summary

• CARTITUDE-1 (MMY2001) was a phase 1b/2, open-label, single-arm, multicenter study that evaluated CARVYKTI in patients with relapsed/refractory multiple myeloma (RRMM) who had previously received a proteasome inhibitor (PI), an immunomodulatory agent, and an anti-CD38 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.^1-4
• 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^® [daratumumab and hyaluronidase], pomalidomide, and dexamethasone [DPd]) in adult patients with lenalidomide-refractory multiple myeloma (MM) after 1-3 prior line(s) of therapy (LOT).^5,6
• The exclusion criteria and prohibited medications for CARTITUDE-1 and CARTITUDE-4 are summarized below.

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-1 - phASE 1B/2 STUDY

CARTITUDE-1 (MMY2001; clinicaltrials.gov identifier: NCT03548207) was a phase 1b/2, open-label, single-arm, multicenter study that evaluated the safety and efficacy of CARVYKTI in patients with RRMM who had previously received a PI, an immunomodulatory agent, and an antiCD38 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.^1-4

Study Design/Methods

CARTITUDE-1 Study Protocol - Exclusion Criteria

Any potential patient who met any of the following criteria were excluded from participating in the study:

• Prior treatment with chimeric antigen receptor-T (CAR-T) cell therapy directed at any target.²
• Any therapy that is targeted to B-cell maturation antigen (BCMA).²
• Diagnosed or treated for invasive malignancy other than multiple myeloma, except²:
  • Malignancy treated with curative intent and with no known active disease present for ≥2 years before enrollment; or
  • Adequately treated non-melanoma skin cancer without evidence of disease.
• Prior antitumor therapy as follows, prior to apheresis²:
  • Targeted therapy, epigenetic therapy, or treatment with an investigational drug or used an invasive investigational medical device within 14 days or at least 5 half-lives, whichever is less.
  • Monoclonal antibody treatment for multiple myeloma within 21 days.
  • Cytotoxic therapy within 14 days.
  • Proteasome inhibitor therapy within 14 days.
  • Immunomodulatory agent therapy within 7 days.
  • Radiotherapy within 14 days. However, if the radiation portal covered ≤5% of the bone marrow reserve, the patient is eligible irrespective of the end date of radiotherapy.
• Toxicity from previous anticancer therapy must resolve to baseline levels or to Grade 1 or less except for alopecia or peripheral neuropathy.²
• The following cardiac conditions²:
  • New York Heart Association (NYHA) stage III or IV congestive heart failure.
  • Myocardial infarction or coronary artery bypass graft (CABG) ≤6 months prior to enrollment.
  • History of clinically significant ventricular arrhythmia or unexplained syncope, not believed to be vasovagal in nature or due to dehydration.
  • History of severe non-ischemic cardiomyopathy.
  • Impaired cardiac function (left ventricular ejection fraction [LVEF] <45%) as assessed by echocardiogram or multiple-gated acquisition (MUGA) scan (performed ≤8 weeks of apheresis).
• Received a cumulative dose of corticosteroids equivalent to ≥70 mg of prednisone within 7 days prior to apheresis.²
• Received either of the following²:
  • An allogeneic stem cell transplant within 6 months before apheresis. Patients who received an allogeneic transplant must be off all immunosuppressive medications for 6 weeks without signs of graft-versus-host disease (GVHD).
  • An autologous stem cell transplant ≤12 weeks before apheresis.
• Known active, or prior history of central nervous system (CNS) involvement or exhibits clinical signs of meningeal involvement of multiple myeloma.²
• Stroke or seizure within 6 months of signing informed consent form (ICF).²
• Plasma cell leukemia at the time of screening (>2.0 × 10⁹/L plasma cells by standard differential), Waldenström’s macroglobulinemia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes), or primary amyloid light-chain (AL) amyloidosis.²
• Seropositive for human immunodeficiency virus (HIV).²
• Vaccinated with live, attenuated vaccine within 4 weeks prior to apheresis.²
• Hepatitis B infection. In the event the infection status is unclear, quantitative levels are necessary to determine the infection status.²
• Hepatitis C infection defined as (anti-hepatitis C virus [HCV] antibody positive or HCV-ribonucleic acid [RNA] positive) or known to have a history of hepatitis C. For patients with known history of HCV infection, confirmation of sustained virologic response (SVR) is required for eligibility, defined as ≥24 weeks after completion of antiviral therapy.²
• Supplemental oxygen use to maintain adequate oxygenation.²
• Known life threatening allergies, hypersensitivity, or intolerance to CARVYKTI or its excipients, including dimethyl sulfoxide (DMSO).²
• Serious underlying medical condition, such as²:
  • Evidence of serious active viral, bacterial, or uncontrolled systemic fungal infection.
  • Active autoimmune disease or a history of autoimmune disease within 3 years.
  • Overt clinical evidence of dementia or altered mental status.
• Any issue that would impair the ability of the patient to receive or tolerate the planned treatment at the treatment site, to understand informed consent or any condition for which, in the opinion of the investigator, participation would not be in the best interest of the patient (eg, compromise the well-being) or that could prevent, limit or confound the protocol-specified assessments.²
• Pregnant or breast-feeding or planning to become pregnant while enrolled in this study or within 1 year after receiving study treatment.²
• Plans to father a child while enrolled in this study or within 1 year after receiving study treatment.²
• Major surgery within 2 weeks prior to apheresis, or has surgery planned during the study or within 2 weeks after study treatment administration. (Note: patients with planned surgical procedures to be conducted under local anesthesia may participate).²

