This is a phase Ib study to assess the safety, tolerability, preliminary efficacy, and renal
response of isatuximab, bortezomib, and dexamethasone in newly diagnosed multiple myeloma
patients with severe renal impairment or dialysis-dependent end-stage renal disease. Such
patients have limited therapeutic options due to renal clearance or nephrotoxicity of many
myeloma therapies and are often excluded from clinical trials. Isatuximab in other regimens
has shown efficacy and tolerability in patients with moderate renal impairment, although data
are lacking for regimens containing CD38-targeting immunotherapies in severe renal
This study will enroll 28 evaluable patients. Fourteen (+/- 2) patients will be required
tto be on dialysis and 14 (+/- 2) patients will not be on dialysis.
- Newly diagnosed multiple myeloma diagnosis according to IMWG criteria. Patients
eligible for autologous stem cell transplant may be enrolled if the intent is to
proceed to transplant after 4 or more cycles of study treatment.
- Severe renal impairment (eGFR < 30ml/min/1.73m^2 using the MDRD calculator) or on
dialysis. The value at screening confirms eligibility (if eGFR improves prior to
enrollment, this does not render a patient ineligible) The renal impairment may be
acute or chronic and may be related to the underlying myeloma (e.g. multiple myeloma
(MM) cast nephropathy, monoclonal immunoglobulin deposition disease [MIDD], myeloma
cell infiltration) or another cause (e.g. diabetes, hypertension), however the
acuity/chronicity and the underlying cause should be documented clearly. Those who
have acute kidney injury from hypercalcemia should receive intravenous hydration and
calcium-lowering therapy to see if this renal impairment is reversible.
- At least 18 years of age.
- ECOG performance status ≤ 2
- Bone marrow and organ function as defined below:
- Absolute neutrophil count ≥ 1,000/mm3 (growth factor to achieve this level is
- Platelets ≥ 50,000/mm3 (transfusion to achieve this level is permissible)
- Bilirubin ≤ 2 mg/dL
- AST(SGOT)/ALT(SGPT) ≤ 3.5 x institutional upper limit of normal (IULN)
- The effects of isatuximab and bortezomib on the developing human fetus are unknown.
For this reason, women of childbearing potential must agree to use adequate
contraception (hormonal or barrier method of birth control, abstinence) prior to study
entry, for the duration of study participation, and for 5 months after discontinuation
of study treatment. Should a woman become pregnant or suspect she is pregnant while
participating in this study, she must inform her treating physician immediately. Men
treated or enrolled on this protocol must also agree to use adequate contraception
prior to the study, for the duration of the study, and 5 months after completion of
- Ability to understand and willingness to sign an IRB approved written informed consent
document (or that of legally authorized representative, if applicable).
- Concomitant use of other anti-neoplastic medications or radiotherapy (except for
localized disease). Note: Participants are permitted to have received one dose of
bortezomib or up to 80 mg of dexamethasone (or equivalent) prior to study treatment
initiation if deemed clinically necessary for disease control.
- Currently receiving any other investigational agents.
- Evidence of myeloma within the CNS
- Presence of amyloidosis without concomitant multiple myeloma. Patients with
concomitant amyloidosis and multiple myeloma are eligible.
- Prior refractoriness, intolerance or hypersensitivity to bortezomib.
- Prior treatment with an anti-CD38 monoclonal antibody.
- A history of allergic reactions attributed to compounds of similar chemical or
biologic composition to isatuximab, bortezomib, or dexamethasone or other agents used
in the study.
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, or cardiac
- Pregnant and/or breastfeeding. Women of childbearing potential must have a negative
pregnancy test within 14 days of study entry.
- Active acute or chronic hepatitis B viral infection.
- Screening with serological tests for HBV with surface antigen and antibody (HBsAg
and HBsAb) and HBV total core antibody (HBcAb IgG and IgM), and screening for HCV
(HCV Ab and HCV RNA level) are required to have been performed within 1 year of
screening, or should otherwise be performed as part of screening.
- Patients with uncontrolled or active HBV infection (patients with positive HBsAg
and/or HBV DNA), as well as patients with active HCV infection (positive HCV RNA
and negative anti-HCV) are not eligible
- In case HBcAb are positive, HBV DNA testing by polymerase chain reaction will
also be done at baseline. For patients with positive anti-HBc IgG, negative HBsAg
and undetectable (under limit of quantification) HBV DNA at study entry (HBV
carriers: past resolved infection, resolving acute infection or receiving
antiviral treatment with controlled infection), specialist advice may be
requested, close monitoring of viral reactivation throughout and following the
end of study treatment should be proposed (alanine aminotransferase, aspartate
aminotransferase, and HBV DNA at least every 3 months, up to 6 months after
treatment discontinuation or initiation of further anticancer therapy.
- Patients with HIV are eligible unless their CD4+ T-cell counts are < 350 cells/mcL or
they have a history of AIDS-defining opportunistic infection within the 12 months
prior to registration. Concurrent treatment with effective ART according to DHHS
treatment guidelines is recommended.
- Baseline Grade 2 or higher peripheral neuropathy