Phase II Clinical Study of Daratumumab Combined With Bortezomib, Lenalidomide and Dexamethasone (DVRd) in the Treatment of Patients With Newly Diagnosed Double-hit Multiple Myeloma
Phase: PHASE2
Conditions: Multiple Myeloma
Sponsor: Institute of Hematology & Blood Diseases Hospital, China

 
Phase II clinical study of daratumumab combined with bortezomib, 
lenalidomide and dexamethasone (DVRd) in the treatment of patients 
with newly diagnosed double-hit multiple myeloma 
(Study Protocol) 
Last updated: Mar 15th 2023 
1. Protocol summary 
Study topic 
Phase II clinical study of daratumumab combined with bortezomib, lenalidomide and 
dexamethasone (DVRd) in the treatment of patients with newly diagnosed double-hit 
multiple myeloma (MM) 
Study applicant 
Chinese Academy of Medical Sciences, Institute of Hematology & Blood Diseases Hospital 
Study objective 
Evaluate the efficacy of DVRd protocol in patients with newly diagnosed double-hit MM 
and the feasibility of tailored maintenance therapy under residual disease (MRD) guidance 
Study population 
Patients with newly diagnosed double-hit MM (with ≥ 2 high-risk cytogenetic abnormalities) 
Study endpoints 
Primary endpoints: 
! 
Negative rate of MRD (after maintenance therapy) 
Secondary endpoints: 
! 
Duration of negative MRD (From the first record of negative MRD to the first record 
of positive MRD or the end of follow-up, whichever came first, assessed up to 3 year) 
! 
sCR 
! 
Objective response rate (ORR): Complete response (CR) + VGPR (Very good partial 
response) + Partial response (PR) 
! 
Duration of response (DOR): The duration from the first observation of achieving at 
least PR to the occurrence of progressive disease (PD) or death caused by PD, whichever 
occurs first 
! 
Mobilization success rate, high-quality mobilization rate and poor-quality mobilization 
! 
Progression-free survival (From date of enrollment of patients until the date of first 
documented progression or date of death from any cause, whichever came first, assessed 
up to 3 year) 
! 
Overall survival (From date of enrollment of patients until the date of death from any 
cause, whichever came first, assessed up to 3 year) 
Study design 
This study is a single arm phase II study using the DVRd protocol in patients with newly 
diagnosed double-hit MM. This study enrolled a total of 40 patients with double-hit MM who 
are suitable for autologous stem cell transplantation (ASCT) to evaluate the efficacy of 
DVRd and the feasibility of tailored maintenance therapy under MRD guidance. The study 
protocol is: DVRd induction therapy for 4 cycles, followed by ASCT, followed by DVRd 
consolidation therapy for 4 cycles, followed by DVR maintenance therapy. MRD monitoring 

 
is conducted after induction therapy, 60 to 90 days after ASCT, after consolidation therapy, 
and every 4 cycles during maintenance therapy. Patients who have sustained MRD negativity 
for at least 12 months will enter the maintenance phase 2 of lenalidomide monodrug therapy. 
Otherwise, DVR will last for a total of 24 cycles or until disease progression, death, 
intolerance, withdrawal due to other reasons, or the termination/end of the study. 
The subjects will participate in the screening period, treatment period, and follow-up period. 
The screening period lasts for a maximum of 28 days before medication. The treatment 
period lasts from the first day of the first cycle to the termination of treatment. The follow-
up period starts at the end of treatment and lasts for 12 months. 
Inclusion 
and 
exclusion criteria 
Inclusion criteria: 
1. Understanding and voluntarily signing the Informed Consent Form (ICF). 
2. Age: ≥ 18 years old and < 70 years old. 
3. Newly diagnosed MM according to International Working Group on Myeloma (IMWG) 
criteria, with measurable lesions that meet at least one of the following criteria:The 
serum M protein detected by serum protein electrophoresis (SPEP) is ≥ 1g/dL (≥ 10 g/L), 
or if it is IgA or IgD myeloma, quantitative levels of IgA or IgD can be used as a 
substitute; Or urine M protein level ≥ 200 mg/24 h; If only the serum free light chain 
(FLC) ratio is abnormal, the affected serum FLC ≥ 100 mg/L (normal FLC ratio: 0.26 to 
1.65). 
4. Have two or more high-risk cytogenetic abnormalities: 
t(4;14), t(14;16), t(14;20), del(17p), gain/amp(1q), del(1p) (deletion or gain/amp 
threshold is 20%, translocation threshold is 10%) 
5. The Eastern Cooperative Oncology Group (ECOG) score is 0, 1, or 2 points. The ECOG 
score of 3 points due to myeloma bone disease can be included. 
6. Subjects had not received anti-MM related chemotherapy, except those who accepted 
bortezomib, lenalidomide and dexamethasone three-drug induction therapy for no more 
than 14 days. Subjects had not received large-area pelvic irradiation (more than half of 
the pelvic area), and anti-MM hormone treatment in the past, except those who used 
hormone for no more than 14 days to control symptoms. 
7. The liver function test meets the following criteria: total bilirubin < 1.5 × upper limit of 
normal (ULN) (total bilirubin in patients with Gilbert's syndrome will be broaden to <3 
× ULN), and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 
2.5 × ULN. 
8. The renal function test meets the following criteria: creatinine clearance rate ≥ 30 
mL/min (calculated by Cockroft and Gault formulas). 
9. Blood routine test within 7 days before C1D1 meets the following criteria: white blood 
cell (WBC) count ≥ 1.5×109/L, absolute neutrophil count ≥ 1.0×109/L, hemoglobin ≥ 75 
g/L, and platelet count ≥ 75×109/L (if bone marrow plasmacyte < 50%) or platelet count 
≥ 50×109/L (if bone marrow plasmacyte ≥ 50%). 
10. Patients receiving hematopoietic growth factor support, including erythropoietin, 
granulocyte colony stimulating factor (G-CSF), granulocyte macrophage colony 

