MAJESTIC-3

Each potential participant must satisfy all of the following criteria to be enrolled in the study:

1. Aged 18 years of age or older.

2. Documented multiple myeloma as defined by the criteria below:

a) Multiple myeloma diagnosis according to the International Myeloma Working Group (IMWG) diagnostic criteria

b) Measurable disease at screening as defined by any of the following:

I) Serum M-protein level greater than or equal to 0.5 g/dL (central laboratory); or

II) Urine M-protein level greater than or equal to 200 mg/24 hours (central laboratory); or

III) Serum immunoglobulin free light chain greater than or equal to 10 mg/dL (central laboratory) and abnormal serum immunoglobulin kappa lambda free light chain ratio.

3. Received 1 to 3 prior line(s) of antimyeloma therapy including a proteasome inhibitor (PI) and lenalidomide. Participants who have received only 1 line of prior line of antimyeloma therapy must be lenalidomide refractory (i.e., have demonstrated progressive disease by IMWG criteria during treatment or within 60 days of completion of lenalidomide- containing regimen).

4. Documented evidence of progressive disease based on investigator’s determination of response by IMWG criteria on or after their last regimen.

5. Have an Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2 at screening and immediately prior to the start of administration of study treatment.

6. Have clinical laboratory values meeting the criteria specified in the study protocol table.

7. A woman of childbearing potential must have a negative highly sensitive serum pregnancy test at screening and again within 24 hours of the start of study treatment and must agree to further serum or urine pregnancy tests during the study.

8. A woman must be:

a. Not of childbearing potential, or

b. Of childbearing potential and

I) Practicing true abstinence; or

II) Have a sole partner who is vasectomised; or

III) Practicing 1 or more highly effective, user independent method of contraception. For participants who are of childbearing potential and treated with DPd in Arm B, see study protocol for details regarding concomitant use of oestrogen containing products and pomalidomide.

- Participant must agree to continue the above throughout the study and for 90 days after the last dose of study treatment.

- If a woman becomes of childbearing potential after start of the study the woman must comply with point (b) as described above.

9. A woman must agree not to donate eggs (ova, oocytes), or freeze for future use for the purposes of assisted reproduction, during the study and for 90 days after receiving the last dose of study treatment.

- A man 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 90 days after receiving the last dose of study treatment.

- If a female partner is of childbearing potential, she must also be practicing a highly effective method of contraception (unless male participant is vasectomised).

10. A male participant must agree not to donate sperm for the purpose of reproduction during the study and for a minimum of 90 days after receiving the last dose of study treatment.

11. Must be willing and able to adhere to the lifestyle restrictions specified in the study protocol.

12. Must sign an informed consent form (ICF) indicating that the participant understands the purpose of, and procedures required for, the study and is willing to participate in the study.

For an exhaustive list please refer to the study protocol. 

Any potential participant who meets any of the following criteria will be excluded from participating in the study:

1. Contraindications or life-threatening allergies, hypersensitivity, or intolerance to any study drug or its excipients.

2. Received any prior B cell maturation antigen (BCMA) -directed therapy.

3. Has disease that is considered refractory to an anti-CD38 monoclonal antibody per International Myeloma Working Group (IMWG) (progression during treatment or within 60 days of completing therapy with an anti CD38 monoclonal antibody).

4. Received the following prior antimyeloma therapy, in the specified time frame prior to randomisation:

a) Targeted therapy, epigenetic therapy, or treatment with an investigational drug or an invasive investigational medical device within 21 days or equal to or greater than 5 half-lives, whichever is less

b) Investigational vaccine within 4 weeks

c) Monoclonal antibody therapy within 21 days

d) Cytotoxic therapy within 21 days

e) PI therapy within 14 days

f) Immunomodulatory drug (IMiD) agent therapy within 14 days

g) Radiotherapy within 14 days or focal radiation within 7 days

h) Gene-modified adoptive cell therapy (for e.g., chimeric antigen receptor modified T cells, NK cells) within 3 months.

5. Stem cell transplant:

a) An allogeneic stem cell transplant within 6 months before randomisation. Participants who received an allogeneic transplant must be off all immunosuppressive medications for equal to or more than 42 days without signs of graft versus host disease before randomisation.

b) An autologous stem cell transplant within 12 weeks before randomisation.

6. Received a cumulative dose of corticosteroids equivalent to 140 mg or greater of prednisone within 14 days before randomisation.

7. Received a live, attenuated vaccine within 4 weeks before randomisation.

8. Myelodysplastic syndrome or active malignancies (i.e., progressing or requiring treatment change in the last 24 months) other than relapsed/refractory multiple myeloma, other than the protocol-specified exceptions.

9. Plasma cell leukaemia at the time of screening, Waldenström’s macroglobulinemia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes), or primary amyloid light chain amyloidosis.

10. Central nervous system (CNS) involvement or clinical signs of meningeal involvement of multiple myeloma. If either is suspected, negative whole brain MRI and lumbar cytology are required.

11. Stroke or seizure within 6 months prior to providing consent.

12. Participant is pregnant, breast-feeding, or planning to become pregnant while enrolled in this study or within 90 days after the last dose of study treatment.

13. Participant plans to father a child while enrolled in this study or within 90 days after the last dose of study treatment.

14. Presence of the following cardiac conditions:

a) New York Heart Association stage III or IV congestive heart failure

b) Myocardial infarction or coronary artery bypass graft within 6 months prior to randomisation

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

15. Any of the following:

a) Known to be seropositive for human immunodeficiency virus (HIV)

b) Hepatitis B infection.

c) Active hepatitis C infection as measured by positive HCV-RNA testing.

d) Chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) lower than 50% of predicted normal.

e) Moderate or severe persistent asthma within the past 2 years or uncontrolled asthma of any classification.

16. 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.

17. Major surgery 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.

For an exhaustive list, and also additional lifestyle considerations, please see the study protocol. 

Research Nurse: Nicola Slawson Ext. No:53062) Nicola.slawson@nhs.net

Administrator- Tamaryn Louw