The n e w e ng l a n d j o u r na l of m e dic i n e

Original Article

Daratumumab, Bortezomib,
and Dexamethasone for Multiple Myeloma
Antonio Palumbo, M.D., Asher Chanan‑Khan, M.D., Katja Weisel, M.D.,
Ajay K. Nooka, M.D., Tamas Masszi, M.D., Meral Beksac, M.D.,
Ivan Spicka, M.D., Vania Hungria, M.D., Markus Munder, M.D.,
Maria V. Mateos, M.D., Tomer M. Mark, M.D., Ming Qi, M.D.,
Jordan Schecter, M.D., Himal Amin, B.S., Xiang Qin, M.S.,
William Deraedt, Ph.D., Tahamtan Ahmadi, M.D., Andrew Spencer, M.D.,
and Pieter Sonneveld, M.D., for the CASTOR Investigators*​​

A BS T R AC T

BACKGROUND
The authors’ affiliations are listed in the Daratumumab, a human IgGκ monoclonal antibody that targets CD38, induces direct
Appendix. Address reprint requests to Dr. and indirect antimyeloma activity and has shown substantial efficacy as monotherapy
Palumbo at the Department of Hematol‑
ogy, University of Turin, Via Genova 3, in heavily pretreated patients with multiple myeloma, as well as in combination with
10126, Turin, Italy, or at a­ppalumbo@​ bortezomib in patients with newly diagnosed multiple myeloma.
­yahoo​.­com.
METHODS
* A complete list of investigators in the In this phase 3 trial, we randomly assigned 498 patients with relapsed or relapsed and
CASTOR Trial is provided in the Supple‑
mentary Appendix, available at NEJM.org.
refractory multiple myeloma to receive bortezomib (1.3 mg per square meter of body-
surface area) and dexamethasone (20 mg) alone (control group) or in combination with
N Engl J Med 2016;375:754-66.
DOI: 10.1056/NEJMoa1606038
daratumumab (16 mg per kilogram of body weight) (daratumumab group). The primary
Copyright © 2016 Massachusetts Medical Society. end point was progression-free survival.
RESULTS
A prespecified interim analysis showed that the rate of progression-free survival was
significantly higher in the daratumumab group than in the control group; the 12-month
rate of progression-free survival was 60.7% in the daratumumab group versus 26.9% in
the control group. After a median follow-up period of 7.4 months, the median progres-
sion-free survival was not reached in the daratumumab group and was 7.2 months in the
control group (hazard ratio for progression or death with daratumumab vs. control, 0.39;
95% confidence interval, 0.28 to 0.53; P<0.001). The rate of overall response was higher
in the daratumumab group than in the control group (82.9% vs. 63.2%, P<0.001), as were
the rates of very good partial response or better (59.2% vs. 29.1%, P<0.001) and complete
response or better (19.2% vs. 9.0%, P = 0.001). Three of the most common grade 3 or 4
adverse events reported in the daratumumab group and the control group were throm-
bocytopenia (45.3% and 32.9%, respectively), anemia (14.4% and 16.0%, respectively),
and neutropenia (12.8% and 4.2%, respectively). Infusion-related reactions that were
associated with daratumumab treatment were reported in 45.3% of the patients in the
daratumumab group; these reactions were mostly grade 1 or 2 (grade 3 in 8.6% of the
patients), and in 98.2% of these patients, they occurred during the first infusion.
CONCLUSIONS
Among patients with relapsed or relapsed and refractory multiple myeloma, daratu-
mumab in combination with bortezomib and dexamethasone resulted in significantly
longer progression-free survival than bortezomib and dexamethasone alone and was
associated with infusion-related reactions and higher rates of thrombocytopenia and
neutropenia than bortezomib and dexamethasone alone. (Funded by Janssen Research
and Development; ClinicalTrials.gov number, NCT02136134.)

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 Dar atumumab, Bortezomib, and Dexamethasone for Multiple Myeloma

