An Efficacy and Safety Study of Daratumumab in Patients With Multiple Myeloma Who Have Received at Least 3 Prior Lines of Therapy (Including a Proteasome Inhibitor [PI] and Immunomodulatory Drug [IMiD]) or Are Double Refractory to a PI and an IMiD

• Sponsor: Janssen Research & Development, LLC (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01985126
• Collaborator: (none)
• Enrollment: 124
• Locations: 23
• Arms: 2
• Actual Duration (Months): 44.1
• Patients Per Site: 5.4
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the efficacy and safety of 2 daratumumab treatment regimens in participants with multiple myeloma who have received at least 3 prior lines of therapy (including a proteasome inhibitor [PI] and immunomodulatory drug [IMiD]) or are double refractory to a PI and an IMiD.

Condition or Disease	Intervention/Treatment	Phase
Multiple Myeloma	Drug: Daratumumab 16 mg/kg (Part 1); Drug: Daratumumab 8 mg/kg (Part 1); Drug: Methylprednisolone; Drug: Acetaminophen; Drug: Diphenhydramine; Drug: Daratumumab (Part 2)	Phase 2

Detailed Description

This is an open-label (identity of assigned study drug will be known) study of daratumumab for the treatment of participants with multiple myeloma who have received at least 3 prior lines of therapy including a PI and an IMiD or whose disease is double refractory to both a PI and an IMiD. Up to approximately 150 participants are to be enrolled. The study includes screening, treatment, and follow-up phases. Participants will receive daratumumab by intravenous infusion (28-day cycles) until disease progression, unacceptable toxicity, or other protocol-defined reasons. For all study drug administrations, participants will receive pre- and post-infusion medications for the prevention of infusion related reactions. Follow-up will continue until death, loss to follow up, consent withdrawal for study participation, or study end, whichever occurs first. The study will consist of 2 sequential parts (Part 1 and Part 2). The purpose of Part 1 is to select a dose and schedule for Part 2 of the study. Assessment of tumor response and disease progression will be conducted according to IMWG response criteria. Serial pharmacokinetic blood samples and a pharmacogenomic blood sample will be collected. Safety will be monitored throughout the study. At the end of the study, participants who are benefiting from treatment with daratumumab will have the option to continue treatment.

Study Design

• Study Type: Interventional
• Actual Enrollment: 124 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-label, Multicenter, Phase 2 Trial Investigating the Efficacy and Safety of Daratumumab in Subjects With Multiple Myeloma Who Have Received at Least 3 Prior Lines of Therapy (Including a Proteasome Inhibitor and IMiD) or Are Double Refractory to a Proteasome Inhibitor and an IMiD
• Actual Study Start Date: Sep 27, 2013
• Actual Primary Completion Date: Jan 9, 2015
• Actual Study Completion Date: May 30, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Part 1 During Stage 1 of Part 1, participants will be randomized to receive daratumumab treatment regimens in Group A and Group B. If in Stage 1, 1 or both of the treatment groups is considered to be ineffective and/or not well tolerated, then that treatment group will be terminated. Participants in Group B will be given the option to cross over to Group A if the investigator deems it in the best interest of the participants.	Drug: Daratumumab 16 mg/kg (Part 1); Daratumumab 16 mg/kg administered at weekly intervals (QW) for 8 weeks, then every 2 weeks (Q2W) for an additional 16 weeks, then every 4 weeks (Q4W) thereafter by intravenous infusion; Drug: Daratumumab 8 mg/kg (Part 1); Daratumumab 8 mg/kg every 4 weeks (Q4W) continuously by intravenous infusion; Drug: Methylprednisolone; Administered in prophylactic doses intravenously (or equivalent in accordance with local standards) prior to and after study drug administration. Intravenous administration is preferred, but oral steroids may be substituted; Drug: Acetaminophen; 650 to 1000 mg administered in prophylactic doses by mouth prior to study drug administration.; Drug: Diphenhydramine; 25 to 50 mg administered in prophylactic doses by mouth (or equivalent in accordance with local standards) prior to and after study drug administration.
Experimental: Part 2 Based on the Part 1 response rate, Group A or B daratumumab treatment will be selected as the treatment regimen for participants enrolled in Part 2.	Drug: Methylprednisolone; Administered in prophylactic doses intravenously (or equivalent in accordance with local standards) prior to and after study drug administration. Intravenous administration is preferred, but oral steroids may be substituted; Drug: Acetaminophen; 650 to 1000 mg administered in prophylactic doses by mouth prior to study drug administration.; Drug: Diphenhydramine; 25 to 50 mg administered in prophylactic doses by mouth (or equivalent in accordance with local standards) prior to and after study drug administration.; Drug: Daratumumab (Part 2); Based on the Part 1 response rate, Group A or B treatment will be selected as the treatment regimen for participants enrolled in Part 2.

