SUMMARY

• DARZALEX for intravenous use (IV) is not approved by the regulatory agencies for the treatment of patients with immunoglobulin light chain (AL) amyloidosis. Janssen does not recommend the use of DARZALEX in a manner that is inconsistent with the approved labeling.
• Kastritis et al (2024)¹ presented (at the European Hematology Association (EHA) Annual Meeting) results from an ongoing, phase 2, open-label, multicenter, European Myeloma Network (EMN) 22 study evaluating the efficacy and safety of DARZALEX monotherapy in patients (N=40) with stage 3B newly diagnosed AL amyloidosis. At a median follow-up duration of 10.3 months, the ORR was 77.5% and overall survival (OS) rates at 6- and 12-month were 65% (95% CI, 48.2-77.6) and 45.0% (95% CI, 29.3-59.5), respectively. At least one serious TEAE was reported by 32 patients (80%), and fatal serious adverse events (SAEs) were reported by 17 patients (42.5%).
• Sanchorawala et al (2020)² reported results of a phase 2 study evaluating the safety and tolerability of DARZALEX in patients (N=22) with relapsed AL amyloidosis. Median progression-free survival (PFS) was 28 months. Grade 1 nausea/vomiting occurred during the first infusion in 3 patients. No grade 3/4 infusion-related reactions (IRRs) occurred.
• Roussel et al (2020)³ reported results of a phase 2 study evaluating the efficacy and safety of DARZALEX in patients (N=36) with previously-treated, systemic AL amyloidosis. The OS rate was 74% (95% confidence interval [CI], 62-81), with a median follow-up of 26 months. Grade 1/2 adverse events (AEs) occurred in 20 patients, grade ≥3 AEs in 11 patients, and SAEs in 6 patients.
• Rabajoli et al (2023)⁴ presented (at the 60th European Renal Association [ERA] congress) the results from a real-life, long-term experience that evaluated DARZALEX monotherapy in patients (N=17) with AL amyloidosis. At the end of a mean follow-up of 30 months, 5 patients had persistent hematological and renal response. Two patients died due to coronavirus disease 2019 (COVID-19) infection and cardiovascular disease, respectively.
• Roccatello et al (2020)⁵ reported on the experience with DARZALEX monotherapy in patients with severe AL amyloidosis and multiorgan and biopsy-proven renal involvement. DARZALEX resulted in the disappearance of M-proteins in all 5 patients, free light chain (FLC) ratio normalization in 4/5 patients, and significant decrease in proteinuria and N-terminal pro-B-type natriuretic peptide (NT-proBNP) values.
• Staron et al (2023)⁶ presented (at American Society of Hematology [ASH] Annual Meeting) results from a prospective study that evaluated the rates of undetectable minimal residual disease (MRD) achievement in patients (N=66) treated with DARZALEX, and rates of MRD clearance and resurgence both during and after completion of DARZALEX therapy for AL amyloidosis. A total of 38%, 46%, and 41% of patients were MRD-negative after <12, 12-23, and 24 cycles of DARZALEX monotherapy. Rates of MRD clearance during and after completion of DARZALEX therapy for AL amyloidosis were 20% and 9%, respectively; rate of MRD resurgence after completion of DARZALEX therapy for AL amyloidosis was 9%.
• Cohen et al (2020)⁷ conducted a retrospective analysis by evaluating DARZALEX monotherapy in patients with relapsed/refractory systemic AL amyloidosis, hematological responses were achieved rapidly, with an ORR of 84%. Complete response (CR) was shown to predict OS and speed of response was shown to be predictive of a longer PFS.
• Chung et al (2020)⁸ conducted a retrospective analysis by evaluating DARZALEX monotherapy in patients with previously-treated AL amyloidosis, a significant proportion of patients achieved deep hematologic response and experienced improvement in organ function.
• Other relevant literature describing retrospective and prospective studies (<50 patients), including but not limited to single-site experience has been identified in addition to the data summarized above.^9-16
• Two case reports that discuss the use of DARZALEX monotherapy in patients with AL amyloidosis have been included.^17,18

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

Phase 2 Study on DARZALEX Monotherapy in Stage 3B AL Amyloidosis

Kastritis et al (2024)¹ presented results from an ongoing, phase 2, open-label, multicenter, EMN 22 study that evaluated the efficacy and safety of DARZALEX monotherapy in patients with stage 3B newly diagnosed AL amyloidosis.

