Inclusion Criteria:
1. Patients must have histologically or cytologically confirmed smoldering multiple
myeloma (SMM) based on the IMWG Criteria10 including:
- - Serum M-protein ≥3 g/dL and/or BMPCs≥10 % (but <60%)
- Absence of anemia: hemoglobin >10 g/dL.
- - Absence of renal failure: serum creatinine <2.0 mg/dL.
- - Absence of hypercalcemia: Calcium <10.5 mg/dL.
- - Absence of lytic bone lesion on X-ray, CT, or positron emission tomography
(PET)/CT and not more than 1 lesion on whole body MRI (NOTE: At the discretion of
the Investigator, whole body CT or PET/CT may replace MRI in patients who have a
contraindication or who are unable to have MRI performed.
)
- - Involved/uninvolved light chain ratio <100 (unless involved light chain is ≤10
mg/dL) NOTE: Anemia, renal failure, and hypercalcemia is allowed if deemed
unrelated to multiple myeloma (MM), see organ function criteria in point #5
below.
2. Patients must have measurable disease within the past 4 weeks, which is defined by any
one of the following:
- - Serum monoclonal protein ≥ 0.5 g/dL.
- - Urine monoclonal protein >200 mg/24 hour.
- - Serum immunoglobulin free light chain ≥10 mg/dL AND abnormal kappa/lambda serum
free light chain ratio (reference: 0.26-1.65)
- Other measurable disease as defined by the International Myeloma Working Group
(IMWG).
- - Because the primary endpoint is MRD negativity based on bone marrow analysis, a
patient without measurable disease in blood or urine may be enrolled and assessed
for MRD negativity.
NOTE: In patients who received minimal prior therapy within
the allowable range per exclusion criteria 1, patients should have had documented
measurable disease within 4 weeks of starting that respective therapy if
currently unmeasurable.
3. Patients age ≥18 years.
4. Patients with Eastern Cooperative Oncology Group (ECOG) performance status 0-1
assessed within the past 45 days. (See Appendix 17.1).
5. Patients must have adequate organ and marrow function ≤45 days as defined below:
- - Absolute neutrophil count (ANC) >1.0 K cells/μL; At the discretion of the
Investigator, patients with an ANC of 0.5 K/μL-1.0 K/μL may also be enrolled if
clinically appropriate (eg, patients with a baseline neutropenia that is chronic
and/or ethnic neutropenia and that does not cause complications, e.
g, no history
of chronic infections).
- - Platelet count >75 K cells/μL.
- - Hemoglobin >8 g/dL (transfusions are permissible if the cause of the anemia is
other than myeloma)
- Total bilirubin <1.5 X upper limit of normal (ULN).
NOTE: Isolated total
bilirubin ≥1.5 X ULN with conjugated [direct] bilirubin <1.5 X ULN is allowed for
those participants with known Gilbert's syndrome.
- - Aspartate aminotransferase (AST)/ alanine transaminase (ALT) ≤2.5 X ULN.
- - ≥30 mL/min based on Modification of Diet in Renal Disease (MDRD) 4-variable
Formula calculation (Appendix 17.2) or creatine clearance (CrCl) measured by a
24-hour urine collection.
The estimated glomerular filtration rate (eGFR) may
also be determined by using other widely accepted methods as clinically
indicated, ie, Cockcroft-Gault method or the chronic kidney disease
(CKD)-epidemiology collaboration (EPI) per institutional standards.
6. Patients must have SMM that is categorized as high-risk for progression to MM-related
end- organ damage by both clinical and genomic characteristics. Patients may be
categorized as high risk by the Program for Study and Treatment of Malignant
Hemopathies (PETHEMA) (immunoparesis and ≥95% aberrant bone marrow plasma cells
(aBMPCs) by flow) and/or Mayo Clinic78 (20/2/20) criteria and/or have clonal BMPCs
≥10% with any one or more of the following criteria4:
- - Serum M protein ≥3 g/dL.
- - Immunoglobulin A (IgA) SMM.
- - Immunoparesis with reduction of 2 uninvolved immunoglobulin isotypes.
- - Serum involved/uninvolved free light chain (FLC) ratio ≥8 (but <100)
- Progressive increase in M-protein level (evolving type of SMM; increase in serum
M- protein by ≥25% on 2 successive evaluations within a 6-month period)
- Clonal bone marrow plasma cells (BMPC) 50%-59%
- Abnormal plasma cell (PC) immunophenotype (≥95% of BMPCs are clonal) and
reduction of ≥1 uninvolved immunoglobulin isotype(s)
- Chromosomal abnormalities specifically translocation of chromosomes 4 or 14
(t(4;14)) or deletion of the short arm of chromosome 17 del(17p)) or gain of the
long arm of chromosome 1 (1q gain) found in ≥5% of cells.
- - Increased circulating PCs (PCs >5 x 106/L and/or >5% PCs per 100 peripheral blood
mononuclear cells (PBMCs)
- MRI with diffuse abnormalities or 1 focal lesion, AND/OR PET-CT with focal lesion
with increased uptake without underlying osteolytic bone destruction.
7. A female participant of childbearing potential must have a negative serum or urine
pregnancy test at screening (at or within 45 days of study enrollment) and within 72
hours of the start of study treatment (Section 4.7) and must agree to further serum or
urine pregnancy tests during the study. 8. A female participant must be (as defined in Appendix 17.3):
1. Not of childbearing potential, or. 2. Of childbearing potential and practicing at least 1 highly effective method of
contraception (see Appendix 17.3). NOTE: Participant must agree to continue the
above throughout the study and for 3 months 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.
