Recurrent Multiple Myeloma, Refractory Multiple Myeloma
Conditions
Brief summary
This phase Ib/II trial compares the effect of teclistamab and pomalidomide to standard treatment with carfilzomib, pomalidomide and dexamethasone in treating patients with multiple myeloma that has come back after a period of improvement (relapsed). Teclistamab is a bispecific antibody that can bind to two different antigens at the same time. Teclistamab binds to B-cell maturation antigen (BCMA), a protein found on some B-cells and myeloma cells, and CD3 on T-cells (a type of white blood cell) and may interfere with the ability of cancer cells to grow and spread. Pomalidomide is in a class of medications called immunomodulatory agents. It works by helping the immune system kill cancer cells and by helping the bone marrow to produce normal blood cells. Carfilzomib blocks the action of enzymes called proteasomes, which may help keep cancer cells from growing and may kill them. It is a type of proteasome inhibitor. Dexamethasone is in a class of medications called corticosteroids. It is used to reduce inflammation and lower the body's immune response to help lessen the side effects of chemotherapy drugs. Giving teclistamab and pomalidomide may be safe, tolerable and improve response by lowering myeloma cells to undetectable levels when compared to standard treatment with carfilzomib, pomalidomide and dexamethasone in treating patients with relapsed multiple myeloma.
Detailed description
PRIMARY OBJECTIVES: I. To evaluate the toxicity of teclistamab and pomalidomide (TP) combination therapy in multiple myeloma (MM) patients in early relapse after one or two lines of therapy and establish the pomalidomide dose to be used with teclistamab in the Phase II portion of the trial. (Phase Ib) II. To determine whether patients with MM in early relapse after one or two lines of therapy who are randomized to teclistamab and pomalidomide (TP) compared to carfilzomib, pomalidomide, and dexamethasone (KPd) have superior efficacy measured by minimal residual disease (MRD)-negative complete response status after 9 cycles of treatment. (Phase II) SECONDARY OBJECTIVES: I. To determine whether patients with MM in early relapse who are randomized to TP compared to KPd have superior progression-free survival (PFS). II. To determine whether patients with MM in early relapse who are randomized to TP compared to KPd have superior overall survival (OS). III. To evaluate safety and compare toxicity rates between TP and KPd arms. IV. To evaluate response by International Myeloma Working Group (IMWG) uniform response criteria. OUTLINE: PHASE IB: Patients are assigned to 1 of 2 arms. ARM A and B: Patients teclistamab subcutaneously (SC) on days 1, 4, 7, 14, and 21 of cycle 1, days 1, 8, 15, and 22 of cycle 2, days 1 and 15 of cycles 3-6, then on day 1 of remaining cycles. Starting with cycle 2, patients receive pomalidomide orally (PO) once daily (QD) on days 1-21 of each cycle. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity. PHASE II: Patients are randomized to 1 of 2 arms. ARM C: Patients teclistamab SC on days 1, 4, 7, 14, and 21 of cycle 1, days 1, 8, 15, and 22 of cycle 2, days 1 and 15 of cycles 3-6, then on day 1 of subsequent cycles. Starting with cycle 2, patients receive pomalidomide PO QD on days 1-21 of subsequent cycles. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity. ARM D: Patients receive carfilzomib intravenously (IV) on days 1, 2, 8, and 15 of cycle 1, on days 1, 8, and 15 of cycle 2, then on days 1 and 15 of subsequent cycles, pomalidomide PO QD on days 1-21 and dexamethasone PO or IV on days 1, 8, 15, and 22 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo urine and blood sample collection, fludeoxyglucose F-18 (FDG) positron emission tomography (PET)/computed tomography (CT), and bone marrow biopsy and/or aspiration throughout the study. After completion of study treatment, patients are followed every 3 months for up to year 2, every 6 months for years 2-5, then yearly for up to 10 years from date of registration/randomization.