Study Design/Methods

• Patients with newly diagnosed stage 3B AL amyloidosis were included.
• Dosing
  • All patients initially received monotherapy with DARZALEX 16 mg/kg IV, followed by DARZALEX FASPRO 1800 mg subcutaneously (SC, since February 2020).
  • Treatment was administered on days 1, 8, 15, and 22 during cycles 1-2; on days 1 and 15 during cycles 3-6; and on day 1 during cycle 7+ until disease progression, start of a new therapy, or for a maximum of 2 years.
• Patients unable to achieve either a hematologic very good partial response (VGPR) or better or a hematologic partial response (PR) with a major organ response by cycle 4 could additionally receive bortezomib 1.3 mg/m² weekly (maximum 6 cycles) and low-dose dexamethasone at investigator’s discretion.
• Primary endpoint: OS rate at 6 months
• Key secondary endpoints: Hematologic ORR at 3 and 6 months, organ response rate, major organ deterioration progression free survival (MOD-PFS, from cycle 1 day 1 until death, clinical manifestation of cardiac/renal failure, or development of hematologic progression of progressive disease [PD] as per consensus guidelines), safety, and tolerability of DARZALEX.

Results

Patient Characteristics

• At a clinical data cutoff of December 15, 2023, 40 patients had been enrolled in the study, of whom 10 (25.0%) patients had completed the study treatment, 4 (10.0%) patients continued the treatment, and 26 patients discontinued the treatment (PD, n=7; safety event, n=3; death, n=14; consent withdrawal, n=1; physician's decision, n=1).
• The median duration of follow-up was 10.3 months (range, <0.1-50.1).
• The median duration of therapy was 6.6 months (range, <0.1-25.3).
• The median number of DARZALEX infusions was 18 (range, 1-36).
• Baseline patient and treatment characteristics are summarized in Table: Baseline Patient and Treatment Characteristics.

Efficacy

• A summary of efficacy outcomes is presented in Table: Efficacy Outcomes at Different Timepoints.

Safety

• A summary of safety outcomes is presented in Table: Summary of Safety Outcomes.
• A list of common SAEs is presented in Table: Common SAEs.
• Mortality rate at 15 days following cycle 1 day 1 of the treatment was 7.5% (deaths, n=3).
• Mortality rate at 1-month following cycle 1 day 1 of the treatment was 10.0% (deaths, n=4).

Phase 2 Study on DARZALEX Monotherapy in Relapsed AL Amyloidosis

Sanchorawala et al (2020)² reported results of a single-arm, phase 2 study (AMY2002; clinicaltrials.gov identifier: NCT02841033) designed to evaluate the safety, tolerability, and response rates of DARZALEX in patients with relapsed AL amyloidosis.

