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: 
Ciltacabtagene Autoleucel (Carvykti)
Ciltacabtagene autoleucel (cilta-cel) is a B-cell maturation antigen (BCMA)-directed genetically modified autologous T cell immunotherapy that was approved by the U.S. FDA in February 2022 for the treatment of adult patients with relapsed or refractory multiple myeloma (MM) after 4 or more prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody. Cilta-cel was previously granted orphan designation by the FDA, as sponsored by the innovator
drug company, for the treatment of MM in February 2019. Carvykti is the second BCMA-directed CAR Tcell therapy approved for MM; the first being Abecma (idecabtagene vicleucel) approved in March 2021. Both have identical indications. Relapsed or refractory MM is an incurable cancer of plasma cell in the bone marrow, and while numerous treatment options are available for relapsed or refractory (r//r) disease, including later-stage therapy, a preferred order for use has not been established. The choice of
therapy is determined by prior therapies used, response and adverse effects to those treatments, duration of responses, patient comorbidities, risk stratification, and drugs costs. The National Comprehensive Cancer Network (NCCN) Multiple Myeloma Guidelines list ciltacabtagene autoleucel as a category 2A recommendation under “Therapies for patients with Late Relapse ( > 3 prior therapies)” under the sub-indication of “After at least four prior therapies, including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent." Idecabtagene vicleucel (Abecma) and belantamab mafodotin-blmf (Blenrep) are also listed in this same section. Of note, there are over 40 different drug regimens listed for previously treated MM.

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

	Idecabtagene vicleucel10,11,12	Ciltacabtagene autoleucel13	Belantamab mafodotin9
FDA status	Approved March 26, 2021	Rolling submission initiated in Dec 2020; FDA decision expected in late 2021	FDA approved August 5, 2020
Proposed/Approved Indication	Treatment of adult individuals with relapsed and/or refractory multiple myeloma who have received at least 3 prior therapies.	Treatment of adult individuals with relapsed and/or refractory multiple myeloma who have received at least 3 prior therapies.	Treatment of adult patients with relapsed or refractory multiple myeloma who have received at least 4 prior therapies including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent
Limitation of use	Black box warning due to the risk of cytokine release syndrome, neurologic toxicity, hemophagocytic lymphohistiocytosis/macrophage activation syndrome, and prolonged cytopenia	Not FDA approved	Black box warning as 30% of participants in the trials experienced a severe decline in vision, with grade 3 decline in BCVA
Pivotal Trials	KarMMa (NCT03361748)	CARTITUDE (NCT03548207)	DREAMM-2 (NCT03525678)
Design	Single-arm, open-label	Single-arm, open-label	Single-arm, open-label
Key eligibility criteria	Received at least 2 cycles of ≥ 3 prior treatment regimens (incl. PI, IMiD, anti-CD38 antibody) and refractory to the last regimen	Received ≥ 3 prior treatment regimens (incl. PI, IMiD, anti-CD38 antibody) or are double refractory to a PI and IMiD	Received ≥ 3 previous lines of treatments Refractory to IMiD and PI, and refractory/intolerant to an anti-CD38 therapy
Population	Mostly triple-class refractory	Mostly triple-class refractory	Quad- and penta-refractory
N	128	126	97 ( for 2.5 mg/kg arm only)
Follow-up Duration	13.3 months	12.4 months	13 months
Efficacy, %
OR (as treated) OR (ITT)	72% 63%	97% 75%	- 32%
Median PFS or OS	As-treated PFS = 8.9 months As treated KM estimated OS = 19.4 months	As-treated PFS >12.4 months	ITT OS = 13.8 months
Toxicity	51% CRS Grade 2+	44% CRS Grade 2+ 6% Treatment-related deaths	30% Severe decline in vision (BCVA scale Grade 3+)

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

Carvykti™ (ciltacabtagene autoleucel) may be considered MEDICALLY NECESSARY for patients with multiple myeloma if they meet ALL of the following criteria:

