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2024-04-01T14:52:38.000Z

Integrating cilta-cel into earlier lines of therapy: Rationale and latest data from CARTITUDE-2 and CARTITUDE-4

Apr 1, 2024
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Learning objective: After reading this article, learners will be able to recall the rationale for and latest clinical trial data supporting the use of cilta-cel in earlier lines of therapy.

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Ciltacabtagene autoleucel (cilta-cel) is a B-cell maturation antigen (BCMA)-targeting chimeric antigen receptor (CAR) T-cell therapy, which is one of only two U.S. Food and Drug Administration (FDA)-approved CAR T-cell therapies for the treatment of relapsed/refractory multiple myeloma (RRMM). Both approved CAR T-cell agents are indicated in the heavily pre-treated setting after four or more prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.1

However, in February 2024, the European Medicines Agency (EMA) Committee for Medicinal Products for Human Use (CHMP) recommended the approval of cilta-cel after at least one prior line of therapy, including an immunomodulatory agent or proteasome inhibitor, for those who have progressed on the last therapy and are refractory to lenalidomide.1

The Multiple Myeloma Hub is pleased to summarize the rationale for and latest data from clinical trials of cilta-cel after one to three lines of therapy for the treatment of MM.

Rationale1

There are multiple justifications for the implementation of CAR T-cell therapies into earlier lines of therapy, including the potential to minimize mechanisms of resistance to CAR T-cell therapies (Figure 1).2

  • Fitter T-cells
    • Treatment with few prior lines of therapy is associated with improved persistence of CAR T-cells, and ultimately increased rates of myeloma cell death
  • Increased immunogenicity of tumor cells
    • Less pre-treatment heterogeneity in the antigen density expressed on tumor cells results in reduced resistant clone selection
    • Lower tumor burden
    • Implementation of CAR T-cells in earlier lines means tumor cells possess a lower proliferative potential

Figure 1. Mechanisms of resistance to CAR T-cells* 

CAR, chimeric antigen receptor; MM, multiple myeloma.
*Adapted from D’Agostino and Raje.3 Created with BioRender.com.

Additional justifications for the implementation of CAR T-cells in earlier lines include the following:

  • Better tolerability
    • Less pre-treatment in MM has been shown to reduce the incidence of cytopenias, infection, and secondary malignancies
    • Reduced tumor load is associated with reduced incidence of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), as well as a reduction in delayed neurotoxicity
  • Impact of prior therapies on the efficacy of CAR T-cell therapies
    • A difference in progression-free survival (PFS) rates of patients treated with CAR T-cell therapies is observed depending on pre-treatment (Figure 2)
    • The PFS rates of patients treated with CAR T-cell therapies were particularly reduced when pre-treated with bispecific antibodies
    • The later CAR T-cell therapies are delivered, the greater the likelihood of prior exposure to a therapy that negatively impacts PFS

Figure 2. PFS rates in patients treated with CAR T-cells by prior treatment* 

ADC, antibody–drug conjugate; BCMA-TT, B-cell maturation antigen targeted therapy; CAR, chimeric antigen receptor; PFS, progression-free survival.
*Adapted from Einsele.2

Additionally, there is an argument for implementing the treatments with the highest response rates in the earlier lines due to the lower documented attrition rates for therapy in the later lines (Figure 3). Notably, in Austria, 85% of patients with MM were unable to receive treatment beyond the third line of therapy, with similar data observed in the US, France, and Australia, highlighting the need for effective therapies in early lines where attrition rates remain high.2

Figure 3. Attrition rates for multiple myeloma therapies by line* 

1L, first-line treatment; 2L, second-line treatment; 3L, third-line treatment; 4L, fourth-line treatment; 5L, fifth-line treatment.
*Adapted from Einsele.2

CARTITUDE-2

CARTITUDE-2 (NCT04133636) is a phase II, multicohort clinical trial evaluating the safety and efficacy of cilta-cel for the treatment of MM. Cohorts A and B included patients with one to three prior lines of therapy who are lenalidomide-refractory and those with early relapse at ≤12-months after autologous stem cell transplant or treatment initiation, respectively.

The trial design of CARTITUDE-2, including primary and secondary endpoints, has been reported previously by the Multiple Myeloma Hub here.