M
ultiple myeloma is associated with bortezomib and dexamethasone alone in
with organ dysfunction, including bone patients with relapsed or relapsed and refractory
lesions, anemia, renal insufficiency, and multiple myeloma.
hypercalcemia.1,2 Proteasome inhibitors (e.g.,
bortezomib) in combination with glucocorticoids Me thods
are standard regimens for relapsed or relapsed
and refractory multiple myeloma3 (definitions of Trial Design and Oversight
these terms are provided in the Supplementary This was a multicenter, randomized, open-label,
Appendix, available with the full text of this arti- active-controlled, phase 3 trial. The trial protocol,
cle at NEJM.org) and have contributed consider- which is available at NEJM.org, was approved by
ably to patient survival.4 Nevertheless, almost all the independent ethics committee or institu-
patients will have a relapse. tional review board at each trial center. All the
Daratumumab is a human IgGκ monoclonal patients provided written informed consent, and
antibody that targets CD38, which is highly ex- the trial was conducted in accordance with the
pressed on myeloma cells and other hematopoi- principles of the Declaration of Helsinki and the
etic cell types.5,6 Daratumumab has direct and International Conference on Harmonisation Good
indirect antitumor activity and diverse mecha- Clinical Practice guidelines.
nisms of action, including induction of apopto- Janssen Research and Development sponsored
sis; immune-mediated actions, including comple- the trial. The sponsor and investigators were
ment-dependent cytotoxicity, antibody-dependent jointly responsible for the trial design and the
cell-mediated cytotoxicity, and antibody-depen- statistical analysis plan (available with the pro-
dent cellular phagocytosis; and immunomodula- tocol). The investigators and associated research
tory functions that target and deplete CD38- teams collected the data, which were compiled
positive regulator immune suppressor cells, which and maintained by the sponsor. One of the au-
leads to T-cell expansion and activation in pa- thors who was an employee of the sponsor was
tients who have a response.7-11 the physician responsible for the trial. Profes-
In heavily pretreated patients with relapsed or sional medical writers were funded by the spon-
relapsed and refractory multiple myeloma, single- sor to prepare the manuscript for submission.
agent daratumumab was associated with an over- All the authors reviewed, revised, and approved
all response rate of 31% and a median overall the manuscript for submission. The sponsor and
survival of 20.1 months.12 On the basis of these investigators vouch for the accuracy and com-
findings, daratumumab monotherapy at a dose pleteness of the data from the prespecified in-
of 16 mg per kilogram of body weight was ap- terim analysis and for the fidelity of the trial to
proved by the Food and Drug Administration for the protocol.
the treatment of multiple myeloma in patients
who have previously received at least three ther­ Patients
apies, including a proteasome inhibitor and an Patients were eligible for enrollment in the trial
immunomodulatory agent, or in patients whose if they had received at least one previous line of
disease is refractory to treatment in both these therapy for multiple myeloma, had at least a
drug classes.13 partial response to one or more of their previous
Treatment with daratumumab in combination therapies, and had documented progressive dis-
with proteasome inhibitors and immunomodu- ease, according to International Myeloma Work-
latory agents has resulted in high response rates ing Group (IMWG) criteria (a list of these criteria
and acceptable safety profiles in early-phase is provided in the Supplementary Appendix),16,17
clinical trials.14,15 Specifically, in a phase 1 trial during or after the completion of their last regi-
involving patients with newly diagnosed multi- men. At screening, all patients were required to
ple myeloma, daratumumab in combination with have measurable disease on the basis of assess-
bortezomib-based regimens, including bortezo- ments of the serum, urine, or both or to have
mib plus dexamethasone, induced responses in measurable disease as assessed by the serum
all patients.14 We report the results of a pre- free light-chain assay, in accordance with the
specified interim analysis of a randomized phase criteria specified by the IMWG.
3 trial of daratumumab in combination with Key exclusion criteria were a neutrophil count
bortezomib and dexamethasone as compared of 1000 or less per cubic millimeter, a hemoglo-

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 The n e w e ng l a n d j o u r na l of m e dic i n e

bin level of 7.5 g or less per deciliter, a platelet were older than 75 years of age, for patients who
count of less than 75,000 per cubic millimeter, a had a body-mass index (the weight in kilograms
creatinine clearance of 20 ml or less per minute divided by the square of the height in meters) of
per 1.73 m2 of body-surface area, an alanine less than 18.5, or for patients who had previous
aminotransferase or aspartate aminotransferase unacceptable side effects associated with gluco-
level of 2.5 or more times the upper limit of the corticoid therapy.
normal range, and a bilirubin level of 1.5 or more
times the upper limit of the normal range; in End Points and Assessments
addition, patients were excluded if they had dis- The primary end point of the trial was progres-
ease that was refractory to bortezomib or if they sion-free survival, which was defined as the time
had unacceptable side effects from bortezomib, from the date of randomization to the date of
if they had disease that was refractory to another disease progression or death, whichever occurred
proteasome inhibitor, or if they had grade 2 or first. We assessed response to treatment and
higher peripheral neuropathy or neuropathic pain. disease progression using a computerized algo-
rithm (details are provided in the Supplementary
Trial Treatments Appendix) that combined all pertinent labora-
Patients were randomly assigned in a 1:1 ratio to tory results and the results of imaging, as as-
receive either daratumumab in combination with sessed by the investigator, for each patient and
bortezomib and dexamethasone (daratumumab derived the outcome in accordance with IMWG
group) or bortezomib and dexamethasone alone criteria.16,17 Results from a previous phase 2 trial
(control group). Randomization was stratified in which the same algorithm was used showed
according to International Staging System (ISS) very strong concordance with the findings of an
disease stage at the time of screening (stage I, II, independent review committee from the trial.19
or III, with higher stages indicating more severe Secondary efficacy end points included the time
disease; definitions are provided in the Supple- to disease progression, the overall response rate,
mentary Appendix), the number of previous the proportion of patients who achieved very
lines of therapy (1 vs. 2 or 3 vs. >3), and previous good partial response or better, the duration of
treatment with bortezomib (no vs. yes). response, the time to response, and overall sur-
All patients received up to 8 cycles (21 days per vival. The time to subsequent antimyeloma treat-
cycle) of bortezomib (on the basis of the dosing ment was an exploratory efficacy end point. Defi-
schedule of the pivotal SUMMIT trial18) and nitions of these efficacy end points are provided
dexamethasone. For patients assigned to the in the Supplementary Appendix. Serum and urine
daratumumab group, daratumumab at a dose of monoclonal proteins and serum free light-chains
16 mg per kilogram was administered intrave- were measured at a central laboratory. Serum
nously once per week (days 1, 8, and 15) during tests and 24-hour urine tests were performed on
cycles 1 to 3, once every 3 weeks (on day 1) dur- day 1 of each cycle for the first 18 months and
ing cycles 4 to 8, and once every 4 weeks there- every other month thereafter until the onset of
after until the patient withdrew consent, the disease progression. All responses, including pro-
disease progressed, or unacceptable toxic effects gressive disease, were confirmed by a second,
developed (Fig. S1 in the Supplementary Appen- consecutive assessment. In cases in which a pa-
dix). Patients in the daratumumab group received tient had a possible complete response but the
medications before or after their infusions of investigator suspected that the patient’s dose of
daratumumab as needed to manage infusion- daratumumab had interfered with the quantita-
related reactions (Table S3 in the Supplementary tion of serum M-protein as determined by either
Appendix). Bortezomib was administered subcu- the electrophoresis assay or the immunofixation
taneously at a dose of 1.3 mg per square meter assay, additional reflex testing with the use of an
on days 1, 4, 8, and 11 of cycles 1 to 8, and antiidiotype antibody was used to confirm the
dexamethasone was administered orally or intra- complete response.20,21 Definitions of all response
venously at a dose of 20 mg on days 1, 2, 4, 5, 8, categories are provided in the protocol. Serum
9, 11, and 12, for a total dose of 160 mg per samples were assessed for the development of
cycle. The dose of dexamethasone could be re- antibodies to daratumumab.
duced to 20 mg once weekly for patients who Safety assessments included the evaluation of