CARTITUDE-1 Study Protocol - Prohibited Therapies

The following medications were prohibited during the study:

• Corticosteroid use should be avoided, except for the treatment of cytokine release syndrome (CRS) or CAR-T cell-related neurotoxicity (eg, immune effector cell-associated neurotoxicity syndrome [ICANS]). Alternative therapies, if feasible, should be given prior to corticosteroids.²
• Any chemotherapy, anticancer immunotherapy (other than CARVYKTI), or experimental therapy, except as described for bridging therapy or protocol-specific therapies which may be used in conjunction with CARVYKTI.²
  • Bridging therapy (anti-plasma cell directed treatment between apheresis and the first dose of the conditioning regimen) was allowed when clinically indicated (ie, to maintain disease stability while waiting for manufacturing of CARVYKTI) with the permission of the sponsor. Additional cycles of bridging therapy may be considered based on patient’s clinical status and timing of availability of CARVYKTI. Enhanced bridging therapy was not implemented in CARTITUDE-1. Bridging therapy must be a short-term treatment with previously used agent resulting in at least a response of stable disease for the patient. The sponsor will not permit patients who are found to be in complete response (CR) after bridging therapy to receive CARVYKTI.²
• While in follow-up, emergency orthopedic surgery or radiotherapy is generally prohibited, but may be allowed in the absence of disease progression. Cases must be discussed and approved by the sponsor. Such emergency radiotherapy may consist of localized radiotherapy for pain control or for stabilization of an extensive bone lesion at high risk of pathologic fracture or damage to surrounding tissues.²
• Nonsteroidal anti-inflammatory agents should be avoided to minimize the risk of exacerbation of potential sub-clinical myeloma-related kidney disease. Based on the healthcare provider’s clinical judgement, low-dose aspirin may be continued for thromboprophylaxis.²
• Other immunosuppressant agents unless used as protocol-specified pre- or post-treatment medications to treat an adverse event (eg, CRS).²
• Vaccination with live, attenuated vaccine after signing consent and in the ≤4 weeks prior to the infusion of CARVYKTI, and for 100 days after infusion of CARVYKTI.²
• The use of intravenous (IV) contrast infusions should be avoided to prevent myeloma-related kidney disease. If administration of IV contrast is necessary, then adequate precautions including hydration are indicated.²
• Pegylated myeloid growth factors (ie, pegfilgrastim) are prohibited within the first 100 days after infusion of CARVYKTI.²

clinical data - cartitude-4 - phase 3 study

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.^5,6

CARTITUDE-4 Study Protocol - Exclusion Criteria

Any potential patient who met any of the following criteria were excluded from participating in the study:

• Prior treatment with CAR-T therapy directed at any target.⁷
• Any previous therapy that is targeted to BCMA.⁷
• Ongoing toxicity from previous anticancer therapy that has not resolved to baseline levels or to Grade 1 or less except for alopecia.⁷
• Patients with Grade 1 peripheral neuropathy with pain or Grade 2 or higher peripheral neuropathy will not be permitted to receive PVd as standard therapy or bridging therapy; however, patient may receive DPd as standard therapy or bridging therapy.⁷
• Received a cumulative dose of corticosteroids equivalent to ≥70 mg of prednisone within the 7 days prior to randomization.⁷
• Vaccinated with live attenuated vaccines within 6 weeks prior to randomization.⁷
• Prior antitumor therapy as follows, prior to randomization⁷:
  • Targeted therapy, epigenetic therapy, or treatment with an investigational drug or used an invasive investigational medical device within 14 days or at least 5 half-lives, whichever is less.
  • Investigational vaccine within 4 weeks.
  • Monoclonal antibody treatment within 21 days.
  • Cytotoxic therapy within 14 days.
  • Proteasome inhibitor therapy within 14 days.
  • Immunomodulatory agent therapy within 7 days.
  • Radiotherapy within 14 days. However, if the radiation is given for palliative purposes and the radiation portal covered ≤5% of the bone marrow reserve, the patient is eligible irrespective of the end date of radiotherapy. Radiotherapy within 14 days on measurable extramedullary plasmacytoma(s) is not permitted even in the setting of palliation for symptomatic management.
• Active malignancies (ie, progressing or requiring treatment change in the last 24 months) other than the disease being treated under study. The only allowed exceptions are⁷:
  • Non-muscle invasive bladder cancer treated within the last 24 months that is considered completely cured.
  • Skin cancer (non-melanoma or melanoma) treated with the last 24 months that is considered completely cured.
  • Non-invasive cervical cancer treated within the last 24 months that is considered completely cured.
  • Localized prostate cancer (N0M0):
    • with a Gleason score of ≤6, treated within the last 24 months or untreated and under surveillance,
    • with a Gleason score of 3+4 that has been treated more than 6 months prior to full study screening and considered to have a very low risk of recurrence, or
    • history of localized prostate cancer and receiving androgen deprivation therapy and considered to have a very low risk of recurrence.
  • Breast cancer: adequately treated lobular carcinoma in situ or ductal carcinoma in situ, or history of localized breast cancer and receiving antihormonal agents and considered to have a very low risk of recurrence.
  • Malignancy that is considered cured with minimal risk of recurrence.
• Plasma cell leukemia at the time of screening, Waldenström’s macroglobulinemia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein and skin changes) or primary AL amyloidosis.⁷
• Contraindications or life-threatening allergies, hypersensitivity, or intolerance to CARVYKTI or its excipients, including DMSO, or to fludarabine, cyclophosphamide, tocilizumab, pomalidomide, dexamethasone.⁷
  • Patients with contraindications or life-threatening allergies, hypersensitivity or intolerance to daratumumab will not be permitted to receive DPd as standard therapy or bridging therapy, however, patients may receive PVd as standard therapy or bridging therapy. Likewise, patients with contraindications or life-threatening allergies, hypersensitivity, or intolerance to bortezomib will not be permitted to receive PVd as standard therapy or bridging therapy; but may receive DPd as standard therapy or bridging therapy.
• Pregnant or breast-feeding or planning to become pregnant while enrolled in this study or within 3 months of receiving the last dose of daratumumab or bortezomib, or within 28 days after the last dose of pomalidomide, whichever is later (standard care arm) or at least within 1 year after receiving CARVYKTI infusion or at least within 3 months after receiving the last dose of daratumumab or bortezomib or within 28 days after the last dose of pomalidomide, whichever is later (CARVYKTI arm).⁷
• Plans to father a child while enrolled in this study or within 3 months after receiving the last dose of daratumumab or bortezomib, or within 28 days after the last dose of pomalidomide, whichever is later (standard care arm) or at least within 1 year after receiving CARVYKTI infusion or at least within 3 months after receiving the last dose of daratumumab or bortezomib or within 28 days after the last dose of pomalidomide, whichever is later (CARVYKTI arm).⁷
• Stroke or seizure within 6 months of signing ICF.⁷
• Received either of the following⁷:
  • An allogeneic stem cell transplant within 6 months before apheresis. Patients who received an allogeneic transplant must be off all immunosuppressive medications for 6 weeks without signs of GVHD. Patients with active GVHD are excluded.
  • An autologous stem cell transplantation ≤12 weeks before apheresis.
• Known active, or prior history of CNS involvement or exhibits clinical signs of meningeal involvement of multiple myeloma.⁷
• Patients with chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 standard (FEV1) <50% of predicted normal will not be able to receive DPd as standard therapy or bridging therapy, but may receive PVd as standard therapy or bridging therapy. Note that FEV1 testing is required for patients who are planned to receive treatment with DPd and area suspected of having COPD.⁷
• Seropositive for HIV.⁷
• Hepatitis B infection: In the event the infection status is unclear, quantitative viral levels are necessary to determine the infection status. Patients who are anti-Hepatitis B serology (HBs) positive and without history of vaccination or for patients who are anti-HBc positive with or without positive anti-HBs should have hepatitis B virus (HBV)-DNA quantification test done.⁷
• Hepatitis C infection (defined as anti-HCV antibody positive or HCV-RNA positive) or known to have a history of hepatitis C. For patients with known history of HCV infection, confirmation of sustained virologic response is required for study eligibility, defined as ≥24 weeks after completion of antiviral therapy.⁷
• Serious underlying medical or psychiatric condition or disease, that is likely to interfere with study procedures or results, or that in the opinion of the investigator would constitute a hazard for participating in this study, such as⁷:
  • Requirement of supplemental oxygen to maintain oxygen saturation.
  • Evidence of serious active viral, or bacterial infection requiring systemic antimicrobial therapy, or uncontrolled systemic fungal infection.
  • Active autoimmune disease.
  • Clinical evidence of dementia or altered mental status.
  • Any history of Parkinson’s disease or other neurodegenerative disorder.
• Clinically significant cardiac disease such as⁷:
  • NYHA Class III or IV congestive heart failure.
  • Myocardial infarction or coronary-artery-bypass graft ≤6 months prior to enrollment.
  • History of clinically significant ventricular arrhythmia or unexplained syncope, not believed to be vasovagal in nature or due to dehydration.
  • History of severe non-ischemic cardiomyopathy.
  • Impaired cardiac function (LVEF <45%) as assessed by echocardiogram or MUGA scan performed ≤8 weeks before randomization.
• Major surgery within 2 weeks before randomization, or has not fully recovered from an earlier surgery, or has major surgery planned during the time the patient is expected to participate in the study (note: kyphoplasty or vertebroplasty are not considered major surgery). If there is a question about whether a procedure is considered a major surgery, the investigator must consult with the sponsor and resolve any issues before enrolling a patient in the study.⁷
• Any issue that would impair the ability of the patient to receive or tolerate the planned treatment at the treatment site, to understand informed consent or any condition for which, in the opinion of the investigator, participation would not be in the best interest of the patient (eg, compromise the well-being) or that could prevent, limit or confound the protocol-specified assessments.⁷

