Overview
The goal of this research study is to test if ciltacabtagene autoleucel (cilta-cel) is safe and effective in treating participants with high-risk, smoldering myeloma.
The names of the treatment interventions used in this study are:
- Cilta-cel (or chimeric antigen receptor T cells)
- Cyclophosphamide (a lymphodepleting chemotherapy)
- Fludarabine (a lymphodepleting chemotherapy)
Description
This is a Phase II study to test the safety and effectiveness of study therapy cilta-cel in treating participants with high-risk smoldering multiple myeloma (SMM). T cells are a part of a person's immune system which usually helps fight infection and prevents/fights cancer cells.
The U.S. Food and Drug Administration (FDA) has approved cilta-cel as a treatment for relapsed and refractory multiple myeloma but not specifically for smoldering myeloma.
The research study procedures include screening for eligibility, study treatment including evaluations, blood collections, radiologic scans of tumors, bone marrow biopsies, and follow-up visits.
Participation in this study is expected to last about 15 years.
It is expected that about 20 people will take part in this research study.
This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational therapy to learn whether the therapy works in treating a specific disease. "Investigational" means that the therapy is being studied.
Janssen Research & Development, LLC is supporting this research study by providing the study treatment and funding.
Eligibility
Inclusion Criteria:
- Age > 18 years.
- High-risk SMM with ≤40% plasma cells in the bone marrow and with high-risk criteria
defined as having 1 of the following 2 criteria:
- High-risk per "20-2-20" Criteria defined as presence of any two of the following:
- Serum M-protein ≥ 2 gm/dL
- Involved to uninvolved free light chain (FLC) ratio≥ 20
- Bone marrow PC% ≥ 20% to <40%.
- OR total score of 9 using the following scoring system:
- FLC Ratio
- >10-25 = 2
- >25-40 = 3
- > 40 = 5
- Serum M-protein (g/dL)
- >1.5-3 = 3
- >3 = 4
- BMPC%
- >15-20 = 2
- >20-30 = 3
- >30-40 = 5
- >40 = 6
- FISH abnormality (t(4,14), t(14,16), 1q gain, or del13q = 2
- FLC Ratio
- Presence of ≥10% BMPC and at least one of the following:
- Evolving pattern:
- eMP (≥10% increase in serum M-protein ) over a 6 month period OR;
- Evolving change in hemoglobin (eHb) ≥ 0.5 g/dl decrease over a 12 months period OR;
- Progressive Involved light chain increase >10% over a 6 month period along with a light chain ration > 8
- Abnormal PC immunophenotype (≥95% of BMPCs are clonal) and reduction of ≥1
uninvolved immunoglobulin isotype. (Only IgG; IgA and IgM will be considered) High risk cytogenetics defined as presence of t(4;14), t(14;16), t(14;20), 17p deletion, TP53 mutation, 1q21 gain
- Evolving pattern:
- High-risk per "20-2-20" Criteria defined as presence of any two of the following:
- No evidence of CRAB criteria* or new criteria of active MM (SLIM-CRAB) which including
the following:
- Increased calcium levels: Corrected serum calcium >0.25 mmol/L (>1mg/dL) above the upper limit of normal or >2.75 mmol/L (>11mg/dL);
- Renal insufficiency (attributable to myeloma);
- Anemia (Hgb 2g/dL below the lower limit of normal or <10g/dL);
- Bone lesions (lytic lesions or generalized osteoporosis with compression fractures)
- No evidence of the following new criteria for active MM including the following:
- Bone marrow plasma cells >60%
- Serum involved/uninvolved FLC ratio ≥100
- MRI with more than one focal lesion
- Participants with CRAB criteria that are attributable to conditions other than the disease under study may be eligible after discussion with the Sponsor Investigator.
- ECOG Performance Status (PS) 0 or 1 (Appendix 8)
- The following laboratory values obtained < 28 days prior to registration:
- ANC >1000/mL
- PLT >75,000/mL
- Total bilirubin ≤ 2.0 mg/dL (If total is elevated check direct and if normal patient is eligible.)
- AST <2.5 x institutional upper limit of normal (ULN)
- ALT <2.5 x institutional upper limit of normal (ULN)
- Estimated creatinine clearance CrCl ≥60 mL/min (Cockcroft Gault equation).
- Voluntary written informed consent before performance of any study-related procedure
not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care.
- Women of childbearing potential must have a negative pregnancy test at screening.
- When a woman is of childbearing potential, the following are required:
• Subject must agree to practice a highly effective method of contraception (failure rate of <1% per year when used consistently and correctly) and agree to remain on a highly effective method of contraception from the time of signing the informed consent form (ICF) until 1 year after receiving a cilta-cel infusion. Examples of highly effective contraceptives include:
- user-independent methods: 1) implantable progestogen-only hormone contraception associated with inhibition of ovulation; 2) intrauterine device; intrauterine hormone- releasing system; 3) vasectomized partner.
- user-dependent methods: 1) combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation: oral or intravaginal or transdermal; 2) progestogen-only hormone contraception associated with inhibition of ovulation (oral or injectable).
- In addition to the highly effective method of contraception, a man:
- Who is sexually active with a woman of childbearing potential must agree to use a barrier method of contraception (eg, condom with spermicidal foam/gel/film/cream/suppository) from the time of signing the ICF until 1 year after receiving a cilta-cel infusion.
- Who is sexually active with a woman who is pregnant must use a condom. Women and men must agree not to donate eggs (ova, oocytes) or sperm, respectively, during the study and for 1 year after the last dose of study treatment.
