Neoplasms

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Blood and Lymph Conditions

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All Conditions

Rare Diseases

Multiple Myeloma

Neoplasms, Plasma Cell

Plasmacytoma

Neoplasms by Histologic Type

Hemostatic Disorders

Blood Coagulation Disorders

Vascular Diseases

Paraproteinemias

Blood Protein Disorders

Hematologic Diseases

Hemorrhagic Disorders

Lymphoproliferative Disorders

Immunoproliferative Disorders

Anti-Inflammatory Agents

Antineoplastic Agents

Antiemetics

Gastrointestinal Agents

All Drugs and Chemicals

Dexamethasone

Immunomodulating Agents

Lenalidomide

Bortezomib

Dexamethasone acetate

Proteasome Inhibitors

Glucocorticoids

Hormones

Hormone Antagonists

Antineoplastic Agents, Hormonal

Immunologic Factors

Angiogenesis Inhibitors

Growth Inhibitors

Cycle 1-8: 1.0 mg/m2 SC at a concentration of 2.5 mg/ml or 1 mg/ml to the thighs or abdomen on days 1, 4, 8, 11 of a 21 day cycle for 8 cycles.

Cycle 1: 15 mg oral daily on days 2-14 of 21 day cycle; Cycle 2-8: 15 mg oral daily on days 1-14 of a 21 day cycle

Cycle 1: 10 mg oral or IV daily on days 2,4,5,8,9,11,12 of a 21 day cycle; Cycle 2-8: 10 mg oral or IV on days 1, 2, 4, 5, 8, 9, 11, 12 of a 21 day cycle

Carl O Landgren, M.D.

Background: Bortezomib is a drug approved by the Food and Drug Administration (FDA) to treat patients with multiple myeloma. It is given by intravenous injection. Lenalidomide is a drug that alters the immune system. It may also help suppress tumor growth. It is approved by the FDA to treat some types of blood cancers. Dexamethasone prevents or treats inflammation. It is sometimes used to treat multiple myeloma.

Objectives: The purpose of this study examine how the combination of the study drugs affects myeloma.

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Eligibility:

* Participants at least 18 years old who have multiple myeloma that has come back, did not respond to treatment, or worsened while being treated.
* Participants who may be pregnant will be tested to ensure that they are not pregnant.

Design:

* Participants will be screened with a history and physical examination. Blood work and urine samples will be taken. A series of x-rays of all bones will be done. A bone marrow biopsy will be done.
* Treatment will be monitored with frequent blood tests and imaging studies.
* Treatment will continue as long as the cancer does not grow or spread and no serious side effects develop.
* There will be up to eight 21-day treatment cycles.
* Bortezomib is given by subcutaneous (under the skin) (SC) injection on days 1, 4, 8, and 11 of the cycle.
* Lenalidomide is given by mouth on days 1 14 of the cycle.
* Dexamethasone is given by mouth on days 1, 2, 4, 5, 8, 9, 11, and 12 of the cycle.
* Following cycle eight, if the disease is stable or better, participants will receive bortezomib SC at the dose given at the end of cycle eight.
* Participants will take valacyclovir or acyclovir while taking bortezomib to prevent virus infections.

Background:

* Multiple myeloma (MM) is an incurable plasma cell neoplasm with a median survival of 3-4 years.
* Increased survival has been achieved with the introduction of the proteasome inhibitor bortezomib and immunomodulatory drugs (IMiDs) such as lenalidomide. Bortezomib and lenalidomide have different but overlapping mechanism of anti-MM activity in preclinical studies.
* Despite the benefits of novel agents, bortezomib and lenalidomide pose clinical challenges. Bortezomib drug toxicity includes neuropathy, GI distress, myelosuppression and herpes zoster reactivation. Together with lenalidomide, the incidence of sensory neuropathy reaches 80%.
* Subcutaneous (SC) Bortezomib was evaluated in a prospective phase I trial for relapsed and/or refractory MM. SC administration was found to be comparable with the established IV route, with no differences in overall systemic availability and pharmacodynamic activity, similar toxicity profiles, and similar response rates.
* Combining SC, rather than IV bortezomib, with lenalidomide and dexamethasone is especially attractive given the potential for less overall neurotoxicity and improved convenience for the patient.
* Also, using bortezomib SC as a maintenance therapy after combination therapy is a novel strategy that has the potential to set the stage for coming oral proteasome inhibitors as potential maintenance strategies in the future.