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Overall Response [Up to 14.4 Months]

   Overall response defined as percentage of participants who achieved stringent complete response (sCR), complete response (CR), very good partial response (VGPR) or partial response (PR). Per IMWG criteria, sCR: is defined as normal free light chain (FLC) ratio, and absence of clonal plasma cells (PCs) by immunohistochemistry, immunofluorescence or 2- to 4-color flow cytometry; CR: Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and < 5 % plasma cells in bone marrow; VGPR: Serum and urine M-protein detectable by immunofixation but not on electrophoresis or >= 90% reduction in serum M-protein plus urine M-protein level < 100mg/24 hours; PR: >= 50 % reduction of serum M-protein and reduction in 24 hour urinary M-protein by >= 90% or to <200 mg/24 hours; if the serum and urine M-protein are not measurable, a decrease of >=50% in the difference between involved and uninvolved FLC levels is required in place of the M-protein criteria.

Secondary Outcome Measures

1. Duration of Response [Up to 14.4 Months]

   Duration of response was calculated from the date of initial documentation of a response (PR or better) to the date of first documented evidence of progressive disease, as defined in IMWG criteria. Disease progression (IMWG criteria): increase of 25 percent (%) from lowest response level in Serum M-component (the absolute increase must be >=0.5 g/dL) and/or; urine M-component (the absolute increase must be >=200 mg/24 hours) and/or; only in participants without measurable serum and urine M-protein levels: the difference between involved and uninvolved free light chain levels (absolute increase must be >10 milligram per deciliter (mg/dL); Development of hypercalcemia (corrected serum calcium >11.5 mg/dL or 2.65 millimole per liter [mmol/L]) that can be attributed solely to the plasma cell proliferative disorder.

2. Overall Survival [Approximately up to 3 years]

   Overall Survival (OS) was defined as the number of days from administration of the first infusion (Day 1) to date of death. Median Overall Survival was estimated by using the Kaplan-Meier method.

3. Percentage of Participants With Clinical Benefit [Up to 14.4 Months]

   Clinical benefit rate defined as percentage of participants who achieved minimal response (MR) or better. MR: >=25% but <= 49% reduction of serum M-protein and reduction in urine M-protein by 50%-89%. If present at baseline 25% to 49% reduction in size of soft tissue plasmacytomas.

4. Time to Response [Up to 14.4 Months]

   Time to response was defined as the time from the date of first dose of daratumumab to the date of initial documentation of a response (PR or better).

5. Progression Free Survival [Up to 14.4 Months]

   Progression free survival (PFS) was defined as the time between the date of first dose of daratumumab and either disease progression or death, whichever occurs first.

6. Time to Disease Progression [Up to 14.4 Months]

   Time to progression was defined as the number of days from the date of first dose of daratumumab to the date of first record of disease progression.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Documented multiple myeloma according to protocol-defined criteria

• Evidence of disease progression on the most recent prior treatment regimen based on International Myeloma Working Group criteria

• Eastern Cooperative Oncology Group performance status score of 0, 1, or 2

• Laboratory values and electrocardiogram within protocol-defined parameters at screening

Exclusion Criteria:

• Received daratumumab or other anti-CD38 therapies previously

• Nonsecretory multiple myeloma

• Previously received an allogenic stem cell transplant or has received an autologous stem cell transplantation within 12 weeks

• Exhibiting clinical signs of meningeal involvement of multiple myeloma

• Known chronic obstructive pulmonary disease, persistent asthma, or a history of asthma within 5 years

• Seropositive for human immunodeficiency virus, hepatitis B or antibodies to hepatitis B surface and core antigens, or hepatitis C

• Has plasma cell leukemia, Waldenstrom's macroglobulinemia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes), or amyloidosis

