Hematopoietic Cell Transplantation Recipient, Plasma Cell Myeloma
Conditions
Brief summary
This phase II trial studies how well ixazomib citrate and lenalidomide after stem cell transplant work in treating patients with newly diagnosed multiple myeloma. Ixazomib citrate may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Biological therapies, such as lenalidomide, may stimulate the immune system in different ways and stop cancer cells from growing. Giving ixazomib citrate together with lenalidomide may be effective in treating multiple myeloma.
Detailed description
PRIMARY OBJECTIVES: I. Establish safety and efficacy of oral ixazomib citrate (MLN 9708) and lenalidomide in the maintenance setting post autologous stem cell transplant (ASCT) in myeloma patients. SECONDARY OBJECTIVES: I. Incidence of secondary primary malignancy. II. Evaluate the best response rate (stringent complete response \[sCR\]/near complete response \[nCR\]/very good partial response \[VGPR\]/partial response \[PR\]). III. Evaluate time to progression. IV. Evaluate time to next therapy. V. Evaluate the tolerability and toxicity. VI. Evaluate M. D. Anderson Symptom Inventory (MDASI)-myeloma symptom evaluation. OUTLINE: Beginning 60-180 days post-transplant, patients receive ixazomib citrate orally (PO) on days 1, 8, and 15 and lenalidomide PO on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days.
Interventions
DRUGIxazomib Citrate
Given PO
DRUGLenalidomide
Given PO
OTHERQuestionnaire Administration
Ancillary studies
Sponsors
National Cancer Institute (NCI)
M.D. Anderson Cancer Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patient must have undergone autologous stem cell transplantation, with melphalan as a preparative regimen, within 12 months of initiation of induction therapy for newly diagnosed myeloma * Time to initiation of maintenance therapy; patients may start maintenance therapy as early as 60 days post-transplant and up to 180 days post-transplant; as long as they meet the following criteria: * Platelet count \>= 100,000/mm\^3; platelet transfusions to help patients meet eligibility criteria are not allowed within 3 days before study enrollment * Neutrophil count \>= 1000/mm\^3; (no growth factors within 5 days prior to first dose of the study drug) * Total bilirubin =\< 1.5 x upper limit of normal (ULN) * Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =\< 3 x ULN * Creatinine \< 2.5 mg/dL * Recovered (i.e., =\< grade 1 toxicity) from the reversible effects of autologous stem cell transplant * Patients whose primary therapy was changed due to suboptimal response of toxicity will be eligible, however no more than 2 regimens will be allowed prior to ASCT * Patients must have an Eastern Cooperative Oncology Group (ECOG) status of 0 to 2 * Voluntary written informed consent 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 * Female patients who: are postmenopausal for at least 1 year before the screening visit, OR are surgically sterile, OR if they are childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent, during study treatment and for 90 days after the last dose of study treatment, AND * Must also adhere to guidelines of any treatment-specific pregnancy prevention program, if applicable, OR * Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject; (periodic abstinence \[e.g. calendar, ovulation, symptothermal, post-ovulation methods\] and withdrawal are not acceptable methods of contraception) * Male patients, even if surgically sterilized (i.e., status post vasectomy), must agree to one of the following: agree to practice effective barrier contraception during the entire study treatment period and through 90 days after the last dose of study treatment, OR * Must also adhere to guidelines of any treatment-specific pregnancy prevention program, if applicable, OR * Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject (periodic abstinence \[e.g. calendar, ovulation, symptothermal, post-ovulation methods\] and withdrawal are not acceptable methods of contraception)
Exclusion criteria
* Patient has \>= grade 3 peripheral neuropathy, or grade 2 with pain on clinical examination during the screening period * Major surgery within 14 days before the first dose of study drug * Radiotherapy within 14 days before enrollment; if the involved field is small, 7 days will be considered a sufficient interval between treatment and administration of the MLN9708 * Known active central nervous system involvement * Systemic treatment, within 14 days before study enrollment, with strong inhibitors of CYP1A2 (fluvoxamine, enoxacin, ciprofloxacin), CYP3A (clarithromycin, telithromycin, itraconazole, voriconazole, ketoconazole, nefazodone, posaconazole) or strong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of Ginkgo biloba or St. John's wort * Inability to swallow oral medication, inability or unwillingness to comply with the drug administration requirements, or gastrointestinal (GI) procedure that could interfere with the oral absorption or tolerance of treatment * Evidence of current uncontrolled cardiovascular conditions, including uncontrolled hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure, unstable angina, or myocardial infarction within the past 6 months * Female subject who are lactating or have a positive serum pregnancy test during the screening period * Serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with participation or completion of treatment according to this protocol * Corrected QT interval using Bazett's formula (QTcB) \> 470 milliseconds (msec) on a 12-lead electrocardiogram (ECG) obtained during the screening