Interventions
PROCEDUREBiospecimen Collection
Undergo urine and blood sample collection
PROCEDUREBone Marrow Aspiration
Undergo bone marrow biopsy and/or aspiration
PROCEDUREBone Marrow Biopsy
Undergo bone marrow biopsy and/or aspiration
DRUGCarfilzomib
Given IV
PROCEDUREComputed Tomography
Undergo FDG PET/CT
DRUGDexamethasone
Given PO or IV
PROCEDUREFDG-Positron Emission Tomography
Undergo FDG PET/CT
OTHERFludeoxyglucose F-18
Given FDG
DRUGPomalidomide
Given PO
DRUGTeclistamab
Given SC
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Phase Ib safety lead in dose finding phase followed by a randomized phase II study
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patient must be ≥ 18 years of age * Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status 0-2 * Patient must have an identifiable dominant sequence (clonotype) established based on Adaptive Biotechnologies clonoSEQ® assay for Phase II only * Patient must have multiple myeloma and meet both of the following criteria for the original diagnosis of myeloma following the International Myeloma Working Group (IMWG) myeloma diagnostic criteria: * Bone marrow plasmacytosis with ≥ 10% plasma cells or sheets of plasma cells or biopsy proven plasmacytoma. * Tissue biopsy of any bone lesion or extramedullary plasmacytoma if applicable (positive/negative for clonal plasma cells) * Any one or more of the following symptomatic myeloma-defining events that prompted initiation of therapy as well as end-organ damage: * Anemia (hemoglobin value of \> 2 g/dL below the lower limit of normal, or a hemoglobin value \< 10 g/dL) * Hypercalcemia (serum calcium \> 1 mg/dL higher than the upper limit of normal or \> 11 mg/dL) * Bone disease (one or more osteolytic lesions on skeletal radiography, CT, or FDG-PET/CT) * Renal dysfunction (creatinine clearance \< 40 mL/min or serum creatinine \> 2 mg/dL). * Clonal bone marrow plasma cells (BMPCs) ≥ 60% * Involved/uninvolved serum free light chain ratio ≥ 100 * \> 1 focal lesions on magnetic resonance imaging (MRI) studies ≥ 5 mm * NOTE: Patients with smoldering myeloma (serum m protein ≥ 3 gm/dL or bone marrow plasma cells ≥ 10% or greater plus no evidence of anemia, hypercalcemia, lytic bone lesions or renal dysfunction) and monoclonal gammopathy of undetermined significance (serum m protein \< 3 gm/dL and bone marrow plasma cells \< 10% or greater plus no evidence of anemia, hypercalcemia, lytic bone lesions or renal dysfunction) are not eligible * Patient must have experienced early relapse disease defined as relapse after one line of lenalidomide therapy including single agent lenalidomide or lenalidomide/dexamethasone or CD38 antibody/lenalidomide +/- dexamethasone. The relapse can be progressive disease as determined by the treating clinician and meeting measurable disease criteria * Patient must have received no more than two lines of IMWG defined therapy (induction +/- transplant + maintenance is considered a single line of therapy) * Patient must not receive non-protocol concurrent chemotherapy for the study disease, or any ancillary therapy considered investigational while participating in the study * Patient must have received an immunomodulatory drug (lenalidomide) and a CD38 antibody (daratumumab or isatuximab) * Patient must have measurable disease as defined by having one or more of the following, obtained within 28 days prior to registration/randomization: * ≥ 0.5 g/dL monoclonal protein (M-protein) on serum protein electrophoresis * ≥ 200 mg/24 hrs of monoclonal protein (M-protein) on a 24-hour urine protein electrophoresis * Involved free light chain ≥ 10 mg/dL AND abnormal serum immunoglobulin kappa to lambda free light chain ratio (\< 0.26 or \> 1.65) * Exception: patients without measurable disease in the serum or urine, but with bone or soft tissue plasmacytoma(s) ≥ 2 cm or who have bone marrow plasma cells ≥ 30% are eligible on study * NOTE: Urine protein electrophoresis (UPEP) (on a 24 hour collection) is required, no substitute method is acceptable. Urine must be followed monthly if the baseline urine M-spike is ≥ 200 mg/24 hr. Please note that if both serum and urine m-components are present, both must be followed in order to evaluate response. * Patient must not be known to be refractory to carfilzomib or pomalidomide * Patient must not have received a prior BCMA therapy * Patient must not be pregnant due to the potential harm to an unborn fetus with the treatment regimens being used * All patients of childbearing potential must have a blood test or urine study within 14 days prior to registration/randomization to rule out pregnancy. Patients must also agree to a second pregnancy test completed within 24 hours prior to the first dose of pomalidomide and teclistamab and agree to ongoing pregnancy testing while on protocol treatment * A patient of childbearing potential is defined as anyone, regardless of whether they have undergone tubal ligation, who meets the following criteria: * Has achieved menarche at some point * Has not undergone a hysterectomy or bilateral oophorectomy * 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 in the preceding 24 consecutive months) * Patient must not expect to conceive or father children by using accepted and effective method(s) of contraception or by abstaining from sexual intercourse for the duration of their participation in the study and for 6 months after the last dose of protocol treatment for patients on Arms A, B, and C and for 1 month after the last dose of protocol treatment for patients on Arm D. In addition, all patients must also agree to register to the mandatory Risk Evaluation and Mitigation Strategies (REMS)® program and be willing and able to comply with the requirements of the REMS® program * Patient must agree to not breastfeed while on protocol treatment due to the potential risk for adverse events in nursing infants, and must agree to continue not breastfeeding for an additional 5 months after the last dose of Arm A, B, or C protocol treatment and for an additional 28 days