A Study Comparing Treatment With Teclistamab and Talquetamab Versus Daratumumab and Lenalidomide in Patients With Multiple Myeloma After Stem Cell Transplant Who Still Have Detectable Disease

Multiple myeloma is a malignant plasma cell disorder characterized by repeated relapses despite advances in treatment. Following induction therapy and high-dose chemotherapy with autologous stem cell transplantation (ASCT), many patients achieve deep clinical responses. However, a proportion of patients remain positive for measurable residual disease (MRD), indicating the presence of residual malignant plasma cells and an increased risk of disease progression.

The TiTan study (protocol PMC011) is a phase III, randomized, open-label, multicenter clinical trial conducted in Poland. The study evaluates the efficacy and safety of two maintenance treatment strategies in adult patients with newly diagnosed multiple myeloma who remain MRD-positive after ASCT.

The study is designed to evaluate whether maintenance therapy with teclistamab in combination with talquetamab can improve treatment outcomes compared with standard maintenance therapy with daratumumab and lenalidomide in participants with newly diagnosed multiple myeloma who remain MRD-positive after ASCT.

This is a randomized, open-label, parallel-group study enrolling approximately 248 adult participants. Eligible participants have newly diagnosed multiple myeloma, have completed high-dose chemotherapy and ASCT, and have confirmed MRD positivity assessed using sensitive laboratory methods.

Participants may receive up to two cycles of consolidation therapy after ASCT. Eligible participants are randomized within a defined period after transplantation to one of two treatment arms in a 1:1 ratio.

Participants assigned to the experimental arm receive maintenance therapy with teclistamab and talquetamab. Participants assigned to the control arm receive maintenance therapy with daratumumab and lenalidomide. Treatment administration and duration follow protocol-defined procedures.

Treatment response is assessed according to International Myeloma Working Group (IMWG) criteria. MRD is evaluated in bone marrow samples using next-generation flow cytometry (NGF) at a sensitivity level of 10-⁵.

Disease assessments include evaluation of monoclonal protein using standard laboratory methods, including serum and urine protein electrophoresis, immunofixation, serum free light chain assessment, and imaging studies when clinically indicated.

Participants are followed throughout the study for evaluation of disease status, response to treatment, safety, and survival outcomes. Following completion of study treatment, participants continue protocol-defined follow-up assessments. After disease progression, information on subsequent anti-myeloma therapies and long-term outcomes is collected until study completion.

Safety and tolerability are assessed throughout the study using adverse event reporting, clinical examinations, and laboratory evaluations. Adverse events are graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 5.0.

Persistence of MRD after ASCT is associated with an increased risk of disease progression in multiple myeloma. This study evaluates whether an immunotherapy-based maintenance strategy can achieve deeper disease control than standard maintenance treatment in patients with residual disease after transplantation and further explores the relationship between MRD status and clinical outcomes.

Inclusion criteria

• Documented diagnosis of MM as per IMWG diagnostic criteria.
• Newly diagnosed patients who have completed a single or tandem autologous stem cell transplant after receiving quadruplet induction (containing an anti-CD38 antibody, an immunomodulatory drug, and a proteasome inhibitor). Up to 2 cycles of post-ASCT consolidation are acceptable.
• Patients must have received high-dose chemotherapy and a first ASCT within 12 months from the initiation of induction therapy.
• Patients must be within 6 months of their most recent ASCT, or within 7 months for patients who received consolidation therapy.
• Positive minimal residual disease (at a 10-⁵ threshold) in the bone marrow assessed by NGF after autologous stem cell transplantation (assessed 60 to 150 days after transplantation and after completion of any consolidation therapy, with the assessment used for eligibility performed prior randomization).
• Males or females ≥ 18 years of age
• Karnofsky performance status score ≥ 50% ( ECOG performance status score of ≤2).
• Adequate hepatic function, with bilirubin ≤ 2.0 x ULN - except in participants with congenital bilirubinemia, such as Gilbert syndrome (in which case direct bilirubin ≤ 1.5 ULN is required) and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN.
• ANC ≥ 1.0 x 109/L (prior growth factor support is permitted but must be without support for 7 days for G-CSF or GM-CSF or 14 days for pegylated-G-CSF), hemoglobin ≥ 8 g/dL (without red blood cell transfusion in the prior 7 days; recombinant human erythropoietin use is permitted), Platelets ≥75×109/L in patients in whom <50% of bone marrow nucleated cells are plasma cells and ≥50×109/L in patients in whom ≥50% of bone marrow nucleated cells are plasma cells (without transfusion support or thrombopoietin receptor agonist within 7 days before the laboratory test)
• Calculated creatinine clearance (by Cockcroft-Gault) ≥ 30 ml/min or creatinine clearance measured by a 24-hour urine collection.
• Serum calcium corrected for albumin ≤ 14 mg/dl or free ionized calcium <6.5 mg/dL.
• Females of childbearing potential (FCBP) must have 2 negative pregnancy tests (sensitivity of at least 50 mIU/mL) prior to initiating treatment. The first pregnancy test must be performed within 10-14 days before and the second pregnancy test must be performed within 24 hours before the drugs are administered.
• Females of childbearing potential must agree to use a highly effective method of contraception (failure rate <1% per year), preferably with low user dependency, throughout the study treatment period and for at least 6 months after the last dose of study treatment.
• Male participants must agree to use a condom during sexual intercourse with a pregnant woman or a woman of childbearing potential during study treatment and for at least 90 days after the last dose of study treatment. In addition, male participants must ensure that their partner of childbearing potential uses effective contraception, (failure rate <1% per year), preferably with low user dependency, during the same period.
• Voluntary written informed consent.

