Teclistamab-Daratumumab and Talquestamab-Daratumumab in Newly Diagnosed High-risk Multiple Myeloma

• Status: Not yet recruiting
• Trial end date: 2029-07-01
• Target enrollment: 0
• Participant gender: All

Summary

The goal of this Phase 2, open-label, multicenter, non-randomized pilot study is to evaluate the efficacy (in terms of MRD negative CR rate after Intensification therapy) and safety of Tec-Dara (Teclistamab+Daratumumab) and Tal-Dara (Talquetamab+Daratumumab) in de novo high-risk multiple myeloma (DNHRMM) patients.

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: PETHEMA Foundation
• Collaborator: Janssen, LP
• Treatments: Bortezomib; Daratumumab; Dexamethasone; Lenalidomide

Criteria

Inclusion Criteria:

1. Patient is, in the investigator's opinion, willing and able to comply with the protocol requirements.

2. Patient has given voluntary written informed consent before performance of any study-related procedure nor part of normal medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to their future medical care.

3. Patient is ≥ 18 years of age (or the legal age of consent in the jurisdiction in which the study is taking place) at the time of informed consent.

4. Patient has documented diagnosis of multiple myeloma according to IMWG diagnostic criteria, with at least one of the following high-risk features:

1. High-risk FISH: del(17p), t(4;14), t(14;16) and 1q amplifications.

2. R-ISS 3

3. Presence of extramedullary disease, defined as presence of paramedullary lesions or extramedullary plasmacytoma.

Note: In order to have a representative population with high-risk features, 50% of patients included will have ultra-high risk disease defined as: i) R-ISS 3; ii) Double hit (at least two high-risk cytogenetic abnormalities); iii) One high-risk cytogenetic abnormality + extramedullary disease.

5. Patient has measurable secretory disease at screening defined as either serum monoclonal protein of ≥ 0.5 g/dl or urine monoclonal (light chain) protein ≥ 200 mg/24 h. For patients whose disease is only measurable by serum free light chain (FLC), the serum immunoglobulin FLC should be ≥ 10mg/dL (100 mg/L), with an abnormal immunoglobulin kappa lambda serum FLC ratio.

6. Human immunodeficiency virus-positive patients are eligible if the meet all of the following:

1. No detectable viral load (ie, < 50 copies/mL) at screening

2. CD4+ count > 300 cells/mm3 at screening

3. No acquired immunodeficiency syndrome (AIDS)-defining opportunistic infection within 6 months of screening

4. Receiving HAART. Any changes in HAART due to resistance/progression should occur at least 3 months prior to screening. A change in HAART due to toxicity is allowed up to 4 weeks prior to screening.

Note: HAART that could interfere with study treatment is excluded (consult the sponsor for a review of medications prior to randomization/enrollment).

7. Patients eligible for transplant with age ≤ 70 years old (young and transplant-eligible) or patients not eligible for transplant with ECOG-PS modified frailty score of 0-1 (elderly-fit).

8. Patient has an ECOG performance status of 0, 1or 2.

9. Patient must have adequate organ function, defined by:

1. Hemoglobin: ≥ 8 g/dL (≥ 5 mmol/L; without prior RBC transfusion within 7 days before the laboratory test; recombinant human erythropoietin use is permitted).

2. Platelets: ≥ 75 x 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).

3. Absolute Neutrophil Count (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 and for 14 days for pegylated G-CSF).

4. ALT and AST: ≤ 2.5 x upper limit normal .

5. eGFR: ≥ 30 mL/min based on Modified Diet in Renal Disease 4 variable Formula calculation or creatine clearance measured by a 24-hour urine collection.

6. Total bilirubin: Total bilirubin < 1.5 x upper limit normal (isolated total bilirubin ≥ 1.5 x upper limit normal with conjugated [direct] bilirubin < 1.5 x upper limit normal is allowed for those patients with known Gilbert's syndrome).

7. Serum calcium corrected for albumin: ≤ 14 mg/dL (≤ 3.5 mmol/L) or free ionized calcium ≤ 6.5 mg/dL (≤ 1.6 mmol/L).

10. A female patient of childbearing potential must have a negative highly sensitive urine or serum (β human chorionic gonadotropin [β hCG]) pregnancy test at screening and within 24hours prior to the start of study treatment and must agree to further urine or serum pregnancy tests during the study.