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Duarte	California	United States
2		Los Angeles	California	United States
3		Atlanta	Georgia	United States
4		Chicago	Illinois	United States
5		Louisville	Kentucky	United States
6		Detroit	Michigan	United States
7		New Brunswick	New Jersey	United States
8		New York	New York	United States
9		Chapel Hill	North Carolina	United States
10		Charlotte	North Carolina	United States
11		Portland	Oregon	United States
12		Philadelphia	Pennsylvania	United States
13		Nashville	Tennessee	United States
14		Houston	Texas	United States
15		Madison	Wisconsin	United States
16		Calgary	Alberta	Canada
17		Edmonton	Alberta	Canada
18		Vancouver	British Columbia	Canada
19		Halifax	Nova Scotia	Canada
20		Montreal	Quebec	Canada
21		Barcelona		Spain
22		Salamanca N/A		Spain
23		Valencia		Spain

Sponsors and Collaborators

• Janssen Research & Development, LLC

Investigators

• Study Director: Janssen Research & Development, LLC Clinical Trial, Janssen Research & Development, LLC

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Janssen Research & Development, LLC
• ClinicalTrials.gov Identifier: NCT01985126
• Other Study ID Numbers: CR102651; 54767414MMY2002; 2013-000752-18
• First Posted: Nov 15, 2013
• Last Update Posted: Jun 25, 2018
• Last Verified: Jun 1, 2018

• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Janssen Research & Development, LLC: Multiple myeloma; Daratumumab; Proteasome inhibitor; Immunomodulatory drug; IMiD
• Additional relevant MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell; Acetaminophen; Diphenhydramine; Promethazine; Methylprednisolone; Daratumumab; Antibodies, Monoclonal

Study Results

Participant Flow

Arm/Group Title	Daratumumab 8 mg/kg	Daratumumab 16 mg/kg
Arm/Group Description	Daratumumab 8 milligram per kilogram (mg/kg) every 4 weeks (Q4W) until disease progression or unacceptable toxicity.	Daratumumab 16 mg/kg weekly for 8 weeks; then every 2 weeks (Q2W) for 16 weeks; then Q4W until disease progression or unacceptable toxicity.
Period Title: Overall Study
STARTED	18	106
COMPLETED	0	0
NOT COMPLETED	18	106

Baseline Characteristics

Arm/Group Title	Daratumumab 8 mg/kg	Daratumumab 16 mg/kg	Total
Arm/Group Description	Daratumumab 8 milligram per kilogram (mg/kg) every 4 weeks (Q4W) until disease progression or unacceptable toxicity.	Daratumumab 16 mg/kg weekly for 8 weeks; then every 2 weeks (Q2W) for 16 weeks; then Q4W until disease progression or unacceptable toxicity.	Total of all reporting groups
Overall Participants	18	106	124
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	8 44.4%	58 54.7%	66 53.2%
>=65 years	10 55.6%	48 45.3%	58 46.8%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	64.2 (7.72)	62.9 (10)	63.1 (9.68)
Sex: Female, Male (Count of Participants)
Female	6 33.3%	54 50.9%	60 48.4%
Male	12 66.7%	52 49.1%	64 51.6%
Region of Enrollment (Count of Participants)
Canada	0 0%	22 20.8%	22 17.7%
Spain	3 16.7%	9 8.5%	12 9.7%
United States	15 83.3%	75 70.8%	90 72.6%
Stage of Disease (ISS) (Count of Participants)
I	2 11.1%	26 24.5%	28 22.6%
II	8 44.4%	40 37.7%	48 38.7%
III	8 44.4%	40 37.7%	48 38.7%
Number of Prior Lines of Therapy (Count of Participants)
<= 3 Lines	6 33.3%	19 17.9%	25 20.2%
> 3 Lines	12 66.7%	87 82.1%	99 79.8%
Refractory to Proteasome Inhibitor (PI)/ Immunomodulatory Drug (IMiD) (Count of Participants)
Both a PI and IMiD	15 83.3%	101 95.3%	116 93.5%
PI only	1 5.6%	3 2.8%	4 3.2%
IMiD only	0 0%	1 0.9%	1 0.8%
None	2 11.1%	1 0.9%	3 2.4%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Overall Response
Description	Overall response defined as percentage of participants who achieved stringent complete response (sCR), complete response (CR), very good partial response (VGPR) or partial response (PR). Per IMWG criteria, sCR: is defined as normal free light chain (FLC) ratio, and absence of clonal plasma cells (PCs) by immunohistochemistry, immunofluorescence or 2- to 4-color flow cytometry; CR: Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and < 5 % plasma cells in bone marrow; VGPR: Serum and urine M-protein detectable by immunofixation but not on electrophoresis or >= 90% reduction in serum M-protein plus urine M-protein level < 100mg/24 hours; PR: >= 50 % reduction of serum M-protein and reduction in 24 hour urinary M-protein by >= 90% or to <200 mg/24 hours; if the serum and urine M-protein are not measurable, a decrease of >=50% in the difference between involved and uninvolved FLC levels is required in place of the M-protein criteria.
Time Frame	Up to 14.4 Months

Outcome Measure Data

Analysis Population Description

All treated analysis set included all participants who received at least 1 dose of daratumumab.