Study Design/Methods

• Key eligibility criteria: AL amyloidosis after ≥1 prior therapy; ≥1 major vital organ involved; estimated glomerular filtration rate (eGFR) >20 mL/min; aspartate aminotransferase/alanine aminotransferase <3x upper limit of normal; Eastern Cooperative Oncology Group performance status (ECOG PS) ≤3; NT-proBNP <8500 pg/mL; left ventricular ejection fraction (LVEF) ≥30%; forced expiratory volume in the first second (FEV1) ≥50% in patients with chronic obstructive pulmonary disease (COPD) or chronic smokers; if prior treatment included high-dose melphalan or stem cell transplant, then must be 6 months prior.
• Treatment plan: DARZALEX 16 mg/kg IV infusion weekly for weeks 1-8, every 2 weeks for weeks 9-24, and every 4 weeks thereafter until progression or unacceptable toxicity, for up to 24 months.
  • First infusion administered in 1000 mL of saline; 2^nd infusion administered in 500 mL if no grade 1 IRRs occurred; subsequent doses administered in 500 mL
  • Pre-infusion medications (30-60 minutes prior to infusion): acetaminophen, diphenhydramine, loratadine (1^st two infusions), famotidine, montelukast, and methylprednisolone (100 mg for 1^st two infusions and 60 mg thereafter), ondansetron
    • The first 2 patients of the study experienced grade 1 nausea/vomiting during their first infusion. Ondansetron was given as treatment and as a pre-medication to all subsequent infusions in the study.
  • During infusion medications (2 hours after the start of the 1^st two infusions): diphenhydramine, famotidine, and methylprednisolone 40 mg
  • Post-infusion medications (24 and 48 hours after the start of infusion): methylprednisolone 20 mg (or its equivalent) for the 1^st two infusions and montelukast
  • All patients received daily acyclovir prophylaxis.
• Primary objective: safety and tolerability of DARZALEX, with respect to IRRs
• Secondary objectives: hematologic response, clinical response, time-to-next-treatment (TTNT)

Results

Treatment Characteristics

• Baseline patient demographics and disease characteristics are presented in Table: Patient Baseline Characteristics.
• Seven patients continued protocol-directed therapy (3 discontinued due to progression of plasma cell (PC) dyscrasia; 2 discontinued by patient choice after 8 cycles; 1 patient discontinued due to persistent grade 3 AE of muscle weakness).
• Median number of infusions per patient (range): 31 (7-34)
• Median duration of 1^st infusion was 7 hours, median duration of 2^nd infusion was 4.30 hours and there was no interruption or delay of infusion.

Efficacy

• Hematologic Responses
  • The median % difference between involved free light chain and uninvolved free light chain (dFLC) after 1 dose of DARZALEX was 68.3%.
  • Hematologic overall response (CR plus VGPR) was achieved in 86% of patients.
  • Nine (41%) patients achieved hematologic CR, 10 (45%) patients achieved VGPR, 1 (4%) patient achieved PR.
  • Stable disease was noted in one (4%) patient.
• Organ Responses
  • Cardiac response occurred in 50% of patients (n/N, 7/14).
    • Median time to 1^st cardiac response was 20 weeks (range, 4-32 weeks), and time-to-best cardiac response was 44 weeks (range, 16-92 weeks)
    • Cardiac progression occurred in 21% of patients.
  • Renal response occurred in 67% of patients (n/N, 10/15).
    • Median time to 1^st renal response was 18 weeks (range, 12-48 weeks), and time-to-best renal response was 54 weeks (range, 12-88 weeks).
    • Renal progression was not reported.

Safety

• No grade 3/4 IRRs were reported.
• Grade 1 nausea/vomiting occurred during the first infusion in 4 patients, which was resolved with antiemetic therapy and was prevented in others with the addition of pre-infusion ondansetron.
• Grade 1 “itchy throat” reported in 1 patient during the 1^st infusion
• Grade 3/4 AEs were reported in 20 patients (91%).
  • Of those, respiratory illnesses were reported in 13 patients (59%).
    • Four (18%) grade 3 (influenza A, rhino/enteroviral upper respiratory infection, Pneumocystis jiroveci pneumonia)
• Grade 3/4 AEs of atrial fibrillation and congestive heart failure occurred in 18% of patients and 14% of patients, respectively.
• Iron deficiency requiring parenteral iron infusion was reported in 9 (40%) patients.
• Among the 22 enrolled patients, death was reported in 3 patients. Two of these patients were taken out of the clinical study due to progression of PC dyscrasia markers after the 9^th and 10^th cycle of DARZALEX, respectively. One patient experienced sudden death after completing 24 cycles of DARZALEX and achieving a CR. The patient deaths were related to sepsis, immunomodulatory agent-related rejection of the transplanted heart, and cardiac arrythmia.