11. A female patient must be:

1. Not of childbearing potential, or

2. Of childbearing potential and

i. Practicing true abstinence; or ii. Have a sole partner who is vasectomized; or iii. Practicing 2 effective methods of contraception (at least 1 highly-effective method of contraception).

NOTE: Nonchildbearing potential is defined as follows (by other than medical reasons):

• ≥ 45 years of age and has not had menses for > 1 year.

• Has been amenorrhoeic for > 2 years without history of a hysterectomy and oophorectomy and has a follicle stimulating hormone value in the postmenopausal range upon screening evaluation.

• Post-hysterectomy, post-bilateral oophorectomy, or post-tubal ligation. Documented hysterectomy or oophorectomy must be confirmed with medical records of the actual procedure or confirmed by an ultrasound. Tubal ligation must be confirmed with medical records of the actual procedure.

NOTE: Patient must agree to continue the above throughout the study and for 3 months after the last dose of study treatment.

NOTE: If a female patient becomes of childbearing potential after start of the study the female patient must comply with point (b) as described above. If a patient's reproductive status is questionable, additional evaluation should be considered.

NOTE: An interaction between hormonal contraception and talquetamab or teclistamab has not been formally studied. Therefore, it is unknown whether talquetamab or teclistamab may reduce the efficacy of the contraception method.

12. A female patient must agree not to donate eggs (ova, oocytes) or freeze for future use for the purposes of assisted reproduction during the study and for 3 months after receiving the last dose of study treatment. A female patient should consider preservation of eggs prior to study treatment as anti-cancer treatments may impair fertility.

13. A male patient must wear a condom when engaging in any activity that allows for passage of ejaculate to another person during the study and for a minimum of 3 months after receiving the last dose of study treatment. If the male patient's partner is a female of childbearing potential, the male patient must use condoms (with or without spermicide) and the female partner of the male patient must also be practicing a highly effective method of contraception as condoms may break or leak.

NOTE: If the male patient is vasectomized, he still must wear a condom (with or without spermicidal foam/gel/film/cream/suppository) but his female partner is not required to use contraception.

14. A male patient must agree not to donate sperm for the purpose of reproduction during the study and for a minimum of 3 months after receiving the last dose of study treatment. Male patients should consider preservation of sperm prior to study treatment as anti-cancer treatments may impair fertility.

15. Patient must be willing and able to adhere to the lifestyle restrictions specified in this protocol.

16. All prior treatment-related toxicities (defined by National Cancer Institute - Common Toxicity Criteria for AEs [NCI-CTCAE], Version 5.0 must be ≤ Grade 1 at the time of enrolment except for alopecia.

Exclusion Criteria:

1. Prior or current systemic therapy or SCT for any plasma cell dyscrasia, with the exception of 1 cycle of antimyeloma treatment or the emergency use of a short course (equivalent of dexamethasone 40 mg/day for a maximum 4 days) of corticosteroids before treatment while waiting for results of genetic analysis. A cycle of therapy may include treatment with proteasome inhibitors, immunomodulatory drugs, alkylators and corticosteroids, and/or anti-CD38 monoclonal antibodies (i.e, bortezomib-thalidomide-dexamethasone, D-VTD, bortezomib-lenalidomide-dexamethasone, or bortezomib-cyclophosphamide-dexamethasone, are valid options).

2. Peripheral neuropathy or neuropathic pain Grade 2 or higher, as defined by the NCI-CTCAE Version 5.

3. Patient has a diagnosis of primary light chain amyloidosis, monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), plasma cell leukemia or active POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes) at the time of screening.

4. Myelodysplastic syndrome or active malignancies (ie, progressing or requiring treatment change in the last 24 months) other than relapsed/refractory multiple myeloma. The only allowed exceptions are malignancies treated within the last 24 months that are considered completely cured:

1. Non-muscle invasive bladder cancer (solitary Ta-papillary urothelial neoplasm of low malignancy or low grade, < 3 cm, no carcinoma in situ).

