| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Newly Diagnosed Multiple Myeloma
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10028228 |
| E.1.2 | Term | Multiple myeloma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To compare the efficacy of teclistamab in combination with lenalidomide (Tec-Len) with that of lenalidomide monotherapy (Len), and the efficacy
of teclistamab monotherapy (Tec) with that of lenalidomide monotherapy (Len) in the maintenance setting as assessed by PFS.
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| E.2.2 | Secondary objectives of the trial |
To further compare the efficacy of Tec-Len to Len, and the efficacy of Tec
to Len in the maintenance setting.
To assess the safety profile of maintenance Tec-Len and Tec, characterize the PK of maintenance Tec-Len and Tec, assess the immunogenicity of maintenance Tec-Len and Tec, evaluate the impact oftreatment with maintenance Tec-Len and Tec on PROs compared with Len.
EXPLORATORY OBJECTIVES:
To compare the rates of responses in maintenance Tec-Len and Tec compared with Len, evaluate the efficacy of maintenance Tec-Len and Tec in high-risk subgroups compared with Len, evaluate the efficacy of maintenance Tec-Len and Tec compared with Len in MRD evaluable participants, compare the efficacy of maintenance Tec-Len with Tec, explore pharmacodynamic biomarkers of antimyeloma and immune activity for maintenance Tec-Len and Tec, explore relationships between pharmacodynamic markers and clinical activity of maintenance Tec-Len and Tec compared with Len. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.2 ≥18 years of age (and the legal age of consent in the jurisdiction in which the study is taking place) at the time of informed consent.
2.2 Must have a new diagnosis of symptomatic MM according to IMWG criteria and have received 4 to 6 cycles of 3 or 4 drug-induction therapy that includes a proteasome inhibitor and/or an IMiD with or without anti-CD38 monoclonal antibody and a single or tandem ASCT. Post ASCT consolidation is permitted for up to 2 cycles as long as the total number of induction plus consolidation cycles does not exceed 6. Participants must complete all previous treatment prior to screening and at least 7 days prior to randomization (C1D1 for the safety run-in) except for cytotoxic therapy, which must be completed at least 21 days prior to randomization (C1D1 for the safety run-in).
3.2 Must have received only one line of therapy and achieved at least a partial response (≥PR) as per IMWG 2016 response criteria based on the
investigator's assessment. Participants with plasmacytomas at the time of diagnosis must meet IMWG 2016 response criteria . for ≥PR based on
repeat imaging utilizing the same modality (Kumar 2016).
4 Must not be intolerant to the starting dose of lenalidomide.
5.2 Must have received high-dose chemotherapy and ASCT within 12 months of the start of induction therapy and be within 6 months of the last ASCT (7 months for participants who received consolidation) at the time of randomization or at the time of Sponsor approval for participants
in safety run-in.
6 Must not have received any maintenance therapy.
7.1 Have an ECOG performance status score of 0-2 at screening and immediately prior to the start of administration of study treatment.
8.1 Have clinical laboratory values meeting the following criteria (see the protocol).
9.1 A woman of childbearing potential must have a negative serum pregnancy test within 10-14 days prior to the start of study treatment 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.
10.2 A woman must be:
a)Not of childbearing potential, or
b)Of childbearing potential practicing 2 reliable methods of contraception simultaneously including one highly effective method of contraception and one other effective method of contraception starting 4 weeks prior to dosing, throughout the study including during dose interruptions and for a minimum of 4 weeks after the last dose of lenalidomide or for a minimum of 6 months after the last dose of teclistamab, whichever occurs later. For participants who are of childbearing potential, see Section 6.11.3 for details regardingconcomitant use of estrogen containing products and lenalidomide.
11.1 A woman must agree not to donate eggs (ova, oocytes) or freezefor future use, for the purposes of assisted reproduction during the studyand for a minimum of 4 weeks after the last dose of lenalidomide or for a minimum of 6 months after the last dose of teclistamab, whichever
occurs later.
12.2 A man must wear a condom (with or without spermicidal foam/gel/film/cream/suppository) when engaging in any activity that allows for passage of ejaculate to another person during the study and for a minimum of 4 weeks after the last dose of lenalidomide or for a minimum of 3 months after the last dose of teclistamab, whichever occurs later. If his female partner is of childbearing potential, the male participant must use condom (with or without spermicide) and the female partner of the male participant must also be practicing a highly effective method of contraception .