period; if a machine reading is above this value, the ECG should be reviewed by a qualified reader and confirmed on a subsequent ECG * Ongoing or active systemic infection, known human immunodeficiency virus (HIV) positive, known active hepatitis B virus hepatitis, or known active hepatitis C virus hepatitis * Infection requiring systemic antibiotic therapy or other serious infection within 14 days before study enrollment * Known allergy to any of the study medications, their analogues, or excipients in the various formulations * Co-morbid systemic illnesses or other severe concurrent disease that, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens * Diagnosed or treated for another malignancy within 2 years before study enrollment or previously diagnosed with another malignancy and have any evidence of residual disease; patients with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival | Time from autologous stem cell transplant (ASCT) to time of clinical progression or death or the time of last contact, assessed up to 30 days after completion of study treatment | Monitored using the method of Thall et al. Estimated using the Kaplan-Meier method. Log-rank test will be performed to test the difference in time-to-event distributions between patient groups. Cox proportional hazards model will be used to include multiple covariates in the time-to-event analysis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Best Response Rate (Stringent Complete Response [sCR]/Near Complete Response [nCR]/Very Good Partial Response [VGPR]/Partial Response [PR]) | through out study treatment and up to 30 days after completion of study treatment, up to 119 months | Estimated along with 95% confidence intervals. |
| Treatment-related Unmanageable Toxicities, Including Grade 3 Non-hematologic Effects, or Grade 4 Hematologic Effects | throughout study treatment and up to 30 days after completion of study treatment, up to 119 months | Toxicity data will be summarized by frequency tables. |
| Number of Participants Incidence of New Primary Malignancy | through out study treatment and up to 30 days after completion of study treatment, up to 119 months | Count of participants |
| Overall Survival | through out study treatment and up to 30 days after completion of study treatment, up to 119 months | Estimated using the Kaplan-Meier method. Cox proportional hazards model will be used to include multiple covariates. Log-rank test will be performed to test the difference in time-to-event distributions between patient groups. Cox proportional hazards model will be used to include multiple covariates in the time-to-event analysis. |
| M. D. Anderson Symptom Inventory (MDASI)-Myeloma Symptom Evaluation | through out study treatment and up to 30 days after completion of study treatment, up to 119 months | Analyzed with descriptive analysis. The MDASI-MM scores measure the how severe the symptoms are, so higher scores are considered to be worse patient outcomes. Five subscales are derived from the 26 questions of the MDASI-MM questionnaire: 1. mean core (13 MDASI core symptom items), ranges from 0 to 130. 2. mean severity (13 MDASI core plus 7 MM-specific items), ranges from 0 to 200. 3. mean interference (6 interference items), ranges from 0 to 60. 4. mean WAW (interference with work, general activity, and walking), ranges from 0 to 30. 5. mean REM (interference with relations with people, enjoyment of life, and mood), ranges from 0 to 30. has context menu |
Countries
United States
Participant flow
Recruitment details
64 participants were enrolled in the study between December 3, 2012 and May 13, 2015
Pre-assignment details
Participants with the following conditions were excluded from the study: grade 2 or higher peripheral neuropathy; major surgery or radiotherapy within 14 days of starting on the study; central nervous system involvement; treatment with modulators of CYP1A2 and CYP3A enzyme activity; and cardiovascular complications or ongoing systemic infections.
Participants by arm
| Arm | Count |
|---|---|
| Treatment (Ixazomib Citrate, Lenalidomide) Beginning 60-180 days post-transplant, participants receive ixazomib citrate PO on days 1, 8, and 15 and lenalidomide PO on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Ixazomib Citrate: Given PO
Lenalidomide: Given PO
Questionnaire Administration: Ancillary studies | 64 |
| Total | 64 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Malignancy | 1 |
| Overall Study | Physician Decision | 7 |
| Overall Study | Progressive Disease | 22 |
| Overall Study | Toxicity | 1 |
| Overall Study | Withdrawal by Subject | 14 |
Baseline characteristics
| Characteristic | Treatment (Ixazomib Citrate, Lenalidomide) |
|---|---|
| Age, Customized >= 60 | 41 participants |
| Age, Customized Between 18-59 | 23 participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 61 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 8 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 54 Participants |
| Region of Enrollment United States | 64 participants |
| Sex: Female, Male Female | 22 Participants |
| Sex: Female, Male Male | 42 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 64 |
| other Total, other adverse events | 64 / 64 |
| serious Total, serious adverse events | 33 / 64 |
Outcome results
Primary
Progression-free Survival
Monitored using the method of Thall et al. Estimated using the Kaplan-Meier method. Log-rank test will be performed to test the difference in time-to-event distributions between patient groups. Cox proportional hazards model will be used to include multiple covariates in the time-to-event analysis.