1. Are adults (age ≥ 18) at the time of infusion
2. Have documented relapsed or refractory Multiple Myeloma
3. Has received at least four (4) prior therapies, including:
   1. proteasome inhibitor (e.g., bortezomib, etc.)
   2. immunomodulatory agent (e.g., lenalidomide, thalidomide, etc.) 
   3. anti-CD38 monoclonal antibody (e.g., daratumumab, isatuximab, etc.)
4. Healthcare facility has enrolled in the CARVYKTI REMS Program and training has been given to providers on the management of cytokine release syndrome (CRS) and neurological toxicities 
5. Has not received prior CAR-T or B-cell maturation antigen (BCMA) targeted therapy
6. Has not received prior allogeneic hematopoietic stem cell transplant within 6 months prior to therapy
7. Does not have an active infection(s) or inflammatory disorder
8. Patient has not received live vaccines within 6 weeks prior to the start of lymphodepleting chemotherapy, and will not receive live vaccines during ciltacabtagene autoleucel treatment, and until immune recovery following treatment
9. Has been screened for cytomegalovirus (CMV), hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus (HIV) in accordance with clinical guidelines prior to collection of cells (leukapheresis)
10. Used as single agent therapy (not applicable to lymphodepleting or additional chemotherapy while awaiting manufacture
11. Does not have known central nervous system (CNS) involvement with myeloma or a history or presence of clinically relevant, active, CNS pathology
12. Does not have active or a history of plasma cell leukemia
13. Has an ECOG performance status of 0 – 1

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 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.

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 chimeric antigen receptor (CAR) T-cell therapy 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 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.

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.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.

Table 1. 2016 International Myeloma Working Group Uniform Response Criteria for Multiple Myeloma^5,

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: Serum M-component (the absolute increase must be ≥ 0.5 g/dL)e 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 FLC 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 FLC 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
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 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

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
Idecabtagene Vicleucel
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 2 and 3, 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 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).

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 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.¹²

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.¹²

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 criteria13, ]) 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 2. Summary of Pivotal Trial Characteristics of Idecabtagene Vicleucel for Relapsed and/or Refractory Multiple Myeloma

Study	Study Type	Country	Dates	Participants	Treatment	Follow-Up
KarMMa (NCT03361748)12	Open-label, Single-arm	Global (24 sites)	2017 – 2018	Individuals aged ≥ 18 years 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) Refractory to last treatmenta ECOG status 0 or 1 Measurable diseaseb Exclusion criteriac Patient characteristics Median age: 62 years (range, 33 to 78) Male: 60% White: 78% ISS Stage 1 or II: 78% High-risk cytogeneticsd: 37% Extramedullary disease: 36% Median number of prior lines of therapy: 6 (range, 3 to 16) % of pts with ≥ 4 prior lines of therapy: 88% Refractory to an anti-CD38 monoclonal antibody: 95% Triple class refractorye: 85% Penta-refractoryf: 26% Received prior autologous stem cell transplantation: 92%	Patient disposition Underwent leukapheresis = 135g 35 (26%) patients excluded from analysis Did not receive CAR T-cells = 11 (8%)h Received CAR T-cells outside of the 300 to 450 x 106 dose range = 23 (18%) Received non-conforming product = 1	10.7 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 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 3. Summary of Results of Pivotal Trial of Idecabtagene Vicleucel for Relapsed and/or Refractory Multiple Myeloma

Study	Responsea, %	Median Duration of Response, months (95% CI)	Progression-free Survival, months (95% CI)	Overall Survival, months (95% CI)
KarMMa, FDA Prescribing Label12
300 to 450 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. 202114;
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)	-

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 4 and 5 ) 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 4. Study Relevance Limitations

Study	Populationa	Interventionb	Comparatorc	Outcomesd	Follow-Upe
KarMMa14,12,					1. Not sufficient duration for benefit 2. Not sufficient duration for harms

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 5. Study Design and Conduct Limitations

Study	Allocationa	Blindingb	Selective Reportingc	Data Completenessd	Powere	Statisticalf
KarMMa14,12	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

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: Idecabtagene Vicleucel
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.