Objectives:

Primary Objective

* Determine response rates, of S.C. bortezomib, lenalidomide, and dexamethasone (VRd) in relapse and/or refractory MM patients

Secondary Objectives

* Assess peripheral blood for immune cell populations in relation to SC bortezomib maintenance
* Evaluate toxicity, including peripheral neuropathy
* Evaluate patterns of change in patient-reported quality of life and symptom distress
* Gauge the feasibility, responsiveness to change and associated effect sizes when using patient-reported outcomes to augment clinician ratings of regimen-related treatment toxicity, including incidence and severity of peripheral neuropathy
* Determine duration of response
* Determine progression free survival

Eligibility:

* Patients with histologically confirmed relapsed and/or refractory multiple myeloma
* Age greater than or equal to 18 years
* Without serious co-morbidity that would interfere with receipt of VRd
* If patient has neuropathy, it must be less than or equal to Grade 1 at the time of first dose or within 14 days of enrollment
* Absolute neutrophil count (ANC) greater than equal to 1.0 K/uL, hemoglobin less than or equal to 8 g/dL, and platelet count greater than or equal to 75 K/uL
* Adequate hepatic function, with bilirubin \< 1.5 times ULN; AST and ALT \< 3.0 times ULN
* Creatinine Clearance greater than or equal to 60 ml/min. CrCl will be calculated by Cockcroft-Gault method. CrCl (calculated) = (140 Age) times Mass (in kilograms) times \[0.85 if Female\] 72 times Serum Creatinine (in mg/dL). If calculated CrCl based on Cockcroft-Gault method is \< 60 mL/min, patient will have a 24 hr urine collection to measure CrCl. The measured CrCl must also be greater than or equal to 60 ml/min for the patient to be eligible.

Design:

Patient will receive treatment in this single arm study for 8 total cycles (each cycle is 21 days) with the following drugs, dosages and schedule:

- Bortezomib

Cycle 1-8: 1.0 mg/m(2) SC at a concentration of 2.5 mg/ml to the thighs or abdomen on days 1, 4, 8, 11 of 21 day cycle

- Lenalidomide

Cycle 1: 15 mg oral daily on days 2-14 of 21 day cycle

Cycle 2-8: 15 mg oral daily on days 1-14 of 21 day cycle

- Dexamethasone

Cycle 1: 10 mg oral on days 2,4,5,8,9,11,12 of 21 day cycle

Cycle 2-8: 10 mg oral on days 1,2,4,5,8,9,11,12 of 21 day cycle

- Maintenance therapy

After completion of cycle 8, patients with greater than or equal to stable disease will receive maintenance with bortezomib S.C. at a dose per end of Cycle 8. Maintenance will be given on days 1 and 15 of a 28 day cycle, and will continue until progression or unacceptable toxicity.

Phase II Study of Subcutaneous (SC) Bortezomib, Lenalidomide and Dexamethasone for Relapsed and/or Refractory Multiple Myeloma; Followed by SC Bortezomib Maintenance

Millennium Pharmaceuticals, Inc.

National Cancer Institute (NCI)

Symptoms and General Pathology

Smoldering Multiple Myeloma

Precancerous Conditions

Hypergammaglobulinemia

Anti-Infective Agents

Ixazomib

HIV Protease Inhibitors

Protease Inhibitors

Enzyme Inhibitors

MLN9708

Background:

- Smoldering multiple myeloma (SMM) is a condition that can lead to multiple myeloma, a type of blood cancer. In many high-risk cases, SMM can develop into multiple myeloma in less than 2 years. The current standard of care for SMM is follow-up without treatment until multiple myeloma develops. However, some drugs are being studied to see if they can slow down or prevent the disease from progressing. One such drug is MLN9708. It has shown some results against multiple myeloma. Researchers want to combine MLN9708 with dexamethasone to see how it works against high-risk SMM.

Objectives:

- To see if MLN9708 with dexamethasone is a safe and effective treatment for high-risk smoldering multiple myeloma.

Eligibility:

- Individuals at least 18 years of age who have high-risk smoldering multiple myeloma.

Design:

* Participants will be screened with a physical exam and medical history. Blood and urine samples will be collected. Imaging studies and a bone marrow biopsy may also be performed.
* Participants will take MLN9708 and dexamethasone on a regular schedule for 28 days. They will take each drug four times at regular intervals during each cycle of treatment.
* Treatment will be monitored with frequent blood tests and imaging studies.
* Participants will have 12 cycles of treatment. After four cycles, patients will be recommended to have their own stem cells collected and stored. This will allow the potential application of a highdose melpahalan/autologous stem cell transplant in the event there is a need in the future (not part of this study).
* After 12 cycles, participants will keep taking MLN9708 as long as the disease does not progress and the side effects are not too severe.