Phase 2 Study on DARZALEX Monotherapy in Previously-Treated Systemic AL Amyloidosis

Roussel et al (2020)³ reported preliminary results of a prospective, multicenter, single-arm, phase 2 study (AMYDARA; clinicaltrials.gov identifier: NCT02816476) evaluating the efficacy and safety of DARZALEX monotherapy in patients with previously-treated systemic AL amyloidosis.

Study Design/Methods

• Key inclusion criteria: >18 years old; histologic diagnosis of AL amyloidosis; ECOG PS <3; received previous systemic therapy; dFLC >50 mg/L; symptomatic organ involvement (heart, kidneys, liver, gastrointestinal tract, peripheral nervous system)
• Key exclusion criteria: symptomatic multiple myeloma or bone marrow (BM) PC infiltration ≥30%; cardiac Mayo Stage III with NT-proBNP ≥8500 ng/L (cardiac Mayo Stage IIIB); supine blood pressure <100 mmHg; NYHA Stage IV; chronic atrial fibrillation; LVEF ≤45%; COPD with FEV1 <50%
• Patients received DARZALEX 16 mg/kg IV weekly for 2 months (cycles 1-2), and then every other week for 4 months (cycles 3-6), for a total of six 28-day cycles.
• Primary endpoint: proportion of patients in ≥VGPR at the end of 6 cycles
• Secondary endpoints: PFS, safety and tolerability, time to hematologic response, best hematologic responses, cardiac and renal responses, OS

Results

Dispositions and Safety Summary

• Baseline patient demographics and disease characteristics are presented in Table: Patient Baseline Characteristics.
• A total of 40 patients received ≥4 infusions of DARZALEX.
  • Thirty-three (82.5%) patients received all 6 cycles.
  • Seven patients discontinued study treatment; n=6 due to organ progression and/or lack of hematological response and n=1 due to lung cancer.
  • No patients discontinued treatment due to AEs.

Efficacy

• Hematologic Responses
  • After completion of all 6 cycles or at last evaluation (n=40):
    • A total of 19 (47.5%) patients achieved ≥VGPR (95% CI, 31.5-63.9; P<0.001).
    • Patients were assessed as VGPR due to missed urine immunofixation (n=2) and due to not normalizing their free light chain ratio with a normal involved free light chain (iFLC; n=2).
    • Sixteen (40%) patients achieved VGPR, 3 (7.5%) patients achieved CR, and 3 (7.5%) patients reported PR.
    • ORR in patients was 55% (95% CI, 38.5-70.7).
    • Thirteen (32%) patients had normal iFLC levels by the end of treatment.
    • Nine (22%) patients reported dFLC <10 mg/L.
  • After 1 dose of DARZALEX, median reduction in dFLC was 49%.
• OS and PFS
  • The median OS was not reached.
  • The 2-year OS estimate was 74.2% (95% CI, 61.6-89.4).
  • Median PFS estimate: 24.8 months (lower bound of 95% CI, 15.7)
  • The 2-year PFS rate was 51.2% (95% CI, 37.6-69.8).

Safety

• Twelve SAEs occurred in 8 patients during the study treatment, including death (n=3), septicemia (n=1), and bradycardia (n=1). None were defined as treatment-related.
• Thirteen patients experienced grade 3/4 AEs.
  • Four (n=4) grade 3 AEs were defined as treatment-related (cutaneous rash after 1^st infusion which did not recur, n=2; leukopenia and orthostatic hypotension, each n=1).
• No grade 4/5 treatment-emergent AEs were noted.
• IRRs were the most common grade 1/2 AEs, occurring in 17 (42.5%) patients after the initial dose.
• At the median actual follow-up of 26.4 months (range, 19.3-30.1):
  • A total of 11 patients died.
    • Three deaths occurred during study treatment due to disease progression (n=2) and lung cancer (n=1).
    • Eight deaths occurred during follow-up due to disease progression (n=7) and colon cancer (n=1).
  • Twenty-four patients started new therapy due to unsatisfactory response (n=17) or hematological progression (n=7) and/or organ progression (renal, n=3).
  • No patients had relapsed or progressed prior to completing the planned 6 months of treatment.