Arm/Group Title	Daratumumab 8 mg/kg	Daratumumab 16 mg/kg
Arm/Group Description	Daratumumab 8 milligram per kilogram (mg/kg) every 4 weeks (Q4W) until disease progression or unacceptable toxicity.	Daratumumab 16 mg/kg weekly for 8 weeks; then every 2 weeks (Q2W) for 16 weeks; then Q4W until disease progression or unacceptable toxicity.
Measure Participants	18	106
Number (95% Confidence Interval) [percentage of participants]	11.1 61.7%	29.2 27.5%

2. Secondary Outcome

Title	Duration of Response
Description	Duration of response was calculated from the date of initial documentation of a response (PR or better) to the date of first documented evidence of progressive disease, as defined in IMWG criteria. Disease progression (IMWG criteria): increase of 25 percent (%) from lowest response level in Serum M-component (the absolute increase must be >=0.5 g/dL) and/or; urine M-component (the absolute increase must be >=200 mg/24 hours) and/or; only in participants without measurable serum and urine M-protein levels: the difference between involved and uninvolved free light chain levels (absolute increase must be >10 milligram per deciliter (mg/dL); Development of hypercalcemia (corrected serum calcium >11.5 mg/dL or 2.65 millimole per liter [mmol/L]) that can be attributed solely to the plasma cell proliferative disorder.
Time Frame	Up to 14.4 Months

Outcome Measure Data

Analysis Population Description

Responders in all treated analysis set. Only those participants with confirmed PR and those who experienced progressive disease were analyzed.

Arm/Group Title	Daratumumab 8 mg/kg	Daratumumab 16 mg/kg
Arm/Group Description	Daratumumab 8 milligram per kilogram (mg/kg) every 4 weeks (Q4W) until disease progression or unacceptable toxicity.	Daratumumab 16 mg/kg weekly for 8 weeks; then every 2 weeks (Q2W) for 16 weeks; then Q4W until disease progression or unacceptable toxicity.
Measure Participants	2	31
Median (95% Confidence Interval) [months]	NA	7.4

3. Secondary Outcome

Title	Overall Survival
Description	Overall Survival (OS) was defined as the number of days from administration of the first infusion (Day 1) to date of death. Median Overall Survival was estimated by using the Kaplan-Meier method.
Time Frame	Approximately up to 3 years

Outcome Measure Data

Analysis Population Description

All treated analysis set included all participants who received at least 1 dose of daratumumab.

Arm/Group Title	Daratumumab 8 mg/kg	Daratumumab 16 mg/kg
Arm/Group Description	Daratumumab 8 milligram per kilogram (mg/kg) every 4 weeks (Q4W) until disease progression or unacceptable toxicity.	Daratumumab 16 mg/kg weekly for 8 weeks; then every 2 weeks (Q2W) for 16 weeks; then Q4W until disease progression or unacceptable toxicity.
Measure Participants	18	106
Median (95% Confidence Interval) [months]	19.45	18.60

4. Secondary Outcome

Title	Percentage of Participants With Clinical Benefit
Description	Clinical benefit rate defined as percentage of participants who achieved minimal response (MR) or better. MR: >=25% but <= 49% reduction of serum M-protein and reduction in urine M-protein by 50%-89%. If present at baseline 25% to 49% reduction in size of soft tissue plasmacytomas.
Time Frame	Up to 14.4 Months

Outcome Measure Data

Analysis Population Description

All treated analysis set included all participants who received at least 1 dose of daratumumab.

