DARZALEX + DARZALEX FASPRO - Use in Monoclonal Gammopathy of Renal Significance

SUMMARY

• DARZALEX for intravenous (IV) use and DARZALEX FASPRO for subcutaneous (SC) use are not approved by the regulatory agencies for the treatment of patients with monoclonal gammopathy of renal significance (MGRS). Johnson & Johnson does not recommend the use of DARZALEX or DARZALEX FASPRO in a manner that is inconsistent with the approved labeling.
• Kastritis et al (2021)¹ reported on the use of DARZALEX-based therapy in patients with MGRS. The best overall hematologic response was complete response (CR) in 5 patients (22%), very good partial response (VGPR) in 5 patients (22%), and partial response (PR) in 7 patients (30%) for an overall response rate (ORR) of 74%.
• Zand et al (2021)² conducted a phase 2 trial to evaluate the safety and efficacy of DARZALEX in patients with proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) and complement 3 glomerulopathy (C3G) with monoclonal gammopathy (MG). At 6 months, the ORR was 80% with 2 patients achieving a CR, 6 achieving a PR, and 2 having no response.
• Several case reports have been published describing the use of daratumumab in patients with MGRS/PGNMID or MGRS/monoclonal immunoglobulin deposition disease (MIDD). The reports are included in the References section for your information.^3-14

PRODUCT LABELING

• DARZALEX (daratumumab) [Prescribing Information]. Horsham, PA: Janssen Biotech, Inc.; https://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/DARZALEX-pi.pdf
• DARZALEX FASPRO (daratumumab and hyaluronidase-fihj) [Prescribing Information]. Horsham, PA: Janssen Biotech, Inc.; https://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/DARZALEX+Faspro-pi.pdf

clinical data

Retrospective Analysis of DARZALEX in Patient with MGRS

Kastritis et al (2021)¹ reported on the use of DARZALEX-based therapy in patients with MGRS.

Study Design/Methods

• Retrospective analysis of 25 consecutive patients with MGRS, treated in a single center.¹
• DARZALEX was given either as primary therapy (n=12) or as second‐ or further line therapy.¹
• DARZALEX was given as 16 mg/kg IV weekly for the first 2 cycles, every 2 weeks for 4 cycles, and monthly thereafter.¹
  • Pre-medications were given including oral steroids (32 mg methylprednisolone) for 2 days prior to the first infusion of DARZALEX with anti-H1 and montelukast. On the day of infusion, paracetamol, anti-H1 and dexamethasone were given 1 hour prior to DARZALEX infusion.
• Patients were treated between February 2017 and August 2019. During the same period, 20 patients were diagnosed with MGRS who had not received prior therapy, of which 12 received DARZALEX‐based therapy.¹
• The criteria for assessment of activity were the criteria used for amyloid light chain (AL) amyloidosis, since there are no standard hematologic response criteria specific for MGRS.¹
• For renal response assessment, AL amyloidosis criteria were used. Renal response was considered a reduction in proteinuria >30% with no reduction of estimated glomerular filtration rate (eGFR) ≥25%. The improvement of eGFR independently of proteinuria reduction was also reported.¹
• Next‐generation multicolor flow cytometry (NGF) in patients with CR was used to assess minimal residual disease (MRD).¹

Results

Patient Characteristics

• Twenty-two patients had MIDD, of which 20 had light chain deposition disease (LCDD) and 2 had heavy chain deposition disease (HCDD). One patient had PGNMID, and 2 patients had C3 nephropathy.¹
• Twelve patients were previously untreated.¹
• All 13 previously treated patients had received bortezomib-based therapy, and 2 had prior autologous stem cell transplant (ASCT).¹
• Median time from end of last line of therapy to DARZALEX treatment was 6 months.¹
• Fourteen patients received DARZALEX and dexamethasone (D-d), 10 patients received DARZALEX, bortezomib, cyclophosphamide, and dexamethasone (D‐VCd), and 1 patient received DARZALEX, lenalidomide, and dexamethasone (D‐Rd).¹
• Patient characteristics are summarized in Table: Select Patient Characteristics.¹