Real-world Experience of DARZALEX Monotherapy in AL Amyloidosis With Renal Involvement

Rabajoli et al (2023)⁴ presented the results from a real-life, long-term experience that evaluated DARZALEX monotherapy in patients with AL amyloidosis.

Study Design/Methods

• Patients with AL amyloidosis, who were treated with DARZALEX alone with 24 IV administrations at a dose of 16 mg/kg, were included in the study.
• All patients had histological confirmation and staging of renal involvement before starting the treatment and were ineligible for autologous stem cell transplantation (ASCT).
• Overt multiple myeloma (MM) was excluded via BM biopsy; patient could have been naïve/refractory.
• Hematological and organ response was evaluated after every 4 infusions via NT-proBNP, dFLC and FLC ratio, serum creatinine up to (24h), and serum and urine testing.
• Responses were defined based on the International Society of Amyloidosis extended criteria.
• Patients who had undergone the whole cycle of therapy underwent a second kidney biopsy at the end of the treatment based on the feasibility.

Results

Baseline Characteristics

• A total of 17 patients (mean age, 73 years) were included; of whom 16 had proteinuria (within the nephrotic range, n=11), which was associated with impairment of renal function in 11 patients.
• Two patients were on dialysis at the time of therapy initiation; 9 patients had completed the treatment; and 13 patients had received at least 12 infusions of DARZALEX.
• The mean duration of follow-up was 30 months (range, 19-46). 

Efficacy

• At the 12th DARZALEX infusion, 11 of 13 patients (84.6%) had achieved an overall hematological response, 6 patients (46.5%) had achieved a complete hematological response, 5 patients (38%) had achieved a VGPR, and 2 patients (15.5%) were non-responders.
• In regard to the renal response, 5 of 13 patients had achieved an organ response, and 6 patients did not meet the renal response criteria; the 2 patients who were on dialysis at the time of therapy initiation, remained on dialysis.
  • One patient had complete hematological and cardiac responses, the remaining patients did not have any response.
  • Seven of 9 patients had achieved a renal response.
  • 24-hour proteinuria values dropped from 6.02 g/24 hours (range, 0.8-16.8) to 1.28 g/day (range 0.9-3.6; P<0.005).
  • Stabilization or improvement of sCr increased from 1.66 mg/dL to 1.1 mg/dL (P=0.17).
  • Eight of 9 patients with cardiac involvement received at least amelioration.
• At the end of follow-up, 5 patients had persistent hematological and renal response.
• One patient with initial PR had a relapse and initiated a treatment with bortezomib + cyclophosphamide + dexamethasone.

Safety

• Two patients died due to COVID-19 infection and cardiovascular disease, respectively.
• By the end of the follow-up, the last patient was alive and was being treated with a second line of therapy, because no hematologic or organ response was achieved with DARZALEX.
• A total of 7 patients underwent a second kidney biopsy at the end of the treatment, which showed stable deposits in 6 patients, while 1 patient showed a reduction in the extension and amount of amyloid deposits.

Prospective Study on DARZALEX Monotherapy in Severe AL Amyloidosis With Renal Involvement

Roccatello et al (2020)⁵ reported on the experience with DARZALEX monotherapy in patients with severe AL amyloidosis and multiorgan and biopsy-proven renal involvement.

Study Design/Methods

• A total of 5 patients (2 males and 3 females) with a mean age of 64 years were treated with DARZALEX following antibody testing and extended red blood cell antigen phenotyping.
• Patients received DARZALEX 16 mg/kg IV infusion weekly for 8 weeks, then 8 times every 2 weeks, and then monthly for 1 year. Pre-infusion medications included oral paracetamol, IV chlorphenamine, and IV methylprednisolone.