Arm/Group Title	Daratumumab 8 mg/kg	Daratumumab 16 mg/kg
Arm/Group Description	Daratumumab 8 milligram per kilogram (mg/kg) every 4 weeks (Q4W) until disease progression or unacceptable toxicity.	Daratumumab 16 mg/kg weekly for 8 weeks; then every 2 weeks (Q2W) for 16 weeks; then Q4W until disease progression or unacceptable toxicity.
Measure Participants	18	106
Number (95% Confidence Interval) [percentage of participants]	22.2 123.3%	34.0 32.1%

5. Secondary Outcome

Title	Time to Response
Description	Time to response was defined as the time from the date of first dose of daratumumab to the date of initial documentation of a response (PR or better).
Time Frame	Up to 14.4 Months

Outcome Measure Data

Analysis Population Description

Responders in all treated analysis set. Only those participants with confirmed PR were analyzed.

Arm/Group Title	Daratumumab 8 mg/kg	Daratumumab 16 mg/kg
Arm/Group Description	Daratumumab 8 milligram per kilogram (mg/kg) every 4 weeks (Q4W) until disease progression or unacceptable toxicity.	Daratumumab 16 mg/kg weekly for 8 weeks; then every 2 weeks (Q2W) for 16 weeks; then Q4W until disease progression or unacceptable toxicity.
Measure Participants	2	31
Median (Full Range) [months]	0.99	0.99

6. Secondary Outcome

Title	Progression Free Survival
Description	Progression free survival (PFS) was defined as the time between the date of first dose of daratumumab and either disease progression or death, whichever occurs first.
Time Frame	Up to 14.4 Months

Outcome Measure Data

Analysis Population Description

All treated analysis set included all participants who received at least 1 dose of daratumumab.

Arm/Group Title	Daratumumab 8 mg/kg	Daratumumab 16 mg/kg
Arm/Group Description	Daratumumab 8 milligram per kilogram (mg/kg) every 4 weeks (Q4W) until disease progression or unacceptable toxicity.	Daratumumab 16 mg/kg weekly for 8 weeks; then every 2 weeks (Q2W) for 16 weeks; then Q4W until disease progression or unacceptable toxicity.
Measure Participants	18	106
Median (95% Confidence Interval) [months]	4.86	3.65

7. Secondary Outcome

Title	Time to Disease Progression
Description	Time to progression was defined as the number of days from the date of first dose of daratumumab to the date of first record of disease progression.
Time Frame	Up to 14.4 Months

Outcome Measure Data

Analysis Population Description

All treated analysis set included all participants who received at least 1 dose of daratumumab.

Arm/Group Title	Daratumumab 8 mg/kg	Daratumumab 16 mg/kg
Arm/Group Description	Daratumumab 8 milligram per kilogram (mg/kg) every 4 weeks (Q4W) until disease progression or unacceptable toxicity.	Daratumumab 16 mg/kg weekly for 8 weeks; then every 2 weeks (Q2W) for 16 weeks; then Q4W until disease progression or unacceptable toxicity.
Measure Participants	18	106
Median (95% Confidence Interval) [months]	4.86	3.71