Efficacy

• Median follow‐up was 14 months.¹
• Patients received a median of 6 cycles of DARZALEX‐based therapy, and treatment was ongoing in 8 patients (32%).¹
• Among 23 patients evaluable by standard criteria, best overall hematologic response was CR in 5 (22%), VGPR in 5 (22%), and PR in 7 (30%) patients for an ORR of 74%.¹
• Two of 5 patients with CR had undetectable MRD. In addition to those patients with measurable disease with serum M‐protein or free light chains (FLCs), 2 patients with detectable clones had undetectable MRD after therapy. Therefore, a total of 4 patients had undetectable clonal disease by NGF after therapy. When including these 2 patients, the ORR was 76% (19/25).¹
• Hematologic responses are summarized in Table: Hematologic Responses to Daratumumab-based Therapy.¹

• All 3 patients on dialysis received DARZALEX monotherapy, and 2 have achieved PR.¹
• Median time to first response was 1 month. Median time to response was similar for D-d and D-VCd.¹

Evaluation of Renal Response

• At 6 months, among 22 patients not on dialysis, 12 (55%) had a reduction of proteinuria by at least 30% and of at least 0.5 g/24 hours, without a reduction of eGFR. Three patients (15%) had improvement in renal function by 25-100%, and 2 patients (10%) had a reduction of eGFR by at least 25%.¹
  • The median 6‐month eGFR was 33.7 mL/min/1.73 m².
• At 12 months, 9/14 evaluable patients (64%) achieved a reduction of proteinuria by at least 30% and of at least 0.5 g/24 hours, without a reduction of eGFR. Three of 14 patients (21%) had a major improvement in their eGFR, and 1 patient progressed to end‐stage renal disease (ESRD) requiring dialysis 19 months after DARZALEX initiation, while he was off therapy and in hematologic VGPR.¹
• Proteinuria reduction was observed more often in patients treated with DARZALEX in combination with bortezomib (78% vs 30% of evaluable patients) and in previously untreated patients (80% vs 20%).¹
• After a median follow‐up of 14 months, only 1 of the responding patients had a hematologic relapse and started subsequent therapy.¹
• Of the 2 patients with C3 nephropathy, the first received D-VCd, achieved a CR but remained MRD‐positive, and had a decrease of proteinuria from 1.9 to <0.5 g/day with improvement in eGFR from 17.5 to 28 mL/min/1.73 m². The second patient received second‐line therapy with D-d, was already on dialysis, and achieved a hematologic PR.¹
• The patient with PGNMID received first‐line therapy with D-VCd and achieved a VGPR. His renal function improved with a decrease of proteinuria from 4.36 to 0.3 g/day and eGFR increase from 30 to 46 mL/min/1.73 m².¹
• Among DARZALEX non-responders, 1 patient who was previously untreated and on DARZALEX monotherapy had bortezomib and dexamethasone added, leading to a CR. One patient exposed to V-Cd and then to DARZALEX started treatment with lenalidomide and dexamethasone, but no deep response was achieved. The patient with hematologic relapse started pomalidomide, cyclophosphamide, and dexamethasone and had a PR. Two patients died a few months after discontinuing therapy.¹

Safety

• Two patients had grade 1 infusion-related reactions (IRRs).¹
• Infections were not frequent (all grades: 16%), and 1 patient had a grade 3 skin infection. This patient was receiving DARZALEX monotherapy and required hospitalization due to complications associated with profound anasarca, complicated with soft‐tissue infection that was considered unrelated to therapy.¹
  • Antibiotic prophylaxis was routinely given in all patients.
• Mild neuropathy occurred in 50% of patients receiving bortezomib with DARZALEX (grade 1 in all cases).¹

Phase 2 Study of DARZALEX in Patients with PGNMID and C3G

Zand et al (2021)² conducted a phase 2 trial to evaluate the safety and efficacy of DARZALEX in patients with PGNMID and C3G with MG.