Ciltacabtagene Autoleucel
Single Arm Trials
The clinical development program for ciltacabtagene autoleucel includes the single-arm, open-label, phase 1b/2 CARTITUDE-1 trial. Characteristics and results of the pivotal CARTITUDE-1 trial are summarized in Tables 6 and 7, respectively. The trial enrolled adult patients with relapsed or refractory multiple myeloma who had received at least 3 prior lines of therapy or were double refractory to a proteasome inhibitor and an immunomodulatory drug. The primary efficacy endpoint was overall response (partial response or better), as assessed by an independent review committee. Responses were defined according to 2016 International Myeloma Working Group uniform response criteria for multiple myeloma (See Table 1 for details). Most patients (75%) treated with ciltacabtagene autoleucel received bridging therapy for control of their multiple myeloma during the manufacturing process. The median time from leukapheresis to product availability was 32 days (range: 27 to 66 days). The most commonly used agents as bridging therapies ( ≥ 20% of patients) included dexamethasone: 62 patients (64%), bortezomib: 26 patients (27%), cyclophosphamide: 22 patients (23%), and pomalidomide: 21 patients (22%).

Trial results after a median follow-up of 12.4 months (data cut-off September 1, 2020) were published by Berdeja et al. (2021).¹⁵ Results with a median follow-up of 18 months (data cut-off February 11, 2021) were reported in the FDA-approved prescribing label16, and are summarized in Table 7. After a median follow-up of 18 months, the 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).

Notable adverse events of grade 3 to 4 included neutropenia (95%), anemia (68%), leukopenia (61%), thrombocytopenia (60%), and lymphopenia (50%). Any grade cytokine release syndrome (as per Lee criteria¹³) and neurotoxicity (investigator-assessed) were observed in 95% and 26% of patients, respectively. Grade 3 or 4 cytokine release syndrome and neurotoxicity were observed in 5% and 11% of patients, respectively. Grade 5 cytokine release syndrome was observed in 1 patient (1%), who later died on day 99 subsequent to prolonged grade 4 cytokine release syndrome sequelae. Grade 5 neurotoxicities occurred in 2 patients (2%).

The purpose of the limitations tables (Tables 8 and 9) is to display notable limitations in the pivotal CARTITUDE-1 study. Follow-up data for efficacy and safety are relatively short at 18 months.

Table 6. Summary of Pivotal Trial Characteristics of Ciltacabtagene Autoleucel for Relapsed and/or Refractory multiple myeloma

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	Individuals aged ≥ 18 years with a diagnosis of RRMM with at least 3 prior lines of therapy or double refractory to an IMiD and PI, and have received a PI, IMiD, and anti-CD38 antibody, with progressive diseasea ECOG status 0 or 1 Measurable diseaseb Exclusion criteriac Patient characteristics Median age: 61 years (range, 43 to 78) Median time since diagnosis: 5.9 years (IQR, 4.4 to 8.4) High tumor burden ( ≥ 60% bone marrow plasma cells): 21 (22%) Extramedullary plasmacytomas ≥ 1: 13 (13%) Stage III diseased: 14 (14%) High-riske: 23 (24%)	Dose levelsf 0.75 x 106 viable CAR T-cells per kg (range 0.5 x 10⁶ to 1.0 x 10⁶) (n = 29 in phase 1b, n = 68 in phase 2) Patient disposition Enrolled and apheresed = 113 Received therapy = 97g Reasons for not receiving Rx: Disease progression = 2 Withdrawal = 5 Death = 9	18 months (median)

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 del(17p), t(14;16), or t(4;14).
^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. 

Table 7. Summary of Results of Pivotal Trial of Ciltacabtagene Autoleucel for Relapsed and/or Refractory Multiple Myeloma

Study	Responsea, % (95% CI)	Duration of Response, months (95% CI)	Overall survival, % (95% CI)
	N = 97	N = 97	N = 97
Berdeja et al. (2021)15; 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 Labe16l; CARTITUDE-1 (data cutoff Feb 11, 2021)	OR = 98% sCR = 78% VGPR = 17% PR = 3%	21.8 (21.8 to NE)	Not reported

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.

