Smoldering Multiple Myeloma
Conditions
Keywords
Smoldering Multiple Myeloma, Denosumab
Brief summary
This study will assess the safety and tolerability of denosumab in smoldering multiple myeloma subjects as well to see if denosumab can reduce subjects' risk of getting multiple myeloma.
Detailed description
This is an open label, Phase II trial of denosumab 120mg subcutaneous (SC) for patients with smoldering multiple myeloma (SMM). Subjects will be recruited from the James P. Wilmot Cancer Center, University of Rochester in Rochester, New York. Patients seen in the inpatient or outpatient setting with histologically confirmed SMM will be evaluated for this study. 20 patients will be treated as follows: Denosumab: day 1 = 120mg SC every 4 weeks for 12 cycles. Cycles will be 28 days in length. Patients will be followed after completion of the study per standard of care for progression free survival for an additional 2 years after the last dose of denosumab. All patients will take daily vitamin D and calcium supplements of at least 1200mg elemental calcium and 800IU of vitamin D unless documented hypercalcemia develops on study. Pre-existing hypocalcemia must be corrected prior to initiating therapy with denosumab. Serum vitamin D levels will be checked during screening and should be repleted to a total 25-hydroxyvitamin D level ≥30ng/mL.
Interventions
DRUGDenosumab
120mg of Denosumab will be administered subcutaneously once every 4 weeks
Sponsors
University of Rochester
Amgen
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
1. Patient has confirmed SMM according to the definition of the International Myeloma Working Group (IMWG) definition: serum M-protein ≥3 g/dL or BMPC \>10% but less than 60%, or both, along with normal organ and marrow function (CRAB) within 4 weeks prior to baseline. C: Absence of hypercalcemia, evidenced by a calcium ≤11 mg/dL. R: Absence of renal failure, evidenced by a creatinine ≤ 2.0mg/dL A: Absence of anemia, evidenced by a hemoglobin ≥10 g/dL. B: Absence of lytic bone lesions per IMWG recommendations: One of either PET-CT, low-dose whole-body CT (LDWBCT) or MRI of the whole body or spine. Increased uptake on PET-CT alone is not adequate for the diagnosis of multiple myeloma; evidence of underlying osteolytic bone destruction is needed on the CT portion of the examination. 2. One of the risk factors below that portends for an increased risk of progression to MM: * An abnormal free light chain ratio * M-spike ≥ 4 g/dL * ≥ 50% bone marrow plasma cells * Immunoparesis ≥ 20% less than the institutional normal standard of the uninvolved immunoglobulins 3. Serum calcium or albumin-adjusted serum calcium ≥ 2.1 mmol/L (8.4 mg/dL) and ≤ 2.9mmol/L (11.5 mg/dL) (Reference range 8.5-10.8 mg/dL) 4. Able to tolerate daily supplementation of calcium and vitamin D 5. Must have a vitamin D level ≥ 30 ng/mL after repletion 6. Participants must have normal organ as defined below: * Total bilirubin ≤ 2.0 x institutional upper limit of normal (ULN); patients diagnosed with Gilbert's syndrome can enroll with a total bilirubin \> 2 after review of the principal investigator * AST(SGOT) ≤2.5 × institutional ULN * ALT(SGPT) ≤2.5 × institutional ULN 7. Age ≥ 18 years. 8. ECOG PS ≤1 9. Life expectancy greater than 12 months 10. Subjects with reproductive potential must be willing to use, in combination with his/her partner, 2 highly effective methods of effective contraception or practice sexual abstinence throughout the study and continue for 5 months after the study duration. Subjects who are surgically sterile (e.g. history of bilateral tubal ligation, hysterectomy) or whose sexual partner is sterile (e.g. history of vasectomy) are not required to use additional contraceptive measures. 11. Ability to understand and the willingness to sign a written informed consent document. -Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up. 12. Statement on Inclusion of Women and Minorities - Men and women of all ethnicities and racial backgrounds are eligible for this study.