Results

• In patient 1, who was refractory to conventional therapies and undergoing dialysis, daratumumab resulted in normalization of the FLC ratio, with disappearance of serum M-component and Bence-Jones (BJ) proteinuria.
• In patient 2, who had relapsing disease, daratumumab resulted in a rapid decrease in proteinuria (from 6.8 to 2.7 grams/24 hours at the 16^th dose) and NT-proBNP levels (from 1844 to 330 pg/mL), with disappearance of serum M-component and BJ proteinuria and normalization of the FLC ratio.
• In patient 3, who was treated front-line, daratumumab resulted in a significant decrease in proteinuria (from 9.3 to 2.2 grams/24 hours) and NT-proBNP levels (from 850 to 225 pg/mL), with disappearance of serum M-component and normalization of FLC ratio.
• In patient 4, who was intolerant to conventional regimens, daratumumab resulted in a decrease in proteinuria, disappearance of serum M-component, and improvement in the FLC ratio, all of which corresponded to a reduction in NT-proBNP levels.
• In patient 5, who had relapsing disease, daratumumab resulted in a decrease in proteinuria (from 2.5 to 1 gram/24 hours), a decrease in serum M-component, and an increase in the FLC ratio. This patient also experienced a grade 1 IRR during the first dose.
• The 4 patients with preserved renal function also demonstrated renal response with serum creatinine improvement or stabilization and a decrease in proteinuria levels. These data were paralleled by reduction in NT-proBNP values in 3 patients with cardiac involvement.

Prospective Study on DARZALEX Monotherapy in Relapsed/Refractory Systemic AL Amyloidosis

Staron et al (2023)⁶ presented results from a prospective study that evaluated the rates of undetectable MRD achievement in patients treated with DARZALEX, and the rates of MRD clearance and resurgence both during and after completion of DARZALEX therapy for AL amyloidosis.

Study Design/Methods

• MRD status was assessed for patients followed at the Boston University Amyloidosis Center, who were treated with a DARZALEX-based regimen and achieved a hematologic VGPR or CR according to the consensus criteria.
• MRD assessments were performed by multiparametric 10-color flow cytometry of BM aspirates (sensitivity level of 10^-5) and repeated at 12-month intervals during follow-up.
• Clonal progression was defined as growth in the aberrant PC clone size of >1 log.

Results

• A total of 66 patients, tested for MRD between 2019 and 2023, achieved hematologic CR (n=48) and hematologic VGPR (n=18).
• MRD assessment was performed once, twice, or ≥3 times for 33, 18, and 15 patients, respectively.
  • First MRD assessment was done in 33 patients while receiving the treatment at a median of 12 cycles (range, 6-23) of treatment; later, MRD was evaluated in the remaining 33 patients after a median of 1 month (range 0-25) of therapy completion.
    • Of the 23 patients (hematologic CR, n=18; hematologic VGPR, n=5) who received DARZALEX in combination with cyclophosphamide + bortezomib + dexamethasone (CyBorD) in the frontline setting, 8 patients (35%) achieved MRD-negativity at the first evaluation.
    • Of the 43 patients (hematologic CR, n=30; hematologic VGPR, n=13) who received DARZALEX monotherapy in the relapsed/refractory setting, 20 patients (47%) achieved MRD-negativity.
  • A summary of MRD profiles in 66 patients based on the number of DARZALEX cycles received at the first MRD evaluation is presented in Table: MRD Profile of Patients Based on the Number of DARZALEX Cycles Received at the First MRD Evaluation.
• Serial MRD monitoring was performed for 33 patients.
  • Of the 10 patients who continued to receive DARZALEX between MRD assessments (group 1), 6 patients had sustained MRD-negativity, 2 patients had MRDclearance (conversion from positive to negative).
  • Of the 23 patients who underwent serial MRD assessments after completing DARZALEX (group 2), 9 patients (39%) had sustained MRD negativity, 2 patients (9%) had MRD clearance, and 2 patients (9%) had MRD resurgence (conversion from negative to positive);
  • Five of ten patients had clonal progression with persistent positivity after DARZALEX completion, of whom 3 experienced a hematologic relapse.
  • A summary of the dynamic MRD tracking at 12-month intervals during (group 1) and after completion of (group 2) is presented in Table: Dynamic MRD Tracking at the 12-month Interval in Group 1 and Group 2.