Adverse Events

Time Frame	Approximately up to 3.8 years
Adverse Event Reporting Description	All treated Analysis Set included all participants who received at least 1 dose of daratumumab.
Arm/Group Title	Daratumumab 8 mg/kg		Daratumumab 16 mg/kg
Arm/Group Description	Daratumumab 8 milligram per kilogram (mg/kg) every 4 weeks (Q4W) until disease progression or unacceptable toxicity.		Daratumumab 16 mg/kg weekly for 8 weeks; then every 2 weeks (Q2W) for 16 weeks; then Q4W until disease progression or unacceptable toxicity.
All Cause Mortality
	Daratumumab 8 mg/kg		Daratumumab 16 mg/kg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Daratumumab 8 mg/kg		Daratumumab 16 mg/kg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/18 (33.3%)		33/106 (31.1%)
Blood and lymphatic system disorders
Anaemia	0/18 (0%)		2/106 (1.9%)
Thrombocytopenia	0/18 (0%)		1/106 (0.9%)
Cardiac disorders
Cardiac Failure Congestive	0/18 (0%)		1/106 (0.9%)
Cardio-Respiratory Arrest	0/18 (0%)		1/106 (0.9%)
Gastrointestinal disorders
Abdominal Pain	0/18 (0%)		1/106 (0.9%)
Faecal Incontinence	0/18 (0%)		1/106 (0.9%)
Large Intestinal Obstruction	0/18 (0%)		1/106 (0.9%)
Nausea	1/18 (5.6%)		0/106 (0%)
Pancreatitis	0/18 (0%)		1/106 (0.9%)
Vomiting	1/18 (5.6%)		0/106 (0%)
General disorders
Asthenia	0/18 (0%)		1/106 (0.9%)
Fatigue	0/18 (0%)		1/106 (0.9%)
General Physical Health Deterioration	1/18 (5.6%)		5/106 (4.7%)
Pyrexia	0/18 (0%)		1/106 (0.9%)
Hepatobiliary disorders
Hepatic Failure	0/18 (0%)		1/106 (0.9%)
Infections and infestations
Bronchitis	0/18 (0%)		1/106 (0.9%)
H1n1 Influenza	0/18 (0%)		1/106 (0.9%)
Herpes Zoster	0/18 (0%)		1/106 (0.9%)
Lobar Pneumonia	0/18 (0%)		2/106 (1.9%)
Parainfluenzae Virus Infection	0/18 (0%)		1/106 (0.9%)
Pneumonia	0/18 (0%)		4/106 (3.8%)
Pneumonia Streptococcal	0/18 (0%)		1/106 (0.9%)
Pyelonephritis	0/18 (0%)		1/106 (0.9%)
Respiratory Tract Infection	0/18 (0%)		1/106 (0.9%)
Sepsis	0/18 (0%)		1/106 (0.9%)
Soft Tissue Infection	0/18 (0%)		1/106 (0.9%)
Upper Respiratory Tract Infection	0/18 (0%)		1/106 (0.9%)
Varicella	0/18 (0%)		1/106 (0.9%)
Injury, poisoning and procedural complications
Spinal Compression Fracture	0/18 (0%)		1/106 (0.9%)
Subdural Haematoma	0/18 (0%)		1/106 (0.9%)
Investigations
Blood Creatinine Increased	0/18 (0%)		1/106 (0.9%)
Oxygen Saturation Abnormal	0/18 (0%)		1/106 (0.9%)
Metabolism and nutrition disorders
Hypercalcaemia	0/18 (0%)		4/106 (3.8%)
Hyperkalaemia	0/18 (0%)		1/106 (0.9%)
Hyperuricaemia	1/18 (5.6%)		0/106 (0%)
Musculoskeletal and connective tissue disorders
Back Pain	1/18 (5.6%)		1/106 (0.9%)
Musculoskeletal Chest Pain	0/18 (0%)		2/106 (1.9%)
Pathological Fracture	0/18 (0%)		1/106 (0.9%)
Spinal Column Stenosis	0/18 (0%)		1/106 (0.9%)
Spinal Pain	0/18 (0%)		1/106 (0.9%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Plasma Cell Leukaemia	1/18 (5.6%)		0/106 (0%)
Nervous system disorders
Headache	0/18 (0%)		1/106 (0.9%)
Spinal Cord Compression	0/18 (0%)		1/106 (0.9%)
Syncope	1/18 (5.6%)		0/106 (0%)
Tremor	0/18 (0%)		1/106 (0.9%)
Psychiatric disorders
Delirium	0/18 (0%)		1/106 (0.9%)
Renal and urinary disorders
