % [95% CI] | 74.0 [67.5 to 79.9] | 22.3 [16.8 to 28.5] | |
| p-valuee | <.0001 | - | |
| Stringent Complete Responsea (sCR), n (%) | 137 (65.9) | 38 (18.0) | |
| Complete Responsea (CR), n (%) | 17 (8.2) | 9 (4.3) | |
| Overall Response Rate, ORR (sCR + CR + VGPR + PR)a, % [95% CI] | 84.6 [79.0 to 89.2] | 67.8 [61.0 to 74.0] | |
| p-valuee | <.0001 | - | |
| Very Good Partial Responsea (VGPR), n (%) | 16 (7.7) | 49 (23.2) | |
| Partial Responsea (PR), n (%) | 6 (2.9) | 47 (22.3) | |
CI: confidence interval; NE: could not be estimated; OR: overall response; PR: partial response; sCR: stringent clinical response; VGPR: very good partial response. a Defined according to International Myeloma Working Group uniform response criteria5 for multiple myeloma as assessed by an independent review committee. b Kaplan-Meier estimate c Based on a stratified Cox proportional hazards model. A hazard ratio <1 indicates an advantage for CARVYKTI Arm. For all stratified analyses, stratification was based on investigator’s choice (PVd or DPd), ISS staging (I, II, III) and number of prior lines (1 vs. 2 or 3) as randomized. d Stratified log-rank test e Stratified Cochran-Mantel-Haenszel Chi-Squared test
| Study | Allocationa | Blindingb | Selective Reportingc | Data Completenessd | Powere | Statisticalf |
| Berdeja et al (2021)16,; CARTITUDE-1 | 1. Participants not randomly allocated; 4. Inadequate control for selection bias | |||||
| CARTITUDE-4 |
The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment. a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias. b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician. c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication. d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials). e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference. f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated.
For individuals who are adults with relapsed and/or refractory multiple myeloma previously treated with 4 or more prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody who receive ciltacabtagene autoleucel, 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 1b/2 multicenter open-label study that enrolled adult patients with relapsed or refractory multiple myeloma who had received at least 3 different prior lines of therapy including proteasome inhibitors, immunomodulatory agents, and anti-CD38 monoclonal antibodies. The primary endpoint was overall response (partial response or better). After a median follow-up of 18 months, the primary efficacy analysis demonstrated an overall response rate of 98% (95 of 97) with a 78% rate of stringent complete response. In the absence of a RCT, it is difficult to draw comparisons with currently available treatments. 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. Notable adverse events of grade 3-4 among 97 patients who received ciltacabtagene autoleucel included neutropenia (95%), anemia (68%), leukopenia (61%), thrombocytopenia (60%), and lymphopenia (50%). Any grade cytokine release syndrome and neurotoxicity were observed in 95% and 26% of patients, respectively. Grade 3 to 4 cytokine release syndrome and neurotoxicity were observed in 5% and 11% of patients, respectively. A notable limitation of the CARTITUDE-1 study included 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.
The evidence for use of ciltacabtagene autoleucel for relapsed and/or refractory multiple myeloma in adults after one or more prior line of therapy includes results from the single-arm, phase II, CARTITUDE-1 trial and open-label RCT, CARTITUDE-4. CARTITUDE-1 included patients after 3 or more prior lines of therapy while CARTITUDE-4 enrolled patients after one or more prior lines of therapy. CARTITUDE-1 enrolled 97 patients. The primary endpoint of overall response (partial response or better) after a median follow-up of 18 months demonstrated an overall response rate of 98% (95 of 97) with a 78% rate of stringent complete response. Results at a median follow-up of 27.7 months reported overall response of 97.9% with a 82.5% rate of stringent complete response. Statistically significant and clinically meaningful improvements in quality of life outcomes were also reported which were consistent with clinical findings. 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. CARTITUDE-4 randomized 419 individuals to receive either ciltacabtagene autoleucel (n=208) or standard regimens (n= 211). After a median follow-up of 15.9 months, the median progression-free survival was not reached in the ciltacabtagene autoleucel group, as compared with 12 months in the standard-regimen group (hazard ratio for disease progression or death, 0.41). A response occurred in 74% of the patients in the ciltacabtagene autoleucel group and in 22% of those in the standard-regimen group (p<.001); a complete response occurred in 66% and 18%, respectively. Data on overall survival were immature at the time of interim analysis. Any grade cytokine release syndrome occurred in 84% of patients, and grade ≥3 cytokine release syndrome occurred in 4% of patients. Neurotoxicity occurred in 24% of patients, reaching grade ≥3 severity in 7% of patients.
| Population Reference No. 2 Policy Statement | [X] MedicallyNecessary | [ ] Investigational |
For individuals who are adults with relapsed and/or refractory multiple myeloma previously treated with4 or more prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody who receive idecabtagene vicleucel, 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 FDA analysis included data from 100 patients who received idecabtagene vicleucel in the dose range of 300 x 106 and 450 x 106. The primary endpoint 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 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.