 
stimulating factor (GM-CSF), platelet agonists (for example, eltrombopag, TPO, 
interleukin-11), must have a 2-week interval between receiving growth factor support 
and screening assessment. 
11. Patients receiving blood product transfusions: at least 2 weeks between hemoglobin 
assessment and the last red blood cell (RBC) transfusion; at least one week between 
platelet assessment in the screening period and the last platelet transfusion. 
12. The subjects are suitable to receive preventive anticoagulant therapy recommended by 
the study. 
13. Female subjects who may become pregnant must meet the following two conditions: 
agree to take effective contraceptive measures during the use of the study drug and within 
3 months after the last administration of the study drug from the date of signing the ICF; 
the serum pregnancy test should be negative in the screening period. 
Exclusion criteria: 
1. Patients who are definitely diagnosed as primary plasma cell leukemia. 
2. Patients with primary or secondary amyloidosis. 
3. Patients with central nervous system (CNS) involvement. 
4. Patients planning to receive allogeneic hematopoietic stem cell transplantation. 
5. At baseline, accompanied by > grade 2 peripheral neuropathy or ≥ grade 2 peripheral 
neuropathy with pain, regardless of whether the patient is currently receiving drug 
therapy. 
6. Known intolerance, allergy or contraindication to glucocorticoid, bortezomib, 
lenalidomide and daratumumab. 
7. Heart diseases with clinical significance, including myocardial infarction before 
randomization, or unstable or uncontrollable diseases related to or affecting cardiac 
function (such as unstable angina, congestive heart failure, Class III-IV of New York 
Heart Function). Uncontrolled arrhythmia or clinically significant electrocardiogram 
(ECG) abnormalities. During screening, the 12-lead ECG showed a QT interval (QTc) 
of > 470 msec after baseline correction. 
8. Patients with poor control of diabetes and hypertension. 
9. Patients with a history of other malignant tumors within 5 years. 
10. Known active human immunodeficiency virus (HIV) infection or positive serum HIV. 
11. Active hepatitis B or C infection. Hepatitis serological test should be performed during 
screening. If hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (HBcAb) 
of patients are positive, DNA polymerase chain reaction (PCR) tests should be negative 
before enrollment. If the hepatitis C antibody of patients is positive, RNA PCR test 
should be performed, and the results should be negative before enrollment. 
12. Pregnant or lactating women. 
13. Expected life span < 6 months. 
14. Any active gastrointestinal dysfunction that affects the patient's ability to swallow tablets 
or may affect the absorption of study drug. 