13.2 A male participant must agree not to donate sperm for the purpose of reproduction during the study and for a minimum of 4 weeks after the
last dose of lenalidomide or for a minimum of 3 months after receiving the last dose of teclistamab, whichever occurs later.
14 Must be willing and able to adhere to the lifestyle restrictions specified in this protocol.
15.1 Must sign an informed consent form (ICF) (in accordance with the local requirements) indicating that the participant understands the purpose of, and procedures required for, the study and is willing to participate in the study.
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| E.4 | Principal exclusion criteria |
Criterion 1 was deleted
2 Any previous therapy with an immune cell redirecting agent or gene modified adoptive cell therapy
3 Discontinued treatment due to any AE related to lenalidomide as determined by the investigator
4.1 History of allogeneic stem cell transplantation or prior organ transplant
5.1 Progressive disease as per IMWG 2016 response criteria at any time prior to randomization or C1D1 for participants in the safety run in
6.1 Radiotherapy within 14 days or focal radiation within 7 days of C1D1 7.2 Received a cumulative dose of corticosteroids equivalent to > 40 mg of dexamethasone within the 14 days prior to C1D1
8.1 Received a live, attenuated vaccine within 4 weeks before C1D1. Non-live vaccines or non-replicating authorized for emergency use are allowed
9.3 Excluded for any of the following
a) Any ongoing myelodysplastic syndrome or B cell malignancy (other than MM)
b) Any history of malignancy, other than multiple myeloma, which is considered at high risk of recurrence requiring systemic therapy
c) Any active malignancy (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
1) Non-muscle invasive bladder cancer (solitary Ta-PUN-LMP or low grade, <3 cm, no CIS)
2) Non-melanoma skin cancers treated with curative therapy melanoma or localized melanoma treated with curative surgical resection alone
3) Non-invasive cervical cancer
4) Breast cancer: adequately treated lobular carcinoma in situ or ductal carcinoma in situ, or history of localized breast cancer
5) Localized prostate cancer (M0, N0) with a Gleason Score ≤7a, treated locally only
6) Other malignancy that is considered cured with minimal risk of recurrence in consultation with the Sponsor's medical monitor
10.1 Plasma cell leukemia, smoldering multiple myeloma, Waldenström's macroglobulinemia, POEMS syndrome or primary light chain amyloidosis. 11 Central nervous system involvement or exhibits clinical signs of meningeal involvement of multiple myeloma.
12.1 Stroke, transient ischemic attack, or seizure within 6 months of C1D1
13 Contraindications or life-threatening allergies, hypersensitivity, or intolerance to any study treatment or its excipients
14.1 Participant is pregnant or breast-feeding or planning to become pregnant while enrolled in this study or within 6 months after the last dose of study drug
15.1 Participant plans to father a child while enrolled in this study or within 3 months after the last dose of study drug
16.1 Presence of the following conditions: a)New York Heart Association stage III or IV congestive heart failure b)Myocardial infarction, or coronary artery bypass graft ≤6 months prior to C1D1 c) History of clinically significant ventricular arrhythmia or unexplained syncope, not believed to be vasovagal in nature or due to dehydration d) Uncontrolled cardiac arrhythmia or clinically significant ECG abnormalities
17.1 Any of the following: a. HIV-positive participants with 1 or more of the following
-History of AIDS-defining conditions
-CD4 count <350 cells/mm3 at screening
-Detectable viral load during screening or within six months prior to screening
-Not receiving highly active ART
-Had a change in antiretroviral therapy within 6 months of the start of screening
-Receiving antiretroviral therapy that may interfere with study treatment as assessed after discussion with the Medical Monitor
18 Hepatitis B infection: In the event the infection status is unclear, quantitative viral levels are necessary to determine the infection status 19 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 HCV infection completed antiviral therapy and has undetectable HCV-RNA 12 weeks following the completion of therapy, the participant is eligible for the study
20.2 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
21.1 Participant had major surgery or had significant traumatic injury within 2 weeks prior to the start of administration of study treatment, or has not fully recovered from an earlier surgery, or has major surgery planned during the time the participant is expected to participate in the study or within 2 weeks after administration of the last dose of study treatment
22.1 Have received an investigational drug (including investigational vaccines) or used an invasive investigational medical device within 4 weeks or 5 PK half-lives, whichever is longer, before C1D1 or is currently enrolled in an interventional investigational study except if only long term survival data is collected and after Sponsor approval is obtained |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint is PFS, defined as the time from the date of randomization to the date of first confirmed disease progression, as defined in the IMWG criteria, or death due to any cause, whichever occurs first.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
From the date of randomization to the date of first confirmed disease progression or death due to any cause, whichever occurs first.
