GMMG-HD11/DSMM XXI/64007957MMY3010

This is an open-label, randomized interventional multicenter Phase 3 clinical trial to investigate the efficacy and safety of Tec-DRd induction therapy and fixed-duration Tec-D maintenance post ASCT in adult participants with TE NDMM, compared with the SoC PERSEUS regimen. The trial will comprise 3 phases: screening, treatment, and follow-up. The treatment phase includes induction therapy (incorporating HDT+ASCT lasting 1-2 months, which is not part of the clinical trial and will be performed as SoC according to local guidelines), followed by maintenance therapy and follow up. A total of 399 participants with TE NDMM aged ≥18 and ≤70 years and an Eastern Cooperative Oncology Group (ECOG) status 0-2 will be included.

Eligible participants will receive one of 3 treatments:

• Arm A (SoC treatment based on the PERSEUS regimen - control): DVRd induction therapy, HD melphalan + ASCT, DVRd consolidation therapy, followed by DR maintenance therapy. After maintenance therapy, the participant will be treated according to SoC.
• Arm B: Tec-DRd induction therapy, HD melphalan + ASCT, followed by DR maintenance therapy. Treatment stopped thereafter.
• Arm C: Tec-DRd induction therapy, HD melphalan + ASCT, followed by Tec-D then DR maintenance therapy. Treatment stopped thereafter. The stratification variables will be age (<65/≥65) and high risk/no-high-risk/unknown based on the International Myeloma Working Group (IMWG) 2025 definition.

Inclusion criteria

• 18 to 70 years of age, inclusive.
• Documented MM as defined by the criteria below:

• MM diagnosis according to IMWG diagnostic criteria (Appendix 3),
• Untreated MM requiring systemic therapy,
• Measurable disease at screening, as defined by any of the following:

i. Serum M-protein level ≥1.0 g/dL (central laboratory); or ii. Urine M-protein level ≥200 mg/24 hours (central laboratory); or iii. Serum immunoglobulin free light chain ≥10 mg/dL (central laboratory) and abnormal serum immunoglobulin kappa lambda free light chain ratio.

• Have an ECOG performance status 0-2 (Appendix 5) at screening and immediately prior to the start of administration of study treatment.
• Have clinical laboratory values meeting the following criteria during the screening period. Refer to Section 5.4.3 for criteria prior to first dose.

Hemoglobin ≥7.5 g/dL (≥4.65 mmol/L; without prior RBC transfusion ≤7 days before the screening laboratory test; recombinant human erythropoietin use is permitted). Platelets ≥75×109/L in participants in whom <50% of bone marrow nucleated cells are plasma cells and ≥50×109/L in participants in whom ≥50% of bone marrow nucleated cells are plasma cells. Absolute neutrophil count ≥1.0×109/L (prior growth factor support is permitted but must be without support for ≥7 days for G-CSF or GM-CSF and ≥14 days for pegylated-G-CSF) before the screening laboratory test.

Chemistry:

AST and ALT ≤3×ULN. Total bilirubin Total bilirubin ≤2.0×ULN; except in participants with congenital bilirubinemia, such as Gilbert syndrome (in which case if total bilirubin is >2.0×ULN, then direct bilirubin ≤1.5×ULN is required).

eGFR ≥30 mL/min based on Cockcroft-Gault formula or creatine clearance measured by a 24-h urine collection. Serum calcium corrected for albumin ≤14 mg/dL (≤3.5 mmol/L) or free ionized calcium ≤6.5 mg/dL (≤1.6 mmol/L; see Appendix 10).

• Eligible for HD melphalan and ASCT (in the opinion of the investigator).
• A female participant of childbearing potential must have a negative highly sensitive serum pregnancy test at screening and again either a serum or urine pregnancy test within 24 hours of the start of study treatment and must agree to further serum or urine pregnancy tests during the study.
• A female participant must be (as defined in Appendix 1):

• Not of childbearing potential, or
• Of childbearing potential and practicing at least 1 highly effective method of contraception
• A female participant must agree not to donate eggs (ova, oocytes) or freeze for future use, for the purposes of assisted reproduction during the study and for 6 months after receiving the last dose of study treatment. Female participants should consider preservation of eggs prior to study treatment because anticancer treatments may impair fertility.
• A male participant must wear a condom (with or without spermicidal foam/gel/film/cream/suppository) when engaging in any activity that allows for
• A male participant must agree not to donate sperm for the purpose of reproduction during the study and for 3 months after receiving the last dose of study treatment. Male participants should consider preservation of sperm prior to study treatment as anticancer treatments may impair fertility.
• Must agree to abstain from donating blood while taking lenalidomide and for 28 days following discontinuation of lenalidomide therapy.
• Must sign an ICF indicating that the participant understands the purpose of, and procedures required for, the study and is willing to participate in the study.
• Must be willing and able to adhere to the lifestyle restrictions specified in this protocol

