Daratumumab, Thalidomide and Dexamethasone in Relapse and/or Refractory Myeloma
Daratumumab, Thalidomide and Dexamethasone in Relapse and/or Refractory Myeloma
Myeloma patients who relapse after prior treatment with bortezomib and lenalidomide have
 survival of less than 1 year. A number of new drugs have been approved for the treatment of
 relapse myeloma in the last couple of years, including, Elotuzumab, Panobinostat, Ixazomib,
 carfilzomib and Pomalidomide. However, most of these drugs either do not have good single
 agent activity or still belongs to the category of immunomodulatory drugs or proteasome
 inhibitors. Daratumumab is a monoclonal antibody against CD38 that is highly expressed on
 myeloma plasma cells. In phase ½ studies, it has impressive single agent activity in relapse
 and refractory myeloma with a very acceptable toxicity profile. This set the stage for
 combinations with daratumumab to increase efficacy and improve outcome of patients with
 myeloma. The use of immunomodulatory drugs, such as thalidomide and lenalidomide, has been
 shown to augment NK cell activity. NK cells are important mediator of antibody dependent
 cellular cytotoxicity. We therefore hypothesize that the combination of Daratumumab with
 thalidomide may therefore improve the efficacy of the treatment.

 In this study, we will plan to perform a phase II trial using the Daratumumab, Thalidomide,
 Dexamethasone combination in 100 myeloma patients with relapse myeloma in Asia.
Daratumumab is a humanized antibody against CD38 which is expressed on myeloma cells.
 Daratumumab exhibited single agent activity in myeloma and is a promising new treatment.
 Recently, 2 phase 1 / 2 studies establishes the dosing regimen for Daratumumab and impressive
 single agent activity of about 30% response rates in patients who relapse after prior
 lenalidomide and bortezomib. Daratumumab also appear to be well tolerated. The most common
 toxicity is infusion-related and almost all confined to the first cycle. On the whole these
 are manageable with early intervention, concurrent corticosteroids and anti-histamines as
 well as slowing infusion rate. More recently, early results from 2 randomise study comparing
 Daratumumab plus lenalidomide and dexamethasone compared to lenalidomide and dexamethasone,
 and Daratumumab plus bortezomib and dexamethasone compared to bortezomib and dexamethasone,
 showed that the addition of Daratumumab significantly improved response and progression free
 survival, including a high minimal residual disease (MRD) negative rate of more than 20% in
 the relapse myeloma populations.

 In addition, the use of immunomodulatory drugs, such as thalidomide and lenalidomide, has
 been shown to augment NK cell activity. NK cells are important mediator of antibody dependent
 cellular cytotoxicity, which is an important mechanism of action for Daratumumab.
 Furthermore, in the studies using another antibody target SLAMF7, Elotuzumab, the addition of
 dexamethasone greatly improve efficacy. Furthermore, thalidomide plus dexamethasone
 combination have a long history in myeloma and is relatively well tolerated and
 cost-effective. We therefore propose to add Daratumumab to thalidomide and dexamethasone, as
 this combination will be relatively easy to deliver in the Asian population because of
 availability and there is good rationale that such a combination will be synergistic and
 well-tolerated

 Patients will be assessed every 28 days (+/-10 days). Patients shall receive the treatment
 until disease progression, unacceptable toxicity as determined by treating physician,
 withdrawal of consent or mortality (whichever occurs first). After disease progression, the
 treating physician should provide long-term follow-up data on disease status and survival.
 For patients who discontinued treatment before disease progression occurred, disease
 assessment measurements shall be performed once every 28 days (+/- 10 days) until disease
 progression. After patients have documented progression of disease, they will be followed for
 survival every 3 months (+/-10 days) until study closure or until patients withdraws consent,
 is lost to follow-up or until death, whichever comes first. For any patient who is lost to
 follow-up, the study site shall attempt to ascertain survival information via public database
 search.
Inclusion Criteria:

 1. Multiple myeloma, diagnosed according to standard criteria, with relapsing and
 refractory disease at study entry

 2. Patients must have evaluable multiple myeloma with at least one of the following
 (within 21 days of starting treatment)

 1. Serum M-protein ≥ 0.5g/dL, or

 2. In subjects without detectable serum M-protein, Urine M-protein ≥ 200mg/24 hour,
 or serum free light chai (sFLC) > 100mg/L (involved light chain) and an abnormal
 kappa/Lambda ratio

 3. Must receive at least 1 line of prior treatment. (Induction therapy followed by stem
 cell transplantation and consolidation/maintenance therapy will be considered as one
 line of treatment)

 4. Must have relapsed disease and/or be refractory to prior treatment except for
 thalidomide or lenalidomide. Refractoriness is defined as disease progression on
 treatment or progression within 6 months after the last dose of a given therapy.
 Relapse is defined according to the criteria of IMWG

 5. Males and females ≥ 18 years of age or > country's legal age for adult consent

 6. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 2

 7. Patients must meet the following clinical laboratory criteria with 21 days of starting
 treatment:

 1. Absolute neutrophil count (ANC) ≥ 1,000/mm3 and platelet ≥ 50,000/mm3 (≥
 30,000/mm3 if myeloma involvement in the bone marrow is >50%)

 2. Total bilirubin ≤ 1.5 x the upper limit of the normal range (ULN). Alanine
 aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x ULN.

 3. Calculated creatinine clearance ≥ 30mL/min.

 8. Written informed consent in accordance with federal, local and institutional
 guidelines

 Exclusion Criteria:

 1. Female patients who are lactating or pregnant

 2. Multiple Myeloma of IgM subtype

 3. Glucocorticoid therapy (prednisolone > 30mg/day or equivalent) within 14 days prior to
 informed consent obtained

 4. POEMS syndrome

 5. Plasma cell leukemia or circulating plasma cells ≥ 2 x 109/L

 6. Waldenstrom's Macroglobulinaemia

 7. Existing peripheral neuropathy of grade 2 or higher or presence of neuropathic pain

 8. Patients with known amyloidosis

 9. Chemotherapy with approved or investigation anticancer therapeutics within 21 days
 prior to starting Dara-TD treatment

 10. Focal radiation therapy within 7 days prior to start of Dara-TD. Radiation therapy to
 an extended field involving a significant volume of bone marrow within 21 days prior
 to start of pomalidomide

 11. Immunotherapy (excluding steroids) 21 days prior to start of Dara-TD

 12. Major surgery (excluding kyphoplasty) within 28 days prior to start of Dara-TD

 13. Active congestive heart failure (New York Heart Association [NYHA] Class III or IV),
 symptomatic ischaemia, or conduction abnormalities uncontrolled by conventional
 intervention. Myocardial infarction within 4 months prior to informed consent obtained

 14. Known HIV seropositive, hepatitis C infection, and/or hepatitis B (except for patients
 with hepatitis B surface antigen or core antibody receiving and responding to
 antiviral therapy directed at hepatitis B: these patients are allowed)

 15. Patients with known cirrhosis

 16. Patients with creatinine clearance <30m/min

 17. Second malignancy within the past 3 years except:

 1. Adequately treated basal cell or squamous cell skin cancer

 2. Carcinoma in situ of the cervix

 3. Breast carcinoma in situ with full surgical resection

 18. Patients with myelodysplastic syndrome

 19. Patients with steroid or thalidomide hypersensitivity

 20. Patients previously treated with daratumumab or other anti-CD38 antibodies.

 21. Ongoing graft-versus-host disease

 22. Patients with pleural effusions requiring thoracentesis or ascites requiring
 paracentesis within 14 days prior to starting Dara-TD treatment

 23. Disease refractory to thalidomide or lenalidomide

 24. Contraindication to any of the required concomitant drugs or supportive treatments

 25. Any clinically significant medical disease or psychiatric condition that, in the
 investigator's opinion, may interfere with protocol adherence or a patient's ability
 to give informed consent.