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| E.5.2 | Secondary end point(s) |
CR conversion is defined as the proportion of participants who were not in CR or better at the time of randomization but later went on to achieve CR or better while on study treatment.
MDR negative conversion is defined as the proportion of participants who were assessed as MRD positive at the time of randomization but later achieved MRD negative status while on study treatment.
CR or better (sCR+CR) is defined as participants who achieve a CR or better response per IMWG criteria.
MRD negative CR is defined as participants who achieve CR or better and are MRD negative before initiation of subsequent therapy.
Sustained MRD negativity is defined as the proportion of participants who achieve MRD-negative CR, confirmed minimum 1 year apart and without any examination showing MRD-positive status in between.
OS will be measured from the date of randomization to the date of the participant's death. If the participant is alive or the vital status is unknown, then the participant's data will be censored at the date the participant was last known to be alive.
PFS2 is defined as the time interval between the date of randomization and date of event, which is defined as progressive disease as assessed by investigator on the first subsequent line of antimyeloma therapy, or death from any cause, whichever occurs first. Those who are alive and for whom a second
disease progression has not been observed will be censored at the last date of follow-up.
TTNT is defined as the time from randomization to the start of subsequent antimyeloma treatment. Death due to progressive disease without start of subsequent therapy will be considered as event. Participants who withdrew full consent to study or are lost to follow-up, or die due to causes other than disease progression will be censored at the date of death or the last date known to be alive.
Incidence and severity of AEs
The PK of teclistamab will be assessed.
Presence and activity of ADAs to teclistamab
Time to worsening in overall HRQoL, symptoms, and functioning
Change from baseline in overall HRQoL, symptoms, and functioning
PFS, depth of response, etc will be determined in participants with high- risk molecular features as defined by IMWG criteria
As part of the PROs, treatment effect will be assessed by change from baseline in overall HRQoL symptoms and functioning at each time point summarized by treatment arm. Time to worsening of symptoms will be measured as the interval from the date of randomization to the start date of worsening. Death due to disease progression will be considered as worsening.
Participants who have not met the definition of worsening will be censored as of the last assessment date.
The analysis methods for binary endpoints (eg, CR/sCR, and MRD negativity) will be conducted using stratified Cochran Mantel Haenszel tests. Mantel Haenszel odds ratios will be provided along with 2-sided 95% CIs, as the measure of treatment effect. For time-to-event endpoints (eg, PFS2, TTNT, OS, and time to worsening of symptoms), similar statistical methods will be applied as for PFS. Longitudinal analysis will be performed for PROs assessed over time. Incidence of AE and incidence of ADA will be summarized. Separate summaries of AE and ADA will be provided for SRI1 and SRI2 cohorts.
EXPLORATORY ENDOPOINTS:
To compare the rates of deepening of responses in maintenance Tec-Len and Tec compared with Len.
To evaluate the efficacy of maintenance Tec-Len and Tec in high-risk subgroups compared with Len.
To evaluate the efficacy of maintenance Tec-Len and Tec compared with Len in MRD evaluable participants.
To compare the efficacy of maintenance Tec-Len with Tec.
To explore pharmacodynamic biomarkers of antimyeloma and immune activity for maintenance Tec-Len and Tec.
To explore relationships between pharmacodynamic markers and clinical activity of maintenance Tec-Len and Tec compared with Len.
To explore predictive biomarkers of response and resistance for maintenance Tec-Len and Tec, including prognostic and disease markers, at baseline, during treatment, and in relation to efficacy parameters.
To explore the relationships between PK, pharmacodynamic, AE profile, and clinical activity of maintenance Tec-Len and Tec. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| During the entire duration of the study |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | Yes |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
Immunogenenicity evaluations, Exploratory Biomarker evaluations
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| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 93 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Switzerland |
| Australia |
| Brazil |
| Canada |
| China |
| Israel |
| Korea, Republic of |
| Serbia |
| United Kingdom |
| United States |
| Austria |
| Belgium |
| Czechia |
| Denmark |
| France |
| Germany |
| Greece |
| Ireland |
| Italy |
| Netherlands |
| Norway |
| Poland |
| Türkiye |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 9 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 9 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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