CARTITUDE-4 Study Protocol - Prohibited Therapies

The following medications were prohibited during the study for patients randomized to treatment with either standard care (physician’s choice of PVd or DPd) or CARVYKTI:

Standard care arm and CARVYKTI arm

• Any chemotherapy, anticancer immunotherapy (other than CARVYKTI), or experimental therapy, except protocol-specified conditioning agents and bridging therapy.⁷
• Other immunosuppressant agents unless protocol-specified pre- or post-treatment medications to treat an adverse event (eg, CRS).⁷
• Orthopedic surgery or radiotherapy is generally prohibited but may be allowed in the absence of disease progression. Prior sponsor notification and approval is required. If necessary, an emergency intervention may proceed without prior approval from sponsor. In these cases, the sponsor should be notified as soon as is feasible. Such emergency radiotherapy may consist of localized radiotherapy for pain control or for stabilization of an extensive bone lesion at high risk of pathologic fracture or damage to surrounding tissues.⁷

CARVYKTI arm

• After the start of lymphodepletion and prior to Day 112, corticosteroid use should be avoided, except for the treatment of CRS or CAR-T cell-related neurotoxicity (ie, ICANS).⁷
• Vaccination with live, attenuated vaccine in the ≤6 weeks prior to the start of conditioning regimen, and for at least 112 days after infusion of CARVYKTI.⁷
• The use of receptor activator of nuclear factor kappa-RANK ligand inhibitors such as denosumab is prohibited due their potential impact on immune function.⁷
• Pegylated myeloid growth factors (ie, pegfilgrastim) are prohibited within the first 112 days after infusion with CARVYKTI.⁷

Therapies to be avoided

• Nonsteroidal anti-inflammatory agents should be avoided to minimize the risk of exacerbation of potential sub-clinical myeloma-related kidney disease. Based on the investigator’s clinical judgement, low-dose aspirin may be continued for thromboprophylaxis.⁷
• The use of IV contrast infusions should be avoided to prevent myeloma-related kidney disease. If administration of IV contrast is necessary, then adequate precautions including hydration are indicated.⁷
• For patients receiving PVd or DPd: avoid concomitant use of pomalidomide with strong inhibitors of cytochrome P450 (CYP)1A2 (eg, ciprofloxacin, enoxacin, and fluvoxamine). If deemed medically necessary, reduce the dose of pomalidomide by 50%.⁷
• For patients receiving PVd, patients should be closely monitored when given bortezomib in combination with potent CYP3A4 inhibitors and caution should be exercised when bortezomib is combined with CYP3A4-or CYP2C19 substrates.⁷

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 27 January 2025.