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 Dar atumumab, Bortezomib, and Dexamethasone for Multiple Myeloma

adverse events (which were graded according to ease status only, were compared between the
the National Cancer Institute Common Termi- daratumumab group and the control group with
nology Criteria for Adverse Events, version 4.03), the use of a stratified log-rank test. Hazard ra-
electrocardiography, vital signs, and clinical tios and corresponding 95% confidence intervals
laboratory testing, which was performed at a lo- were estimated with the use of a stratified Cox
cal laboratory. An independent data and safety regression model, with treatment as the sole
monitoring committee periodically reviewed the explanatory variable. The Kaplan–Meier method
safety data. was used to estimate the distributions. A strati-
fied Cochran–Mantel–Haenszel chi-square test
Statistical Analysis was used to test between-group differences in the
In this trial, we used a group sequential design overall response rate, the rate of very good par-
with one prespecified interim analysis to evalu- tial response or better (i.e., very good partial re-
ate the primary end point. We estimated that a sponse, complete response, or stringent complete
sample size of approximately 480 patients would response), and the rate of complete response or
result in a total of 295 events of disease progres- better (i.e., complete response or stringent com-
sion or death, which would give the trial 85% plete response). The duration of response was
power to detect a risk of disease progression or summarized by means of the Kaplan–Meier
death that was lower by 30% (hazard ratio, 0.70) method.
with daratumumab in combination with bortezo-
mib and dexamethasone than with bortezomib R e sult s
and dexamethasone alone, using a log-rank test
at an overall two-sided alpha level of 0.05. The Patients and Treatment
interim analysis was to be performed after ap- From September 4, 2014, to September 24, 2015,
proximately 177 events had been observed (i.e., patients were recruited at 115 centers in 16
60% of the planned events for the final analy- countries across Europe, North America, South
sis). The O’Brien–Fleming stopping boundary at America, and the Asia-Pacific region. A total of
the time of the interim analysis for the primary 498 patients were enrolled; 251 were randomly
end point was calculated with the use of a Lan– assigned to the daratumumab group and 247 to
DeMets alpha-spending function on the basis the control group. The demographic, disease, and
of the number of events observed at the data- clinical characteristics of the two groups were
cutoff date.22,23 well balanced at baseline (Table 1). Across the two
If the results of the primary end point were treatment groups, the median age of the patients
found to be significant at the interim analysis, was 64 years (range, 30 to 88). The median time
the major secondary end points were to be tested since the initial diagnosis of multiple myeloma
sequentially in the order of time to disease pro- was 3.8 years. Patients had received a median of
gression, rate of very good partial response, over- 2 (range, 1 to 10) previous lines of therapy; 23.9%
all response rate, and overall survival, each at an of the patients had received at least 3 previous
overall two-sided alpha level of 0.05. Efficacy lines of therapy. Across the two treatment groups,
analyses were based on the intention-to-treat 61.2% of the patients had undergone autologous
population, which included all patients who stem-cell transplantation, 65.5% had received
underwent randomization. The safety population previous treatment with bortezomib, 75.7% had
included all patients who received at least one received immunomodulatory drugs, 48.4% had
dose of trial treatment. The population of pa- received both proteasome inhibitors and immu-
tients who could be evaluated for response in- nomodulatory drugs, 32.3% had disease that
cluded patients who had measurable disease at was refractory to their last line of therapy, and
the baseline or screening visit and who received 32.9% had disease that was refractory to immu-
at least one dose of trial treatment and had at nomodulatory drugs.
least one assessment of disease after the base- At the time of the data-cutoff date of January
line visit. 11, 2016, among the patients who had received
The end points of progression-free survival, at least one dose of trial treatment (safety popu-
which included disease status and deaths, and lation: 243 patients in the daratumumab group
time to disease progression, which included dis- and 237 in the control group), 74 patients (30.5%)

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 The n e w e ng l a n d j o u r na l of m e dic i n e

Table 1. Demographic, Baseline Disease, and Clinical Characteristics in the Intention-to-Treat Population.*

