Description:
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.

Background: 
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. African-Americans 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 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 Currently, belantamab mafodotin is the only 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 an 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.⁹

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

BCMA: B-cell maturation antigen; BCVA: best corrected visual acuity; CRS: cytokine release syndrome; FDA: Food and Drug Administration; IMiD: immunomodulatory agents (e.g., lenalidomide or pomalidomide); ITT: intention-to-treat analysis; KM: Kaplan Meir; OR: overall response; OS: overall survival: PDUFA: Prescription Drug User Fee Act; PFS: progression free survival; PI: proteasome inhibitors (e.g., bortezomib or carfilzomib).

Regulatory Status
On March 26, 2021, idecabtagene vicleucel (Abecma) was approved by the U.S. Food and Drug Administration 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.

Policy: 
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 4 or more prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody (see Policy Guidelines)
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 chimeric antigen receptor T therapy or any other gene therapy or are being considered for treatment with any other gene therapy

Policy Guidelines: 
FDA Recommended Dose of Idecabtagene Vicleucel for Multiple Myeloma
300 to 460 x 10⁶ chimeric antigen receptor-positive viable T cells intravenously.

Black Box Warning and Associated Restricted Program under a Risk Evaluation and Mitigation Strategy (REMS)
Idecabtagene vicleucel (Abecma) has a black box warning because of the risks of cytokine release syndrome, neurologic toxicity, hemophagocytic lymphohistiocytosis/macrophage activation syndrome, and prolonged cytopenia. Idecabtagene vicleucel should not be administered to patients 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. Patients should be monitored for neurologic events after treatment.

Idecabtagene vicleucel (Abecma) is available only through a restricted program under a risk evaluation and mitigation strategy (REMS) called the Abecma REMS. The requirement for the REMS components are as follows:

• Health care facilities that dispense and administer this chimeric antigen receptor 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 patient for administration within 2 hours after infusion of this chimeric antigen receptor 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 chimeric antigen receptor T therapies are trained to manage cytokine release syndrome and neurologic toxicities.

Guidance for Definitions for Relapsed and Refractory Multiple Myeloma
Relapsed Multiple Myeloma
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

Refractory Multiple Myeloma
In the protocol of the pivotal KarMMa study, 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

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).

Coding
See the Codes table for details.

Benefit Application 
BlueCard/National Account Issues 
State or federal mandates (e.g., 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.

Rationale: 
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 uses 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.

Relapsed/Refractory Multiple Myeloma
Clinical Context and Therapy Purpose
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 question addressed in this evidence review is: Does the use of the intervention improve the net health outcome in 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.

Populations
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.

Interventions
The therapy being considered is idecabtagene vicleucel, a B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell therapy. Manufacturing of idecabtagene vicleucel 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 idecabtagene vicleucel 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.

Comparators
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.

Outcomes
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.¹⁴ 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.¹⁵

The 2016 International Myeloma Working Group response criteria is the standard response criteria used for multiple myeloma and are summarized in Table 2.

Table 2. 2016 International Myeloma Working Group Uniform Response Criteria for Multiple Myeloma⁵

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.

Study Selection Criteria
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.

Review of Evidence
Single Arm Trials
The clinical development program for idecabtagene vicleucel includes the single arm, open-label, phase 2, KarMMa trial. Characteristics and results of the pivotal KarMMa trial are summarized in Tables 3 and 4, respectively. The trial 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. The primary end point was an overall response (partial response or better); a key secondary end point 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 myeloma⁶ (See Table 2 for details).

A total of 149 patients were enrolled in the trial. FDA analysis included data from 100 patients who received idecabtagene vicleucel in the dose range of 300 x 10⁶ and 450 x 10⁶. The overall manufacturing failure rate for patients who underwent leukapheresis for the 300 x 10⁶ and 450 x 10⁶ CAR-positive T cell dose cohorts was 1.5% (2 out of 135 patients). Of these 2 patients, 1 received CAR-positive T cells that did not meet product release specifications for idecabtagene vicleucel, and in an another patient there was an inability to manufacture idecabtagene vicleucel. 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.¹⁰

After a median follow-up of 10.7 months, the primary efficacy analysis demonstrated an overall response of 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.¹⁰

Idecabtagene vicleucel was approved with a black box warning due to the risk of cytokine release syndrome, neurologic toxicity, hemophagocytic lymphohistiocytosis/macrophage activation syndrome, and prolonged cytopenia. Any grade cytokine release syndrome (as per Lee criteria¹⁶) and neurotoxicity (investigator identified) were observed in 85% and 28% of patients, respectively. Grade 3 or higher cytokine release syndrome and neurotoxicity were observed in 9% and 4% of patients, respectively. The median time-to-onset of cytokine release syndrome, any grade, was 1 day (range: 1 to 23 days), and the median duration of cytokine release syndrome was 7 days (range: 1 to 63 days). The most common manifestations of cytokine release syndrome included pyrexia (98%), hypotension (41%), tachycardia (35%), chills (31%), hypoxia (20%), fatigue (12%), and headache (10%). The median time-to-onset of neurotoxicity was 2 days (range: 1 to 42 days), and the median duration of neurotoxicity was 6 days (range: 1 to 578 days). Hemophagocytic lymphohistiocytosis/macrophage activation syndrome occurred in 4% of patients, 1 of whom died of multiorgan hemophagocytic lymphohistiocytosis/macrophage activation syndrome with cytokine release syndrome. A second patient died of bronchopulmonary aspergillosis with hemophagocytic lymphohistiocytosis/macrophage activation syndrome as a contributing factor.