Retrospective Study on DARZALEX Monotherapy in Relapsed/Refractory Systemic AL Amyloidosis

Cohen et al (2020)⁷ conducted a retrospective analysis of single-agent DARZALEX in patients with relapsed/refractory systemic AL amyloidosis, evaluating the impact of timing of response on survival outcomes.

Study Design/Methods

• All patients treated with DARZALEX monotherapy for relapsed/refractory systemic AL amyloidosis between 2016 and 2019 were identified from the database at the UK National Amyloidosis Centre.
• Patients received DARZALEX 16 mg/kg IV weekly for 8 doses, fortnightly for 8 doses, and then monthly until disease progression.
• All patients received acyclovir and co-trimoxazole as standard antimicrobial prophylaxis.
• Outcomes included hematological and organ responses, OS, PFS, and AEs; all survival outcomes were calculated on an intention-to-treat basis.

Results

Baseline Characteristics

• Baseline patient demographics and disease characteristics are presented in Table: Patient Baseline Characteristics.

Patient Disposition

• From the start of DARZALEX therapy, patients were followed for a median of 9 months (range, 2-35 months).
  • Thirty-five (66.0%) patients continued on DARZALEX, 10 (18.9%) patients died, 4 (7.5%) patients discontinued treatment, and 4 (7.5%) patients moved to next line therapy (addition of pomalidomide to DARZALEX in 3 cases and addition of lenalidomide in the fourth case).

Efficacy

• A total of 53 patients were included in the study, of which 50 had assessable hematological response at 3 months, as presented in the Table: Hematologic Response by Cardiac Stage.

• Median time to response was 1 month (range, 1-6 months). Of 26 patients who responded at 1 month, 19 (73.1%) achieved a CR/VGPR compared to 12/15 (80%) who responded at 2-3 months.
• Organ responses were evaluated 6 months after DARZALEX initiation. At 6 months, 16/39 patients were evaluable for cardiac involvement, 8/30 patients were evaluable for renal involvement and 8/14 patients were evaluable for hepatic involvement.
  • Cardiac response occurred in 43.8% (n/N, 7/16) of patients:
    • Cardiac progression occurred in 25.0% (n/N, 4/16) and 31.3% (n/N, 5/16) were non-responders.
    • Of cardiac responders, 71.4% (n/N, 5/7) demonstrated a hematologic response at 1 month and 85.7% (n/N, 6/7) achieved a CR.
  • Renal response occurred in 25.0% of patients (n/N, 2/8):
    • Renal progression occurred in 12.5% (n/N, 1/8) and 62.5% (n/N, 5/8) were non-responders.
    • Within patients evaluable for a renal response, hematologic response were evaluable in 5/6 (83.3%) non responders (CR, 1 [20%]; VGPR, 1 [2.0%]; PR, 2 [50.0%]; and NR, 1 [20.0%]).
  • Hepatic response occurred in 0% of patients:
    • Hepatic progression occurred in 37.5% (n/N, 3/8) and 62.5% (n/N, 5/8) were non-responders.
• The hematological response in patients achieving any organ response were: CR, 7 (77.8%) and PR, 2 (22.2%).
  • At 1 month, 77.8% (n/N, 7/9) patients achieved a hematologic response vs 52% (n/N, 26/50) patients within the entire cohort.
• Patients achieving a CR had a significantly longer median OS vs those with a lesser hematological response (not reached vs 22.7 months, respectively [95% CI, 17.028.4 months]; P=0.036).
• At 1 month, patients achieving a rapid response had a significantly longer median PFS vs those responding at a later time point (not reached vs 9 months, respectively [95% CI, 5.8-12.2 months]; P=0.013).

Safety

• No deaths or grade ≥3 IRRs occurred in patients treated with DARZALEX.
• The most common grade 1/2 AEs were infusion reactions (n=7; 13.2%), thrombocytopenia (n=6; 11.3%), fatigue (n=6; 11.3%), infection (n=5; 9.4%), anemia (n=5; 9.4%), and fluid overload (n=4; 7.5%).

