Addition of Subcutaneous Daratumumab to SOC Continues to Improve Responses in Newly Diagnosed AL Amyloidosis

The addition of subcutaneous daratumumab (Darzalex) to the standard of care combination of bortezomib (Velcade), cyclophosphamide, and dexamethasone (D-VCd) continued to induce hematologic and organ responses, compared with VCd alone, in patients with newly diagnosed light chain (AL) amyloidosis, according to data from an 18-month follow-up to the phase 3 ANDROMEDA study (NCT03201965) that were presented during the 63rd American Society of Hematology Annual Meeting.¹

“Systemic light chain amyloidosis, are AL amyloidosis, is a rare plasma cell disease characterized by extracellular deposition of insoluble amyloid fibrils into organs, such as the heart and kidneys, leading to progressive organ dysfunction and ultimately death,” Raymond Comenzo, MD, of Tufts Medical Center in Boston, said during a presentation of the data. “Due to the variety of clinical presentations and nonspecific symptoms that patients can experience, it may take several years before patients receive a diagnosis, so they are more advanced [at presentation].”

Previously, the 6- and 12-month analyses of the ANDROMEDA study showed that the addition of daratumumab to VCd was superior to VCD alone, including higher rates of complete responses (CRs), prolonged major organ deterioration progression-free survival (PFS), improved organ response, and an acceptable safety profile.²

As of the May 2021 cutoff, median durations of treatment in the D-VCd and VCd arms were 21.3 months (range, 0.03-25.8) and 5.3 months (range, 0.03-7.3), respectively. In the daratumumab combination arm, 149 patients (77.2%) continued with monotherapy after 6 cycles of D-VCd. Of note, 17 patients (11.4%) in that arm are still receiving treatment with daratumumab.

The D-VCd arm demonstrated sustained superiority rates of deep hematological responses (n = 179; 91.8%), compared with the VCd arm (n = 149; 77.2%).

After a median follow-up of 25.8 months, hematologic CR rates were significantly higher in the D-VCd arm, compared with the VCd arm, at 60% vs 19%, respectively (odds ratio [OR], 6.0; 95% CI, 3.8-9.6; P < .0001). With 14.4 months of additional follow-up, the CR rate deepened from 53% to 60% in the D-VCd arm. Similarly, the D-VCd arm demonstrated higher rates of very good partial responses (VGPRs) compared with the VCd arm at 79.0% vs 50.3% (OR, 3.74; 95% CI, 2.39-5.86; P < .0001), which was improved from 77% at the 11.4-month follow-up previously conducted.

Of the patients who experienced a response among both arms, the median time to VGPR or better was shorter with the addition of daratumumab (0.56 months), compared with the standard of care regimen (0.82 months).

At 18 months, the cardiac response analysis demonstrated greater responses in the D-VCd arm vs VCd arm (53% vs 24%, respectively; OR, 3.7; 95% CI, 2.1-6.6; P < .001). From the 6-month analysis, the D-VCd arm improved from 42%. “The hematological improved response rates continued to favor D-VCd over VCd across all prespecified subgroups, including subgroups of patients with stage III cardiac involvement, patients with any cardiac involvement at baseline, and patients with the t(11;14) translocation represented in perhaps 50% to 60% of AL patients,” Comenzo said.

Similarly, renal response rates continued to be superior with the addition of daratumumab at 18 months (58% vs 26%, respectively; OR, 4.4; 95% CI, 2.4-7.9; P < .001). From the 6-month analysis, the D-VCd arm was improved from 54%.

At 18 months, 79 deaths occurred, 34 in the D-VCD group (17%) and 45 in the VCd group (24%). “The difference in the number of deaths between D-VCd and VCd increased over time, with a greater number of deaths related to disease progression in the VCD group. With a longer treatment time for the D-VCd group, more deaths occurred, compared with VCd. Importantly, overall survival will be analyzed after about 200 events have occurred,” Comenzo said.