Time frame: Time from autologous stem cell transplant (ASCT) to time of clinical progression or death or the time of last contact, assessed up to 30 days after completion of study treatment
Population: The upper bound of the 95% CI has not been reached.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Ixazomib Citrate, Lenalidomide) | Progression-free Survival | 73.3 Months |
Secondary
Best Response Rate (Stringent Complete Response [sCR]/Near Complete Response [nCR]/Very Good Partial Response [VGPR]/Partial Response [PR])
Estimated along with 95% confidence intervals.
Time frame: through out study treatment and up to 30 days after completion of study treatment, up to 119 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (Ixazomib Citrate, Lenalidomide) | Best Response Rate (Stringent Complete Response [sCR]/Near Complete Response [nCR]/Very Good Partial Response [VGPR]/Partial Response [PR]) | 98.4 percentage of participants |
Secondary
M. D. Anderson Symptom Inventory (MDASI)-Myeloma Symptom Evaluation
Analyzed with descriptive analysis. The MDASI-MM scores measure the how severe the symptoms are, so higher scores are considered to be worse patient outcomes. Five subscales are derived from the 26 questions of the MDASI-MM questionnaire: 1. mean core (13 MDASI core symptom items), ranges from 0 to 130. 2. mean severity (13 MDASI core plus 7 MM-specific items), ranges from 0 to 200. 3. mean interference (6 interference items), ranges from 0 to 60. 4. mean WAW (interference with work, general activity, and walking), ranges from 0 to 30. 5. mean REM (interference with relations with people, enjoyment of life, and mood), ranges from 0 to 30. has context menu
Time frame: through out study treatment and up to 30 days after completion of study treatment, up to 119 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment (Ixazomib Citrate, Lenalidomide) | M. D. Anderson Symptom Inventory (MDASI)-Myeloma Symptom Evaluation | Core Score at Cycle 1 | 1.13 scores on a scale | Standard Deviation 1.35 |
| Treatment (Ixazomib Citrate, Lenalidomide) | M. D. Anderson Symptom Inventory (MDASI)-Myeloma Symptom Evaluation | Severity Score at Cycle 1 | 1.01 scores on a scale | Standard Deviation 1.27 |
| Treatment (Ixazomib Citrate, Lenalidomide) | M. D. Anderson Symptom Inventory (MDASI)-Myeloma Symptom Evaluation | Interference Score at Cycle 1 | 0.97 scores on a scale | Standard Deviation 1.52 |
| Treatment (Ixazomib Citrate, Lenalidomide) | M. D. Anderson Symptom Inventory (MDASI)-Myeloma Symptom Evaluation | WAW Score at Cycle 1 | 1.12 scores on a scale | Standard Deviation 1.67 |
| Treatment (Ixazomib Citrate, Lenalidomide) | M. D. Anderson Symptom Inventory (MDASI)-Myeloma Symptom Evaluation | REM Score at Cycle 1 | 0.81 scores on a scale | Standard Deviation 1.54 |
Secondary
Number of Participants Incidence of New Primary Malignancy
Count of participants
Time frame: through out study treatment and up to 30 days after completion of study treatment, up to 119 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment (Ixazomib Citrate, Lenalidomide) | Number of Participants Incidence of New Primary Malignancy | 9 Participants |
Secondary
Overall Survival
Estimated using the Kaplan-Meier method. Cox proportional hazards model will be used to include multiple covariates. Log-rank test will be performed to test the difference in time-to-event distributions between patient groups. Cox proportional hazards model will be used to include multiple covariates in the time-to-event analysis.
Time frame: through out study treatment and up to 30 days after completion of study treatment, up to 119 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Ixazomib Citrate, Lenalidomide) | Overall Survival | NA months |
Secondary
Treatment-related Unmanageable Toxicities, Including Grade 3 Non-hematologic Effects, or Grade 4 Hematologic Effects
Toxicity data will be summarized by frequency tables.
Time frame: throughout study treatment and up to 30 days after completion of study treatment, up to 119 months
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment (Ixazomib Citrate, Lenalidomide) | Treatment-related Unmanageable Toxicities, Including Grade 3 Non-hematologic Effects, or Grade 4 Hematologic Effects | Serious AE-Lung Infections | 12 Participants |
| Treatment (Ixazomib Citrate, Lenalidomide) | Treatment-related Unmanageable Toxicities, Including Grade 3 Non-hematologic Effects, or Grade 4 Hematologic Effects | Serious AE-Treatment-related secondary malignancy | 9 Participants |
| Treatment (Ixazomib Citrate, Lenalidomide) | Treatment-related Unmanageable Toxicities, Including Grade 3 Non-hematologic Effects, or Grade 4 Hematologic Effects | Serious AE-Respiratory Disorders including respiratory failures | 8 Participants |
| Treatment (Ixazomib Citrate, Lenalidomide) | Treatment-related Unmanageable Toxicities, Including Grade 3 Non-hematologic Effects, or Grade 4 Hematologic Effects | Serious AE-other infections | 5 Participants |