Table 3. Summary of Pivotal Trial Characteristics of Idecabtagene Vicleucel for Relapsed and/or Refractory Multiple Myeloma

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/mm^3
d Cytogenetic abnormality defined as del(17p), t(4;14), or t(14;16).
^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).

Table 4. Summary of Results of Pivotal Trial of Idecabtagene Vicleucel for Relapsed and/or Refractory Multiple Myeloma

CAR: chimeric antigen receptor; CI: confidence interval; CR: complete response; 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.

The purpose of the limitations tables (Tables 5 and 6) is to display notable limitations in the pivotal KarMMa study. The main limitation 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.

Table 5. Study Relevance Limitations

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.

Table 6. Study Design and Conduct Limitations

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.

Section Summary: Indication
The evidence for use of idecabtagene vicleucel for relapsed and/or refractory multiple myeloma in adults who have received 4 or more prior lines of therapy includes results from the single arm, phase II, KarMMa trial involving 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. 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.

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 anti-CD38 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. 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 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 RCT, 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.

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Practice Guidelines and Position Statements
Guidelines or position statements will be considered for inclusion in ‘Supplemental Information' if they were issued by, or jointly by, a U.S. professional society, an international society with U.S. 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.

Institute for Clinical and Economic Review
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 CAR-T cell and antibody drug conjugate therapy for heavily pre-treated relapsed and refractory multiple myeloma.¹²

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 therapy is superior to the other. There are no studies comparing these agents directly, nor sufficient data to perform quantitative indirect comparisons.

Note: ciltacabtagene autoleucel is an investigational BCMA -directed CAR-T therapy in development for the treatment of adults with relapsed and/or refractory multiple myeloma who have received at least 3 prior therapies. Rolling submission to the FDA was initiated in Dec 2020 and an approval is expected in late 2021/early 2022.

National Comprehensive Cancer Network
The NCCN Clinical Practice Guidelines in Oncology (Version 5.2021 March 15, 2021) do not include idecabtagene vicleucel as these were issued prior to the FDA approval of the agent.⁶

U.S. Preventive Services Task Force Recommendations
Not applicable

Ongoing and Unpublished Clinical Trials
Some currently ongoing and unpublished trials that might influence this review are listed in Table 7. The phase III RCT KarMMa-3 (NCT03651128) is underway and intends to compare the safety and efficacy of idecabtagene vicleucel with standard regimens as per investigator's discretion (daratumumab in combination with pomalidomide and low-dose dexamethasone or daratumumab in combination with bortezomib and low-dose dexamethasone or ixazomib in combination with lenalidomide and low-dose dexamethasone or carfilzomib in combination with low-dose dexamethasone or elotuzumab in combination with pomalidomide and low-dose dexamethasone). This trial will enroll 381 participants and is expected to be completed in 2025.

Table 7. Summary of Key Trials

NCT: national clinical trial.
^a Denotes industry-sponsored or cosponsored trial.

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/key-statistics.html. Accessed April 5, 2021.
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. Lonial S, Lee HC, Badros A, et al. Belantamab mafodotin for relapsed or refractory multiple myeloma (DREAMM-2): a two-arm, randomised, open-label, phase 2 study. Lancet Oncol. Feb 2020; 21(2): 207-221. PMID 31859245
10. Prescribing Label: Abecma (idecabtagene vicleucel), suspension for intravenous infusion. Available at https://packageinserts.bms.com/pi/pi_abecma.pdf. Accessed on April 6, 2021
11. 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
12. Institute for Clinical and Economic Review. Evidence Report: Anti B-Cell Maturation Antigen CAR T-cell and Antibody Drug Conjugate Therapy for Heavily Pre-Treated Relapsed and Refractory Multiple Myeloma. April 5, 2021 https://34eyj51jerf417itp82ufdoe-wpengine.netdna-ssl.com/wp-content/uploads/2020/10/ICER_Multiple-Myeloma_Evidence-Report_040521.pdf. Accessed April 5, 2021.
13. 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/early-deep-durable-responses-ciltacabtagene-autoleucel-cilta-cel-observed-phase-1b2-cartitude-1. Accessed April 7, 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

Coding Section 

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive. 

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

"Current Procedural Terminology © American Medical Association. All Rights Reserved" 

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