International Journal of Myeloma 6(3): 13–16, 2016
©Japanese Society of Myeloma

ORIGINAL

Safety and efficacy of denosumab in patients with multiple myeloma
Morio MATSUMOTO1, Yuri MIYAZAWA1, Hiroko KOYA1, Yohei OSAKI1,Atsushi ISODA1, Morio SAWAMURA1 and Hirokazu MURAKAMI2
The safety and efficacy of denosumab were retrospectively assessed in patients with multiple myeloma. This study
included 25 patients treated with denosumab from May 2012 to March 2014. No skeletal-related events (SREs) dueto multiple myeloma occurred. Urine N-telopeptide/creatinine decreased in all of 5 assessed patients 1 month after
denosumab treatment, and urine deoxypyridinoline/creatinine decreased in 4 of 5 assessed patients. Osteonecrosisof the jaw was not observed. Hypocalcemia developed in 11 patients (44%). One patient with Grade 4 hypocalcemia
complained of numbness of the extremities; however, the other patients had no complaint. On univariate analysis,
the incidence of hypocalcemia was significantly higher in patients with than in those without renal insufficiency(p = 0.007) and patients with high than in those with low β-2-microglobulin (p = 0.017). On multivariate analysis,
renal insufficiency was a risk factor for the development of hypocalcemia (p = 0.01). The patients who had prophylactic Ca and vitamin D3 supplementation had a significantly lower incidence of hypocalcemia than the others(p = 0.047). In conclusion, treatment with denosumab is safe and effective to prevent SREs in patients with multiple
myeloma. Prophylaxis for hypocalcemia with calcium and/or vitamin D3 supplementation is necessary, especially inpatients with renal insufficiency.
Key words:

multiple myeloma, denosumab, RANK ligand, hypocalcemia

Introduction

in all patients. Renal toxicity may limit the dose and use of
these agents in myeloma patients with renal dysfunction 7).

Bone disease is one of the clinical features of multiple

Denosumab is a fully monoclonal antibody to RANKL that­myeloma and has a significant negative impact on both sur-has high affinity and specificity for RANKL, and it has beenvival and quality of life in patients with multiple myeloma.

­reported to be effective in patients with bone disease induced

Bone disease of myeloma is the result of signals that promoteby many malignancies, including multiple myeloma 8,9). The

bone resorption and inhibit bone formation. In particular,

safety and efficacy of denosumab were retrospectively assessed­osteoclastic activity is magnified by cell to cell signals mediatedin Japanese patients with multiple myeloma.

by RANK (receptor activator of NF-kappa B)/RANKL (RANKligand) and negatively regulated by osteoprotegerin 1–6).
­Patients and Methods­Despite the availability of bisphosphonates such as zoledronic
acid for the treatment of multiple myeloma bone disease, anThis study included 25 myeloma patients treated with deno-unmet medical need exists for a more convenient, effective,

sumab for their bone disease from May 2012 to March 2014

and safe therapy. Parenteral bisphosphonates must be ad­in order to evaluate the safety and efficacy of denosumab.

ministered by intravenous infusion, and they are not effective

The diagnosis of multiple myeloma was made according to thecriteria of the International Myeloma Working Group 10).
Patients received subcutaneous denosumab 120 mg every 4

Received: May 2, 2016, accepted: August 1, 2016
1
Department of Hematology, National Hospital Organization
Shibukawa Medical Center, Shibukawa, Japan2Gunma University Graduate School of Health Sciences, Maebashi,Japanweeks. Since the launch on April 2012, denosumab has been

Corresponding author: Morio MATSUMOTO
National Hospital Organization Shibukawa Medical Center, 383
Shiroi, Shibukawa, Gunma 377-0280, Japan
E-mail: morioma@sbmc.hosp.go.jp

Agency (PMDA) instructed the Daiichi-Sankyo CO., LTD to dis-administered to about 7,300 patients as of August 2012, and32 cases of serious hypocalcemia, including 2 deaths, havebeen reported in Japan. The Ministry of Health, Labour andWelfare (MHLW)/ Pharmaceuticals and Medical Devices
tribute the Dear Healthcare Professional Letter of Rapid Safety
Communication (“Blue Letter”) on September 2012 (https://www.pmda.go.jp/files/000148439.pdf ). This letter highly rec-International Journal of Myeloma

vol. 6 no. 3 (2016)13

MATSUMOTO et al.

