Daratumumab Based Response Adapted Therapy for Older Adults With Newly Diagnosed Multiple Myeloma

Study Overview
=================
Brief Summary
-----------------
This is a Phase II study of daratumumab based therapies for older adults with multiple myeloma.

Detailed Description
-----------------
In this response adapted approach, older adults with newly diagnosed symptomatic multiple myeloma will receive daratumumab and dexamethasone for 2 months. Patients who achieve a partial response or better will continue on daratumumab. Patients who achieve less than a partial response will have lenalidomide or bortezomib added to their therapy. Patients who experience progressive disease on daratumumab after the initial 2 months of monotherapy or on the combination of daratumumab and either lenalidomide or bortezomib will come off study

Official Title
-----------------
Phase II Study of Daratumumab Based Response Adapted Therapy for Older Adults With Newly Diagnosed Multiple Myeloma

Conditions
-----------------
Multiple Myeloma

Intervention / Treatment
-----------------
* Drug: Daratumumab Injection
* Drug: Dexamethasone Oral
* Drug: Lenalidomide Pill
* Drug: Bortezomib Injection


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Understand and voluntarily sign an informed consent form Age 65 years or older and presence of coexisting conditions which in the opinion of the treating physician are likely to result in the development of unacceptable side effects associated with high-dose chemotherapy with stem-cell transplantation Able to adhere to the study visit schedule and other protocol requirements. Diagnosed with multiple myeloma and be considered to have active disease with either elevated Calcium, Renal Failure, Anemia, Bone Lesions (CRAB) criteria (hypercalcemia, renal failure, anemia, or bone lesions) or myeloma defining events (bone marrow ≥ 60% plasma cells, serum free light chain (sFLC) ratio≥ 100 or MRI or Positron Emission Tomogrphy [PET] defined lesions). Patients must not have received an active chemotherapy regimen. Patients may have received palliative radiotherapy at least 2 weeks prior to the study start. Dexamethasone up to 160 mg total dose is allowed prior to participation Measurable myeloma paraprotein levels in serum (≥ 0.5 g/dL), urine (≥ 0.2 g excreted in a 24-hour urine collection sample) or by serum free light chains (involved free light chain greater than 100mg/L) Eastern Cooperative Group (ECOG) Performance Status of 0 - 2. Serum bilirubin levels </=1.5 times the upper limit of the normal range for the laboratory (ULN). Serum Aspirtate Transaminase (AST) or serum Alanine Aminotransferase (ALT) levels </=2 x Upper Limit of Normal (ULN) Must have adequate bone marrow function: a. Absolute neutrophil count > 1,000 cells/mm3 (1.0 x 109/L). b. Platelets >/= 75,000 /mm3. Hemoglobin > 8 g/dL (transfusions are allowed) Calculated creatinine clearance >/=30ml/min by Cockcroft-Gault formula. Men must agree to use a latex condom during sexual contact with a female of child bearing potential even if they have had a successful vasectomy. See Appendix C: Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control Methods. Exclusion Criteria: Ongoing severe infection requiring intravenous antibiotic treatment. Prior malignancy, except for adequately treated basal cell or squamous cell skin cancer, in-situ cervical cancer, or other cancer from which the subject has been disease-free for at least 2 years. Solitary bone or solitary extramedullary plasmacytoma as the only evidence of plasma cell dyscrasia. Patients with known Chronic Obstructive Pulmonary Disease (COPD) with a forced expiratory volume in 1 second (FEV1) <50% of predicted normal and , moderate or severe persistent asthma within the past 2 years or uncontrolled asthma. Patients with a history of COPD will have pulmonary function testing to include FEV1 Uncontrolled medical problems such as diabetes mellitus, congestive heart failure, coronary artery disease, hypertension, unstable angina, arrhythmias), pulmonary, hepatic and renal diseases unless renal insufficiency is felt to be secondary to multiple myeloma. Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent form. Pregnant or lactating females. Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study. Concurrent use of other anti-cancer agents or treatments with the exception for hormonal therapy, which is allowed. Known allergy or hypersensititvity or intolerance to any of the study drugs, hyaluronidase, monocolonal antibodies (mAbs), human proteins, or their excipients (refer to daratumumab IB), or known sensitivity to mammalian derived products Seropositive for human immunodeficiency virus (HIV) Seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]). Subjects with resolved infection (ie, subjects who are HBsAg negative but positive for antibodies to hepatitis B core antigen [anti-HBc] and/or antibodies to hepatitis B surface antigen [anti-HBs]) must be screened using real-time polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) DNA levels. Those who are PCR positive will be excluded. EXCEPTION: Subjects with serologic findings suggestive of HBV vaccination (anti-HBs positivity as the only serologic marker) AND a known history of prior HBV vaccination, do not need to be tested for HBV DNA by PCR. Seropositive for hepatitis C (except in the setting of a Sustained Virologic Response [SVR], defined as aviremia at least 12 weeks after completion of antiviral therapy).

