Long-Term Benefits in Patient-Reported Outcomes and Time to Next Anti-Myeloma Therapy of Ciltacabtagene Autoleucel (Cilta-cel) Versus Standard of Care for Patients with Lenalidomide-Refractory Multiple Myeloma: Results from the Phase 3 CARTITUDE-4 Clinical Trial

Noffar Bar¹, Roberto Mina², Anne K. Mylin³, Hisayuki Yokoyama⁴, Hila Magen^5,6, Winfried Alsdorf⁷, Monique C. Minnema⁸, Leyla O. Shune⁹, Iris Isufi¹⁰, Simon J. Harrison^11,12,13, Urvi A. Shah^14,15, André De Champlain¹⁶, Katherine S. Gries¹⁷, Diana Chen¹⁸, Quanlin Li¹⁹, Tzu-Min Yeh²⁰, Ana Slaughter²¹, Carolina Lonardi²², Nina Benachour²³, Arnab Ghosh²⁰, William Deraedt²³, Martin Vogel²⁴, Nikoletta Lendvai²⁰, Nitin Patel²⁵, Octavio Costa Filho²⁵, Erika Florendo²⁵, Lionel Karlin²⁶, Katja C. Weisel⁷

 

Introduction

• Earlier use of lenalidomide therapy in multiple myeloma (MM) has led to an increase in patients who are lenalidomide refractory after first relapse¹
  • Health-related quality of life (HRQoL) deteriorates with each relapse and additional line of therapy (LOT)²
• CARTITUDE-4 evaluated cilta-cel vs standard of care (SOC) in patients with lenalidomide-refractory MM after 1–3 prior LOT^3,4
  • At median 15.9-month follow-up, a single cilta-cel infusion significantly improved progression-free survival (PFS; weighted hazard ratio [HR], 0.26; P<0.0001) and had a manageable safety profile³
  • At median 33.6-month follow-up, cilta-cel significantly prolonged overall survival (OS), reducing the risk of death vs SOC by 45% (HR, 0.55; P=0.0009)⁴
• Here, we report patient-reported outcomes (PROs) and time to next antimyeloma therapy from patients randomized to cilta-cel vs SOC in CARTITUDE-4 at ~3 years of median follow-up

 

Methods

• CARTITUDE-4 is an ongoing global, randomized, phase 3 study³
  • Patients were randomized 1:1 to receive cilta-cel or SOC (pomalidomide, bortezomib, and dexamethasone [PVd] or daratumumab, pomalidomide, and dexamethasone [DPd])
  • Primary endpoint was PFS; key secondary endpoints included efficacy, safety, and time to worsening (TTW) of symptoms as assessed by the Multiple Myeloma Symptom and Impact Questionnaire (MySIm-Q) total symptom scale, which was part of the statistical testing hierarchy among the major efficacy endpoints
  • Changes from baseline (BL) in PRO scores were also secondary endpoints
• PROs scales were assessed at BL (apheresis for cilta-cel and cycle 1 day 1 for SOC); post-BL assessments occurred on day 28 postinfusion in the cilta-cel arm, at cycle 4 (DPd) or 5 (PVd) in the SOC arm, and at months 3, 6, 9, 12, 18, 24, 30 or until disease progression (Figure 1)
• TTW of symptoms and impact were defined as the time from randomization to an increase in score of ≥0.5 standard deviation from BL without an observed superior subsequent improvement
  • Patients were censored at last PRO assessment if they had not worsened, or had started subsequent therapy; patients were also censored at randomization if they did not have a BL or ≥1 post-BL PRO assessments
• Least squares (LS) mean changes from BL were evaluated using mixed model for repeated measures

 

Figure 1: PRO assessments

 

EORTC QLQ-C30, European Organisation for Research and Treatment of Cancer quality of life questionnaire core 30-item.

• Time to next antimyeloma therapy was defined as time from randomization to the start of subsequent antimyeloma therapy or death due to progressive disease (PD), whichever comes first
• Treatment-free survival was defined as the duration of time from the date of the last study treatment to subsequent therapy or death due to PD, whichever comes first
• Outcomes were assessed using the Kaplan-Meier method. Stratified Cox proportional hazards models were used to estimate HR and 95% CI

 

Results

PRO compliance

• As of May 2024, median follow-up was 33.6 months (range, 0.1–45.0)
  • Compliance rates were generally high for both MySIm-Q and EORTC QLQ-C30 assessments in both treatment arms (Figure 2)
  • Main reasons for noncompliance were other (ie, mistakes, forgot, site error/oversight, unknown, site staff not available, administrative failure, used paper, tablet issues) and technical failure

   

Figure 2: PRO compliance rates^a

^aCompliance was defined as the number of forms received as a percentage of the number of forms expected.
M, month(s).

 

MySIm-Q total symptom and impact scales

• Overall, 86% of patients in the cilta-cel arm and 77% in the SOC arm were censored from the MySIm-Q time to sustained worsening analysis
  • Among patients censored, the primary reasons were PD/receipt of subsequent antimyeloma therapy (cilta-cel: 32%; SOC: 64%) and study cut-off (cilta-cel: 57%; SOC: 22%)
• Median time until symptom worsening was not reached (NR) in the cilta-cel arm and was 34.3 months in the SOC arm (Figure 3)
  • Event-free rates at 30 months were 77% in the cilta-cel arm and 63% in the SOC arm

   

Figure 3: TTW in MySIm-Q total symptom scale

mTTW, median time to worsening; NE, not estimable.

