Newly diagnosed mutliple myeloma (MM) patients who are ineligible for hematopoietic stem cell transplant (HSCT) have inferior outcomes compared to HSCT eligible patients. These patients require more innovative therapeutic approaches based on novel agents with different mechanism of action. Daratumumab is a monoclonal antibody that targets CD38 expressed at high levels on MM cells. In phase 1/2 studies, daratumuab has demonstrated impressive single agent activity in relapse and refractory (R/R)　MM with acceptable toxicity profiles. This set the stage for daratumumab-based combination regimens to achieve deeper response and thereby improve clinical outcomes in both R/R MM and newly diagnosed MM patients. We hypothesized that daratumumab addition to bortezomib-dexamethasone induces improved efficacy and outcomes. As such, we planned this phase 2 clinical trial targeting HSCT ineligible, newly diagnosed MM patients in Korea and Singapore. The major objective is to assess the efficacy and toxicity of daratumumab in combination with bortezomib and dexamethasone in non-transplant eligible Asian patients with newly diagnosed myeloma.

Treatment

Patients will receive daratumumab according to the following schedule: 
daratumumab 16mg/kg weekly for weeks 1-9 
daratumumab 16mg/kg every 3 weeks from weeks 10 to 24 
then daratumumab 16mg/kg once every 4 weeks from weeks 25 onwards until disease progression
Patients will also receive weekly subcutaneous bortezomib and po dexamethasone 40mg for 9 months. Each cycle consists of 4 weeks of treatment, thus patient will receive 13 cycles of bortezomib plus dexamethasone in total during the 9 months of treatment. After 9 months, patients will receive daratumumab only until progression. 
For patients > 75 years old, initial dose of dexamethaone is set at 20mg/week. This can be given concurrently with daratumumab or can be given at a divded dose over 2 days per attending physician’s choice. 
For patients ≤75 years old, dexamethasone 20mg will be given on the day of daratumumab and the day after, totalling 40mg per week.

Arm Label

Target Number of Participant

Arm Type

Arm Description

Patients will receive daratumumab according to the following schedule: 
daratumumab 16mg/kg weekly for weeks 1-9 
daratumumab 16mg/kg every 3 weeks from weeks 10 to 24 
then daratumumab 16mg/kg once every 4 weeks from weeks 25 onwards until disease progression
Patients will also receive weekly subcutaneous bortezomib and po dexamethasone 40mg for 9 months. Each cycle consists of 4 weeks of treatment, thus patient will receive 13 cycles of bortezomib plus dexamethasone in total during the 9 months of treatment. After 9 months, patients will receive daratumumab only until progression. 
For patients > 75 years old, initial dose of dexamethaone is set at 20mg/week. This can be given concurrently with daratumumab or can be given at a divded dose over 2 days per attending physician’s choice. 
For patients ≤75 years old, dexamethasone 20mg will be given on the day of daratumumab and the day after, totalling 40mg per week.

Gender

Age

Description

1. Newly diagnosed Multiple myeloma, diagnosed according to standard criteria, in subjects who are not eligible for high dose Melphalan and stem cell transplant. 
2. Patients must have evaluable multiple myeloma with at least one of the following (within 21 days of starting treatment) 
a. Serum M-protein ≥ 0.5g/dL, or 
b. 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 have received no prior treatment. Short duration of steroids are acceptable. 
4. Males and females ≥ 18 years of age or > country’s legal age for adult consent 
5. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 2 
6. Patients must meet the following clinical laboratory criteria with 21 days of starting treatment: 
a. Absolute neutrophil count (ANC) ≥ 1,000/mm3 and platelet ≥ 50,000/mm3 (≥ 30,000/mm3 if myeloma involvement in the bone marrow is >50%) 
b. Total bilirubin ≤ 1.5 x the upper limit of the normal range (ULN). Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x ULN. 
c. Calculated creatinine clearance ≥ 30mL/min. 
7. Written informed consent in accordance with federal, local and institutional guidelines

1. Female patients who are lactating or pregnant or those with plans for pregnancy within 3 months of last daratumumab infusion 
2. Multiple Myeloma of IgM subtype 
3. Glucocorticoid therapy (prednisolone > 30mg/day or equivalent) within 7 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. Any Chemotherapy with approved or investigational anticancer therapeutics within 21 days prior to starting Dara-VD treatment 
10. Focal radiation therapy within 7 days prior to start of Dara-VD. Radiation therapy to an extended field involving a significant volume of bone marrow within 21 days prior to start of Dara-VD. 
11. Immunotherapy (excluding steroids) 21 days prior to start of Dara-VD 
12. Major surgery (excluding kyphoplasty) within 28 days prior to start of Dara-VD 
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 <30ml/min 
17. Second malignancy within the past 3 years except: 
a. Adequately treated basal cell or squamous cell skin cancer 
b. Carcinoma in situ of the cervix 
c. Breast carcinoma in situ with full surgical resection 
18. Patients with myelodysplastic syndrome 
19. Patients with steroid/bortezomib hypersensitivity 
20. Patients previously treated with daratumumab or other anti-CD38 antibodies. 
21. Patients with pleural effusions requiring thoracentesis or ascites requiring paracentesis within 14 days prior to starting Dara-VD treatment 
22. Contraindication to any of the required concomitant drugs or supportive treatments 
23. 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. 
24. Known COPD with FEV1 < 50% of normal. 
25. Moderate or severe persistent asthma within the last 2 years, or uncontrolled asthma of any classification  
26. Uncontrolled diabetes mellitus 
27. history of allergic reaction to bortezomib or its ingredients (mannitol, boron) 
28. history of allergic reaction to dexamethasone or its ingredients 
29. patients with diffuse interstitial lung disease and/or pericardial disease 
30. live vaccination within 1 year 
31. patients with genetic enzyme deficiency disorders including galactose intolerance, lapp lactase deficiency and glucose-galatcose malabsorption 
32. active infection with HSV, zoster or varicella 
33. active infection without treatable antibiotics or current systemic fungal infection 
34. history of allergy or resistance to monoclonal antibody or humanized protein products or mammal-based products

Overall response rate (ORR) is defined as the percentage of patients enrolled that achieve a complete response (CR), or stringent complete response (sCR), or very good partial response (VGPR), or partial response (PR) based on the International Myeloma Working Group criteria anytime from commencement of treatment.

The period from the beginning of treatment to the time of death due to disease progression or other causes

Progression-free survival

From the start of treatment to the time leading up to the progression or death of the disease

Overall survival

From the start of treatment to the death.