Daratumumab Group Control Group

Characteristic (N = 251) (N = 247)
Age
Median (range) — yr 64 (30–88) 64 (33–85)
Distribution — no. (%)
<65 yr 132 (52.6) 125 (50.6)
65–74 yr   96 (38.2)   87 (35.2)
≥75 yr 23 (9.2)   35 (14.2)
Type of measurable disease — no. (%)
IgG 125 (49.8) 138 (55.9)
IgA   56 (22.3)   54 (21.9)
Other   5 (2.0)   4 (1.6)
Detected in urine only   40 (15.9)   36 (14.6)
Detected in serum free light-chains only   25 (10.0) 14 (5.7)
Not evaluated 0   1 (0.4)
ISS disease staging — no. (%)†
I 98 (39.0)   96 (38.9)
II 94 (37.5) 100 (40.5)
III 59 (23.5)   51 (20.6)
Cytogenetic profile — no. (%)‡
Standard-risk cytogenetic abnormality 140/181 (77.3) 137/174 (78.7)
High-risk cytogenetic abnormality   41/181 (22.7)   37/174 (21.3)
Del17p   28/181 (15.5)   21/174 (12.1)
t(4;14) 14/181 (7.7) 15/174 (8.6)
t(14;16)   4/181 (2.2)   5/174 (2.9)
Median time since initial diagnosis of multiple myeloma 3.87 (0.7–20.7) 3.72 (0.6–18.6)
(range) — yr
Number of previous lines of therapy — no. (%)
1 122 (48.6) 113 (45.7)
2   70 (27.9)   74 (30.0)
3   37 (14.7)   32 (13.0)
>3 22 (8.8)   28 (11.3)
Median no. of previous lines of therapy (range)   2 (1–9)    2 (1–10)
Previous autologous stem-cell transplantation — no. (%) 156 (62.2) 149 (60.3)
Previous alkylating agent therapy — no. (%) 240 (95.6) 224 (90.7)
Previous proteasome inhibitor therapy — no. (%) 169 (67.3) 172 (69.6)
Previous immunomodulatory drug therapy — no. (%) 179 (71.3) 198 (80.2)
Previous proteasome inhibitor + immunomodulatory drug 112 (44.6) 129 (52.2)
therapy — no. (%)
Disease refractory to last line of therapy — no. (%)   76 (30.3)   85 (34.4)

* There were no significant between-group differences in the characteristics evaluated at baseline, with the exception of
previous immunomodulatory drug therapy (P = 0.02). The intention-to-treat population was defined as all patients who
underwent randomization.
† International Staging System (ISS) disease staging was derived on the basis of the combination of serum β2-microglobulin
and albumin. The ISS consists of three stages: stage I, serum β2-microglobulin level lower than 3.5 mg per liter (300 nmol
per liter) and albumin level 3.5 g per deciliter or higher; stage II, neither stage I nor III; and stage III, serum β2-micro­
globulin 5.5 mg per liter or higher (470 nmol per liter). Higher stages indicate more severe disease.
‡ Complete cytogenetic data were not available at the data-cutoff date. High-risk patients could be counted in more than
one subcategory.

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 Dar atumumab, Bortezomib, and Dexamethasone for Multiple Myeloma

in the daratumumab group and 104 (43.9%) in trol group with respect to very good partial re-
the control group had discontinued treatment, sponse or better (59.2% vs. 29.1%, P<0.001) and
primarily because of progressive disease (19.3% complete response or better (19.2% vs. 9.0%,
and 25.3%, respectively) and adverse events (7.8% P = 0.001). Similar results were observed in the
and 9.7%, respectively) (Fig. S2 in the Supple- intention-to-treat population (Table S1 in the
mentary Appendix). A total of 79.8% of the pa- Supplementary Appendix). No very good partial
tients in the daratumumab group and 57.4% in responses with positive serum immunofixation
the control group had received the maximum of of IgGκ were reclassified as either complete re-
eight cycles of bortezomib treatment. The me- sponses or stringent complete responses as a
dian relative dose intensity (the proportion of result of additional immunofixation electropho-
administered doses relative to planned doses) resis reflex testing to account for daratumumab.
for bortezomib and dexamethasone was similar Deeper responses (i.e., very good partial responses
in the two treatment groups (86.5% and 93.5% or better) translated into a greater benefit in
for bortezomib in the daratumumab group and progression-free survival in the daratumumab
the control group, respectively, and 98.2% and group than in the control group (Fig. S3 in the
100% for dexamethasone in the two groups, Supplementary Appendix). The median time to
respectively). The median relative dose intensity the first response was 0.9 months in the daratu-
for daratumumab was 99.2%. mumab group and 1.6 months in the control
group, and the median duration of response was
Efficacy longer in the daratumumab group than in the
After a median follow-up period of 7.4 months, control group (not reached [95% CI, 11.5 months
a total of 189 events of disease progression or to not estimable] vs. 7.9 months [95% CI, 6.7 to
death had occurred (64% of the 295 planned 11.3]) (Fig. S4 in the Supplementary Appendix).
events for the final analysis): 67 in the daratu- Prespecified subgroup analyses of progression-
mumab group and 122 in the control group. The free survival confirmed the superiority of dara-
12-month rate of progression-free survival (i.e., tumumab in combination with bortezomib and
the absence of disease progression or death), dexamethasone over bortezomib and dexametha-
which was estimated with the use of the Kaplan– sone alone in all subgroups, including the sub-
Meier method, was 60.7% (95% confidence in- group of patients who had previously received
terval [CI], 51.2 to 69.0) in the daratumumab bortezomib (Fig. 2). In addition, median progres-
group as compared with 26.9% (95% CI, 17.1 to sion-free survival was significantly longer in the
37.5) in the control group. The median progres- daratumumab group than in the control group
sion-free survival was not reached (95% CI, 12.3 among patients with ISS stage I disease (hazard
to not estimable) in the daratumumab group ratio for progression or death with daratumumab
and was 7.2 months (95% CI, 6.2 to 7.9) in the vs. control, 0.25). The rate of progression-free
control group (hazard ratio for disease progres- survival was higher among patients in the dara-
sion or death with daratumumab vs. control, 0.39; tumumab group than among patients in the
95% CI, 0.28 to 0.53; P<0.001, which crossed the control group in the subgroup of patients who
prespecified stopping boundary), which repre- had received one previous line of therapy; the
sented a 61.4% lower risk of progression or death 12-month progression-free survival rate was
in the daratumumab group than in the control 77.5% (95% CI, 65.2 to 86.0) in the daratumumab
group (Fig. 1A). In the time-to-event analysis of group as compared with 29.4% (95% CI, 12.5 to
disease progression, the percentage of patients 48.7) in the control group (hazard ratio for pro-
who were free from disease progression after 12 gression or death, 0.31; 95% CI, 0.18 to 0.52;
months was 65.4% (95% CI, 56.1 to 74.8) in the P<0.001) (Fig. S5 in the Supplementary Appen-
daratumumab group as compared with 28.8% dix). Among patients who had received two or
(95% CI, 17.8 to 39.8) in the control group (haz- three previous lines of therapy, median progres-
ard ratio for disease progression, 0.30; 95% CI, sion-free survival was 9.3 months (95% CI, 7.6 to
0.21 to 0.43; P<0.001) (Fig. 1B). not estimable) in the daratumumab group as
The overall response rate was 82.9% in the compared with 6.5 months (95% CI, 5.7 to 8.1)
daratumumab group and 63.2% in the control in the control group (hazard ratio for progres-
group (P<0.001) (Table 2). Rates were also high- sion or death, 0.52; 95% CI, 0.33 to 0.81; P = 0.004)
er in the daratumumab group than in the con- (Fig. S6 in the Supplementary Appendix).