Ages Eligible for Study
-----------------
Minimum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A: Daratumumab & Dexamethasone<br>All participants will receive 1800 mg in 15 ml Daratumumab by subcutaneous injection weekly and be given 20 mg of Dexamethasone orally once a week for 2 months. Patients who receive a partial response or better will continue on this arm. | Drug: Daratumumab Injection<br>* Patient will receive daratumumab (1800 mg in 15 ml) administered by manual subcutaneous injections weekly for the first 8 weeks, every other week for the next 16 weeks and every 4 weeks after.<br>* Other names: Darzalex;Drug: Dexamethasone Oral<br>* The dexamethasone starting dose will be 20 mg PO once a week. Commercial dexamethasone will be used. Dexamethasone is often supplied in 4 mg tablets. Accordingly, patients will take 5 (4 mg tablets) one day of the week prior to the administration of daratumumab if this corresponds to a daratumumab dosing days. In non daratumumab dosing days, dexamethasone will be taken by the patient at home, usually in the morning with breakfast.<br>* Other names: Decadron;|
| Experimental: B: Daratumumab, Dexamethasone and Lenalidomide<br>Participants who have less than a partial response to Arm A may have Lenalidomide added to their treatment. Lenalidomide will be given orally on days 1-21 of each 28 day treatment cycle. | Drug: Daratumumab Injection<br>* Patient will receive daratumumab (1800 mg in 15 ml) administered by manual subcutaneous injections weekly for the first 8 weeks, every other week for the next 16 weeks and every 4 weeks after.<br>* Other names: Darzalex;Drug: Dexamethasone Oral<br>* The dexamethasone starting dose will be 20 mg PO once a week. Commercial dexamethasone will be used. Dexamethasone is often supplied in 4 mg tablets. Accordingly, patients will take 5 (4 mg tablets) one day of the week prior to the administration of daratumumab if this corresponds to a daratumumab dosing days. In non daratumumab dosing days, dexamethasone will be taken by the patient at home, usually in the morning with breakfast.<br>* Other names: Decadron;Drug: Lenalidomide Pill<br>* Lenalidomide will be given orally on days 1-21 of a 28 days cycle. The starting dose of lenalidomide will be based on the patient creatinine clearance per the package insert. Specifically patients with a creatinine clearance ≥ 50 ml/min will receive 25 mg of lenalidomide PO Days 1-21. Patients with a creatinine clearance ≥ 30 but less than 50 ml/min will receive 10 mg of lenalidomide. Patients with a creatinine clearance < 30 ml/min are not eligible but patients who experience a deterioration in the renal function during screening or treatment may continue on lenalidomide therapy as long as the risk / benefit profile is deemed acceptable, that study therapy is in the best interest of the patient and after discussion with the study principal investigator / sponsor.<br>* Other names: Revlimid;|
| Experimental: C: Daratumumab, Dexamethasone and Bortezomib<br>Participants who have less than a partial response to Arm A may have Bortezomib added to their treatment. Bortezomib will be given weekly in subcutaneous injections at a starting dose of 1/3 mg/m^2 Days 1,8 and 15 of each 28 day treatment cycle. | Drug: Daratumumab Injection<br>* Patient will receive daratumumab (1800 mg in 15 ml) administered by manual subcutaneous injections weekly for the first 8 weeks, every other week for the next 16 weeks and every 4 weeks after.<br>* Other names: Darzalex;Drug: Dexamethasone Oral<br>* The dexamethasone starting dose will be 20 mg PO once a week. Commercial dexamethasone will be used. Dexamethasone is often supplied in 4 mg tablets. Accordingly, patients will take 5 (4 mg tablets) one day of the week prior to the administration of daratumumab if this corresponds to a daratumumab dosing days. In non daratumumab dosing days, dexamethasone will be taken by the patient at home, usually in the morning with breakfast.<br>* Other names: Decadron;Drug: Bortezomib Injection<br>* Bortezomib will be given weekly subcutaneously in an effort to decrease the toxicity of the therapy. Specifically patients will receive a starting dose of bortezomib of 1.3 mg/m^2 Days 1,8,15 of a 28 day cycle. Bortezomib will be administered in the cancer center per standard of care procedures.<br>* Other names: Velcade;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate | Overall Response Rate (partial response or better) of the response adapted strategy using the uniform response criteria of the International Myeloma Working Group (IMWG). | Up to 8 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival | Progression Free Survival (PFS) from start of treatment to death of any cause, disease progression or relapse of the date of last follow-up, whichever comes first. he PFS will be estimated by the Kaplan-Meier method and 95% confidence interval (CI) will be computed by complementary log-log transformation. The 1 and 2 year PFS and 95% Confidence Intervals will be reported. | Up to 2 years | 
| Overall Survival | Overall Survival (OS) from start of treatment to death of any cause or the date of last follow-up, whichever comes first. OS will be estimated by the Kaplan-Meier method and 95% confidence interval will be computed by complementary log-log transformation. The 2 year OS and 95% CI will be reported. | Up to 2 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
myeloma, daratumumab