A Multi-arm Phase 1b Study of Talquetamab With Other Anticancer Therapies in Participants with Multiple Myeloma

1. Be >=18 years of age.
2. 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,
including the requirement to provide information during the Posttreatment
Follow-up Period. Consent must be obtained prior to the initiation of any
study-related tests or procedures that are not part of standard of care for the
participant*s disease.
3. Have documented initial diagnosis of multiple myeloma according to IMWG
diagnostic criteria.
4. Meet treatment regimen-specific requirements as follows:
a. Treatment Regimen A (talquetamab + carfilzomib): Participants with multiple
myeloma who have received >=3 prior lines of therapy, including a PI, an IMiD,
and an anti-CD38 mAb
b. Treatment Regimen B (talquetamab + daratumumab + carfilzomib): Participants
with multiple myeloma who have received >=3 prior lines of therapy, including a
PI and an IMiD
c. Treatment Regimen C (talquetamab + lenalidomide): Participants with multiple
myeloma who have received >=1 prior lines of therapy,
including a PI and an IMiD
d. Treatment Regimen D (talquetamab + daratumumab + lenalidomide):
o Participants with >=1 prior lines, including a PI and an IMiD.
o Participants who are lenalidomide naïve or have newly diagnosed disease. Any
newly diagnosed participants must be transplant ineligible. Where local
treatment guidelines allow, newly diagnosed transplant-eligible participants
who chose to defer ASCT as initial therapy may also be enrolled.
e. Treatment Regimen E (talquetamab + pomalidomide): Participants with multiple
myeloma who have received >=2 prior lines of therapy, including a PI and
lenalidomide
5. Have measurable disease at screening as defined by at least 1 of the
following:
a. Serum M-protein level >=1.0 g/dL; or
b. Urine M-protein level >=200 mg/24 hours; or
c. Light chain multiple myeloma: Serum Ig FLC >=10 mg/dL and abnormal serum Ig
kappa lambda FLC ratio.
6. Have an ECOG performance status score of 0 or 1 at screening and immediately
before the start of study treatment administration.
7. Have clinical laboratory values meeting the following criteria during the
Screening Period:
Hemoglobin 8.0 g/dL ( 5 mmol/L) (without prior RBC transfusion within 7 days
before the laboratory test; recombinant human erythropoietin use is permitted)
Platelets 50×109/L (without transfusion support in the 7 days prior to the
laboratory test)
ANC 1.0×109/L (prior growth factor support is permitted but must be without
support for 7 days if received G-CSF or GM-CSF or 14 days if received peg-G-CSF)
AST and ALT <=2.5×ULN
Creatinine clearance 30 mL/min based upon Modified Diet in Renal Disease
formula calculation (Appendix 7) or a 24-hour urine collection.
Total bilirubin <=1.5×ULN; except in participants with congenital bilirubinemia,
such as Gilbert syndrome (in which case, direct bilirubin <=1.5×ULN is required)
Serum calcium corrected for albumin: <=14 mg/dL (<=3.5 mmol/L) or free ionized
calcium <=6.5 mg/dL (<=1.6 mmol/L)
8. A woman of childbearing potential must have a negative highly sensitive
serum (β-hCG) pregnancy test at screening and a negative urine or serum
pregnancy test within 24 hours before the start of study treatment
administration.
9. A woman must be:
a. Not of childbearing potential, or
b. Of childbearing potential and
-practicing true abstinence;
-or have a sole partner who is vasectomized;
-or practicing at least 1 highly effective user-independent method of
contraception. If hormonal contraception is used (eg, oral estrogen/progestin),
a male or female condom with or without spermicide (eg, spermicidal
foam/gel/film/cream/suppository) must also be used.
•For participants enrolled in IMiD-containing regimens (Treatment Regimens C,
D, and E), women of childbearing potential must be on 2 methods of reliable
birth control simultaneously while receiving study treatment and until 100 days
after last dose of study treatment: 1 highly effective form of contraception
(tubal ligation, intrauterine device, hormonal [oral, injectable, transdermal
patches, vaginal rings, or implants], or partner*s vasectomy), and 1 additional
effective contraceptive method (male latex or synthetic condom, diaphragm, or
cervical cap).
-Agree to pregnancy testing (serum or urine) within 100 days after the last
dose of study
treatment.
10. 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 100 days after
the last dose of study treatment. Male participants should also be advised of
the benefit for a female partner to use a highly effective method of
contraception as condoms may break or leak.
11. A woman must agree not to donate eggs (ova, oocytes) for the purposes of
assisted reproduction during the study and for at least 100 days after the last
dose of study treatment.
12. A man must agree not to donate sperm for the purpose of reproduction during
the study and for a minimum of 100 days after receiving the last dose of study
treatment.
13. Be willing and able to adhere to the lifestyle restrictions specified in
this protocol, including adherence to the applicable IMiD global PPP or local
PPP/REMS program.

Please refer to protocol pages 91-94 for full inclusion criteria.