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 The n e w e ng l a n d j o u r na l of m e dic i n e

A Progression-free Survival Figure 1. Median Progression-free Survival and Median

Daratumumab Control Time to Disease Progression.
Group Group Panel A shows Kaplan–Meier estimates of progression-
(N=251) (N=247)
free survival among patients in the intention-to-treat
Median progression-free NE 7.2
survival (mo)
population, which included all patients who underwent
1.0 randomization. Panel B shows Kaplan–Meier esti‑
mates of disease progression in a time-to-event analy‑
Proportion Surviving without Progression

sis of data from patients in the intention-to-treat popu‑

0.8 lation. The daratumumab group received treatment
with daratumumab, bortezomib, and dexamethasone;
Daratumumab the control group received treatment with bortezomib
0.6 and dexamethasone alone. The interim analysis of me‑
dian progression-free survival was performed after 189
events of disease progression or death had occurred
0.4 (64% of the planned 295 events for the final analysis);
the results of the analysis crossed the prespecified
Hazard ratio for progression or death, stopping boundary. NE denotes not estimable.
0.2 daratumumab vs. control,
Control
0.39 (95% CI, 0.28–0.53), P<0.001

0.0 therapy be offered to patients in the control

0 3 6 9 12 15 group who had disease progression) because the
Months since Randomization prespecified statistical boundary (an alpha level
No. at Risk of 0.0102) for the primary end point of progres-
Daratumumab 251 215 146 56 11 0
group
sion-free survival had been crossed. An addi-
Control group 247 182 106 25 5 0 tional analysis of progression-free survival was
performed, which included data from the time
B Time to Disease Progression of randomization to progression or death while
Daratumumab Control patients were receiving the next line of therapy
Group Group
(N=251) (N=247) (progression-free survival 2 analysis). Because of
Median time to disease NE 7.3 the short follow-up period, median progression-
progression (mo)
1.0 free survival while patients were receiving the
next line of therapy (progression-free survival 2)
Proportion Surviving without Progression

as well as overall survival were not reached in

0.8
either treatment group; 80 events of progression
Daratumumab or death while patients were receiving the next
0.6 line of therapy (31 in the daratumumab group
vs. 49 in the control group; hazard ratio, 0.57;
95% CI, 0.37 to 0.90) and a total of 65 deaths
0.4
during the course of the study (29 in the daratu-
Hazard ratio for progression, mumab group vs. 36 in the control group; haz-
daratumumab vs. control,
0.2 0.30 (95% CI, 0.21–0.43), P<0.001 Control
ard ratio, 0.77; 95% CI, 0.47 to 1.26) were reported
(Fig. S7 and Table S2 in the Supplementary Ap-
pendix). Long-term follow-up is continuing to
0.0
0 3 6 9 12 15
better characterize the effect of daratumumab
Months since Randomization
on these longer-term clinical end points.
No. at Risk
Daratumumab 251 214 145 56 11 0 Safety
group Most patients in the daratumumab group and
Control group 247 181 106 25 5 0
the control group had at least one adverse event
after the start of treatment (98.8% and 95.4%,
On the basis of the results of the interim respectively). The most common adverse events
analysis, the independent data and safety moni- of any grade (occurring in at least 15% of pa-
toring committee recommended that the trial be tients in either treatment group) and the most
unblinded early (and that daratumumab mono- common adverse events of grade 3 or 4 (occur-

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 Dar atumumab, Bortezomib, and Dexamethasone for Multiple Myeloma

Table 2. Summary of Responses among Patients Who Could Be Evaluated for Response.*

Daratumumab Group Control Group

Response Category (N = 240) (N = 234) P Value†
Overall response
No. with response 199 148
Rate — % (95% CI) 82.9 (77.5–87.5) 63.2 (56.7–69.4) <0.001
Best overall response — no. (%)
Complete response or better   46 (19.2) 21 (9.0) 0.001
Complete response   35 (14.6) 16 (6.8)
Stringent complete response‡ 11 (4.6)   5 (2.1)
Very good partial response or better 142 (59.2)   68 (29.1) <0.001
Very good partial response   96 (40.0)   47 (20.1)
Partial response   57 (23.8)   80 (34.2)
Minimal response 10 (4.2) 20 (8.5)
Stable disease   24 (10.0)   47 (20.1)
Progressive disease   5 (2.1) 16 (6.8)
Response could not be evaluated   2 (0.8)   3 (1.3)