ommends supplemental calcium and vitamin D administration­immunoglobulin subtypes were: IgG, 14 patients (56%); IgA, 7for all patients unless the serum calcium level is high. Accord-patients (28%); and light chain only, 4 patients (16%). Perfor-

ing to this recommendation, 12 patients diagnosed after Sep-mance statuses were: 0, 9 patients; 1, 11 patients; 2, 2 patients;

tember 2012 received prophylaxis of calcium and vitamin D3.

and 3, 3 patients. Clinical stages stratified by the Durie &The following data were collected from medical records: SREs,

Salmon staging system at diagnosis were: stage I, 4 patients

physical examinations, performance status, vital signs, con-(16%); II, 4 patients (16%); and III, 17 patients (47%). ISS stages

comitant medications, hematology, and serum chemistry. In 5

were: 1, 6 patients (24%); 2, 9 patients (36%); and 3, 10 patientspatients, bone turnover markers, including urine N-telopeptide/(40%). There were 23 (92%) patients with a bone scale scorecreatinine (uNTx/uCr), urine deoxypyridinoline/creatinine (uDPD/

over 2. The numbers of patients with anemia (Hb <10 g/dL),uCr), serum bone-specific ALP (BSAP), osteocalcin (OC), andrenal dysfunction (creatinine clearance <60 mL/min), and highserum albumin-adjusted calcium, were assessed at the time ofbeta-2-microglobulin (>3.5 mg/L) were 18 (72%), 8 (32%), andinitiation of denosumab and 1 month after the start of therapy.

9 (36%), respectively. The number of patients previously

Adverse events were evaluated according to CTCAE version 5.

treated with bisphosphonate was 15 (60%).

Univariate and multivariate analyses of the risk factors for

The duration of treatment with denosumab was 3–22

hypocalcemia were performed using Fisher’s exact test andmonths (median 12 months). The anti-myeloma therapies

logistic regression analysis.

that were administered with denosumab were a bortezomibbased regimen (11 patients, 44%), a lenalidomide-based

Results

regimen (10 patients, 40%), and a thalidomide-based regimen(1 patient, 4%), respectively. Three patients (12%) received noPatient characteristics

anti-myeloma therapy.

The characteristics of the 25 patients are shown in Table 1;
16 (64%) were newly-diagnosed patients, and 9 (36%) wereEfficacy

relapsed patients. The median age was 65 years (range 46–85

No SREs due to multiple myeloma occurred. Denosumabyears), and the male/female ratio was 0.67 (10/15). The

was discontinued in 5 patients because of disease progression
or death (3 patients), patient’s preference (1 patient), and an
adverse event (hypocalcemia, 1 patient).
Of the bone resorption markers, uNTx/uCr decreased in 5Table 1. Patient characteristics n = 25
newly-diagnosed/ relaplsed patientsMedian age (range), years
MalePS (0:1:2:3:4)
Immunoglobulin subtype
IgG
IgA
Light chain only
Durie & Salmon stage at diagnosis
IIIIIIISS stage at diagnosis
123
Bone scale >1Anemia (Hb <10 g/dL)
Renal dysfunction (CCr <60)
Beta-2-microglobulin >3.5
Previous bisphosphonate treatment
Anti-myeloma therapy
Bortezomib-based regimen
Lenalidomide-based regimen
Thalidomide-based regimen
None

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International Journal of Myeloma

16/9 (64%/36%)
65 (46–85)
10 (40%)
9:11:2:3:0

vol. 6 no. 3 (2016)

14 (56%)7 (28%)
4 (16%)

patients 1 month after denosumab treatment, uDPD/uCr andBSAP decreased in 4 patients, and OC decreased in 3 patients(Fig. 1).
Adverse events
Osteonecrosis of the jaw due to denosumab was notobserved in this study. Hypocalcemia developed in 11 patients(44%). Grades 1, 2, 3, and 4 hypocalcemia were observed in 8

4 (16%)
4 (16%)
17 (47%)6 (24%)
9 (36%)
10 (40%)23 (92%)18 (72%)8 (32%)
9 (36%)
15 (60%)11 (44%)10 (40%)1 (4%)
3 (12%)

patients, 2 patients, 0 patients, and 1 patient, respectively. The
patient with Grade 4 hypocalcemia was only one who had
severe renal impairment (creatinine clearance <30 mL/min),and complained of numbness of the extremities; however, theother patients had no complaints.
On univariate analysis, the incidence of hypocalcemia wassignificantly higher in patients with than in those without
renal insufficiency (p = 0.007) and patients with high than inthose with low β-2-microglobulin (p = 0.017). On multivariate
analysis, renal insufficiency was the only risk factor for thedevelopment of hypocalcemia (p = 0.01). The patients who
had prophylactic Ca and vitamin D3 supplementation had asignificantly lower incidence of hypocalcemia than the others(p = 0.047) (Table 2). In patients with normal creatinine clearance (≥60 mL/min), 2 of 6 patients (33.3%), who did notSafety and efficacy of denosumab in patients with multiple myeloma