Acute Kidney Injury	1/18 (5.6%)		0/106 (0%)
Haematuria	0/18 (0%)		1/106 (0.9%)
Renal Impairment	1/18 (5.6%)		0/106 (0%)
Urinary Retention	1/18 (5.6%)		0/106 (0%)
Urinary Tract Obstruction	0/18 (0%)		1/106 (0.9%)
Reproductive system and breast disorders
Pelvic Pain	1/18 (5.6%)		0/106 (0%)
Respiratory, thoracic and mediastinal disorders
Acute Pulmonary Oedema	0/18 (0%)		1/106 (0.9%)
Pleural Effusion	1/18 (5.6%)		1/106 (0.9%)
Pneumonia Aspiration	0/18 (0%)		1/106 (0.9%)
Respiratory Failure	0/18 (0%)		1/106 (0.9%)
Vascular disorders
Deep Vein Thrombosis	0/18 (0%)		1/106 (0.9%)
Hypotension	0/18 (0%)		1/106 (0.9%)
Other (Not Including Serious) Adverse Events
	Daratumumab 8 mg/kg		Daratumumab 16 mg/kg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	18/18 (100%)		105/106 (99.1%)
Blood and lymphatic system disorders
Anaemia	9/18 (50%)		39/106 (36.8%)
Leukopenia	2/18 (11.1%)		8/106 (7.5%)
Lymphopenia	3/18 (16.7%)		5/106 (4.7%)
Neutropenia	2/18 (11.1%)		26/106 (24.5%)
Thrombocytopenia	6/18 (33.3%)		28/106 (26.4%)
Cardiac disorders
Sinus Tachycardia	1/18 (5.6%)		1/106 (0.9%)
Tachycardia	1/18 (5.6%)		3/106 (2.8%)
Ear and labyrinth disorders
Cerumen Impaction	1/18 (5.6%)		0/106 (0%)
Ear Discomfort	1/18 (5.6%)		0/106 (0%)
Eye disorders
Cataract	1/18 (5.6%)		1/106 (0.9%)
Gastrointestinal disorders
Abdominal Discomfort	1/18 (5.6%)		3/106 (2.8%)
Abdominal Distension	1/18 (5.6%)		3/106 (2.8%)
Abdominal Pain	1/18 (5.6%)		7/106 (6.6%)
Aphthous Stomatitis	1/18 (5.6%)		0/106 (0%)
Constipation	1/18 (5.6%)		19/106 (17.9%)
Diarrhoea	4/18 (22.2%)		22/106 (20.8%)
Dry Mouth	1/18 (5.6%)		0/106 (0%)
Gastritis	1/18 (5.6%)		0/106 (0%)
Nausea	4/18 (22.2%)		34/106 (32.1%)
Vomiting	2/18 (11.1%)		19/106 (17.9%)
General disorders
Asthenia	2/18 (11.1%)		12/106 (11.3%)
Chest Discomfort	1/18 (5.6%)		3/106 (2.8%)
Chills	6/18 (33.3%)		10/106 (9.4%)
Fatigue	6/18 (33.3%)		42/106 (39.6%)
Non-Cardiac Chest Pain	1/18 (5.6%)		6/106 (5.7%)
Oedema	1/18 (5.6%)		2/106 (1.9%)
Oedema Peripheral	2/18 (11.1%)		9/106 (8.5%)
Pain	1/18 (5.6%)		6/106 (5.7%)
Pyrexia	5/18 (27.8%)		20/106 (18.9%)
Hepatobiliary disorders
Hepatic Steatosis	1/18 (5.6%)		0/106 (0%)
Immune system disorders
Cytokine Release Syndrome	1/18 (5.6%)		0/106 (0%)
Infections and infestations
Bronchitis	0/18 (0%)		7/106 (6.6%)
Candida Infection	1/18 (5.6%)		1/106 (0.9%)
Influenza	2/18 (11.1%)		4/106 (3.8%)
Nasopharyngitis	1/18 (5.6%)		8/106 (7.5%)
Pneumonia	1/18 (5.6%)		4/106 (3.8%)
Sinusitis	1/18 (5.6%)		7/106 (6.6%)
Upper Respiratory Tract Infection	2/18 (11.1%)		21/106 (19.8%)
Urinary Tract Infection	0/18 (0%)		7/106 (6.6%)
Injury, poisoning and procedural complications
Contusion	1/18 (5.6%)		5/106 (4.7%)
Investigations
Aspartate Aminotransferase Increased	1/18 (5.6%)		4/106 (3.8%)
Blood Alkaline Phosphatase Increased	3/18 (16.7%)		4/106 (3.8%)
Blood Creatinine Increased	7/18 (38.9%)		9/106 (8.5%)
Blood Urea Increased	1/18 (5.6%)		0/106 (0%)
Gamma-Glutamyltransferase Increased	1/18 (5.6%)		1/106 (0.9%)
Transaminases Increased	1/18 (5.6%)		0/106 (0%)
Weight Decreased	2/18 (11.1%)		5/106 (4.7%)
Weight Increased	1/18 (5.6%)		4/106 (3.8%)
