A randomized phase III study comparing Daratumumab, Bortezomib, Lenalidomide, and Dexamethasone (DVRd), followed by Ciltacabtagene Autoleucel, versus Daratumumab, Bortezomib, Lenalidomide, and Dexamethasone (DVRd), followed by autologous stem cell transplantation (ASCT), in participants with newly diagnosed multiple myeloma eligible for transplantation.

Zusammenfassung der Studie

The main objective of the study is to assess how well Ciltacabtagene Autoleucel (Cilta-cel) works compared to standard treatment with autologous stem cell transplantation (ASCT). Cilta-cel is a CAR-T cell therapy. In this treatment, your white blood cells (which are part of the immune system) are genetically modified to become Cilta-cel. These cells are then used to treat your multiple myeloma. Each participant will belong to one of two different treatment groups (A or B). The groups will be selected by a computer that has no information about the individuals. This means that the assignment is random, like flipping a coin. This process is called “randomization.” The medication in this study is assigned in a 1 to 1 ratio. This means that the probability of receiving either one or the other study treatment combination is 50 percent. The two different treatment groups are: • Treatment Group A: Daratumumab, Bortezomib, Lenalidomide, and Dexamethasone (DVRd), followed by an autologous stem cell transplantation (ASCT), a consolidation therapy with DVRd, and a maintenance therapy with Lenalidomide (standard therapy group) • Treatment Group B: Daratumumab, Bortezomib, Lenalidomide, and Dexamethasone (DVRd), followed by Cilta-cel and a post-CAR-T therapy with Lenalidomide (experimental therapy group)

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Untersuchte Intervention

• Treatment Group A

Induction chemotherapy:

Cycles 1 to 4 (28 days each)

Daratumumab: subcutaneous injections (under the skin), weekly during the first 8 weeks, then every 2 weeks in the following 8 weeks

Bortezomib: subcutaneous injections (under the skin) on days 1, 4, 8, and 11 of each cycle

Lenalidomide: capsules, 25 mg on days 1 to 21 of each cycle

Dexamethasone: tablets, 40 mg once weekly on days 1, 8, 15, and 22 of each cycle

Visit dates: Cycle 1‒2: Days 1, 4, 8, 11, 15, and 22

Cycle 3‒4: Days 1, 4, 8, 11, and 15

Chemotherapy followed by stem cell collection:

This is part of the standard treatment. In brief: 4‒6 weeks after the last induction cycle, you will be treated with Cyclophosphamide and/or the bone marrow stimulating factor and/or Plerixafor. After a few days, the stem cells appear in the blood and are collected through the so-called “stem cell apheresis.”

High-dose chemotherapy followed by autologous stem cell transplantation:

This is part of the standard treatment. In brief: 1‒2 weeks after the stem cell collection, you will be hospitalized for an intensification therapy. The goal is to eliminate as many (remaining) malignant plasma cells as possible and to reinfuse the previously collected stem cells via infusion.

Consolidation therapy:

Cycles 5 to 6 (28 days each)

Daratumumab: subcutaneous injections every 2 weeks

Bortezomib: subcutaneous injections on days 1, 4, 8, and 11 of each cycle

Lenalidomide: capsules, 25 mg on days 1 to 21 of each cycle

Dexamethasone: tablets, 40 mg once weekly on days 1, 8, 15, and 22 of each cycle

Visit dates: Cycles 5‒6: Days 1, 4, 8, 11, and 15

Maintenance therapy:

Cycles 7 and subsequent cycles (28 days each)

Continuous treatment for up to 2 years (unless the investigator believes you would benefit from a longer duration of maintenance therapy)

Lenalidomide: capsules, 10 to 15 mg daily on days 1 to 28 of each cycle

Visit dates: Every 4 weeks (28 days) for laboratory tests

Follow-up:

After maintenance therapy, visits will occur every 4 weeks for 2 years, and then every 8 weeks. Laboratory tests will be conducted to obtain information on how your myeloma responds.

