SUMMARY  

• Renal impairment studies of CARVYKTI were not conducted. CARVYKTI maximum concentration and area under the curve in the first 28 days following CARVYKTI administration in patients with mild renal dysfunction (60 mL/min ≤creatinine clearance [CRCL] <90 mL/min) or moderate renal dysfunction (30 mL/min ≤CRCL <60 mL/min) were similar to patients with normal renal function (CRCL ≥90 mL/min).¹
• CARTITUDE-1 (MMY2001) was a phase 1b/2, open-label, single-arm, multicenter study evaluating CARVYKTI in patients with relapsed/refractory multiple myeloma (RRMM) who had previously received a proteasome inhibitor, an immunomodulatory agent, and an anti-cluster of differentiation (CD) 38 antibody. The combined analysis from the phase 1b/2 portions of the CARTITUDE-1 study evaluated the safety and efficacy of CARVYKTI in 97 patients with RRMM.^2-4
  • Per protocol, patients enrolled in the study were required to have adequate renal function during the screening phase described as: estimated glomerular filtration (eGFR) ≥40 mL/min/1.73 m² based upon Modified Diet in Renal Disease (MDRD) formula calculation or directly measured via a 24-hour urine collection.⁵
• CARTITUDE-4 (MMY3002) is a phase 3, randomized, open-label study evaluating the efficacy and safety of CARVYKTI versus standard care (physician’s choice of pomalidomide, bortezomib, and dexamethasone [PVd] or DARZALEX FASPRO^® [DPd]) in adult patients with lenalidomide refractory multiple myeloma (MM) after 1-3 prior line(s) of therapy (LOT).^6,7
  • Per protocol, patients enrolled in the study were required to have adequate renal function during the screening phase described as eGFR ≥40 mL/min per 1.73 m² based on the MDRD formula calculation.⁸
    • Re-testing was allowed but the criteria must have been met in the latest test prior to randomization.⁸
  • Efficacy was evaluated in the intention-to-treat (ITT) population (all randomized patients; CARVYKTI, n=208; standard care, n=211). Subgroup analyses of progression-free survival (PFS) in the CARVYKTI vs standard care arms included patients based on baseline renal function. All analyses favored the CARVYKTI arm and showed effects similar to that observed in the analysis of the ITT population.^6,9
• Pak et al (2024)¹⁰ reported 2 cases of CARVYKTI use in patients with RRMM who were on maintenance hemodialysis (HD) for kidney failure at the Memorial Sloan Kettering Cancer Center, New York.

PRODUCT LABELING

• CARVYKTI (ciltacabtagene autoleucel) [Prescribing Information]. Horsham, PA: Janssen Biotech, Inc.; https://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/CARVYKTI-pi.pdf.
• DARZALEX FASPRO (daratumumab and hyaluronidase-fihj) [Prescribing Information]. Horsham, PA: Janssen Biotech, Inc.; https://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/DARZALEX+Faspro-pi.pdf

CLINICAL DATA - cartitude-4

CARTITUDE-4 (MMY3002; clinicaltrials.gov identifier: NCT04181827) is an ongoing, phase 3, randomized, open-label study evaluating the efficacy and safety of CARVYKTI versus standard care (physician's choice of PVd or DPd) in adult patients with lenalidomide-refractory MM after 1-3 prior LOT.⁶

Study Design/Methods

• Per protocol, patients enrolled in the study were required to have adequate renal function during the screening phase described as eGFR ≥40 mL/min per 1.73 m² based on the MDRD formula calculation.⁸
  • Re-testing was allowed but the criteria must have been met in the latest test prior to randomization.⁸

Results

Patient Demographics and Disease/Treatment Characteristics

• Overall, 419 patients were randomized to receive CARVYKTI (n=208) or standard care (n=211; DPd [n=183] or PVd [n=28]).⁶

Efficacy

ITT Population

• Efficacy was evaluated in the ITT population (all randomized patients; CARVYKTI, n=208; standard care, n=211).⁶
  • At a median follow-up of 15.9 months (range, 0.1-27.3), CARVYKTI significantly prolonged PFS vs. standard care (hazard ratio [HR] 0.26; 95% confidence interval [CI], 0.18–0.38; P<0.001); the median PFS was not reached in the CARVYKTI arm and was 11.8 months (95% CI, 9.7-13.8) in the standard care arm. The 12-month PFS rates (95% CI) for the CARVYKTI arm and standard care arms were 75.9% (69.4-81.1) and 48.6% (41.5-55.3), respectively.⁶
    • In an unweighted sensitivity analysis, CARVYKTI improved PFS compared with standard care (HR, 0.40; 95% CI, 0.29–0.55; P<0.0001).⁹
  • Subgroup analyses of PFS in the CARVYKTI vs standard care arms in patients with baseline renal function <60 mL/min/1.73 m² and ≥60 mL/min/1.73 m² (based on the MDRD formula) favored the CARVYKTI arm and showed effects similar to that observed in the analysis of the ITT population.⁹
    • Baseline renal function <60 mL/min/1.73 m²: HR 0.29; 95% CI (0.13-0.68).⁹
    • Baseline renal function ≥60 mL/min/1.73 m²: HR 0.28; 95% CI (0.14-0.59).⁹

Case reports

Pak et al (2024)¹⁰ reported 2 cases of CARVYKTI use in patients with RRMM who were on maintenance HD for kidney failure at the Memorial Sloan Kettering Cancer Center, New York.