For individuals who are adults with relapsed and/or refractory multiple myeloma previously treated with 4 or more prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody who receive ciltacabtagene autoleucel, 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 1b/2 multicenter open-label study that enrolled adult patients with relapsed or refractory multiple myeloma who had received at least 3 different prior lines of therapy including proteasome inhibitors, immunomodulatory agents, and anti-CD38 monoclonal antibodies. The primary endpoint was overall response (partial response or better). After a median follow-up of 18 months, the primary efficacy analysis demonstrated an overall response rate of 98% (95 of 97) with a 78% rate of stringent complete response. In the absence of a RCT, it is difficult to draw comparisons with currently available treatments. 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. Notable adverse events of grade 3-4 among 97 patients who received ciltacabtagene autoleucel included neutropenia (95%), anemia (68%), leukopenia (61%), thrombocytopenia (60%), and lymphopenia (50%). Any grade cytokine release syndrome and neurotoxicity were observed in 95% and 26% of patients, respectively. Grade 3 to 4 cytokine release syndrome and neurotoxicity were observed in 5% and 11% of patients, respectively. A notable limitation of the CARTITUDE-1 study included 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.
The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.
Guidelines or position statements will be considered for inclusion in ‘Supplemental Information' if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.
On November 30, 2023, the NICE issued issued a technology appraisal guidance [TA936] and stated that it is unable to make a recommendation on idecabtagene vicleucel for treating relapsed and refractory multiple myeloma after 3 or more treatments in adults because BMS did not provide a complete evidence submission.20,
On May 17, 2023, the NICE issued issued a technology appraisal guidance [TA889] and stated that it is unable to make a recommendation on on ciltacabtagene autoleucel (Carvykti) for treating relapsed or refractory multiple myeloma in adults because Janssen withdrew its evidence submission for the appraisal.21,
The Institute for Clinical and Economic Review (ICER) published an evidence report to assess the comparative clinical effectiveness and value of anti-B-cell maturation antigen chimeric antigen receptor (CAR) T-cell and antibody drug conjugate therapy for heavily pre-treated relapsed and refractory multiple myeloma.22,
The ICER report notes that the evidence suggests that CAR T-cell therapies (idecabtagene vicleucel and ciltacabtagene autoleucel) for patients with triple class refractory multiple myeloma likely provides small to substantial net health benefits over current usual care (Evidence rating B+). Benefits included longer survival as well as improved quality of life. Counterbalancing these benefits were the harms, including cytokine release syndrome, which is temporary but often requires hospitalization and intensive care unit level care. Further, the report concludes that the evidence is insufficient to determine whether 1 CAR T-cell therapy is superior to the other. There are no studies comparing these agents directly, nor sufficient data to perform quantitative indirect comparisons.
Current National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines for multiple myeloma (Version 1.2025 Sep 17, 2024) recommend (category 1) ciltacabtagene autoleucel as a treatment option for patients after one prior line of therapy including immunomodulatory agent and a proteasome inhibitor, and refractory to lenalidomide5,.
Current National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines for multiple myeloma (Version 1.2025 Sep 17, 2024) recommend (category 1) idecabtagene vicleucel as a treatment option for patients after two prior lines of therapy including immunomodulatory agent and a proteasome inhibitor.5,
Not applicable.
There is no national coverage determination. In the absence of a national coverage determination, coverage decisions are left to the discretion of local Medicare carriers.
Some currently ongoing and unpublished trials that might influence this review are listed in Table 9.
| NCT No. | Trial Name | Planned Enrollment | Completion Date |
| Idecabtagene vicleucel | |||
| Ongoing | |||
| NCT04855136 (KarMMa-7) | Safety and Efficacy of bb2121 (Ide-cel) Combinations in Multiple Myeloma | 312 | Dec 2026 |
| NCT03601078 (KarMMa-2) | An efficacy and safety study of bb2121 in subjects with relapsed and refractory multiple myeloma and in subjects with high-risk multiple myeloma | 235 | Dec 2030 |
| NCT05032820 | MM CAR-T to Upgrade Response BMTCTN1902 | 40 | Feb 2025 |
| Unpublished | |||
| NCT02786511a | Long-term follow-up of subjects treated with bb2121 | 50 | Oct 2019 |
| NCT04196491 (KarMMa-4) | A study to evaluate the safety of bb2121 in subjects with high risk, newly diagnosed multiple myeloma | 13 | Dec 2023 |
| Ciltacabtagene autoleucel | |||
| Ongoing | |||
| NCT04133636 (CARTITUDE-2) | A study of JNJ-68284528, a CAR T-cell therapy directed against BCMA in participants with multiple myeloma | 237 | Nov 2028 |
| NCT04923893 (CARTITUDE-5) | A study of bortezomib, lenalidomide and dexamethasone (VRd) followed by Cilta-cel, a CAR T-cell therapy directed against BCMA versus VRd followed by lenalidomide and dexamethasone (Rd) therapy in participants with newly diagnosed multiple myeloma for whom ASCT is not planned as initial therapy | 743 | Jan 2034 |
| NCT05257083 (CARTITUDE-6) | A Study of Daratumumab, Bortezomib, Lenalidomide and Dexamethasone (DVRd) Followed by Ciltacabtagene Autoleucel Versus Daratumumab, Bortezomib, Lenalidomide and Dexamethasone (DVRd) Followed by Autologous Stem Cell Transplant (ASCT) in Participants With Newly Diagnosed Multiple Myeloma | 750 | Aug 2040 |
| NCT05201781 | A Long-term Study for Participants Previously Treated With Ciltacabtagene Autoleucel | 228 | Jul 2037 |
NCT: national clinical trial. a Denotes industry-sponsored or cosponsored trial.