* Response was assessed on the basis of International Uniform Criteria Consensus recommendations (details on the cri‑
teria for disease responses are provided in the protocol). The population of patients who could be evaluated for response
included patients who had a confirmed diagnosis of multiple myeloma and measurable disease at baseline or screening.
In addition, patients must have received at least one dose of trial treatment and must have had at least one disease
­assessment after the baseline visit.
† P values were calculated with the use of the Cochran–Mantel–Haenszel chi-square test.
‡ Criteria for a stringent complete response include the criteria for a complete response plus a normal free light-chain ratio
and absence of clonal plasma cells as assessed by immunohistochemical or immunofluorescence analysis or by two-
color-to-four-color flow cytometry.

ring in at least 5% of patients in either treatment group (47.3% vs. 37.6%), although the rate of
group) in the safety population are summarized grade 3 or 4 peripheral sensory neuropathy was
in Table 3. Higher rates of grade 3 or 4 adverse similar in the two groups (4.5% and 6.8%, re-
events were observed in the daratumumab group spectively). The rates of grade 3 or 4 infections
than in the control group (76.1% vs. 62.4%). and infestations were similar in the two groups
Three of the most common grade 3 or 4 adverse (21.4% and 19.0%, respectively), and the rates of
events reported in the daratumumab group and bleeding events of any grade were 7.0% in the
the control group were thrombocytopenia (45.3% daratumumab group and 3.8% in the control
and 32.9%, respectively), anemia (14.4% and group. The rates of secondary primary cancers
16.0%, respectively), and neutropenia (12.8% were 2.5% and 0.4%, respectively; a majority of
and 4.2%, respectively). these cancers had developed within 6 months
With respect to hematologic adverse events, after the initiation of trial treatment and oc-
we observed higher rates in the daratumumab curred in patients who had previous exposure to
group than in the control group of any grade of immunomodulatory drugs and alkylating agents
thrombocytopenia (58.8% vs. 43.9%), neutropenia (details are provided in the Supplementary Ap-
(17.7% vs. 9.3%), and lymphopenia (13.2% vs. pendix).
3.8%), and this trend was also observed for The percentage of patients who discontinued
grade 3 or 4 thrombocytopenia, neutropenia, treatment because of at least one adverse event
and lymphopenia (Table 3). With respect to non- was similar in the daratumumab group and the
hematologic adverse events, the rate of any grade control group (7.4% and 9.3%, respectively). The
of peripheral sensory neuropathy was higher in most common adverse events (occurring in at
the daratumumab group than in the control least 1% of patients in either group) that led to

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 The n e w e ng l a n d j o u r na l of m e dic i n e

Control Daratumumab Control Daratumumab

Subgroup Group Group Group Group Hazard Ratio (95% CI)
no. of progression or median progression-free
death events/total no. survival (mo)
Age
<65 yr 59/125 39/132 7.3 10.3 0.44 (0.28–0.68)
≥65 yr 63/122 28/119 6.7 NE 0.35 (0.22–0.57)
Sex
Male 80/147 38/137 6.3 NE 0.41 (0.27–0.61)
Female 42/100 29/114 7.6 NE 0.38 (0.22–0.64)
ISS disease staging
I 36/96 15/98 8.4 NE 0.25 (0.13–0.48)
II 55/100 26/94 6.2 NE 0.37 (0.23–0.61)
III 31/51 26/59 5.3 8.6 0.55 (0.31–0.98)
No. of previous lines of therapy
1 51/113 20/122 7.5 NE 0.31 (0.18–0.52)
2 37/74 22/70 6.5 10.3 0.50 (0.28–0.89)
3 17/32 16/37 6.6 8.8 0.66 (0.31–1.41)
>3 17/28 9/22 5.4 8.4 0.48 (0.20–1.16)
Previous autologous stem-cell transplantation
Yes 74/149 42/156 6.7 NE 0.38 (0.26–0.57)
No 48/98 25/95 7.2 NE 0.34 (0.19–0.59)
Previous bortezomib therapy
Yes 81/164 52/162 6.7 12.3 0.46 (0.32–0.66)
No 41/83 15/89 7.5 NE 0.25 (0.13–0.47)
Previous therapy with immunomodulatory agent
Yes 101/198 51/179 6.6 12.3 0.38 (0.27–0.55)
No 21/49 16/72 9.1 NE 0.50 (0.24–1.04)
Disease refractory to previous therapy with
immunomodulatory agent
Yes 58/97 34/83 5.4 9.2 0.50 (0.31–0.80)
No 43/101 17/96 7.4 12.3 0.32 (0.18–0.59)
Disease refractory to last line of previous therapy
Yes 51/85 30/76 5.0 9.3 0.42 (0.25–0.70)
No 71/162 37/175 7.9 12.3 0.38 (0.25–0.58)
Type of multiple myeloma
IgG 70/138 39/125 6.6 12.3 0.38 (0.25–0.59)
Non-IgG 28/58 12/61 7.3 NE 0.33 (0.16–0.70)
Baseline creatinine clearance
>60 ml/min 82/163 45/186 7.2 NE 0.30 (0.20–0.44)
≤60 ml/min 40/70 19/57 6.5 NE 0.55 (0.30–1.02)
0.1 1.0 10.0

Daratumumab Better Control Better

Figure 2. Prespecified Subgroup Analysis of Progression-free Survival.