Table 8. Relevance Limitations

Study	Populationa	Interventionb	Comparatorc	Outcomesd	Follow-Upe
Berdeja et al. (2021)15; CARTITUDE-1					1. Not sufficient duration for benefit 2. Not sufficient duration for harms

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 9. Study Design and Conduct Limitations

Study	Allocationa	Selective Reportingc	Data Completenessd	Powere	Statisticalf
Berdeja et al. (2021)15; CARTITUDE-1	1. Participants not randomly allocated; 4. Inadequate control for selection bias

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.

Summary of Evidence
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.

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.¹⁷

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.

National Comprehensive Cancer Network
Current National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines for multiple myeloma (Version 4.2022 Dec 14, 2021) recommend (category 2A) idecabtagene vicleucel as a treatment option for patients with late relapses after at least 4 prior therapies, including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory 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 10.

Table 10. Summary of Key Trials

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	415	Nov 2024
NCT04196491 (KarMMa-4)	A study to evaluate the safety of bb2121 in subjects with high risk, newly diagnosed multiple myeloma	60	Jan 2025
NCT03651128 (KarMMa-3)	Efficacy and safety study of bb2121 versus standard regimens in subjects with relapsed and refractory multiple myeloma	381	Nov 2025
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	181	May 2026
Unpublished
NCT02786511a	Long-term follow-up of subjects treated with bb2121	50	Oct 2019
Ciltacabtagene autoleucel
Ongoing
NCT04133636 (CARTITUDE-2)	A study of JNJ-68284528, a CAR T-cell therapy directed against BCMA in participants with multiple myeloma	160	May 2025
NCT04181827 (CARTITUDE-4)	A study comparing JNJ-68284528, a CAR T-cell therapy directed against BCMA, versus pomalidomide, bortezomib and dexamethasone (PVd) or daratumumab, pomalidomide and dexamethasone (DPd) in participants with relapsed and lenalidomide-refractory multiple myeloma	400	Apr 2026
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	650	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	Jun 2026
NCT05201781	A Long-term Study for Participants Previously Treated With Ciltacabtagene Autoleucel	228	Aug 2036
NCT03758417 (CARTIFAN-1)	A Study of LCAR-B38M CAR-T Cells, a Chimeric Antigen Receptor T-cell (CAR-T) Therapy Directed Against B-cell Maturation Antigen (BCMA) in Chinese Participants With Relapsed or Refractory Multiple Myeloma	130	Nov 2022

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 May 23, 2022.
3. Key Statistics About Multiple Myeloma. https://www.cancer.org/cancer/multiple-myeloma/about/key-statistics.html. Accessed March 1, 2022.
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 4.2022- Dec 14, 2021. https://www.nccn.org/professionals/physician_gls/pdf/myeloma.pdf. Accessed March 1, 2022.
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. 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
11. 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
12. Prescribing Label: Abecma (idecabtagene vicleucel), suspension for intravenous infusion. Available at https://packageinserts.bms.com/pi/pi_abecma.pdf. Accessed on March 1, 2022
13. Lee DW, Santomasso BD, Locke FL, et al. ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells. Biol Blood Marrow Transplant. Apr 2019; 25(4): 625-638. PMID 30592986
14. 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
15. Berdeja JG, Madduri D, Usmani SZ, et al. Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b/2 open-label study. Lancet. Jul 24 2021; 398(10297): 314-324. PMID 34175021
16. Prescribing Label: Carvykti (ciltacabtagene autoleucel) suspension for intravenous infusion. Available at https://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/CARVYKTI-pi.pdf. Accessed March 1, 2022
17. 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 March 1, 2022.

Coding Section 

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 (eff 10/01/2022)
	C9098	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 (new eff 7/01/22-09/30/2022)
	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
Type of Service	Therapy
Place of Service	Inpatient/Outpatient

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may or 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" 

History From 2020 Forward     

03/06/2023	Interim review adding description, policy criteria and coding for Carvykti.
10/18/2022	Updated Coding Section. Added HCPCS Q2056 to be effective 10/01/2022
06/20/2022	Annual Review, no change to policy intent.
10/01/2021	Updating coding section adding code C9081 effective 10/01/2021. No other change
06/01/2021	New Policy