Any potential participant who meets any of the following criteria will be
excluded from participating in the study:
1. Prior treatment with any therapy that targets GPRC5D.
2. Prior antitumor therapy as follows, in the specified time frame prior to the
first dose of study treatment:
a. Targeted therapy, epigenetic therapy, or treatment with an investigational
drug or an invasive investigational medical device within 21 days or at least 5
half lives, whichever is less.
b. Gene-modified adoptive cell therapy (eg, CAR modified T-cells, NK cells)
within 3 months.
c. mAb treatment or bispecific T-cell redirector therapy for multiple myeloma
within 21 days.
d. Cytotoxic therapy within 21 days.
e. PI therapy within 14 days.
f. Immunomodulatory agent therapy within 7 days.
g. Radiotherapy within 14 days. However, if palliative focal radiation is used,
the participant is eligible irrespective of the end date of radiotherapy.
3. Live, attenuated vaccine within 4 weeks before the first dose of study
treatment.
4. Non-hematologic toxicity from prior anticancer therapy that has not resolved
to baseline levels or to Grade <=1 (except alopecia [any grade] or peripheral
neuropathy Grade <=3).
5. Received a cumulative dose of corticosteroids equivalent to >=140 mg of
prednisone within the 14-day period before the start of study treatment
administration
6. Received either of the following:
a. An allogeneic SCT within 6 months before the first dose of study treatment.
Participants who received an allogeneic transplant must be off all
immunosuppressive medications during the 6 weeks before the start of study
treatment administration without signs of graft-versus-host disease.
b. An autologous SCT within 12 weeks before the start of study treatment
administration.
7. Active CNS involvement or exhibition of clinical signs of meningeal
involvement of multiple
8. Active plasma cell leukemia (>2.0×109/L plasma cells by standard
differential), Waldenstro*m*s macroglobulinemia, POEMS syndrome
(polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes), or
primary amyloid light chain amyloidosis.
9. Known to be seropositive for human immunodeficiency virus.
10. Seropositive for HBV, defined by a positive test for HbsAg. Participants
with resolved infection (ie, participants who are HbsAg negative but positive
for hepatitis B core antibody[anti-HBc] and/or positive for hepatitis B surface
antibody [anti-HBs]) must be screened using real-time PCR measurement of HBV
DNA levels. Those who are PCR positive will be excluded. EXCEPTION:
Participants with serologic findings suggestive of HBV vaccination (anti-HBs
positivity as the only serologic marker) and a known history of prior HBV
vaccination do not need to be tested for HBV DNA by PCR.
11. Active hepatitis C infection as measured by positive HCV-RNA testing.
Participants with a history of HCV antibody positivity must undergo HCV-RNA
testing.
12. Known allergies, hypersensitivity, or intolerance to any study treatment or
their excipients
13. Any serious underlying medical condition, such as:
a. Evidence of serious active viral, bacterial, or uncontrolled systemic fungal
infection.
b. Active autoimmune disease requiring systemic immunosuppressive therapy
within 6 months before start of study treatment. EXCEPTION: Participants with
vitiligo, type I diabetes, and prior autoimmune thyroiditis that is currently
euthyroid based on clinical symptoms and laboratory testing are eligible
regardless of when these conditions were diagnosed.
c. Disabling psychiatric conditions (eg, ongoing alcohol or drug abuse), severe
dementia, or altered mental status.
d. Any other issue that would impair the ability of the participant to receive,
absorb, 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 well-being) or that could prevent, limit, or
confound the protocol-specified assessments.
14. History of stroke or seizure within 6 months prior to the first dose of
study treatment.
15. Any of the following cardiac conditions:
a. New York Heart Association stage III or IV congestive heart failure.
b. Myocardial infarction, unstable angina, or coronary artery bypass graft <=6
months prior to enrollment.
c. History of clinically significant ventricular arrhythmia or unexplained
syncope not believed to be vasovagal in nature or due to dehydration.
d. History of severe nonischemic cardiomyopathy. e. Treatment Regimen A
(tal-cfz) and Treatment Regimen B (tal-dara-cfz) only: transthoracic
echocardiography showing LVEF < 40%. Please refer to protocol pages 79-82 for
full exclusion criteria.
16. Pregnant or breastfeeding or planning to become pregnant while enrolled in
this study or within 100 days after the last dose of study treatment.
17. Planning to father a child while enrolled in this study or within 100 days
after the last dose of study treatment.
18. Major surgery within 2 weeks of the first dose of study treatment, or will
not have fully recovered from surgery, or has surgery planned during the time
the participant is expected to be treated in the study or within 2 weeks after
the last dose of study treatment administration. Note: participants with
planned surgical procedures to be conducted under local anesthesia may
participate.
19. Treatment Regimen B (taldara-cfz) and Treatment Regimen D (taldaralen)
only: Has either of the following:
a. COPD with FEV1<50% of predicted normal. Note that FEV1 testing is required
for participants suspected of having COPD, and participants must be excluded if
FEV1 is
<50% of predicted normal; testing done as standard of care within 6 months of
the first dose of study treatment is acceptable for this criterion.
b. Moderate or severe persistent asthma within the past 2 years, or
uncontrolled asthma of any classification. Note: participants who currently
have controlled intermittent asthma or controlled mild persistent asthma are
allowed to participate in the study.
Cfr protocol p. 94-96 voor volledige exclusiecriteria.