The purpose of this study was to evaluate the effects of daratumumab with dexamethasone (DaraD) in subjects with relapsed or refractory multiple myeloma and renal impairment.

This was a multicenter, single arm, open-label phase 2 study. 38 subjects were enrolled to receive daratumumab and dexamethasone. Treatment cycles had a duration of 28 days. Subjects received treatment until either disease progression, death, unacceptable toxicity or for a maximum of 30 months. Drug administration and follow-up visits occurred more frequently for early cycles (weekly for the first 8 weeks, every two weeks for weeks 9-24 and then every 4 weeks). Disease evaluations occurred monthly and involved mainly measurements of myeloma proteins. Other assessments included bone marrow examinations, skeletal surveys, assessment of extramedullary plasmacytomas, and measurements of serum calcium corrected for albumin, and β2- microglobulin and albumin.

Inclusion Criteria:

1. Males and females at least 18 years of age.

2. Voluntary written informed consent before performance of any study-related procedure.

3. Subject must have documented multiple myeloma as defined by the criteria below:

   Monoclonal plasma cells in the bone marrow ≥ 10% or presence of a biopsy proven plasmacytoma.

   AND any or more of the following myeloma defining events:

   • Evidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically:

     • Hypercalcaemia: serum calcium >0.25 mmol/L (>1 mg/dL) higher than the upper limit of normal or >2.75 mmol/L (>11 mg/dL)
     • Renal insufficiency: creatinine clearance <40 mL per min or serum creatinine >177 μmol/L (>2 mg/dL)
     • Anaemia: haemoglobin value of >20 g/L below the lower limit of normal, or a haemoglobin value <100 g/L
     • Bone lesions: one or more osteolytic lesions on skeletal radiography, CT, or PETCT

   • Any one or more of the following biomarkers of malignancy:

     • Clonal bone marrow plasma cell percentage ≥60%
     • Involved:uninvolved serum free light chain ratio ≥100
     • >1 focal lesions on MRI studies

4. Prior treatment with at least two lines of treatment that included both bortezomib- and lenalidomide based regimens.

5. Documented evidence of progressive disease (PD) as defined by the modified IMWG criteria on or after the last regimen if the patient responded to previous regimens.

6. Subjects must have measurable disease as defined by any of the following:

   • Serum monoclonal paraprotein (M-protein) level ≥ 1.0 g/dL (except for IgA subtype: ≥ 0.5 g/dL) or urine M-protein level ≥ 200 mg/24 hours; or
   • Light chain multiple myeloma: Serum immunoglobulin free light chain ≥ 10 mg/dL (100 mg/L) and abnormal serum immunoglobulin kappa lambda free-light-chain ratio.

7. Renal impairment defined as eGFR < 30 ml/min/1.73 m2 (calculated with the CKD-EPI formula) or in need for dialysis. Patients who undergo intraperitoneal dialysis may also be included.

8. Eastern Cooperative Oncology Group (ECOG) performance status score of ≤ 2.

9. Willingness and ability to participate in study procedures.

10. Reproductive Status

    1. Women of childbearing potential (WOCBP) must have two negative serum or urine pregnancy tests, one 10-14 days prior to start of the study drug and one within 24 hours prior to the start of study drug. Females are not of reproductive potential if they have been in natural menopause for at least 24 consecutive months, or have had a hysterectomy and/or bilateral oophorectomy.
    2. Women must not be breastfeeding.
    3. WOCBP must agree to follow instructions for methods of contraception for 4 weeks before the start of treatment with study drugs, for the duration of treatment with study drugs, and for 3 months after cessation of study treatment.
    4. Males who are sexually active must always use a latex or synthetic condom during any sexual contact with females of reproductive potential, even if they have undergone a successful vasectomy. They must also agree to follow instructions for methods of contraception for 4 weeks before the start of treatment with study drugs, for the duration of treatment with study drugs, and for a total of 3 months post-treatment completion.
    5. Male patients must not donate sperm for up to 90 days post treatment completion.
    6. Female patients must not donate eggs for up to 90 days post treatment completion.
    7. Azoospermic males and WOCBP who are not heterosexually active are exempt from contraceptive requirements. However, WOCBP will still undergo pregnancy testing as described in this section.