Exclusion criteria
1. Prior administration of denosumab. 2. Any history of IV bisphosphonate use prior to or during the study 3. Prescription oral fluorides or bisphosphonate usage \> 3 months within the past 2 years 4. Systemic corticosteroids \> 10mg prednisone per day 5. Known secondary cause for osteopenia or osteoporosis 6. Patient has symptomatic MM, as defined by any of the following: * Lytic lesions or pathologic fractures. * Anemia (hemoglobin \<10 g/dL) * Hypercalcemia (corrected serum calcium \> 11.0 mg/dL) * Renal insufficiency (creatinine \> 2.0 mg/dL). * Clonal bone marrow plasma cells \> 60% * An involved serum free light chain (kappa or Lambda) \> 100mg/L with the ratio of the involved/uninvolved free light chains also \> 100 mg/L * One or more osteolytic lesions on radiography, but more than one lesion is required if \< 10% marrow plasma cells. From MRI imaging, there must be more than one lesion of \> 5mm in size. 7. Other: symptomatic hyperviscosity, amyloidosis, plasma cell leukemia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein) 8. Prior history or current evidence of osteonecrosis/osteomyelitis of the jaw. 9. Active dental or jaw condition that requires oral surgery, including tooth extraction. 10. Non-healed dental/oral surgery, including tooth extraction. 11. Planned invasive dental procedures during the course of study. 12. Evidence of any of the following conditions per subject self-report or medical chart review: * Any prior invasive malignancy within 3 years of enrollment that may affect outcome of study * Any non-invasive malignancy not treated with curative intent or with known active disease within 3 years before enrollment that may affect outcome of study * Major surgery or significant traumatic injury occurring within 4 weeks before enrollment * Active infection with Hepatitis B virus or Hepatitis C virus * Known infection with human immunodeficiency virus (HIV) requiring IV anti-infective therapy 13. Subject is pregnant or breast feeding, or planning to become pregnant within 5 months after the end of treatment. 14. Female subject of child-bearing potential is not willing to use, in combination with her partner, 2 methods of highly effective contraception during treatment and for 5 months after the end of treatment. 15. Clinically significant hypersensitivity to denosumab or any components of denosumab 120mg. 16. Known sensitivity to any of the products to be administered during the study (e.g., calcium, or vitamin D). 17. Subject is receiving or is less than 14 days since ending other experimental drug (no marketing authorization for any indication). 18. Any major medical or psychiatric disorder that, in the opinion of the investigator, might prevent the subject from completing the study or interfere with the interpretation of the study results.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Subjects With a Downgraded Risk of Progression of Smoldering Multiple Myeloma if the Risk Category Decreases. | 1 year | Risk Categories: Low Risk:Patient has SMM, but none of the listed risk factors Low-Intermediate Risk: 1 risk factor is present High-Intermediate Risk: 2 risk factors are present High Risk: 3 risk factors are present Risk Factors: 1. BM plasma cell % ≥50 2. M-protein ≥ 3g/dL 3. Involved/ un-involved free light chains ≥ 8 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Participants With Skeletal Related Events | 1 year | Skeletal related events were defined as pathological fractures, radiation to bone, surgery to bone, or fractures requiring stabilization, confirmed by imaging. Participants were counted once if they experienced at least one skeletal related event during the 1 year follow up period. |
| Proportion of Participants With Progression to Multiple Myeloma | 1 year | Progression to multiple myeloma was assessed according to International Myeloma Working Group criteria during the 1 year follow up period following treatment initiation. |
| Proportion of Participants With Progression Free Survival at 3 Years | 3 years | Progression free survival was defined as the absence of disease progression or death from any cause at the 3 year assessment time point. |
| Proportion of Participants With Change in Bone Mineral Density From Screening to 1 Year | 1 year | Bone mineral density was assessed using dual energy X ray absorptiometry scans at screening and approximately 1 year after treatment initiation. Participants with evaluable scans within the protocol specified assessment window were included in the analysis. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORBrea Lipe
University of Rochester Wilmot Cancer Center
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Denosumab Denosumab: 120mg of Denosumab will be administered subcutaneously once every 4 weeks | 20 |
| Total | 20 |
Baseline characteristics
| Characteristic | Denosumab |
|---|---|
| Age, Customized 30-39 | 1 Participants |
| Age, Customized 40-49 | 1 Participants |
| Age, Customized 60-69 | 6 Participants |
| Age, Customized 70-79 | 9 Participants |
| Age, Customized 80-89 | 3 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 19 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 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 | 0 Participants |
| Race (NIH/OMB) White | 18 Participants |
| Region of Enrollment United States | 20 participants |
| Sex: Female, Male Female | 9 Participants |
| Sex: Female, Male Male | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 20 |
| other Total, other adverse events | 20 / 20 |
| serious Total, serious adverse events | 6 / 20 |
Outcome results
Primary
Proportion of Subjects With a Downgraded Risk of Progression of Smoldering Multiple Myeloma if the Risk Category Decreases.
Risk Categories: Low Risk:Patient has SMM, but none of the listed risk factors Low-Intermediate Risk: 1 risk factor is present High-Intermediate Risk: 2 risk factors are present High Risk: 3 risk factors are present Risk Factors: 1. BM plasma cell % ≥50 2. M-protein ≥ 3g/dL 3. Involved/ un-involved free light chains ≥ 8
Time frame: 1 year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Denosumab | Proportion of Subjects With a Downgraded Risk of Progression of Smoldering Multiple Myeloma if the Risk Category Decreases. | 0 proportion of participants |
Secondary
Proportion of Subjects With Change in Bone Mineral Density
baseline and each post-treatment point
Time frame: 1 year
Secondary
Proportion of Subjects With Disease Progression to Multiple Myeloma
Risk Categories: Low Risk:Patient has SMM, but none of the listed risk factors Low-Intermediate Risk: 1 risk factor is present High-Intermediate Risk: 2 risk factors are present High Risk: 3 risk factors are present Risk Factors: 1. BM plasma cell % ≥50 2. M-protein ≥ 3g/dL 3. Involved/ un-involved free light chains ≥ 8
Time frame: 1 year
Secondary
Proportion of Subjects With Progression Free Survival
time to progression or death from any cause, whichever occurs first.
Time frame: 3 year
Secondary
Proportion of Subjects With Skeletal Related Events
To be determined by the investigator
Time frame: 1 year