Study Design/Methods

• Phase 2, single-center, open-label study.²
• Key eligibility criteria: aged ≥18 years, biopsy-proven PGNMID or C3G considered secondary to MG (patients with C3G needed a positive serum protein electrophoresis [SPEP] and serum immunofixation [SIF]), proteinuria ≥1 g/24 hours with an eGFR ≥20 mL/min/1.73 m².²
• Key exclusion criteria: multiple myeloma (MM), hemoglobin (Hgb) <8.5 g/dL, platelet <100 x 10⁹/L, white blood cells (WBC) <3.5 x 10⁹/L.²
• Patients could not have received cyclophosphamide within 6 months of enrollment or oral prednisone or glucocorticoid equivalent within 6 weeks of enrollment. Prednisone or its equivalent at a dosage of ≤10 mg daily for a condition unrelated to PGNMID or C3G (e.g., asthma or gout) was allowed.²
• Patients on mycophenolate mofetil (MMF), tacrolimus, cyclosporine, or azathioprine were eligible if proteinuria was not improving, or kidney function was declining. Once DARZALEX therapy was started, these medications had to be discontinued.²
• Patients receiving rituximab therapy had to have reconstitution of their B-cells (CD19 count >5 cells/dL).²
• Patients received DARZALEX 16 mg/kg IV once weekly for 8 weeks, followed by once every 2 weeks for an additional 8 doses.²
• Prior to first infusion of DARZALEX, patients received methylprednisolone 100 mg IV, acetaminophen 1000 mg, and diphenhydramine 50 mg was given orally before subsequent infusions. All patients received dexamethasone 4 mg orally once daily for 2 days beginning the day after DARZALEX infusion. All patients received acyclovir 400 mg orally twice daily, beginning within one week of starting DARZALEX, up to 3 months after the last infusion of DARZALEX. Single-strength trimethoprim/sulfamethoxazole once daily (or equivalent) was given up to 6 months after the last DARZALEX infusion ²
• Primary objective: safety of DARZALEX.²
• Secondary objective: response at 12 months and change in proteinuria, eGFR, hematuria, and C3 levels at 6 and 12 months.²
  • CR was defined as proteinuria <500 mg/24 hours and <15% decline in baseline eGFR, as determined by quantified creatinine clearance (CrCl). PR was defined as >50% reduction in 24-hour proteinuria and <30% decline in baseline eGFR.

Results

Patient characteristics

• Twelve patients were included (C3G with MG, n=1; PGNMID, n=11), but 10 were included in the efficacy analysis.²
  • The patient with C3G and MG was later determined to not have true MGRS, since C3G was not related to MG, and was not included in the efficacy analysis.
  • One patient with PGNMID did not complete the first infusion of DARZALEX due to a serious adverse event (SAE), was removed from the study, and was not included in the efficacy analysis.
• Among the 10 patients, mean age was 51.2 years (range, 18-87), males and females were equally divided, and all patients were white.²
• Baseline clinical and hematologic characteristics are summarized in Table Clinical and Hematologic Characteristics at 6 and 12 Months.²
• Seven patients had no prior immunosuppressive therapy, 2 patients had prior rituximab, and 1 patient had prior MMF and prednisone.²
• An intent-to-treat (ITT) analysis included all 12 patients, of which 10 completed the 6-month treatment period.²