Exclusion criteria

• Any ongoing myelodysplastic syndrome or B-cell malignancy (other than MM).
• Any history of malignancy, other than MM, which is considered at high risk of recurrence requiring systemic therapy.
• Any active malignancy (ie, progressing or requiring treatment change in the last 24 months) other than MM. The only allowed exceptions are malignancies treated within the last 24 months that are considered cured:

• Nonmuscle invasive bladder cancer (solitary Ta-PUN-LMP or low grade, <3 cm, no carcinoma in situ).
• Nonmelanoma skin cancers treated with curative therapy or localized melanoma treated with curative surgical resection alone.
• Noninvasive cervical cancer.
• Breast cancer: adequately treated lobular carcinoma in situ or ductal carcinoma in situ or history of localized breast cancer (antihormonal therapy is permitted).
• Localized prostate cancer (M0, N0) with a Gleason Score ≤7a, treated locally only (radical prostatectomy/radiation therapy/focal treatment).
• Other malignancy that is considered cured with minimal risk of recurrence in consultation with the sponsor's medical monitor.
• Plasma cell leukemia (presence of ≥5% circulating plasma cells in peripheral blood smears in patients otherwise diagnosed with symptomatic MM; Fernández de Larrea 2021), smoldering MM, Waldenström's macroglobulinemia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes), primary light chain amyloidosis.
• CNS involvement or clinical signs of meningeal involvement of MM. If either is suspected, negative whole brain MRI and lumbar cytology are required to exclude CNS involvement.
• Prior BCMA-directed therapy.
• Prior T-cell redirection therapy.
• History of allogeneic or autologous stem cell transplant or prior organ transplant.
• Prior or concurrent exposure to any of the following within the specified timeframe prior to randomization:

• Targeted therapy, epigenetic therapy, or treatment with an investigational drug or an invasive investigational medical device within 21 days or ≥5 half-lives, whichever is less.
• Investigational vaccine within 4 weeks.
• Monoclonal antibody therapy within 21 days.
• Radiotherapy within 14 days or focal radiation within 7 days.
• Received a cumulative dose of corticosteroids equivalent to dexamethasone ≥160 mg within 14 days before treatment randomization (see Appendix 7).
• Received a live, attenuated vaccine within 4 weeks before the first dose of study treatment. Nonlive or nonreplicating vaccines authorized for emergency use (eg, COVID-19) by local health authorities are allowed.
• 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.
• Concurrent medical or psychiatric condition or disease that is likely to interfere with study procedures or results, ie, those listed below, or any others that in the opinion of the investigator would constitute a hazard for participating in the study.

• Acute diffuse infiltrative pulmonary disease.
• Evidence of active systemic viral, fungal, or bacterial infection, requiring systemic antimicrobial therapy.
• Active autoimmune disease requiring systemic immunosuppressive therapy within 6 months before start of study treatment. Exception: Participants with vitiligo, controlled type I diabetes, and prior autoimmune thyroid disease that is currently euthyroid based on clinical symptoms and laboratory testing are eligible regardless of when these conditions were diagnosed.
• 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 study 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.
• Stroke, transient ischemic attack, or seizure within 6 months prior to randomization.
• Any of the following:

• Seropositive for human immunodeficiency virus (HIV).
• Hepatitis B infection (ie, positive HBsAg or detectable HBV DNA levels by RTPCR).

In the event the infection status is unclear, quantitative viral levels are necessary to determine the infection status see Section 6.8.2.8 for further required assessments.

• Active hepatitis C infection as measured by detectable HCV RNA. 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.
• 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.
• Moderate or severe persistent asthma within the past 2 years (see Appendix 8), or 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.
• Presence of the following cardiac conditions:

• New York Heart Association stage III or IV congestive heart failure (Appendix 12).
• Myocardial infarction, unstable angina, 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.
• Participant is pregnant, breastfeeding, or planning to become pregnant while enrolled in this study or within 6 months after the last dose of study treatment.
• Participant plans to father a child while enrolled in this study or within 3 months after the last dose of study treatment.
• History of hypersensitivity to study intervention or to any drug with similar chemical structure or to any excipient present in the pharmaceutical form of the investigational medicinal product.
• Participation in other clinical studies or observation period of competing clinical studies, respectively.
• Held in an institution by legal or official order.
• Legally incapacitated.