Treatment Group B:

Apheresis and manufacturing of Cilta-cel:

To manufacture Cilta-cel, white blood cells are collected from your blood through a so-called “apheresis.” If necessary, the investigator may give you calcium before the apheresis begins to help you recover more quickly. During the apheresis, 2 tubes (intravenous catheters, also called “IV access”) will be inserted (one in each arm). You may also need a central access (a so-called apheresis catheter) for the collection of your white blood cells. During this process, which can take 2 to 4 hours, your blood is passed through a machine that separates the white blood cells from the rest of the blood. The white blood cells collected are sent to the CAR-T cell lab and genetically modified to produce the investigational product Cilta-cel.

Induction chemotherapy:

Cycles 1 to 6 (28 days each)

Daratumumab: subcutaneous injections, weekly during the first 8 weeks, then every 2 weeks in the following 16 weeks

Bortezomib: subcutaneous injections on days 1, 4, 8, and 11 of each cycle

Lenalidomide: capsules, 25 mg on days 1 to 21 of each cycle

Dexamethasone: tablets, 40 mg once weekly on days 1, 8, 15, and 22 of each cycle

Visit dates: Cycle 1‒2: Days 1, 4, 8, 11, 15, and 22

Cycle 3‒6: Days 1, 4, 8, 11, and 15

Conditioning therapy before administration of Cilta-cel: Cyclophosphamide and Fludarabine

Chemotherapy:

Cyclophosphamide: intravenous infusion, once daily on days -5, -4, and -3

Fludarabine: intravenous infusion, once daily on days -5, -4, and -3

* These medications prepare your body to receive your CAR-T cells.

On all these days, your investigator will assess whether you need premedication before the infusions.

Cilta-cel infusion:

On Day 1, you will receive a single infusion of Cilta-cel in the hospital. You will receive premedication to mitigate potential side effects.

Observation:

After receiving Cilta-cel, you will be closely monitored for the effects of the investigational product on your health and your disease.

If you are hospitalized during or immediately after the infusion of Cilta-cel:

• You will stay in the hospital for up to two weeks (10‒14 days) after receiving Cilta-cel.

• You may be discharged early on Day 10 if you have no side effects requiring further hospitalization. The study center staff will contact you for the following 4 days (except on weekends and holidays).

• You will be asked to stay for another week or until study day 21 (whichever comes first) at a location that is no more than 1 hour's drive from the hospital. Additionally, a capable adult must always be with you.

If you are not hospitalized during or immediately after the infusion of Cilta-cel:

• You will be asked to stay at a location that is no more than 30 minutes' drive from the hospital until your admission to the hospital 4 days after your Cilta-cel infusion. Additionally, a capable adult must always be with you.

• You will return to the hospital (on Day 5 after the Cilta-cel infusion) and stay for up to 10 days (until Day 14).

• You may be discharged early on Day 10 if you have no side effects requiring further hospitalization.

Post-CAR-T therapy with Lenalidomide:

Cycles 7 and subsequent cycles (28 days each)

Continuous treatment for up to 2 years (unless the investigator believes you would benefit from a longer duration of maintenance therapy)

Lenalidomide: capsules, 10 to 15 mg daily on days 1 to 28 of each cycle

Visit dates: Every 4 weeks (28 days) for laboratory tests

Follow-up:

After completing the Lenalidomide therapy following CAR-T therapy, visits will occur every 4 weeks for 2 years, and then every 8 weeks. During these visits, laboratory tests will be conducted to obtain information on how your myeloma responds.

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Untersuchte Krankheit(en)

This study is being conducted to treat patients with newly diagnosed multiple myeloma (MM).

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Sponsor

European Myeloma Network B.V. (EMN), Netherlands PAREXEL International (CH) AG C/O VISCHER AG, Basel

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Name der bewilligenden Ethikkommission (bei multizentrischen Studien nur die Leitkommission)

Ethikkommission Bern

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Datum der Bewilligung durch die Ethikkommission

19.06.2023

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Ergebnisse der Studie