Results are shown of an analysis of progression-free survival in prespecified subgroups of the intention-to-treat population that were de‑
fined according to baseline characteristics. No significant interaction was observed between the treatment groups with regard to any of
the subgroups. The International Staging System (ISS) consists of three stages, with higher stages indicating more severe disease: stage I,
serum β2-microglobulin level lower than 3.5 mg per liter (300 nmol per liter) and albumin level 3.5 g per deciliter or higher; stage II, neither
stage I nor III; and stage III, serum β2-microglobulin 5.5 mg per liter or higher (470 nmol per liter). The subgroup analysis of disease that
was refractory to immunomodulatory agents was performed on data from patients who had previously received an immunomodulatory
agent. The subgroup analysis of the type of multiple myeloma was performed on data from patients who had measurable disease in serum.
Baseline creatinine clearance was used to assess renal function. To convert the values for creatinine clearance to milliliters per second,
multiply by 0.01667.

treatment discontinuation were peripheral sen- Adverse events that led to death were reported in
sory neuropathy (0.4% and 2.5%, respectively) 13 patients (5.3%) in the daratumumab group
and pneumonia (1.2% and 0.4%, respectively). and in 14 patients (5.9%) in the control group;

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 Dar atumumab, Bortezomib, and Dexamethasone for Multiple Myeloma

Table 3. Most Common Adverse Events in the Safety Population.*

Daratumumab Group Control Group

Event (N = 243) (N = 237)

Any Grade Grade 3 or 4 Any Grade Grade 3 or 4

number of patients (percent)

Common hematologic adverse event
Thrombocytopenia 143 (58.8) 110 (45.3) 104 (43.9)   78 (32.9)
Anemia   64 (26.3)   35 (14.4)   74 (31.2)   38 (16.0)
Neutropenia   43 (17.7)   31 (12.8) 22 (9.3) 10 (4.2)
Lymphopenia   32 (13.2) 23 (9.5)   9 (3.8)   6 (2.5)
Common nonhematologic adverse events
Peripheral sensory neuropathy 115 (47.3) 11 (4.5)   89 (37.6) 16 (6.8)
Diarrhea   77 (31.7)   9 (3.7)   53 (22.4)   3 (1.3)
Upper respiratory tract infection   60 (24.7)   4 (1.6)   43 (18.1)   2 (0.8)
Fatigue   52 (21.4) 11 (4.5)   58 (24.5)   8 (3.4)
Cough   58 (23.9) 0   30 (12.7) 0
Constipation   48 (19.8) 0   37 (15.6)   2 (0.8)
Dyspnea   45 (18.5)   9 (3.7)   21 (8.9)   2 (0.8)
Insomnia   41 (16.9) 0   35 (14.8)   3 (1.3)
Peripheral edema   40 (16.5)   1 (0.4) 19 (8.0) 0
Asthenia 21 (8.6)   2 (0.8)   37 (15.6)   5 (2.1)
Pyrexia   38 (15.6)   3 (1.2)   27 (11.4)   3 (1.3)
Pneumonia   29 (11.9) 20 (8.2)   28 (11.8) 23 (9.7)
Hypertension 21 (8.6) 16 (6.6)   8 (3.4)   2 (0.8)
Secondary primary cancer†   6 (2.5) NA   1 (0.4) NA

* The safety population included all patients who received at least one dose of trial treatment. Adverse events of any grade
that were reported in at least 15% of patients in either treatment group and grade 3 or 4 adverse events that were re‑
ported in at least 5% of patients in either treatment group are listed. NA denotes not applicable.
† The presence of a secondary primary cancer was prespecified in the statistical analysis plan as an adverse event of clini‑
cal interest. The other adverse events of clinical interest included infusion-related reactions, infections or infestations,
peripheral neuropathies, and cardiac disorders.

these events were mainly a result of the general ported in 45.3% of the patients; for 98.2% of
deterioration of the patients’ physical health these patients, the events occurred during the
(0.4% and 1.3%, respectively). Other adverse first infusion. Infusion-related reactions were
events leading to death that were reported in mostly limited to grade 1 or 2 events; at least
2 or more patients in either treatment group one grade 3 event was reported in 21 patients
were pneumonia (1 patient in the daratumumab (8.6%), and no grade 4 events were reported. The
group and 2 in the control group), ischemic most common adverse event terms that were
stroke (2 patients and no patients, respectively), documented by the investigator as infusion-­
and respiratory failure (2 patients and no pa- related reactions were dyspnea (10.7%), broncho-
tients, respectively). No cases of immunogenicity spasm (9.1%), and cough (7.0%) (Table S3 in the
were reported in the daratumumab group, and Supplementary Appendix). Two patients discon-
no cases of hemolysis were reported in either tinued treatment because of infusion-related re-
treatment group. actions: bronchospasm in 1 patient and broncho-
Infusion-related reactions of any grade that spasm, laryngeal edema, and rash in the other
were associated with daratumumab were re- patient.

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 The n e w e ng l a n d j o u r na l of m e dic i n e