Efficacy4

At a median follow up of 29.9 months in cohort A and 27.0 months in cohort B:

  • High rates of measurable residual disease negativity at a sensitivity rate of x10-5 were observed in both cohorts A and B at 100% and 93.3%, respectively.
    • Sustained measurable residual disease negativity at ≥6 months was 40% and 52.6%, respectively.
    • At ≥12 months, sustained measurable residual disease negativity was 35% and 36.8%, respectively.
  • Response data was also consistently high, with slightly increased overall response rates observed in cohort B; however, a higher proportion of responders in cohort A experienced a stringent complete response (Figure 4).

Figure 4. Response rates in Cohorts A and B from CARTITUDE-2* 

CR, complete response; ORR, overall response rate; PR, partial response; sCR, stringent complete response; VGPR, very good partial response.
*Data from Hillengrass, et al.4

At 24 months, median overall survival, PFS, and duration of response were not reached in either cohort (Figure 5).

Figure 5. 24-month OS, PFS, and DOR from CARTITUDE-2* 

DOR, duration of response; OS, overall survival; PFS, progression-free survival.
*Data from Hillengrass, et al.4

Safety3

  • Rates of adverse events, and particularly CRS, remained high: 95% and 84.2% in cohorts A and B, respectively. However, rates of Grade 3 or 4 events were markedly lower, at 10% and 5.3% (Table 1).
  • Treatment-emergent cytopenias, such as neutropenia, lymphopenia, and thrombocytopenia, were common in both cohorts, with a high proportion of Grade 3/4 events, consistent with cilta-cel use in later lines.
  • Secondary primary malignancies (SPMs) are being investigated increasingly for their association with CAR T-cell therapies, with SPMs only observed in cohort B.
    • However, due to a small cohort size, these proportions are likely unrepresentative of the larger population.

Table 1. Cytopenias and adverse events of special interest from CARTITUDE-2*

Adverse events, %

Cohort A
(n = 20)

Cohort B
(n = 19)

Any grade

Grade 3/4

Any grade

Grade 3/4

Treatment-emergent cytopenias

 

 

 

 

Neutropenia

95

95

94.7

89.5

Lymphopenia

80

80

47.4

47.4

Thrombocytopenia

80

40

57.9

26.3

Anemia

75

45

57.9

47.4

Leukopenia

60

60

31.6

31.6

AEs of special interest

 

 

 

 

CRS

95

10

84.2

5.3

CAR T-cell neurotoxicity

30

5

31.6

5.3

ICANS

15

0

5.3

0

Other neurotoxicities

15

5

26.3

5.3

MNT

0

0

5.3

5.3

SPM

0

0

10.5

5.3

AE, adverse event; CAR, chimeric antigen receptor; CRS, cytokine release syndrome; ICANS, immune effector cell-associated neurotoxicity syndrome; MNT, movement/neurocognitive treatment-emergent adverse event.
*Data from Hillengrass, et al.4

CARTITUDE-4

CARTITUDE-4 (NCT04181827) is a phase III, randomized trial evaluating the safety and efficacy of cilta-cel in patients with lenalidomide-refractory MM after one to three prior lines of therapy. The control group was standard-of-care treatment consisting of pomalidomide, bortezomib, and dexamethasone or daratumumab, pomalidomide, and dexamethasone.

The trial design of CARTITUDE-4, including primary and secondary endpoints, has been reported previously by the Multiple Myeloma Hub here.

Efficacy

High rates of overall response were observed in the 176 patients enrolled in CARTITUDE-4, with a majority (86.4%) reaching a complete response or higher (Figure 6).

Figure 6. Response rates from CARTITUDE-4* 

CR, complete response; ORR, overall response rate; PR, partial response; sCR, stringent complete response; VGPR, very good partial response.
*Adapted from Einsele.2

Safety2

As compared with CARTITUDE-1, a trial of cilta-cel in RRMM four or more prior lines of therapy, a lower incidence and severity of CRS, ICANS, and MNTs was observed in CARTITUDE-4, highlighting the potentially increased tolerability of CAR T-cell therapies in earlier lines. However, these data are likely confounded by differences in patient populations and treatment regimens, requiring further direct clinical trial comparisons to draw any conclusion.