Metabolism and nutrition disorders
Decreased Appetite	4/18 (22.2%)		19/106 (17.9%)
Fluid Retention	1/18 (5.6%)		0/106 (0%)
Hypercalcaemia	2/18 (11.1%)		16/106 (15.1%)
Hyperglycaemia	3/18 (16.7%)		9/106 (8.5%)
Hyperkalaemia	1/18 (5.6%)		3/106 (2.8%)
Hyperuricaemia	1/18 (5.6%)		4/106 (3.8%)
Hypoalbuminaemia	4/18 (22.2%)		5/106 (4.7%)
Hypocalcaemia	1/18 (5.6%)		3/106 (2.8%)
Hypoglycaemia	1/18 (5.6%)		1/106 (0.9%)
Hypokalaemia	4/18 (22.2%)		11/106 (10.4%)
Hypomagnesaemia	2/18 (11.1%)		8/106 (7.5%)
Hyponatraemia	6/18 (33.3%)		7/106 (6.6%)
Hypophosphataemia	1/18 (5.6%)		0/106 (0%)
Metabolic Acidosis	1/18 (5.6%)		0/106 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	2/18 (11.1%)		20/106 (18.9%)
Back Pain	5/18 (27.8%)		25/106 (23.6%)
Bone Pain	0/18 (0%)		10/106 (9.4%)
Flank Pain	1/18 (5.6%)		0/106 (0%)
Muscle Spasms	2/18 (11.1%)		9/106 (8.5%)
Musculoskeletal Chest Pain	2/18 (11.1%)		15/106 (14.2%)
Musculoskeletal Pain	1/18 (5.6%)		12/106 (11.3%)
Myalgia	0/18 (0%)		6/106 (5.7%)
Pain in Extremity	1/18 (5.6%)		20/106 (18.9%)
Nervous system disorders
Anaesthesia	1/18 (5.6%)		0/106 (0%)
Dizziness	1/18 (5.6%)		10/106 (9.4%)
Dysgeusia	2/18 (11.1%)		3/106 (2.8%)
Encephalopathy	1/18 (5.6%)		1/106 (0.9%)
Headache	2/18 (11.1%)		13/106 (12.3%)
Hypoaesthesia	1/18 (5.6%)		6/106 (5.7%)
Peripheral Sensory Neuropathy	1/18 (5.6%)		6/106 (5.7%)
Sciatica	1/18 (5.6%)		0/106 (0%)
Tremor	2/18 (11.1%)		2/106 (1.9%)
Psychiatric disorders
Anxiety	0/18 (0%)		8/106 (7.5%)
Confusional State	1/18 (5.6%)		7/106 (6.6%)
Depression	1/18 (5.6%)		3/106 (2.8%)
Mental Status Changes	1/18 (5.6%)		1/106 (0.9%)
Nervousness	1/18 (5.6%)		0/106 (0%)
Renal and urinary disorders
Bladder Spasm	1/18 (5.6%)		0/106 (0%)
Haematuria	2/18 (11.1%)		2/106 (1.9%)
Micturition Urgency	1/18 (5.6%)		0/106 (0%)
Urinary Incontinence	2/18 (11.1%)		1/106 (0.9%)
Reproductive system and breast disorders
Nipple Pain	1/18 (5.6%)		1/106 (0.9%)
Prostatitis	1/18 (5.6%)		0/106 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	6/18 (33.3%)		27/106 (25.5%)
Dyspnoea	3/18 (16.7%)		18/106 (17%)
Dyspnoea Exertional	1/18 (5.6%)		9/106 (8.5%)
Epistaxis	0/18 (0%)		9/106 (8.5%)
Nasal Congestion	2/18 (11.1%)		22/106 (20.8%)
Oropharyngeal Pain	1/18 (5.6%)		9/106 (8.5%)
Pleural Effusion	1/18 (5.6%)		3/106 (2.8%)
Productive Cough	1/18 (5.6%)		8/106 (7.5%)
Throat Irritation	0/18 (0%)		7/106 (6.6%)
Wheezing	1/18 (5.6%)		7/106 (6.6%)
Skin and subcutaneous tissue disorders
Actinic Keratosis	1/18 (5.6%)		0/106 (0%)
Nail Discolouration	1/18 (5.6%)		0/106 (0%)
Pruritus	1/18 (5.6%)		3/106 (2.8%)
Rash	1/18 (5.6%)		2/106 (1.9%)
Rash Macular	1/18 (5.6%)		1/106 (0.9%)
Urticaria	1/18 (5.6%)		1/106 (0.9%)
Vascular disorders
Deep Vein Thrombosis	1/18 (5.6%)		1/106 (0.9%)
Hypertension	8/18 (44.4%)		12/106 (11.3%)
Hypotension	2/18 (11.1%)		6/106 (5.7%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

A copy of the manuscript must be provided to the sponsor for review at least 60 days before submission for publication or presentation. If requested in writing, such publication will be withheld for up to an additional 60 days.