Background:

* SMM is a precursor condition to MM defined by the clinical parameters of M-protein greater than or equal to 3.0 g/dL or bone marrow plasma cells greater than or equal to 10% and absence of end organ disease.
* Risk of progression of high risk SMM at 5 years is 72-75% with median time to progression less than 2 years.
* The current standard of care for SMM is close follow-up without treatment until symptomatic MM develops. However, IMWG states Preventive clinical trials need to be considered for patients with high risk smoldering myeloma .
* MLN9708 is a new oral proteasome inhibitor with potent anti-MM effects

Objectives:

Primary Endpoint:

-The primary objective of the study is to assess the response rate of MLN9708/low-dose

dexamethasone in patients with high-risk SMM.

Secondary Endpoints:

* To determine progression free survival (PFS)
* To determine duration of response (DOR)
* To evaluate toxicity of combination therapy (MLN9708 and low-dose dexamethasone).
* To evaluate biological activity of MLN9708 and correlate to clinical outcomes (gene expression profiling and proteasome activity and ubiquination assays, and effects on downstream signaling targets using pre- and post-MLN9708 exposure bone marrow samples)

Eligibility:

* SMM according to the International Myeloma Working Group definition i.e.:

  * Serum M-protein greater than or equal to 3 g/dl and/or bone marrow plasma cells greater than or equal to 10 %,
  * Absence of anemia: Hemoglobin greater than10 g/dl
  * Absence of renal failure: calculated creatinine clearance (according to MDRD) greater than 80 ml/min (or alternatively based on standard creatinine level criteria of 2 mg/dl)
  * Absence of hypercalcemia: Ca \< 10.5 mg/dl or less than or equal to 2.5 mmol/L
  * Absence of lytic bone lesion
* Measurable disease within the past 4 weeks defined by any one of the following:

  * Serum monoclonal protein greater than or equal to 1.0 g/dl
  * Urine monoclonal protein \>200 mg/24 hour
  * Serum immunoglobulin free light chain \>10 mg/dL AND abnormal kappa/lambda ratio (reference 0.26-1.65)
* High-risk SMM per Mayo Clinic or Spanish PETHEMA criteria
* Age greater than18 years
* Eastern Cooperative Oncology Group (ECOG) performance status 0-2
* Ability to give informed consent
* Patients must have normal organ and marrow function as defined below:

  * absolute neutrophil count greater than1.0 K/uL
  * platelets greater than75 K/uL (Platelet transfusions to help patients meet eligibility criteria are not allowed within 3 days before study enrolment.)
  * hemoglobin greater than 8 g/dL(transfusions are permissible)
  * total bilirubin less than1.5 X institutional upper limit of normal
  * AST(SGOT)/ALT(SGPT) less than 3.0 X institutional upper limit of normal

Design:

-Single arm pilot trial of combination therapy (MLN9708 and dexamethasone) for high risk smoldering multiple myeloma

* Patients will receive 12 cycles (28 days each) of induction combination therapy of MLN9708 and low-dose dexamethasone. After 12 cycles of MLN9708/low-dose dexamethasone, patients will receive MLN9708 maintenance until progression or unacceptable toxicity.
* Patients will have routine blood work with SPEP and free light chains monthly
* Pre- and post-treatment bone marrow biopsies will be obtained for confirmation of diagnosis and correlative studies
* Patients will also undergo evaluation for minimal residual disease at complete remission/completion of 12 cycles of therapy, using multi-parametric flow cytometry and FDG PET-CT
* This single arm pilot study will enroll 12 evaluable patients and determine M-spike levels on each patient immediately pre-treatment as well as after completing 12 cycles of treatment. The study aim is to find 9 or more patients (out of 12) with a partial response (PR) or better; which would provide strong evidence that the true probability of an overall response is consistent with 80% or more.

MLN9708 and Dexamethasone for High-Risk Smoldering Multiple Myeloma

MLN9708 and Dexamethasone in High Risk Smoldering Multiple Myeloma: A Clinical and Correlative Pilot Study

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Phase II Study of Subcutaneous (SC) Bortezomib, Lenalidomide and Dexamethasone for Relapsed and/or Refractory Multiple Myeloma; Followed by SC Bortezomib Maintenance	NCT01647165	Multiple Myelom...	Bortezomib Lenalidomide Dexamethasone	18 Years - 99 Years	National Institutes of Health Clinical Center (CC)
MLN9708 and Dexamethasone for High-Risk Smoldering Multiple Myeloma	NCT01660997	Multiple Myelom...	MLN9708 Dexamethasone	18 Years - 99 Years	National Institutes of Health Clinical Center (CC)

Spots Global Cancer Trial Database for maintenance strategy