after the last dose of Arm D protocol treatment * Patient must agree to abstain for donating eggs (ova, oocytes) while on study treatment and for 6 months after the last dose of Arm A, B or C protocol treatment * Patient must agree to abstain from donating sperm while on study treatment and for 3 months after the last dose of protocol treatment even if they have had a successful vasectomy * Patient must agree to abstain from donating blood during study participation and for at least 28 days after the last dose of protocol treatment * Patient must not receive non-protocol concurrent chemotherapy, or any ancillary therapy considered investigational while participating in the study * NOTE: Bisphosphonates are considered supportive care rather than therapy and are thus allowed while on protocol treatment * Patient must not have peripheral neuropathy \> grade 2 on clinical examination at the time of registration/randomization * Patient must not have known uncontrolled congestive heart failure (CHF), New York Heart Association (NYHA) class III or IV, uncontrolled hypertension as defined as systolic \> 180 and/or diastolic \> 100, uncontrolled atrial (A) fib, or left ventricular ejection fraction (LVEF) \< 40% within 6 months prior to registration/randomization * Patient must not have known allergies, hypersensitivity, or intolerance to corticosteroids, monoclonal antibodies or human proteins, or their excipients, or known sensitivity to mammalian-derived products * Patient must have the ability to understand and the willingness to sign a written informed consent document. Patients with impaired decision-making capacity (IDMC) who have a legally authorized representative (LAR) or caregiver and/or family member available will also be considered eligible * Absolute neutrophil count (ANC) ≥ 1,500/uL (≤ 14 days prior to registration/randomization) * Platelets ≥ 100,000/uL (≤ 14 days prior to registration/randomization) * Total bilirubin ≤ 3 x institutional upper limit of normal (ULN) (≤ 14 days prior to registration/randomization) * Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase \[SGOT\]) and alanine aminotransferase (ALT)(serum glutamic pyruvic transaminase \[SGPT\]) ≤ 3.0 x institutional ULN (≤ 14 days prior to registration/randomization) * Calculated creatinine clearance ≥ 30 mL/min (≤ 14 days prior to registration/randomization) * Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months of registration/randomization are eligible for this trial * For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated * Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load * Patients with past central nervous system (CNS) involvement are eligible if there is no current CNS involvement * Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of dose limiting toxicities (Phase Ib) | During cycle 2 (cycle length = 28 days) | Will be defined by the toxicities (per National Cancer Institute \[NCI\] Common Terminology Criteria for Adverse Events \[CTCAE\] version \[v\] 5.0)possibly, probably, or definitely related to the combination regimen after the teclistamab dose is stable and the combination of teclistamab and pomalidomide has been administered for one full cycle. |
| Rate of minimal residual disease negativity (Phase II) | After 9 cycles of treatment (cycle length = 28 days) | Will be determined by the Adaptive Biotechnologies clonoSEQ, registered trademark, assay results. Analysis will be a comparison using Cochran-Mantel-Haenszel (CMH) test, stratified on prior autologous stem cell transplant, CD38 antibody refractory and high risk at registration. The CMH estimate of odds ratio with 80% confidence interval (CI) and p-value will be reported. The treatment effect will be evaluated in select subgroups including stratification factors as well as PI-exposed or not and 1st or 2nd relapse. Additionally, logistic regression will be used to assess the treatment effect after adjusting for known prognostic factors. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free survival | From randomization until the earlier of progression or death due to any cause or censored at date of last disease evaluation, assessed up to 10 years | Will be estimated in the eligible and randomized population using the Kaplan-Meier method and compared between arms using the stratified log-rank test. Stratified cox proportional hazards (PH) regression will be used to produce the treatment hazard ratio (HR; Arm C/Arm D) along with the 90% CI, provided PH assumption is valid. Sensitivity analyses excluding untreated patients will be conducted. |
| Overall survival | From randomization to death due to any cause, or censored at date last known alive, assessed up to 10 years | Will be estimated in the eligible and randomized population using the Kaplan-Meier method and compared between arms using the stratified log-rank test. Stratified cox PH regression will be used to produce the treatment HR (Arm C/Arm D) along with the 90% CI, provided PH assumption is valid. Sensitivity analyses excluding untreated patients will be conducted. |
| Incidence of adverse events (AE) | Up to 30 days after last dose of study treatment | Will be graded according to NCI CTCAE v 5.0 and classified by Medical Dictionary for Regulatory Activities system organ class. Maximum grade toxicity by AE type will be tabulated. Summaries (count and percentages) will be reported by AE type by arm. Rates of maximum grade 3 or higher (including grade 5) non-hematologic, hematologic and overall toxicity will be calculated along with 90% CIs. AEs will be further analyzed by arm in subsets of serious adverse events per protocol, lethal AEs and treatment-emergent adverse events status. |
| Best response | By cycles 12 and 24 (cycle length = 28 days) | Will be based on International Myeloma Working Group uniform criteria and will include rates of partial response (PR), very good PR, complete response (CR) and stringent CR. |
Contacts
PRINCIPAL_INVESTIGATORMurali Janakiram
ECOG-ACRIN Cancer Research Group
Outcome results
None listed