Immuno-PRISM (PRecision Intervention Smoldering Myeloma): A Randomized Phase II Platform Study of Select Immunotherapies for High-Risk Smoldering Myeloma

Protocol # :
High-risk Smoldering Multiple Myeloma
Smoldering Multiple Myeloma
Multiple Myeloma
Disease Sites
Multiple Myeloma
Principal Investigator
Ghobrial, Irene, M
Site Research Nurses
Barrell, Anna
Davie, Christine, M.
Doherty, Randi
Goguen, Amy
Ricciardi, Caroline
Spillane, Kerry, L.
Tattersall, Alice, Emily
Ward, Mackenna

Trial Description

The purpose of this study is to test the anti-cancer activity of Teclistamab and to compare
it with Lenalidomide + Dexamethasone combination in people with high risk smoldering multiple

People with smoldering multiple myeloma (SMM) usually do not have symptoms but are at risk
for progressing to active multiple myeloma (MM). Multiple Myeloma is a cancer of the plasma
cells, which are an important part of the immune system. Patients with active multiple
myeloma generally require treatment but there are currently no approved therapies for
smoldering multiple myeloma.

The names of the study drugs involved in this study are:

- Teclistamab

- Lenalidomide (also called Revlimid)

- Dexamethasone (also called Decadron)

Eligibility Requirements

Inclusion Criteria:

- Age ≥18 years.

- 1) High risk SMM defined as having 1 of the following 2 criteria: High risk per
"20-2-20" Criteria defined as presence of any two of the following:

-- Serum M spike ≥ 2 gm/dL, Involved to uninvolved free light chain (FLC) ratio≥ 20,
Bone marrow Plasma Cell (BMPC) % ≥ 20%

- OR total score of 9 using the following scoring system:

- FLC Ratio >10-25 = 2, >25-40 = 3, > 40 = 5

- Serum M-Protein (g/dL) >1.5-3 = 3, >3 = 4

- BMPC% >15-20 = 2, >20-30 = 3, >30-40 = 5, >40 = 6

- Fluorescence In Situ Hybridization (FISH) abnormality (t(4,14), t(14,16), 1q gain, or
del13q = 2

- 2) Presence of ≥10% BMPC and at least one of the following:

-- Evolving pattern:

- evolving Monoclonal Protein (eMP) (≥10% increase in Monoclonal
Protein/Immunoglobulin (Ig)) within the first 6 months (only if M-protein ≥3
g/dl) and/or ≥25% increase in M/Ig within the first 12 months, with a minimum
required increase of 0.5 g/dl in M-protein and/or 500 mg/dl in Ig.

- Evolving change in hemoglobin (eHb) ≥0.5 g/dl decrease within 12 months of

- Progressive involved light chain increase on two successive evaluation

- Abnormal Plasma Cell immunophenotype (≥ 95% of BMPCs are clonal) and reduction of
≥1 uninvolved immunoglobulin isotype. (Only IgG; IgA and IgM will be considered)

- High risk cytogenetics defined as presence of t(4;14), t(14;16), t(14;20), 17p
deletion, TP53 mutation, 1q21 gain

- No evidence of CRAB criteria* or new criteria of active MM (SLIM-CRAB) which include
the following:

- Increased calcium levels: Corrected serum calcium >0.25 mmol/L (>1mg/dL) above
the upper limit of normal or >2.75 mmol/L (>11mg/dL);

- Renal insufficiency (attributable to myeloma);

- Anemia (Hgb 2g/dL below the lower limit of normal or <10g/dL);

- Bone lesions (lytic lesions or generalized osteoporosis with compression

- No evidence of the following new criteria for active MM including the following:

- Bone marrow plasma cells >60%

- Serum involved/uninvolved FLC ratio ≥100

- MRI with more than one focal lesion

- Participants with CRAB criteria that are attributable to conditions other than the
disease under study may be eligible after discussion with the Sponsor Investigator.

- Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0, 1, or 2

- The following laboratory values obtained <28 days prior to registration:

- Absolute Neutrophil Count (ANC) >1000/mL

- Platelets Count (PLT) >75,000/mL

- Total bilirubin ≤ 2.0 mg/dL (If total is elevated check direct and if normal
patient is eligible.)

- Aspartates Aminotransferase (AST) <2.5 x institutional upper limit of normal

- Alanine Transaminase (ALT) <2.5 x institutional upper limit of normal (ULN)

- Estimated creatinine clearance (CLcr) ≥60 mL/min (Cockcroft Gault equation).

- Voluntary written informed consent will be obtained before performance of any
study-related procedure not part of normal medical care, with the understanding that
consent may be withdrawn by the subject at any time without prejudice to future
medical care.

- Females of child-bearing potential* randomized to Lenalidomide must have a negative
serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL within 10 - 14
days and again within 24 hours prior to prescribing lenalidomide for Cycle 1
(prescriptions must be filled within 7 days as required by Revlimid Risk Evaluation
and Mitigation Strategies (REMS®) and must either commit to continued abstinence from
heterosexual intercourse or begin TWO acceptable methods of birth control, one highly
effective method and one additional effective method AT THE SAME TIME, at least 28
days before she starts taking lenalidomide.

- A female of child-bearing potential is a sexually mature female who: has not
undergone a hysterectomy (the surgical removal of the uterus) or bilateral
oophorectomy (the surgical removal of both ovaries), or has not been naturally
postmenopausal (amenorrhea following cancer therapy does not rule out
childbearing potential) for at least 24 consecutive months (i.e., has had menses
at any time during the preceding 24 consecutive months)

- 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 ≥1 highly-effective, user-independent method of
contraception NOTE: Participant must agree to continue the above throughout the
study and for 90 days after the last dose of study treatment.