• The first case was a 50-year-old female patient who was initially diagnosed with κ-free light chain (FLC) International Staging System (ISS) stage III MM with high-risk cytogenetics (del[1p] and del[17p]). The patient presented with an acute kidney injury that required urgent HD. The patient received induction treatment with cyclophosphamide-bortezomib-dexamethasone and autologous hematopoietic stem cell transplantation for MM. Despite attaining a very good partial response (VGPR) and substantial decrease in serum FLC with treatment, the patient remained dependent on dialysis. The patient relapsed several times after initial treatment and received lenalidomide-bortezomib-dexamethasone, daratumumab-lenalidomide-dexamethasone, and carfilzomib-pomalidomide-dexamethasone. The patient achieved a VGPR after each regimen. The patient experienced disease progression 2.5 years after carfilzomib-pomalidomide-dexamethasone therapy, with a serum κ-FLC of 368 mg/L and κ/λ ratio of 20. A decision was made to administer CARVYKTI for relapsed MM.
  • Due to the underlying kidney failure, the patient received modified lymphodepletion and HD.
    • Lymphodepletion: cyclophosphamide 300 mg/m² (standard dose) and fludarabine 15 mg/m² (50% reduced dose)were administeredon days -5, -4, and -3.
    • During lymphodepletion, HD was performed 10.5-15 hours after each fludarabine dose using a high-flux dialyzer (Optiflux F160Nre) with blood flow rates of 300-350 ml/min. Each HD session lasted 6 hours. On day -3, the patient’s dialysis arteriovenous graft infiltrated during cannulation, necessitating urgent insertion of HD catheter.
  • CARVYKTI was administered on day 0 without issue. On day +1 (>24 hours post CARVYKTI infusion), the patient underwent a standard 4-hour HD session.
  • The patient did not experience cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), or fludarabine-related neurotoxicity after treatment.
  • The absolute neutrophil count reached a nadir on day +4 (0.7 x 10⁹/L) and normalized without intervention on day +10.
  • On day -1, the patient received 1 unit of packed red blood cells for a hemoglobin of 6.8 g/dL and remained tranfusion-free while the patient’s hemoglobin returned to baseline on day +40 (9.4 g/dL).
  • The platelet count remained above 100 x 10⁹/L.
  • The serum κ-FLC decreased from 141 mg/L to 0.8 mg/L and the κ/λ ratio decreased from 19.29 to 0.42 after treatment. These values remained low on the latest patient follow-up on day +64.
  • No immunohistochemical or immunophenotypic evidence of disease was identified on bone marrow examination on day +28.
• The second case was a 70-year-old male patient with a history of κ-FLC ISS stage III MM with high-risk cytogenetics (del[17p]), polycythemia vera, hypertension, and MM-related kidney disease. The patient had received induction treatment with bortezomib-dexamethasone for MM and had achieved good hematologic response. The patient experienced disease progression and received treatment with carfilzomib-dexamethasone. Despite therapy, the patient developed kidney failure and was dependent on maintenance dialysis. Subsequently, the patient received treatment with carfilzomib-lenalidomide-dexamethasone followed by daratumumab-bortezomib-dexamethasone and was on maintenance treatment with daratumumab-bortezomib for the last 3 years before presenting with a serum M-spike of 0.74 g/dL, serum κ-FLC of 168 mg/L, and κ/λ ratio of 8.26. Bone marrow examination revealed 20%-25% plasma cells (97.6% of the cells were abnormal). A decision was made to administer CARVYKTI for cytoreduction of MM to achieve eligibility for kidney transplant.
  • Lymphodepletion was modified to include administration of cyclophosphamide 300 mg/m² (standard dose) on days -5, -4, and -3. Fludarabine was not included in the lymphodepletion regimen.
  • HD was performed on days -6, -3, and -1 using a high-flux dialyzer (Optiflux F160Nre) with blood flow rates of 400 mL/min. Each HD session lasted 4 hours. HD sessions on days -1 and +1 were performed at least 24 hours apart from CARVYKTI infusion.
  • CARVYKTI was administered on day 0.
  • The patient experienced grade 1 CRS with fevers on days +6, +8, and +9. The fever subsided after treatment with tocilizumab on day +6 and dexamethasone on days +8 and +9.
  • The patient did not experience ICANS after treatment.
  • The absolute neutrophil count dropped below 0.5 x 10⁹/L on day +9; however, the count normalized by day +17 without any intervention.
  • The lowest hemoglobin count was 8.8 g/dL on day +10.
  • The lowest platelet count was 95 x 10⁹/L on day +10.
  • The patient did not require transfusions.
  • Disease restaging on day +28 showed a decrease in serum M-spike, κ-FLC, and κ/λ ratio.
  • No plasma cell neoplasm was identified on bone marrow biopsy (via immunohistochemistry and flow cytometry).
  • The serum M-spike further decreased to 0.18 g/dL and κ/λ ratio remained normal at 0.93 on day +90.

Literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File databases (and/or other resources, including internal/external databases) was conducted on 12 August 2024.