Exclusion Criteria:

1. Previous therapy with daratumumab or other anti-CD38 therapy.

2. Anti-myeloma treatment within 2 weeks prior to Cycle 1, Day 1.

3. Cumulative dose of corticosteroids greater than or equal to the equivalent of 140mg prednisone for ≥ 4 days or a dose of corticosteroids greater than or equal to the equivalent of 40 mg/day of dexamethasone for ≥ 4 days within the 2-week period prior to Cycle 1, Day 1.

4. Previous allogenic stem cell transplant; or Autologous Stem Cell Transplantation (ASCT) within 12 weeks before Cycle 1, Day 1.

5. Clinical signs of meningeal involvement of multiple myeloma.

6. Subject has either of the following:

   1. Chronic obstructive pulmonary disease (COPD) with a Forced Expiratory Volume in 1 second (FEV1) <50% of predicted normal. Note that FEV1 testing is required for subjects suspected of having COPD and subjects must be excluded if FEV1 <50% of predicted normal.
   2. Known moderate or severe persistent asthma (see Appendix 7), within 2 years from C1D1, or currently has uncontrolled asthma of any classification. Note that subjects who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed to participate in the study.

7. Clinically significant cardiac disease, including:

   1. Myocardial infarction within 1 year, or unstable or uncontrolled condition (e.g., unstable angina, congestive heart failure, New York Heart Association Class III-IV).
   2. Uncontrolled cardiac arrhythmia (CTCAE Grade 2 or higher) (atrial fibrillation with controlled ventricular rate is allowed) or clinically significant ECG abnormalities.
   3. ECG showing a baseline QT interval as corrected by Fridericia's formula (QTcF) >470 msec.

8. Any of the following:

   1. Known active hepatitis A
   2. Patient is seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]). Subjects with resolved infection (ie, subjects who are HBsAg negative but positive for antibodies to hepatitis B core antigen [anti-HBc] and/or antibodies to hepatitis B surface antigen [anti-HBs]) must be screened using real-time polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) DNA levels. Those who are PCR positive will be excluded. EXCEPTION: Subjects with serologic findings suggestive of HBV vaccination (anti-HBs positivity as the only serologic marker) AND a known history of prior HBV vaccination, do not need to be tested for HBV DNA by PCR.
   3. Known to be seropositive for hepatitis C (except in the setting of a sustained virologic response [SVR], defined as aviremia at least 12 weeks after completion of antiviral therapy).

9. Known to be seropositive for human immunodeficiency virus (HIV).

10. Amyloidosis, or any prior or concurrent malignancy, except for the following:

    1. Adequately treated basal cell or squamous cell skin cancer.
    2. Any cancer (other than in-situ) from which the subject has been disease-free for 3 years prior to study entry.

11. Any of the following laboratory test results during screening:

    1. Absolute neutrophil count ≤ 1.0 × 10^9/L;
    2. Hemoglobin level ≤ 7.5 g/dL (≤ 4.65 mmol/L);
    3. Platelet count < 75 × 10^9/L in patients in whom < 50% of bone marrow nucleated cells are plasma cells and < 50x10^9/L in patients in whom more than 50% of bone marrow nucleated cells are plasma cells;
    4. Alanine aminotransferase level ≥ 2.5 times the upper limit of normal (ULN);

12. Pregnant or nursing women.

3 years.

The incidence of AEs was tabulated by the Medical Dictionary for Regulatory Activities (MedDRA) System Organ Class (SOC) and Preferred Term (PT), overall and by maximum Common Terminology Criteria for Adverse Events (CTCAE) grade.

None reported.