Added Daratumumab Leads to Significant Hematologic Responses in Amyloidosis

Raymond L. Comenzo, MD

Results for the phase 3 ANDROMEDA study showed an improvement in hematologic complete response (CR) rates with the combination of daratumumab (Darzalex) plus bortezomib (Velcade), cyclophosphamide, and dexamethasone (VCd) compared with VCd alone in patients with newly diagnosed amyloid light-chain (AL) amyloidosis.

The rate of hematologic CR, defined as normalization of free light chain (FLC) levels and FLC ratio, and negative serum and urine immunofixation, was 53% in patients who received daratumumab plus VCd (D-VCd; n = 195) versus 18% in patients who received VCd alone (n = 193; odds ratio [OR], 5.1; 95% CI, 3.2-8.2; P < .0001), according to data presented at the 2020 ASH Annual Meeting.

Moreover, higher rates of best hematologic response at any time were observed with D-VCd vs VCd in patients evaluated for the primary end point (56.9% vs 18.7%, respectively; OR, 5.68; 95% CI, 3.58-9.00; P < .0001), those with involved FLC of 20 mg/L or lower (71.3% vs 20.2%, respectively; OR, 9.8; 95% CI, 6.1-15.7; P < .0001), patients with a difference between involved and uninvolved FLC of less than 10 mg/L (65.6% vs 30.6%, respectively; OR, 4.3; 95% CI, 2.8-6.6; P < .0001), and those with International Society of Amyloidosis criteria (49.2% vs 23.3%, respectively; OR, 3.25; 95% CI, 2.09-5.06; P < .0001).

“No matter what criteria for response we use, daratumumab added to VCd increased the depth of hematologic responses in newly diagnosed patients with AL [amyloidosis] and also prevented major organ deterioration in patients,” said lead study author Raymond L. Comenzo, MD, director of Transfusion Services and the John C. Myeloma and Amyloid Program and Tufts Medical Center. “This is extremely important because it is the organ deterioration that causes the impact on quality of life.”

No therapies are approved to treat AL amyloidosis, but standard options, such as VCd have been extrapolated from multiple myeloma. As such, treatment options are needed to combat multiorgan involvement that is often observed with delayed AL amyloidosis diagnosis, while inducing rapid and deep hematologic responses.

After screening, the open-label, active-controlled ANDROMEDA protocol randomized eligible patients (n = 388) 1:1 to receive weekly VCd for 6 cycles plus 1800 mg of subcutaneous daratumumab for 2 weekly cycles, followed by an additional 3 to 6 cycles every 2 weeks, followed by 1800 mg of subcutaneous daratumumab every 4 weeks until major organ deterioration–progression-free survival (MOD-PFS) or a maximum of 24 cycles, or weekly VCd for 6 cycles. Patients were observed until MOD-PFS.

Eligible patients had AL amyloidosis with at least 1 organ impacted, no prior therapy for AL amyloidosis or multiple myeloma, cardiac stage I to IIIA disease, and an estimated glomerular filtration rate of at least 20 mL/min.

Patients were stratified by cardiac stage, whether transplant was typically offered in the patient’s local country, and creatinine clearance.

The primary end point was overall hematologic CR rate, with secondary end points including MOD-PFS, organ response rate, time to hematologic response, overall survival, and safety.

Baseline patient characteristics and demographics, including age, sex, race, ECOG performance status, baseline difference between involved and uninvolved FLC, cardiac stage, and renal stage, were well balanced across cohorts.

In both groups, patients had a median of 2 involved organs, including heart, kidney, liver, and other; 66% of patients receiving D-VCd and 65% of patients receiving VCd had 2 or more organs involved.

The median follow-up time was 15.7 months (range, 0.0-24.1). The median duration of treatment was 15.8 months (range, 0.1-24.1) in patients who received D-VCd and 5.3 months (range, 0.03-7.3) in patients who received VCd.

Additionally, D-VCd induced a significantly prolonged MOD-PFS compared with VCd alone. MOD-PFS events occurred in 17.4% (n = 34) of patients on D-VCd vs 27.5% (n = 53) of patients on VCd alone (HR, 0.58; 95% CI, 0.36-0.93; P = .0211).

MOD-PFS was defined as the first-occurring event: death, cardiac deterioration that required cardiac transplant, left ventricular assist device, or intra-aortic balloon pump, end-stage renal disease that required hemodialysis or renal transplant, or hematologic progression per consensus guidelines.

Further analysis revealed that 23.5% (n = 8) of patients in the D-VCd group had hematologic progressive disease, with 1 patient dying after hematologic progressive disease, vs 47.2% (n = 25) of patients in the VCd group, with 6 deaths. End-stage cardiac or renal failure occurred in 2.9% (n = 1) and 13.2% (n = 7) of patients, respectively, with 1 patient each dying after end-stage organ failure. Moreover, 73.5% (n = 25) of patients on D-VCd and 39.6% (n = 21) of patients on VCd died during the study.

Additional findings showed that the depth of response, measured by all hematologic response criteria, was prolonged in the D-VCd group vs the VCd group.

Observed safety signals were consistent with the known toxicities associated with subcutaneous daratumumab and VCd. Notably, higher rates of cardiac and renal responses at 6 months were observed with D-VCd vs VCd (cardiac, 42% vs 22%, respectively; renal, 54% vs 27%, respectively).

“These results clearly support the activity and the benefit of daratumumab subcutaneously in this population. Obviously, longer follow-up, which is underway, is needed to determine the overall impact of depth of response and prolongation of [MOD-PFS] on overall survival,” concluded Comenzo.

_Reference

_{Comenzo RL, Kastritis E, Minnema MC, et al. Reduction in absolute involved free light chain and difference between involved and uninvolved free light chain is associated with prolonged major organ deterioration progression-free survival in patients with newly diagnosed AL amyloidosis receiving bortezomib, cyclophosphamide, and dexamethasone with or without daratumumab: results from ANDROMEDA. Presented at: 2020 ASH Annual Meeting & Exposition; December 5-8, 2020; virtual. Abstract 552.}