Discussion in this patient population,28 including carfilzo-

mib plus dexamethasone (median progression-
Among patients with relapsed or relapsed and free survival of 18.7 months, vs. 9.4 months in
refractory multiple myeloma, the combination of the control group, with a hazard ratio of 0.53
daratumumab, bortezomib, and dexamethasone and an objective response rate of 77%)29 and
resulted in significantly longer progression-free panobinostat in combination with bortezomib
survival than bortezomib and dexamethasone and dexamethasone, which resulted in a hazard
alone, with a risk of disease progression or ratio of 0.63 (median progression-free survival
death that was 61.4% lower in the daratumumab of 12.0 months, vs. 8.1 months in the control
group than in the control group. The benefit was group, with an overall response rate of 61%).30
maintained across all subgroups, including the Recently, a phase 2 trial of elotuzumab in com-
subgroups of patients with ISS stage III disease, bination with bortezomib and dexamethasone
those who had received two or three previous versus bortezomib and dexamethasone alone
lines of therapy, those who had previously re- showed a median progression-free survival of
ceived immunomodulatory drugs, and those who 9.7 months versus 6.9 months (hazard ratio for
had previously received bortezomib. In the dara- progression or death, 0.72).31
tumumab group, deep, rapid, and durable re- The addition of daratumumab to bortezomib
sponses were reported, with the rates of very and dexamethasone was associated with a higher
good partial response or better and complete incidence of adverse events, primarily thrombo-
response or better approximately double those in cytopenia and infusion-related reactions. Grade 3
the control group. The median duration of re- or 4 hematologic adverse events were more com-
sponse and time to subsequent antimyeloma mon in the daratumumab group than in the
therapy were shorter in the control group than control group; however, the rates of grade 3 or 4
in the daratumumab group, which suggests that infections as well as the rates of adverse events
patients who received daratumumab were also that led to treatment discontinuation were simi-
able to maintain longer periods of remission. lar in the two groups. The rate of infusion-related
Overall, these findings are consistent with ob- reactions was expected and was consistent with
servations from phase 1 and phase 1/2 trials that findings from previous trials of daratumumab
showed an additive benefit of daratumumab in administered either as monotherapy19,32 or as
combination with proteasome inhibitors or im- combination therapy.15,24
munomodulatory drugs (pomalidomide or lena­ In this prespecified interim analysis, no analy-
lidomide) and dexamethasone14,15,24 and high- ses according to baseline cytogenetic features
light the advantages of combination therapy.25 were possible because the evaluation of these
The benefit of combining antibodies that data is ongoing. In addition, because of the rela-
target CD38 with proteasome inhibition may be tively short follow-up period, we could not assess
explained in part by enhanced direct cytotoxicity whether the addition of daratumumab to bortezo-
on myeloma cells, an effect that was shown in mib and dexamethasone confers an overall sur-
vitro in preclinical studies.26,27 The direct and vival benefit. The final analysis of overall sur-
indirect mechanisms of action of daratumumab vival will be confounded by the treatment effects
in combination with bortezomib and dexameth- of daratumumab in the control group because
asone, as well as the recently identified role patients in the control group were allowed to
of daratumumab in the inhibition of regulatory receive daratumumab after the interim analysis
T cells,11 may have multiplicative effects. was completed.
Cross-trial comparisons are often confounded In summary, among patients with relapsed or
by differences in design, methods, and patient relapsed and refractory multiple myeloma, dara-
population. However, our trial, in which the tumumab in combination with bortezomib and
hazard ratio for progression or death with dara- dexamethasone resulted in significantly longer
tumumab versus control was 0.39, shows the progression-free survival than bortezomib and
benefit of the triplet regimen with daratumumab dexamethasone alone. The addition of daratu-
over other proteasome-inhibitor–based combina- mumab was associated with infusion-related
tion therapies without immunomodulatory drugs reactions and higher rates of thrombocytopenia

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 Dar atumumab, Bortezomib, and Dexamethasone for Multiple Myeloma

and neutropenia. The infusion-related reactions them; the members of the data and safety monitoring commit-
tee (Amrita Krishnan, M.D. [chair]; Helmut Ostermann, M.D.;
occurred primarily during the first infusion. and Yu Shyr, Ph.D. [statistician]); representatives of the spon-
Supported by Janssen Research and Development. sor who were involved in data collection and analyses (in particu-
Disclosure forms provided by the authors are available with lar, Brian Berkey, Chris Velas, Nele Boeykens, Dorien Druyts,
the full text of this article at NEJM.org. and Ward Lemaire); and Jason Jung, Ph.D., and Christopher
We thank the patients who volunteered to participate in this Jones, Ph.D., of MedErgy, for editorial assistance in the devel-
trial and the staff members at the trial sites who cared for opment of an earlier draft of the manuscript.

Appendix
The authors’ affiliations are as follows: the Department of Hematology, University of Turin, Turin, Italy (A.P.); the Division of Hematol-
ogy and Medical Oncology, Mayo Clinic Florida, Jacksonville (A.C.-K.); Universitaetsklinikum Tuebingen der Eberhard-Karls-Universi-
taet, Abteilung fuer Innere Medizin II, Tuebingen (K.W.), and University Medical Center of the Johannes Gutenberg-University, Third
Department of Medicine, Mainz (M.M.) — both in Germany; Winship Cancer Institute, Emory University, Atlanta (A.K.N.); the Depart-
ment of Hematology and Stem Cell Transplantation, St. László Hospital, Semmelweis University, Budapest, Hungary (T.M.); Ankara
University, Department of Hematology, Ankara, Turkey (M.B.); Clinical Department of Hematology, 1st Medical Department, Charles
University in Prague, Prague, Czech Republic (I.S.); Irmandade Da Santa Casa De Misericordia De São Paulo, São Paulo (V.H.); Univer-
sity Hospital of Salamanca–Instituto de Investigación Biomédica de Salamanca, Salamanca, Spain (M.V.M.); Weill Cornell Medical
College, New York (T.M.M.); Janssen Research and Development, Spring House, PA (M.Q., X.Q., T.A.); Janssen Research and Develop-
ment, Raritan, NJ (J.S., H.A.); Janssen Research and Development, Beerse, Belgium (W.D.); Malignant Haematology and Stem Cell
Transplantation Service, Alfred Health–Monash University, Melbourne, VIC, Australia (A.S.); and the Department of Hematology,
Erasmus MC, Rotterdam, the Netherlands (P.S.).

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