 

• Median time until impact worsening was 39.2 months (95% CI, 38.7–NE) in the cilta-cel arm and 35.9 months (95% CI, 32.2–NE) in the SOC arm (HR [95% CI], 0.42 [0.26–0.70]; P=0.0007)
  • Event-free rates at 30 months were 83% in the cilta-cel arm and 69% in the SOC arm
• LS mean change from BL in the MySIm-Q total symptom and impact scores showed greater change with cilta-cel vs SOC at month 30 (Figure 4)
  
  

Figure 4 LS mean change from BL on the MySIm-Q total symptom and impact scores at month 30

 

 

EORTC QLQ-C30 global health status/quality of life (QoL)

• Clinically meaningful improvements in global health status, physical functioning, and fatigue and pain symptoms were achieved in a numerically higher proportion of patients in the cilta-cel arm than the SOC arm at month 30 (Figure 5A)
• LS mean change from BL showed greater improvement with cilta-cel vs SOC at month 30 in global health status, physical functioning, and fatigue and pain symptoms (Figure 5B)
• Cognitive, emotional, role and social functioning, and nausea and vomiting symptoms showed greater improvement in the cilta-cel arm compared with SOC arm (Figure 5C)

 

Figure 5: (A) Clinically meaningful improvement and (B) LS mean change from BL on EORTC QLQ-C30 scales at month 30

^aLiterature-based minimum importance difference of 10 points was used.

 

 

Figure 5 (continued): (C) LS mean change from BL on EORTC QLQ-C30 scales at month 30

 

 

Time to next antimyeloma therapy

Median time to next antimyeloma therapy was NR (95% CI, 38.4 months–NE) for cilta-cel, and was 13.4 months (95% CI, 12.0–17.1) for SOC (Figure 6)

 

Figure 6: Time to next antimyeloma therapy

 

 

Treatment-free survival

• Median treatment-free survival was NR (95% CI, 36.6 months–NE) for cilta-cel, and was 1.0 months (95% CI, 0.8–1.2) for SOC (Figure 7)

 

Figure 7: Treatment-free survival

 

 

References

1. de Arriba de la Fuente F, et al. Cancers (Basel) 2022;15:155. 2. Fonseca R, et al. Clin Lymphoma Myeloma Leuk 2023;23:426-37. 3. San-Miguel J, et al. N Engl J Med 2023;389:335-47.4. Mateos M-V, et al. Clin Lymphoma Myeloma Leuk 2024;24(suppl 2):S290. 5. Gries KS, et al. Value Health 2021;24:1807-19. 6. Aaronson NK, et al. J Natl Cancer Inst 1993;85:365-76.

 

Acknowledgments

We thank the patients who participated in the study and their families and caregivers, the physicians and nurses who cared for patients and supported this clinical trial, staff members at the study sites, and staff members involved in data collection and analyses. This study was funded by Janssen Research & Development, LLC, and Legend Biotech USA Inc. Medical writing support was provided by Joy Lin, PhD, of Eloquent Scientific Solutions, and funded by Janssen Global Services, LLC.

 

¹Yale Cancer Center, Yale University, New Haven, CT, USA; ²University of Turin and Azienda Ospedaliero-Universitaria (A.O.U.) Città della Salute e della Scienza di Torino, Turin, Italy; ³Rigshospitalet, Copenhagen, Denmark; ⁴Tohoku University Graduate School of Medicine, Sendai, Japan; ⁵Chaim Sheba Medical Center, Ramat-Gan, Israel; ⁶Sackler Faculty of Medicine, Tel Aviv University, Petach Tikva, Israel; ⁷University Medical Center Hamburg-Eppendorf, Hamburg, Germany; ⁸University Medical Center Utrecht, Utrecht, Netherlands; ⁹The University of Kansas Medical Center, Kansas City, KS, USA; ¹⁰Yale School of Medicine, Yale University, New Haven, CT, USA; ¹¹Peter MacCallum Cancer Centre, Melbourne, Australia; ¹²Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Australia; ¹³Royal Melbourne Hospital, Melbourne, Australia; ¹⁴Memorial Sloan Kettering Cancer Center, New York, NY, USA; ¹⁵Weill Cornell Medical College, New York, NY, USA; ¹⁶Janssen Global Services, LLC, Horsham, PA, USA; ¹⁷Janssen Global Services, LLC, Raritan, NJ, USA; ¹⁸Janssen Research & Development, Shanghai, China; ¹⁹Janssen Research & Development, Apex, NC, USA; ²⁰Janssen Research & Development, Raritan, NJ, USA; ²¹Cilag GmbH International, Zug, Switzerland; ²²Janssen, Buenos Aires, Argentina; ²³Janssen Research & Development, Beerse, Belgium; ²⁴Janssen Research & Development, Neuss, Germany; ²⁵Legend Biotech USA Inc., Somerset, NJ, USA; ²⁶Centre Hospitalier Lyon Sud, Pierre-Bénite, France