- When a woman is of childbearing potential, the following are required:
Note: Hormonal contraception may be susceptible to interaction with the study treatment,
which may reduce the efficacy of the contraceptive method.
Exclusion Criteria:
- Prior SMM directed therapy.
- Symptomatic Multiple Myeloma or any evidence of CRAB criteria, including presence of
myeloma defining events (MDE). Any prior therapy for active Myeloma should also be
excluded. Bisphosphonates are not excluded.
- Other concurrent chemotherapy, immunotherapy, radiotherapy, or any ancillary therapy
considered investigational. Prior therapy with bisphosphonate is allowed. Prior
radiation therapy to a solitary plasmacytoma is allowed but had to be at least 1 year
prior to enrollment on the trial. Prior clinical trials or therapy for smoldering MM
or MGUS are not allowed per exclusion criteria described above.
- Serious medical or psychiatric illness likely to interfere with participation in this
clinical study.
- Diagnosed or treated for another malignancy within 2 years of enrollment, with the
exception of complete resection of basal cell carcinoma or squamous cell carcinoma of
the skin, an in-situ malignancy, or low-risk prostate cancer after curative therapy.
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, inflammatory disorders, unstable
angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that
would limit compliance with study requirements.
- Plans to father a child while enrolled in this study or within 1 year after receiving
the last dose of study drug.
- Pregnant or breast-feeding or planning to become pregnant while enrolled in this study
or within 1 year after receiving the last dose of study drug.
- Known seropositive for or active viral infection with human immunodeficiency virus
(HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV) or SARS-CoV-2 (COVID-19).
- Participants who are seropositive because of hepatitis B virus vaccine are
eligible.
- Participants who are positive for SARS-COV-2 antibody, HIV1 and 2 antibody,
hepatitis B core antibody or hepatitis B surface antigen must have a negative
polymerase chain reaction (PCR) result before enrollment. Those who are PCR
positive will be excluded.
- Participants who are positive for HIV1 or 2 infections, with undetectable viral
load and on stable antiretrovirals, will not be excluded.
- Participants with past HCV infection that have now cleared will not be excluded.
- Contraindications or life-threatening allergies, hypersensitivity, or intolerance to
any study drug or its excipients (refer to Investigator's Brochure and appropriate
package inserts).
- Prior or concurrent exposure to any of the following:
1. Teclistamab, Belantamab, or any anti-BCMA therapy
2. Investigational vaccine within 4 weeks of study therapy
3. Live, attenuated vaccine within 4 weeks of study therapy.
4. Monoclonal antibody therapy within 21 days except for those unrelated to MM
therapy such as rituximab or other monoclonal antibodies for RA for example.
5. Cytotoxic therapy within 14 days of study therapy
6. PI therapy within 14 days of study therapy
7. IMiD agent therapy within 14 days of study therapy
8. Radiotherapy within 14 days or focal radiation within 7 days of study therapy.
- Known active CNS involvement or exhibits clinical signs of meningeal involvement of
multiple myeloma. If either is suspected, negative whole brain MRI and lumbar cytology
are required.
- Myelodysplastic syndrome or active malignancies (i.e., progressing or requiring
treatment change in the last 24 months). The only allowed exceptions are:
1. Non-muscle invasive bladder cancer treated within the last 24 months that is
considered completely cured.
2. Skin cancer (non-melanoma or melanoma) treated within the last 24 months that is
considered completely cured.
3. Noninvasive cervical cancer treated within the last 24 months that is considered
completely cured.
4. 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 or 4 that has been treated > 6months prior to
study screening and considered to have a very low risk of occurrence, or
5. History of localized prostate cancer and receiving androgen deprivation therapy
and considered to have a very low risk of recurrence.
6. Breast cancer: Adequately treated lobular carcinoma in situ or ductal carcinoma
in situ, or history of localized breast cancer and receiving anti-hormonal agents
and considered to have a very low risk of recurrence.
7. Other malignancy that is considered cured with minimal risk of recurrence in the
judgement of the investigator.
- Stroke or seizure within 6 months prior to signing ICF.
- Presence of the following cardiac conditions:
1. New York Heart Association stage III or IV congestive heart failure
2. Myocardial infarction or coronary artery bypass graft ≤6 months
3. History of clinically significant ventricular arrhythmia or unexplained syncope,
not believed to be vasovagal in nature or due to dehydration
4. History of severe non-ischemic cardiomyopathy
- Major surgery within 2 weeks prior to the start of administration of study treatment,
or will not have fully recovered from surgery, or has major surgery planned during the
time the participant is expected to be treated in the study or within 2 weeks after
administration of the last dose of study treatment.
- Concurrent 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 as:
1. Uncontrolled diabetes.
2. Acute diffuse infiltrative pulmonary disease.
3. Evidence of active systemic viral, fungal, or bacterial infection, requiring
systemic antimicrobial therapy.
4. History of inflammatory disorders with the exception of vitiligo, type I
diabetes, and prior autoimmune thyroiditis that is currently euthyroid based on
clinical symptoms and laboratory testing. Participants with mild rheumatoid
arthritis will not be excluded.
5. Disabling psychiatric conditions (e.g., alcohol or drug abuse), severe dementia,
or altered mental status.
6. Any other issue that would impair the ability of the participant to receive or
tolerate the planned treatment at the investigational 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 participant (e.g.,
compromise the well-being) or that could prevent, limit, or confound the
protocol-specified assessments.
7. History of non-compliance with recommended medical treatments.