Efficacy

• At 6 months, the ORR was 80% with 2 patients achieving a CR, 6 achieving a PR, and 2 having no response.²
• At 12 months, the 2 patients who had no response achieved PR, and 2 patients that had achieved PR entered CR, but 1 patient who had achieved CR and 2 patients who had achieved PR relapsed. Therefore, at 12 months, 3 patients achieved CR, 6 achieved PR, and 1 had no response.²
  • Of the 3 patients who relapsed, 2 restarted DARZALEX, had improvement in proteinuria, and continued treatment with DARZALEX every 2 months. The other patient was treated with VCd.
• At 12 months, best response was a PR rate of 100% and CR rate of 40%.²
• In the ITT analysis, PR rate was 83% (10/12 patients), and CR rate was 33% (4/12 patients).²
• Three patients with serum albumin levels <30 g/L at baseline achieved response at 12 months (CR, n=1; PR, n=2).²
• One patient with PGNMID who withdrew from the study due to SAEs of eye chemosis and headache with 1 DARZALEX infusion had resolution of proteinuria (0 mg/24 hours) at 6 months, which remained at 12 months, and improvement in serum creatinine at 6 and 12 months despite not receiving additional infusions.²
• Clinical and hematologic characteristics at 6 and 12 months are summarized in Table: Clinical and Hematologic Characteristics at Baseline and at 6 and 12 Months.²
  • Overall proteinuria was significantly reduced from baseline by 6 and 12 months, but there was no statistically significant difference in proteinuria between 6 and 12 months.
  • The improvement in proteinuria occurred in conjunction with an improvement in serum albumin.
  • Significant reduction was seen in in low density lipoprotein (LDL) cholesterol at 6 and 12 months.
  • Absolute values of kappa (κ) and lambda (λ) significantly decreased at 6 and 12 months, but there was no change in κ/λ ratio.
  • There was no significant change in kidney function based on creatinine, eGFR, or 24-hour CrCl measurements from baseline to follow-up at 6 and 12 months.
  • All immunoglobulin (Ig) levels (IgG, IgA, and IgM) decreased significantly with DARZALEX treatment.

Safety

• The most common side effects were IRRs (commonly with first infusion), including cough, congestion, throat irritation, and blurred vision. These side effects were self-limiting with limited recurrence in subsequent infusions.²
• No grade 3 or 4 anemia, thrombocytopenia, or leukopenia occurred.²
  • There was a statistically significant decrease in platelet count from baseline to 6 months but not 12 months; however, clinical relevance of this decrease is unclear.
• Five SAEs were reported, including eye chemosis, headache, acute glaucoma, fever (possibly related to viral infection), and C. difficile infection.²
  • Eye chemosis and severe headache occurred in the same patient at the end of the first DARZALEX infusion and resolved within 48 hours. This patient withdrew from the study and did not receive further DARZALEX infusions.
  • Fever and C. difficile occurred in a patient with C3G with MG who was receiving additional immunosuppression with tacrolimus, MMF, and prednisone due to lack of response to DARZALEX at 6 months.
    • A febrile episode occurred 2 months into combination immunosuppressive treatment, leading to discontinuation of tacrolimus and MMF and dose-reduction of prednisone. Once fever resolved, the patient was restarted on tacrolimus but not MMF.
    • C. difficile colitis occurred a few days after completing antibiotic treatment for an uncomplicated urinary tract infection (UTI) 1 month after the febrile episode. The patient required hospitalization for volume depletion and administration of IV fluids, and her C. difficile resolved with vancomycin treatment. After a course of antibiotic treatment for another uncomplicated UTI 3 months later, she experienced another episode of C. difficile and required fecal transplantation. No recurrence of UTI or C. difficile has occurred since.
  • One patient had acute closed-angle glaucoma that occurred 45 minutes into DARZALEX infusion and was subsequently withdrawn from the study.
• Uncomplicated UTIs occurred in 2 patients. One patient (detailed above) had 2 events, and 1 patient had 1 event that resolved with antibiotic treatment.²
• One episode of upper respiratory infection was reported and required no treatment.²

literature search

A literature search of MEDLINE®, Embase®, BIOSIS Previews®, Derwent Drug File (and other resources, including internal/external databases) was conducted on 08 April 2026.