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

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

- 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 (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 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

- If the male participant is vasectomized, he still must wear a condom (with spermicidal
foam/gel/film/cream/suppository), but his female partner is not required to use

- 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

- Must be willing and able to adhere to the lifestyle restrictions specified in this

- All study participants randomized to lenalidomide must be registered into the
mandatory Revlimid REMS® program and be willing and able to comply with the
requirements of the REMS® program.

- Females of child-bearing potential must adhere to the scheduled pregnancy testing as
required in the Revlimid REMS® program if randomized to lenalidomide

- Men must agree to use a latex condom during sexual contact with a female of
childbearing potential even if they have had a successful vasectomy

- Ability to understand and the willingness to sign a written informed consent.

Exclusion Criteria:

- Prior SMM directed therapy administered within 6 months of beginning treatment on
study. To avoid including primary refractory cases to the lenalidomide arm,
participants who received a prior lenalidomide-based therapy should have had at least
an Minimal Response (MR) to be considered on this trial.

- Symptomatic Multiple Myeloma or any evidence of CRAB criteria, including presence of
myeloma defining events (MDE). Any prior therapy for active Myeloma should also be
excluded. Prior therapy for smoldering myeloma is not an exclusion criterion.
Bisphosphonates are not excluded

- Other concurrent chemotherapy, immunotherapy, radiotherapy, or any ancillary therapy
considered investigational. Prior therapy with bisphosphonate is allowed. Prior
radiation therapy to a solitary plasmacytoma is allowed but had to be at least 6
months prior to enrollment on the trial. Prior clinical trials or therapy for
smoldering MM or Monoclonal Gammopathy of Unknown Significance (MGUS) are allowed per
exclusion criteria described above.

- Serious medical or psychiatric illness likely to interfere with participation in this
clinical study.

- Diagnosed or treated for another malignancy within 2 years of enrollment

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements.

- Plans to father a child while enrolled in this study or within 90 days after receiving
the last dose of study drug.

- Pregnant or breast-feeding or planning to become pregnant while enrolled in this study
or within 90 days after receiving the last dose of study drug.

- Known seropositive for or active viral infection with human immunodeficiency virus
(HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV) or SARS-CoV-2 (COVID- 19).

- Participants who are seropositive because of hepatitis B virus vaccine are eligible.

- Participants who are positive for SARS-COV-2 antibody, HIV1 and 2 antibody, hepatitis
B core antibody or hepatitis B surface antigen must have a negative polymerase chain
reaction (PCR) result before enrollment. Those who are PCR positive will be excluded.

- Contraindications or life-threatening allergies, hypersensitivity, or intolerance to
any study drug or its excipients (refer to the teclistamab Investigator's Brochure and
appropriate package inserts).

- Prior or concurrent exposure to any of the following:

- Investigational vaccine within 4 weeks

- Live, attenuated vaccine within 4 weeks before randomization.

- Monoclonal antibody therapy within 21 days

- Cytotoxic therapy within 14 days

- PI therapy within 14 days

- IMiD agent therapy within 14 days

- Radiotherapy within 14 days or focal radiation within 7 days

- A maximum cumulative dose of corticosteroids of ≥140 mg of prednisone or equivalent
within 14-day period before the first dose of study drug (does not include
pretreatment medications)

- Known active Central Nervous System (CNS) involvement or exhibits clinical signs of
meningeal involvement of multiple myeloma. If either is suspected, negative whole
brain MRI and lumbar cytology are required.

- Myelodysplastic syndrome or active malignancies (i.e., progressing or requiring
treatment change in the last 24 months). The only allowed exceptions are: a.
Non-muscle invasive bladder cancer treated within the last 24 months that is
considered completely cured b. Skin cancer (non-melanoma or melanoma) treated within
the last 24 months that is considered completely cured. c. Noninvasive cervical cancer
treated within the last 24 months that is considered completely cured d. Localized
prostate cancer (N0M0): With a Gleason score of ≤6, treated within the last 24 months,
or untreated and under surveillance With a Gleason score of 3+4 that has been treated
>6 months prior to full study screening and considered to have a very low risk of
recurrence, or e. History of localized prostate cancer and receiving androgen
deprivation therapy and considered to have a very low risk of recurrence. f. Breast
cancer: adequately treated lobular carcinoma in situ or ductal carcinoma in situ, or
history of localized breast cancer and receiving antihormonal agents and considered to
have a very low risk of recurrence. g. Other malignancy that is considered cured with
minimal risk of recurrence

- Stroke or seizure within 6 months prior to signing informed consent form

- Presence of the following cardiac conditions:

-- New York Heart Association stage III or IV congestive heart failure, 2) Myocardial
infarction or coronary artery bypass graft ≤6 months prior to randomization,3) History
of clinically significant ventricular arrhythmia or unexplained syncope, not believed
to be vasovagal in nature or due to dehydration,4) History of severe non-ischemic

- 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. NOTE: Participants 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
participant in the study.

- 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:

- Uncontrolled diabetes defined by Hemoglobin A1C > 8.5, Acute diffuse infiltrative
pulmonary disease, Evidence of active systemic viral, fungal, or bacterial infection,
requiring systemic, antimicrobial therapy, History of autoimmune disease with the
exception of vitiligo, type I diabetes, and, prior autoimmune thyroiditis that is
currently euthyroid based on clinical symptoms and laboratory testing, . Disabling
psychiatric conditions (e.g., alcohol or drug abuse), severe dementia, or altered
mental status, Any other issue that would impair the ability of the participant 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 participant (e.g., compromise
the wellbeing) or that could prevent, limit, or confound the protocol-specified
assessments, History of non-compliance with recommended medical treatments