Clinical Scorecard: A Phase 2 Study of Denosumab in Multiple Myeloma Patients With Severe Renal Impairment

At a Glance

Key Highlights

• Twenty-two patients received denosumab 120 mg subcutaneously every four weeks for up to 12 cycles; median follow-up was 2.8 years.
• At three months, median serum CTX decreased by 73% from baseline (n=18; p=0.0002).
• One-year skeletal-related-event-free survival was 85.4% (95% CI, 71.4–100%); three patients experienced skeletal-related events.
• Hypocalcemia and infection each occurred in 77.3% of patients across grades. Hypocalcemia was grade 3 or higher in 31.8%; four patients received intravenous calcium.
• The study was limited by small enrollment and closed early because of slow accrual.

Guideline-Based Recommendations

Diagnosis

• Eligibility required creatinine clearance <30 mL/min, determined using either the CKD-EPI or Cockcroft-Gault equation according to local practice.
• Before treatment, participants were required to have a 25-OH vitamin D concentration of at least 30 ng/mL.

Management

• The study administered denosumab 120 mg subcutaneously every four weeks for 12 cycles.
• All patients received calcium supplementation, such as calcium citrate 2000 mg daily, and vitamin D 1000 IU daily.
• No denosumab dose reductions occurred. Treatment holds were reported for hypocalcemia, dental concerns or osteonecrosis of the jaw, pneumonia, and other reasons; patients held for hypocalcemia restarted on the same schedule after interruption.

Monitoring & Follow-up

• The primary endpoint was change in serum CTX from baseline to three months.
• Hypocalcemia was frequent despite supplementation and adequate baseline 25-OH vitamin D; four patients required intravenous calcium.
• Osteonecrosis of the jaw or dental concerns led to treatment holds in three patients.

Risks

• Grade ≥3 hypocalcemia occurred in 31.8% of participants; dialysis patients had a higher observed proportion of grade ≥2 hypocalcemia than those not receiving dialysis (77.8% vs 38.5%; p=0.099).
• Suspected grade 2 osteonecrosis of the jaw occurred in two patients.
• Grade ≥3 neutropenia occurred in 31.8% and infection in 22.7%; the authors noted these events were likely attributable to concomitant multiple myeloma therapy.
• The study was small, closed early, and included both newly diagnosed and relapsed disease.

Patient & Prescribing Data

Of 24 enrolled adults, 22 received denosumab and were included in outcome analyses. Median age was 68 years, median creatinine clearance was 23.8 mL/min, 41% were receiving dialysis, and 55% had newly diagnosed multiple myeloma.

Patients received a median of 11 doses. Hypocalcemia led to seven treatment holds; the seven patients restarted at the same schedule without dose reduction after a mean interruption of 64 ± 14 days. One patient later had another hypocalcemia-related hold lasting 84 days.

Clinical Best Practices

• Study protocol: all participants received calcium and vitamin D supplementation and were required to have baseline 25-OH vitamin D ≥30 ng/mL.
• Observed safety finding: hypocalcemia occurred despite supplementation; some patients received intravenous calcium or had treatment interrupted.
• Observed subgroup finding: grade ≥2 hypocalcemia occurred in 77.8% of dialysis patients and 38.5% of patients not receiving dialysis; the comparison was not statistically significant (p=0.099).
• Dental concerns or osteonecrosis of the jaw prompted treatment holds in three patients.

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