 
15. The subjects have accepted major surgery (such as that requiring general anesthesia) 
within 2 weeks before screening, or will not fully recover from the surgery, or are 
scheduled for surgery during the planned study period. Kyphoplasty or vertebroplasty is 
not considered as a major surgery. Notes: Subjects who plan to undergo surgical 
procedures under local anesthesia can participate in the study. 
16. Patients who received attenuated alive vaccines within 4 weeks prior to the first 
administration of the study drug. 
17. Any active serious mental illness, medical illness, or other symptoms/conditions that 
may affect treatment, compliance, or the ability to provide informed consent according 
to the researcher’s judgment. 
18. Patients with contraindications to any concomitant drugs or supportive therapy. 
19. Patients with any diseases or complications that may interfere with the study procedure. 
20. Patients who are unwilling or unable to follow the protocol. 
Study duration 
The enrollment period for this study is expected to be 12 months. When all patients complete 
a 36-month visit/follow-up period starting from the use of the study drug, or the last patient 
dies, loses follow-up, or withdraws ICF, whichever occurs first, the study ends. 
Study protocol 
The patients receive 4 cycles of DVRd induction therapy. After achieving PR or better 
response, hematopoietic stem cells are collected and ASCT is performed. Then, DVRd 
consolidation therapy is performed for 4 cycles, and DVR maintenance therapy is performed. 
The endpoint of triple drug maintenance therapy is sustaining MRD negativity for at least 12 
months. Those who meet this condition enter the maintenance stage of lenalidomide 
monotherapy. Otherwise, the triple drug maintenance therapy is continued for a total of 24 
cycles or until disease progression, death, intolerance, withdrawal due to other reasons, or 
termination/end of the study. 
Induction and consolidation therapy (28 days as one treatment cycle, cycles 1-8) 
DVRd protocol dose: 
Daratumumab 16 mg/kg, d1,8,15,22 (cycles 1-2); d1,15 (cycles 3-6); d1 (cycles 7-8) 
Bortezomib 1.3 mg/m2, d1,8,15,22 
Lenalidomide 25 mg, d1-21 
Dexamethasone 20 mg, biw 
Maintenance therapy (28 days as one treatment cycle, cycles 9-32) 
Phase 1 maintenance therapy (DVR): 
Daratumumab 16 mg/kg, d1 
Bortezomib 1.3-1.0 mg/m2, d1,15 
Lenalidomide 10 mg, d1-21 
Phase 2 maintenance therapy (R): 
Lenalidomide 10 mg, d1-21 
Dynamic stem cell mobilization protocol: HD-CTX 50 mg/kg d1-2 + PEG-G-CSF 12 mg 
± Plerixafor 0.24 mg/kg 
Static stem cell mobilization protocol: PEG-G-CSF 12 mg ± Plerixafor 0.24 mg/kg 
Expected number of stem cells: ≥ 2×106 CD34+ cells/kg, preferably capable of collecting ≥ 
4×106 CD34+ cells/kg 

 
ASCT pretreatment protocol: Melphalan (Mel) 200 mg/m2 
Efficacy 
evaluation 
Efficacy evaluation parameters include serum immunoglobulin quantification, blood/urine 
M protein (protein electrophoresis and immunofixation electrophoresis), blood biochemical 
total protein, 24h urine protein, bone marrow plasmacyte ratio (aspirate+biopsy 
immunohistochemistry), serum FLC, bone disease examination, and extramedullary 
plasmacytoma evaluation. 
MRD monitoring parameters include next-generation sequencing, next-generation multi-
parameter flow cytometry, and if necessary, PET-CT test. 
Follow-up plan 
At any time, subjects can voluntarily withdraw from the study treatment or terminate the 
treatment based on the researcher's judgment. All subjects receiving the study treatment 
should terminate the visit after treatment. All subjects receiving the study treatment (except 
for death, loss of follow-up, and withdrawl of ICF) are required to monitor adverse events 
(AEs) and concomitant medication or non-drug therapy (including anti-tumor therapy) after 
the end of treatment. If the subject terminates the study treatment due to AEs, he should be 
evaluated until the AEs disappear or improve. After all treatments are completed, patients are 
followed up every 3 months until PD, new anti-tumor therapy, death, loss of follow-up, 
withdrawl of ICF, and at least 3 years after the first treatment of the last subject. 
Statistical 
analysis 
Unless otherwise specified, all statistical tests are conducted using bilateral tests, and P ≤ 
0.05 is considered statistically significant for the differences tested. The quantitative 
parameters are described by mean, standard deviation, median, minimum, and maximum. 
The categorical parameters are described by the number and percentage of cases for each 
category. The effectiveness analysis is based on full analysis set (FAS) and per protocol set 
(PPS). The primary and secondary study endpoints are evaluated by an independent review 
committee. All subjects who have received study treatment are included in the safety 
analysis. All AEs are classified using the MedDRA classification system. The severity of 
toxic reactions is graded based on NCI CTCAE v5.0. The same AE is summarized according 
to the most severe NCI CTCAE grade. The AEs leading to death or termination of treatment, 
Grade 3 or 4 AEs by NCI CTCAE, AEs related to study treatment, AEs related to study drug 
and serious adverse events are summarized separately. The frequency of AEs is listed 
according to human organ system and preferred terms. In the subject-by-subject analysis, 
subjects who experienced the same AE more than once are only counted once. Descriptive 
statistical data (mean, median, standard deviation, minimum, and maximum) are provided 
for vital signs and weight. Only data within 28 days prior to the last medication are analyzed 
in the safety assessment. However, if the subject terminates the study treatment due to AEs, 
he should be evaluated until the AEs disappear or improve. Even if it exceeds 28 days prior 
to the last medication, the data should be included in the analysis.