Exclusion criteria

• Peripheral neuropathy or neuropathic pain Grade 2 or higher, as defined by the NCI CTCAE Version 5.0.
• COPD with a FEV1 <50% of predicted normal. Note that FEV1 testing is required for participants with known or suspected of having COPD or asthma and participants must be excluded if FEV1 <50% of predicted normal.
• Severe persistent asthma within the past 2 years (see Appendix x[DS2.1] [for severity of Asthma]), uncontrolled asthma of any classification. Note that FEV1 testing is required for participants known or suspected asthma and participants must be excluded if FEV1 <50% of predicted normal.
• CNS involvement or clinical signs of meningeal involvement of multiple myeloma. If either is suspected, negative whole brain MRI and lumbar cytology are required.
• Plasma cell leukemia, Waldenström's macroglobulinemia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes), or primary light chain amyloidosis.
• Any ongoing myelodysplastic syndrome or B cell malignancy (other than multiple myeloma).
• Any history of malignancy, other than multiple myeloma, which is considered at high risk of recurrence requiring systemic therapy.
• Active malignancies (ie, progressing or requiring treatment change in the last 24 months) other than multiple myeloma. The only allowed exceptions are malignancies treated within the last 24 months that are considered cured:

• Non-muscle invasive bladder cancer (solitary Ta-PUNLMP or low grade, <3 cm, no CIS).
• Non-melanoma skin cancers treated with curative therapy or localized melanoma treated with curative surgical resection alone
• Noninvasive cervical cancer
• Localized prostate cancer (M0, N0) with a Gleason Score ≤7a, treated locally only (radical prostatectomy/radiation therapy/focal treatment)
• Breast cancer: adequately treated lobular carcinoma in situ or ductal carcinoma in situ, or history of localized breast cancer (antihormonal therapy is permitted)
• Other malignancy that is considered cured with minimal risk of recurrence in consultation with the Sponsor
• Stroke, transient ischemic attack, or seizure within 6 months prior to signing ICF.
• Presence of the following cardiac conditions:

• New York Heart Association stage 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
• Uncontrolled cardiac arrhythmia or clinically significant ECG abnormalities
• History of severe non-ischemic cardiomyopathy
• 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:

• Acute diffuse infiltrative pulmonary disease
• Evidence of active systemic viral, fungal, or bacterial infection, requiring systemic antimicrobial therapy
• History of autoimmune disease with the exception of vitiligo, type I diabetes, and prior autoimmune thyroid disease that is currently euthyroid based on clinical symptoms and laboratory testing.
• Disabling psychiatric conditions (eg, alcohol or drug abuse), severe dementia, or altered mental status.
• 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 (eg, compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments.
• History of noncompliance with recommended medical treatments
• Contraindications or life-threatening allergies, hypersensitivity, or intolerance to any study drug (daratumumab, lenalidomide, teclistamab or talquetamab) or its excipients (refer to the appropriate IBs and SmPCs) or analogues and study-required co-medication.
• Incidence of gastrointestinal disease that may significantly alter the absorption of oral drugs.
• Received a strong CYP3A4 inducer within 5 half-lives prior to the first dose of study treatment (Flockhart 2021).
• Plasmapheresis within 28 days prior to the first dose of study treatment.
• Participant had major surgery or had significant traumatic injury 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.

NOTE: Participants with planned surgical procedures to be conducted under local anesthesia may participate. Kyphoplasty or vertebroplasty are not considered major surgery. If there is a question whether a procedure is considered a major surgery, the investigator must consult with the appropriate Sponsor representative and resolve any issues before enrolling a participant in the study.

• Taken any disallowed therapies as noted in Section 6.8, Concomitant Therapy before the planned first dose of study treatment.
• Received a live, attenuated vaccine within 4 weeks before the first dose of study drug. Non-live or replicating vaccines approved or authorized for emergency use (eg, COVID-19) by local health authorities are allowed.
• HIV infection (positive, history, treatment for HIV).
• Hepatitis B infection (ie, HbsAg or HBV-DNA positive). In the event the infection status is unclear, quantitative viral levels are necessary to determine the infection status.
• Active hepatitis C infection as measured by positive HCV-RNA testing. Participants with a history of HCV antibody positivity must undergo HCV-RNA testing. If a participant with history of chronic hepatitis C infection (defined as both HCV antibody and HCV-RNA positive) completed antiviral therapy and has undetectable HCV-RNA 12 weeks following the completion of therapy, the participant is eligible for the study.