Retrospective Study on DARZALEX Monotherapy in Previously-Treated AL Amyloidosis

Chung et al (2020)⁸ conducted a retrospective analysis to evaluate use of DARZALEX monotherapy plus dexamethasone in patients with previously-treated AL amyloidosis, reporting on hematologic and organ outcomes.

Study Design/Methods

• Patients treated with DARZALEX monotherapy and dexamethasone between January 2016 and January 2019 were included in the study.
• Patients received DARZALEX at 16 mg/kg weekly for 8 weeks, followed by every other week for 8 doses, and then every 4 weeks.
• All patients received dexamethasone 20 mg routinely with the initial infusion and subsequently tapered per physician discretion.

Results

Baseline Characteristics

• Baseline patient demographics and disease characteristics are presented in Table: Patient Baseline Characteristics.
• Median duration of follow-up was 27 months (interquartile range [IQR], 18-34.4).

Efficacy

• OS and TTNT
  • Eleven deaths occurred during follow-up. Median 2-year OS and TTNT was not reached. The 2-year OS was 86.9% (95% CI, 78.9-94.9) and 2-year TTNT-free survival was 62% (95% CI, 48.2-73.4).
  • Among patients with dFLC ≥5 mg/dL at DARZALEX initiation, the median TTNT was 20 months, with a 2-year TTNT-free survival rate of 47.3% (95% CI, 29.3-65.3).
• Hematologic Responses
  • Only 52/72 patients were evaluable for hematologic response (dFLC >2 mg/dL at DARZALEX initiation). Of these, 40 (77%) achieved hematologic response, 21 (40%) achieved CR, 12 (23%) achieved VGPR, 4 (8%) achieved low dFLC PR, 3 (6%) achieved PR, and 12 (23%) patients had no response.
• Among the 31 patients with an initial dFLC ≥5 mg/dL, a similar high response rate of 81% was observed, 10 (32%) patients achieved CR, 12 (39%) patients achieved VGPR, 3 (10%) patients achieved PR, and 6 (19%) had no response.
• Fifty-seven patients were determined to have cardiac involvement and 47 patients were determined to have renal involvement.
  • Cardiac response occurred in 55% (n/N, 17/31) of patients with improvement of NT-proBNP by ≥30% and 300 ng/mL.
    • The median time to achieve a PR was 3.2 (IQR, 1.2-5.4) months, cardiac VGPR or CR was 6.9 months (IQR, 3.1-18.3), and time-to-best cardiac response was 16.8 months (IQR, 4-26.7).
    • Among cardiac responders, 4 (13%) patients achieved CR, 6 (20%) patients achieved VGPR, and 7 (23%) patients achieved PR.
  • Renal response occurred in 52% (n/N, 13/25) of patients based on a >30% reduction in 24-hour proteinuria.
    • The median time to renal response was 6 (IQR, 4.3-7) months, renal VGPR or CR was 11.4 (IQR, 7.7-22.9) months, and time-to-best renal response was 12.9 (IQR, 6.2-26.2) months.
    • Among renal responders, 2 (8%) patients achieved renal CR, 5 (20%) patients achieved renal VGPR, 6 (24%) patients achieved renal PR, and 12 (54%) patients had no response.

Safety

• During the first cycle of DARZALEX therapy, 33 (50%) patients had IRRs.
• Two patients had grade 3 infusion reactions.
• The most common AEs reported were chest tightness/dyspnea (49%), cough (30%), nasal congestion/rhinorrhea (24%), eye irritation (18%), and nausea/vomiting (18%).
• Within the first cycle of DARZALEX therapy, 9 patients had hospitalizations because of infection (n=3), infusion reactions (n=2), myocardial infarction (n=2), syncope (n=1), and volume overload (n=1).
• In total, 74% of patients were able to complete the first cycle without any treatment interruptions or delays.

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 02 July 2024. This information is intended to include clinical trial studies, prospective study and retrospective analyses, rather than being all-inclusive; therefore, case reports have been excluded.