2. Skin cancer (non-melanoma skin cancers treated with curative therapy or localized melanoma treated with curative surgical resection alone).

3. Noninvasive cervical cancer.

4. Localized prostate cancer (M0, N0) with a Gleason score of ≤ 7a, treated locally only (radical prostatectomy/radiation therapy/focal treatment).

5. Breast cancer: adequately treated lobular carcinoma in situ or ductal carcinoma in situ, localized breast cancer and receiving antihormonal agents.

6. Other malignancy that is considered cured with minimal risk of recurrence.

5. Patient has CNS or exhibits clinical signs of meningeal involvement of multiple myeloma. If either is suspected, negative whole brain MRI and lumbar cytology are required.

6. Patient is pregnant, breastfeeding, or planning to become pregnant while enrolled in this study or within 3 months after the last dose of study treatment.

7. Patient plans to father a child while enrolled in this study or within 3 months after the last dose of study treatment.

8. Patient is simultaneously enrolled in other interventional clinical trial.

9. Patient has received prior radiotherapy within 2 weeks of start of study therapy. Patients must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤ 2 weeks of radiotherapy) to non-central nervous system (CNS) disease.

10. Plasmapheresis within 28 days of starting study treatment defined as C1D1 of D-VRD.

11. Chronic obstructive pulmonary disease (COPD) with a Forced Expiratory Volume in 1 second (FEV1) < 50% of predicted normal. Note that FEV1 testing is required for patients with known or suspected of having COPD or asthma and patients must be excluded if FEV1 < 50% of predicted normal.

12. Moderate or severe persistent asthma within the past 24 months (See APPENDIX 20), or uncontrolled asthma of any classification. Note that FEV1 testing is required for patients known or suspected asthma and patients must be excluded if FEV1 < 50% of predicted normal.

13. Patient has a known immediate or delayed hypersensitivity reaction or idiosyncrasy to other molecular antibodies.

14. Patient 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 patient is expected to be treated in the study or within 2 weeks after administration of the last dose of study treatment.

NOTE: Patients 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 patient in the study.

15. Prior or concurrent exposure to any of the following, in the specified time frame prior to starting study treatment:

• Investigational vaccine other than SARS CoV-2 vaccine approved/ in use under emergency approval within 4 weeks.

• Live, attenuated vaccine within 4 weeks. Killed or inactivated vaccines may be administered, however, the response to such vaccines cannot be predicted.

• Monoclonal antibody therapy within 21 days (not use for the treatment of multiple myeloma).

16. Received a strong CYP3A4 inducer within 5 half-lives prior to starting study treatment (Flockhart 2021).

17. A maximum cumulative dose of corticosteroids of ≥ 140 mg of prednisone or equivalent within 14-day period before the first dose of Tec-Dara or Tal-Dara (does not include pretreatment medications).

18. Allergy, hypersensitivity, or intolerance to boron or mannitol, corticosteroids, monoclonal antibodies or human proteins, or their excipients (refer to the Investigator's Brochure and appropriate package inserts), or sensitivity to mammalian-derived products or lenalidomide.

19. 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 prior to starting study treatment.

3. History of clinically significant ventricular arrhythmia or unexplained syncope, not believed to be vasovagal in nature or due to dehydration.

4. Uncontrolled cardiac arrhythmia or clinically significant ECG abnormalities.

20. Stroke, transient ischemic attack or seizure within 6 months prior to signing informed consent form (ICF).

21. Any of the following:

1. 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.

2. Active hepatitis C infection as measured by positive hepatitis C virus-ribonucleic acid (HCV)-RNA testing. Patients with a history of HCV antibody positivity must undergo HCV-RNA testing. If a patient with history of chronic hepatitis C infection (defined as both HCV antibody and HCV-RNA positive) completed antiviral therapy and has udetectable HCV-RNA for at least 12 weeks following the completion of therapy, the patient is eligible for the study.

22. 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 active autoimmune disease. with exception of patients with vitiligo, type I diabetes, and prior autoimmune thyroiditis that is currently euthyroid based on clinical symptoms and laboratory testing.

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 patient 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 patient (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.