Common adverse events included CRS and neurotoxicity, consistent with CAR T-cell use in later lines. However, the majority of these adverse events were Grade 1 or 2, with most cases of CRS resolved after 3 days (Table 2).

Table 2. Adverse events from CARTITUDE-4*

Adverse event, % unless otherwise specified

As-treated patients (n = 176)

Any grade

Grade 3/4

Median time to onset, days

Median duration, days

Resolved, n

CRS

76.1

1.1

8

3

134

Neurotoxicity

20.5

2.8

-

-

-

ICANS

4.5

0

10

2

8

Other

17

2.3

-

-

-

Cranial nerve palsy

9.1

1.1

21

77

14

Peripheral neuropathy

2.8

0.6

63

201

3

MNT

0.6

0

85

-

0

CRS, cytokine release syndrome; ICANS, immune effector cell-associated neurotoxicity syndrome; MNT, movement/neurocognitive treatment-emergent adverse event.
*Adapted from Einsele.2

CAR T-cell therapy in the first line1

Multiple trials investigating the safety and efficacy of CAR T-cell therapies in the first line setting in newly diagnosed MM are ongoing; including:

  • CARTITUDE-5 (NCT04923893)
    • Phase 3 randomized trial of bortezomib-lenalidomide-dexamethasone, followed by cilta-cel or followed by lenalidomide-dexamethasone in newly diagnosed MM where transplant is not planned as initial therapy
    • Status: Ongoing
  • CARTITUDE-6 (NCT05257083)
    • Phase 3 randomized trial of daratumumab-bortezomib-lenalidomide-dexamethasone followed by cilta-cel or autologous stem cell transplant in newly diagnosed MM
    • Status: Recruiting

Conclusion

A multitude of data support the investigation of cilta-cel in earlier lines of therapy, particularly highlighting the reduced likelihood of prior exposure to BCMA-directed therapies and lower incidence of toxicities, which have the potential to improve quality of life. Increased attrition rates paired with this reduction in toxicities highlight where CAR T-cell therapy may become appropriate and tolerable to a higher proportion of patients with MM. Data from CARTITUDE-2 and CARTITUDE-4 provide evidence for the efficacy of cilta-cel in this setting, although in relatively small cohorts.

This educational resource is independently supported by Johnson & Johnson. All content is developed by SES in collaboration with an expert steering committee; funders are allowed no influence on the content of this resource.

As a result of this content, I commit to reviewing the CARTITUDE clinical program to guide my understanding of cilta-cel in clinical practice.
16 votes - 16 days left

  1.  Janssen Receives Positive CHMP Opinion for CARVYKTI®▼ (ciltacabtagene autoleucel; cilta-cel) for Treatment in Earlier Lines of Relapsed and Refractory Multiple Myeloma. https://www.jnj.com/media-center/press-releases/janssen-receives-positive-chmp-opinion-for-carvykti-ciltacabtagene-autoleucel-cilta-cel-for-treatment-in-earlier-lines-of-relapsed-and-refractory-multiple-myeloma#:~:text=About%20Ciltacabtagene%20Autoleucel%20(cilta%2Dcel)&text=In%20February%202022%2C%20the%20U.S.,an%20anti%2DCD38%20monoclonal%20antibody. Published February 23, 2024. Accessed Mar 8, 2024.
  2. Einsele H. Moving CAR-T into first-line therapy in Multiple Myeloma. Physician session #PS08-1. Presented at: 6th European CAR T-cell Meeting; Feb 17, 2024; Valencia, ES.
  3. D’Agostino M and Raje N. Anti-BCMA CAR T-cell therapy in multiple myeloma: Can we do better? Leukemia. 2020;34(1):21-34. DOI: 1038/s41375-019-0669-4
  4. Hillengass J. The phase 2 Cartitude-2 trial: Updated efficacy and safety of ciltacabtagene autoleucel in patients with multiple myeloma and 1–3 prior lines of therapy (cohort A) and with early relapse after first line treatment (cohort B). Oral abstract #42. Presented at: 2024 Transplantation and Cellular Therapy Meetings of the ASTCT and CIMBTR; Feb 23, 2024; San Antonio, US.

Your opinion matters

As a result of this content, I commit to reviewing the CARTITUDE clinical program to guide my understanding of cilta-cel in clinical practice.
16 votes - 16 days left ...

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