DARZALEX + DARZALEX FASPRO - Use in Patients with Multiple Myeloma and Central Nervous System Involvement

SUMMARY  

• No formal studies of assessing DARZALEX for intravenous (IV) use or DARZALEX FASPRO for subcutaneous (SC) use crossing the blood brain barrier (BBB) or in patients with central nervous system (CNS) involvement have been conducted.
• Patients with known or clinical signs of meningeal involvement of multiple myeloma (MM) were excluded from DARZALEX + DARZALEX FASPRO clinical studies: ALCYONE, APOLLO, CASSIOPEIA, CASTOR, CEPHEUS, COLUMBA, EQUULEUS, GEN503, MAIA, PERSEUS, PLEIADES, POLLUX, and SIRIUS.^1-13
• Johnson & Johnson does not recommend the administration of DARZALEX or DARZALEX FASPRO in a manner that is inconsistent with the product labeling and not approved by regulatory agencies.
• Several case reports have been identified which evaluate BBB penetration properties of DARZALEX in patients with CNS involvement. Descriptions of the case reports are summarized below:
  • Portillo et al (2023)¹⁴ analyzed cerebrospinal fluid (CSF) and peripheral blood in a patient with stage IIIA IgD-lambda MM on second-line treatment with DARZALEX.
  • Zajec et al (2020)¹⁵ evaluated the BBB penetration properties of DARZALEX and
    intrathecal (IT) M-protein production, and M-protein in serum and CSF in a patient who presented with CNS MM.
• Several case reports have been identified which discuss the use of DARZALEX in patients with CNS involvement. Descriptions of the case reports are summarized below:
  • Kamili et al (2023)¹⁶ published a case report of a patient with CNS relapse after first-line treatment of MM who was subsequently treated with DARZALEX in combination with bortezomib, thalidomide, dexamethasone, cisplatin, doxorubicin, cyclophosphamide and etoposide (D-VDT-PACE) followed by autologous peripheral blood stem cell transplant (autoPBSCT) after CNS directed conditioning.
  • Marics et al (2022)¹⁷ published a case report of a patient with relapsed MM and CNS involvement who was administered DARZALEX in combination with pomalidomide and dexamethasone (Pd).
  • Kuan et al (2022)¹⁸ published a case report of a patient with relapsed/progressed MM and CNS involvement who was administered DARZALEX in combination with pomalidomide, vincristine, procarbazine, and dexamethasone (PVPD).
  • Farheen et al (2021)¹⁹ published a case report of a patient with non-secretory multiple myeloma (NSMM) with atypical involvement of the liver, spleen and CNS who was administered DARZALEX in combination with bortezomib, lenalidomide, and dexamethasone (VRd).
  • Mousavi-Fatemi (2020)²⁰ published a case report of a patient with relapsed MM with CNS involvement without systemic evidence of relapse who was treated with DARZALEX in combination with dexamethasone, carfilzomib, bendamustine, pomalidomide, and clarithromycin.

PRODUCT LABELING

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

clinical data

Evaluation of CSF and Peripheral Blood in stage IIIA IgD-lambda MM on second-line treatment with DARZALEX

Portillo et al (2023)¹⁴ evaluated CSF and peripheral blood of a patient with stage IIIA IgD-lambda MM on second-line treatment with DARZALEX.

• To detect the total and free heavy chains (IgG, IgA, IgM, and IgD) and light chains (κ and λ) in both samples, cytological, immunophenotypic and biochemical studies (protein study by electrophoresis and immunofixation on agarose gel) were performed.
• IgD-lambda monoclonal protein (MP) was detected in the peripheral blood as was IgG-kappa paraprotein secondary to DARZALEX.
• CSF showed IgD-lambda MP and IgG-kappa paraprotein with same characteristics as the peripheral blood.
• A demonstrated infiltration by plasma cells with aberrant phenotype and loss of CD38 expression was identified by cytological and immunophenotypic studies of the CSF.

Evaluation of BBB Penetration Properties of DARZALEX in a Patient with CNS MM

Zajec et al (2020)¹⁵ evaluated the BBB penetration properties of DARZALEX along with IT M-protein production by measuring the concentration of DARZALEX and M-protein in serum and CSF in a 54-year-old female patient with CNS MM.

• Fifteen months after the start of DARZALEX maintenance treatment (16 mg/kg every 8 weeks), the patient presented with neurological symptoms including pain and fasciculations in the right leg, loss of muscle strength in lower legs, paresthesias in both hands, and painful nodular lesions in both upper arms with biopsy-confirmed extramedullary (EM) plasmacytomas of ulnar nerves and right plexus brachialis. Contrast-enhanced craniospinal Magnetic Resonance Imaging (MRI) revealed multiple enhancing leptomeningeal nodules.
• At the time of relapse, 3 paired serum and CSF samples were obtained on day 12, 15, and 19 after the last DARZALEX infusion. All serum and CSF samples were analyzed using mass spectrometry (MS).
  • In serum samples, the DARZALEX concentration was 277, 221, and 213 mg/L at day 12, 15, and 19, respectively.
  • In CSF samples, the DARZALEX concentration was 4, 3, and 3 mg/L at day 12, 15, and 19, respectively.
• Additionally, MS was also used to calculate DARZALEX index at three independent sampling time-points (range, 0.33 to 0.37).