9. A female participant must agree not to donate eggs (ova, oocytes) or freeze for future
use for the purposes of assisted reproduction during the study and for a period of 3
months after receiving the last dose of study treatment. Female participants should
consider preservation of eggs prior to study treatment, as anti-cancer treatments may
impair fertility.
10. A female participant must agree to not breastfeed during the study and for a period of
5 months after receiving the last dose of study treatment.
11. A male participant must wear a condom when engaging in any activity that allows for
passage of ejaculate to another person during the study and for a period of 3 months
after receiving the last dose of study treatment. If the male participant's partner is
a female of childbearing potential, the male participant must use condoms (with or
without spermicide), and the female partner of the male participant must also be
practicing a highly effective method of contraception (see Appendix 17.3).
NOTE: If the male participant is vasectomized, he still must wear a condom (with or
without spermicidal foam/gel/film/cream/suppository), but his female partner is not
required to use contraception.
12. A male participant must agree not to donate sperm for the purpose of reproduction
during the study and for period of 3 months after receiving the last dose of study
treatment. Male participants should consider preservation of sperm prior to study
treatment, as anti-cancer treatments may impair fertility.
13. Ability of the patient to understand and the willingness to sign a written informed
consent document.
14. Have any condition that, in the opinion of the Investigator, would compromise the
well-being of the patient or the study or prevent the patient from meeting or
performing study requirements.
15. Must be willing and able to adhere to the lifestyle restrictions specified in this
protocol (Section 3.3).
Exclusion Criteria:
1. Patients who have received prior systemic therapies for SMM/MM. One prior cycle (4-5
weeks) of therapy for SMM is allowed provided that patient undergoes a 4-week washout
period prior to first dose of study treatment. Treatment with corticosteroids for
other indications is permitted.
2. Patients who are receiving any other investigational agents for any reasons.
3. Patients who receive a live attenuated vaccine within 4 weeks of scheduled study
treatment administration.
4. Contraindication to any concomitant medication, including those medications
administered for infusion reaction, antiviral, antibacterial, anticoagulation, tumor
lysis, or hydration prophylaxis given prior to therapy.
5. Patient has any of the following:
1. Human immunodeficiency virus (HIV)-positive with 1 or more of the following:
- - History of acquired immune deficiency syndrome (AIDS)-defining conditions
cluster of differentiation (CD4)count <350 cells/mm3.
- - Detectable viral load during screening or within 6 months prior to screening.
- - Not receiving highly active anti-retroviral therapy.
- - 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.
2. Hepatitis B infection (ie, hepatitis B surface antigen (HBsAg) or hepatitis B
virus (HBV)- DNA positive). Patients with resolved infection (ie, patients who
are HBsAg negative but positive for antibodies to hepatitis B core antigen
(anti-HBc) and/or antibodies to hepatitis B surface antigen [anti-HBs]) must be
screened using real-time polymerase chain reaction (PCR) measurement of HBV DNA
levels. Those who are PCR positive will be excluded. In the event the infection
status is unclear, quantitative viral levels are necessary to determine the
infection status; see Section 10.3.5.2.1 for further required assessments.
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.
3. Active hepatitis C infection as measured by positive HCV-ribonucleic acid (RNA)
testing.
Participants with a history of hepatitis C virus (HCV) antibody positivity must
undergo HCV-RNA testing (Section 10.3.5.2.2). If a participant with history of
chronic hepatitis C infection (defined as both HCV antibody and HCV-RNA positive)
completed antiviral therapy and has undetectable HCV-RNA 12 weeks following the
completion of therapy, the participant is eligible for the study.
4. Chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1
second (FEV1) <50% of predicted normal. Note that FEV1 testing is required for
participants with known or suspected of having COPD or asthma, and participants
must be excluded if FEV1 <50% of predicted normal.
5. Moderate or severe persistent asthma within the past 2 years or uncontrolled
asthma of any classification. Note that FEV1 testing is required for participants
with known or suspected asthma, and participants must be excluded if FEV1 <50% of
predicted normal.
6. History of allergic reactions attributed to compounds of similar chemical or biologic
composition to the experimental agents used in study.
7. Female patient refuses to discontinue breastfeeding her infant during study treatment
or within 5 months after receiving the last dose of study treatment.
8. Participant plans to father a child while enrolled in this study or within 3 months
after the last dose of study treatment.
9. Presence of the following cardiac conditions:
1. New York Heart Association stage III or IV congestive heart failure. 2. Myocardial infarction or coronary artery bypass graft ≤6 months prior to study
enrollment. 3. History of clinically significant ventricular arrhythmia or unexplained syncope,
not believed to be vasovagal in nature or due to dehydration. 4. Uncontrolled cardiac arrhythmia or clinically significant electrocardiogram (ECG)
abnormalities. 5. Unstable or uncontrolled disease/condition related to or affecting cardiac
function (eg, unstable angina)
10. Uncontrolled intercurrent illness including but not limited to ongoing or active
infection, venous thromboembolic disease, hemorrhage, pulmonary fibrosis, pneumonitis,
active autoimmune disease or a documented 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, or psychiatric
illness/social situations within 2 weeks that would limit compliance with study
requirements.
11. Active malignancy other than SMM requiring treatment in the past 24 months.
Malignancies treated within the past 24 months that are considered cured with minimal
risk of recurrence are allowed.
12. Have any condition that, in the opinion of the Investigator, would compromise the
well-being of the patient or the study or prevent the patient from meeting or
performing study requirements.
13. Patients with impaired decision-making capacity will not be enrolled on this trial.