Figure 1. Bone turnover markers, including urine N-telopeptide/creatinine (uNTx/uCr), urine deoxypyridinoline/creatinine (uDPD/uCr), serumbone-specific ALP (BSAP), and osteocalcin (OC).

Table 2.

Risk factors of hypocalcemia
hypocalcemia

Univariate analysis

Multivariate analysis–+p value<65≥657756NSNSmalefemale

6847NS

NS

Previous bisphosphonate treatment–+8674NSNSProphylaxis with Ca/Vitamine D3–+410830.047

NSCreatinine clearance

<60
≥60

113740.007

p = 0.01<10 g/dL≥10 g/dL

122

65NSNS

<3.5
≥3.5

122

470.017

NSAgeGender

HbBeta-2-microglobulin
NS: not significant

received prophylactic Ca and vitamin D3 supplementation,

Discussion

showed hypocalcemia, but only 2 of 11 patients (18.2%), whoreceived prophylaxis, showed hypocalcemia. Four patients

Denosumab (Ranmark®, Daiichi Sankyo Co., LTD, Tokyo,

showed hypocalcemia within one week, and the median timeJapan) was approved as a drug for the treatment of bone

to hypocalcemia was 14 days.

­disease in myeloma patients in April 2014 in Japan, theIn this study, there were no other serious adverse events
due to denosumab, including anaphylaxis and skin infection.

only country in the world; thus, it is very important to assess
its efficacy and safety in myeloma patients.
In this study, no SREs were observed. Fizazi et al. reported

International Journal of Myeloma

vol. 6 no. 3 (2016)15

MATSUMOTO et al.

that the incidence of SREs was 8% over a 25-week treatment
period with denosumab 11). In the present study, uNTx anduDPD, which are bone resorption markers, decreased markedly 1 month after denosumab treatment. According to thesedata, denosumab might be effective to prevent SREs inpatients with multiple myeloma; however, long-term observation is necessary for an accurate evaluation.
The present data showed that hypocalcemia occurred
between 1 week and 2 months after the initiation of denosumab treatment. In 4 cases, hypocalcemia occurred within 1week. It has been reported that single subcutaneous doses ofdenosumab of 1.0 and 3.0 mg/kg demonstrated non-linear
pharmacokinetics, with a maximum serum concentration
between 7 and 14 day 12,13). According to these reports, it issuspected that hypocalcemia will occur within 14 days
because of the maximum serum concentration of denosumab;
thus, careful observation is necessary 2 weeks after the initiation of denosumab treatment.
Block et al. evaluated pharmacokinetics and pharmaco­
dynamics of denosumab in patients with renal function­ranging from normal to severe renal failure requiring dialysis,
and they discussed that this drug might be less nephrotoxic
than bisphosphonate in patients with renal impairment 14). In
the present study, renal function did not deteriorate withdenosumab; however, the frequency of hypocalcemia was sig­
nificantly higher in myeloma patients with renal insufficiency
during denosumab treatment, especially with severe renal
impairment (creatinine clearance <30 mL/min). Okada et al.
assessed the frequency of hypocalcemia in 53 patients treatedwith denosumab and reported that non-administration ofzoledronic acid and creatinine clearance less than 50.0 mL/min
were independent risk factors for denosumab-induced hypocalcemia 15). According to this report and the present study,
careful observation of serum Ca levels is necessary in myeloma
patients with renal insufficiency. The present study showedthat calcium and/or vitamin D3 supplementation is useful toprevent hypocalcemia in patients with normal renal functionlike patients with renal insufficiency, as previously reported 16).
In conclusion, treatment with denosumab is safe and­effective to prevent SREs in Japanese patients with multiple
myeloma. Prophylaxis for hypocalcemia with calcium and/or
vitamin D3 supplementation is necessary, especially in patientswith renal insufficiency.

Conflict of Interest
The authors declare no conflict of interest.

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International Journal of Myeloma

vol. 6 no. 3 (2016)

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