Compared with the 12-month analyses, only 1 additional grade 3/4 treatment-emergent adverse event (TEAE) occurred, and there were no additional infusion-related reactions reported. Serious AEs occurred in 47% of the D-VCd group and 36% of the VCd group. The most frequently reported serious AE in both treatment groups was pneumonia (7% vs 5%, respectively). Lastly, discontinuation rates dues to TEAEs were similar in both groups (5% vs 4%).

Based on the findings presented at the 2020 ASH Annual Meeting and Exposition,2 the 4-drug combination was approved for this indication by the FDA in January 2021 and the EMA in June 2021.

In the randomized, open-label, active-controlled phase 3 study, investigators randomized 388 patients 1:1 to receive either D-VCd (n = 195) or VCd (n = 193) for six 28-day cycles. In the treatment phase, doses of each agent were administered as follows:

• 1800 mg daratumumab administered once weekly in cycles 1 and 2, and every 2 weeks in cycles 3 to 6;
• 1.3 mg/m2 bortezomib;
• 300 mg/m2 cyclophosphamide (up to 500 mg per week); and
• 20 to 40 mg dexamethasone.

Moreover, patients in the D-VCd arm received only subcutaneous daratumumab at 1800 mg after cycle 6 every 4 weeks, up to a maximum of 24 cycles from their first dose, or until major organ deterioration-PFS.

In the posttreatment phase, both groups of patients were observed until major organ deterioration-PFS.

Included in the study were patients with newly diagnosed AL amyloidosis with measurable hematologic disease, no prior therapies, 1 or more involved organs, cardiac stage I to IIIA, estimated glomerular filtration rate of 20 mL/min or more, and absence of symptomatic multiple myeloma.

Overall hematologic CR rate, defined as normalization of free light chain (FLC) levels and ratio (FLCr) and negative serum and urine immunofixation, served as the primary end point. Secondary end points included major organ deterioration PFS, organ response rate, time to hematologic response, overall survival (OS), and safety.

Patients were stratified by cardiac stage, transplant offering in local country, and creatine clearance.

Comenzo noted that baseline characteristics were well balanced between arms. Median ages in the D-VCd and VCD arms were 62 (range, 34-87) and 64 (range, 35-86) years. The majority were White men. Time from diagnosis in both arms, respectively was 48 (range, 8-1611) and 43 (range, 5-1102) days. Both arms reported a median of 2 organs involved in their diagnosis. Moreover, the majority has cardiac stage II disease and renal stage 1 disease.

In the findings presented at last year’s meeting, the median follow-up was 11.4 months (range, 0.03-21.3+), and the median durations of treatment were 9.6 months and 5.3 months in the D-VCd and VCd groups, respectively.2

Patients treated with D-VCd demonstrated higher rates of deep hematological responses by all criteria compared with the VCd arm (53% vs 18%, respectively; OR, 5.1; 95% CI, 3.2-8.2; P < .0001). Moreover, major organ deterioration PFS was longer in those who experienced a deep hematological response, regardless of the hematological response criteria used.2

“The results of this updated analysis and conclusion confirm the treatment benefit of D-VCd in patients with AL amyloidosis. D-VCd continued to significantly improve outcomes with over 2 years of follow-up, including a deeper hematologic response and higher rates of cardiac/renal response with no new safety signals,” Comenzo said. “This update of the ANDROMEDA study demonstrates the continued benefit of D-VCd over VCd, and together, with its recent approval in 9 countries globally, support D-VCd as a new standard of care for patients with newly diagnosed AL amyloidosis.”

Reference

1. Comenzo R, Palladini G, Kastritis E, et al. Subcutaneous daratumumab with bortezomib, cyclophosphamide, and dexamethasone in patients with newly diagnosed light chain (AL) amyloidosis: 18-month analysis of the phase 3 ANDROMEDA Study. Presented at: 2021 ASH Annual Meeting and Exposition; December 11-14, 2021; Atlanta, Georgia. Abstract 159.
2. 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. Blood. 2020;136(suppl 1):48-50. doi:10.1182/blood-2020-137582