Case Report of Patient with Kappa Light Chain MM with CNS Invasion

Kamili et al (2023)¹⁶ published a case report of a 43-year-old male patient with kappa light chain MM who was initially treated with bortezomib, cyclophosphamide and dexamethasone induction, followed by high-dose melphalan and autoPBSCT achieving very good partial response (VGPR). Patient declined maintenance therapy.

• Four years later, he presented with acute back pain and paresthesia of the right leg.
• Spinal and cranial MRI confirmed multiple barrier-disrupted lesions in the brain and spinal cord.
• Without detectable active MM in the serum, urine, and bone marrow; Confirmation of CNS invasion of MM was achieved with intradural biopsy of a mass lesion and flow cytometry of liquor.
• Patient subsequently received two cycles of D-VDT-PACE achieving partial remission as shown by MRI imaging.
• Salvage therapy was completed with a third cycle and subsequent high-dose CNS directed conditioning with busulfan / thiotepa followed by autoPBSCT.
• Patient achieved complete remission as documented by MRI imaging.
• Maintenance therapy was initiated with DARZALEX, lenalidomide, and dexamethasone (DRd).

Case Report of Patient with Relapsed MM with CNS involvement

Marics et al (2022)¹⁷ published a case report of a 62-year-old female patient with relapsed MM and CNS involvement who was treated with D-Pd.

• After initiation of D-Pd, it was reported that the patient's CNS related symptoms recovered and the main treatment side effect was grade 4 neutropenia.
• After 3- and 6-month follow-up, immunofixation was still positive, no M-protein was detected in the serum electrophoresis, serum free light chain (FLC) ratio was 0.89 (range, 0.31-1.56), and MRI revealed a decrease in the size of intracranial lesions. Patient is currently ongoing treatment and has completed 7 cycles of D-Pd.

Case Report of Patient with Relapsed/Progressed MM with CNS Involvement of Leptomeningeal Myelomatosis

Kuan et al (2022)¹⁸ published a case report of a 61-year-old male patient with MM with paravertebral plasmacytoma and later developed systemic relapse and progression to MM with CNS involvement in the form of leptomeningeal myelomatosis.

• The patient was administered D-PVPD. After 2 cycles of treatment with D-PVPD, rapid clinical improvement was reported.
• After cycle 4, patient achieved VGPR. CSF analysis in the middle of the cycle 4 showed protein 0.58 g/L, glucose, 3.2 mmol/L, cell count 6 ×10⁶/L, cytology of low cellularity with no malignant cell, and immunophenotyping with no evidence of clonal plasma cells and myeloma involvement was reported.
  • The follow-up MRI revealed disappearance of leptomeningeal lesion in the cerebrum, cerebellum, spinal cord, and cauda equina, except partial response at left internal auditory canal and left external capsule.
• After cycle 6, further CNS improvement, complete response with CSF and stable external capsule lesion were reported.

Case Report of Patient with NSMM with Atypical Involvement of the Liver, Spleen, and CNS

Farheen et al (2021)¹⁹ published a case report of a 59-year-old female patient with NSMM with atypical involvement of the spleen, liver, and CNS.

• The patient was diagnosed with NSMM with multiple lytic lesions with biopsy-proven plasmacytoma in absence of monoclonal spike (M spike) and started on VRd.
• After being treated for 1.5 months, the patient began complaining of right frontal headache, decreased sensation on the right side of the face and angle of the mouth, and double vision. Positron emission tomography (PET) scan revealed multiple metabolically active lytic lesions in the liver, spleen, and lungs. Additionally, an MRI of the brain revealed meningeal involvement with dural deposits. A final diagnosis of highly aggressive NSMM with EM involvement of the liver, spleen, and CNS was made. DARZALEX was added to the VRd regimen (D-VRd).
• The patient has responded slowly over 2 months with repeat imaging showing a reduction in lytic lesions. Patient is currently on maintenance therapy with regular follow-up.

Case Report of Patient with Relapsed MM with CNS Involvement without Systemic Involvement

• Mousavi-Fatemi (2020)²⁰ published a case report of a 58-year-old patient with MM relapsed following autologous stem cell transplant (ASCT) with CNS involvement without evidence of systemic involvement.  
• Five months post-ASCT, the patient experienced bilateral pupil edema, severe headache and pelvic pain. The CSF smear identified the presence of plasma cells, suggesting relapse of MM. Laboratory values, serum, and urine electrophoresis, were within normal ranges.
• The patient was administered a combination of dexamethasone, carfilzomib, bendamustine, pomalidomide, clarithromycin and DARZALEX (28-day cycle). It was reported the patient was in complete remission after 6 months of being on this treatment regimen.

Literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File databases (and/or other resources, including internal/external databases) was conducted on 11 June 2026.