| Codes | Number | Description |
|---|---|---|
| CPT | 0537T | Chimeric antigen receptor T-cell (CAR-T) therapy; harvesting of blood-derived T lymphocytes for development of genetically modified autologous CAR-T cells, per day |
| 0538T | Chimeric antigen receptor T-cell (CAR-T) therapy; preparation of blood-derived T lymphocytes for transportation (eg, cryopreservation, storage) | |
| 0539T | Chimeric antigen receptor T-cell (CAR-T) therapy; receipt and preparation of CAR-T cells for administration | |
| 0540T | Chimeric antigen receptor T-cell (CAR-T) therapy; CAR-T cell administration, autologous | |
| HCPCS | 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 | |
| J8999 | Prescription drug, oral, chemotherapeutic, NOS (use Revlimid (lenalidomide) | |
| ICD10 CM | C90.00 | Multiple myeloma not having achieved remission |
| C90.02 | Multiple myeloma in relapse | |
| Z80.7 | Family history of other malignant neoplasms of lymphoid, hematopoietic and related tissues | |
| Z85.79 | Personal history of other malignant neoplasms of lymphoid, hematopoietic and related tissues | |
| ICD10 PCS | XW033A7 | Introduction of Ciltacabtagene Autoleucel 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 | |
| XW033K7 | Introduction of Idecabtagene Vicleucel Immunotherapy into Peripheral Vein, Percutaneous Approach, New Technology Group 7 | |
| XW033C7 | Introduction of Autologous Engineered Chimeric Antigen Receptor T-cell Immunotherapy into Peripheral Vein, Percutaneous Approach, New Technology Group 7 | |
| XW033G7 | Introduction of Allogeneic Engineered Chimeric Antigen Receptor T-cell Immunotherapy into Peripheral Vein, Percutaneous Approach, New Technology Group 7 | |
| XW043C7 | Introduction of Autologous Engineered Chimeric Antigen Receptor T-cell Immunotherapy into Central Vein, Percutaneous Approach, New Technology Group 7 | |
| XW043G7 | Introduction of Allogeneic Engineered Chimeric Antigen Receptor T-cell Immunotherapy into Central Vein, Percutaneous Approach, New Technology Group 7 | |
| Type of Service | Therapy | |
| Place of Service | Inpatient/ Outpatient |
N/A
| Date | Action | Description |
|---|---|---|
| 01/15/2025 | Annual Policy Review | Simplification of policy statements to align with the prescribing label and multiple editorial and formatting changes to improve clarity. References were added. |
| 12/16/2024 | Codes review | Code Changes Effective 01/01/25, Category III codes 0537T-0540T are being deleted |
| 04/19/2024 | Replace policy | Policy updated with literature review through January 6, 2024; references added. Minor editorial refinements to policy statements; intent unchanged. Policy guidelines updated to include revision to the prescribing label due to the risk of T-cell malignancies, with serious outcomes, including hospitalization and death. |
| 08/09/2023 | Annual Review | Policy updated with literature review through January 19, 2023; no references added. Policy statements unchanged. |
| 08/11/2022 | Annual Review | Policy governance (review and vote for approval) transferred to National Pharmacy and Therapeutics Committee in March 2022. Policy updated with literature review through March 1, 2022. Relevant information on ciltacabtagene autoleucel for individuals with relapsed and/or refractory multiple myeloma was added. Ciltacabtagene autoleucel is considered medically necessary for adult patients with relapsed and/or refractory multiple myeloma and have received four or more prior lines of therapy and when certain conditions are met. |
| 07/01/2022 | Replace Policy | No change |
| 60/02/2022 | Annual Review | No change |
| 06/17/2021 | New policy | Policy created with literature review through April 2, 2021. The use of idecabtagene vicleucel is considered medically necessary for individuals with relapsed and/or refractory multiple myeloma and have received four or more prior lines of therapy and when certain conditions are met. |