ANDROMEDA: Dara-VCd for newly diagnosed AL amyloidosis: the next galaxy or a new standard of care?

1. Introduction

Immunoglobulin light chain (AL) amyloidosis is a clonal plasma cell disorder characterized by abnormal deposition of insoluble amyloid fibrils in the vital organs including heart (75%), kidneys (65%), liver (17%), soft tissues (17%), and the peripheral and autonomic nervous system (15%), causing end-organ dysfunction [1]. Diagnosis is often challenging and survival outcomes are poor due to advanced stage organ damage at the time of presentation2 Until recently, treatment for newly diagnosed AL amyloidosis comprised chemotherapy combinations traditionally used for multiple myeloma including the triplet, bortezomib, cyclophosphamide, and dexamethasone (VCd) [2].

In January 2021, the US Food and Drug Administration approved daratumumab (Dara) in combination with VCd for treatment of newly diagnosed AL amyloidosis based on the ANDROMEDA study. ANDROMEDA was a randomized, multicenter, open label, phase 3 trial, investigating safety and efficacy of Dara-VCd in patients with measurable hematologic disease and organ involvement [3]. Patients were randomized to receive VCd or VCd in combination with Dara (D-VCd). All patients received subcutaneous (SC) bortezomib 1.3 mg/m², cyclophosphamide 300 mg/m² orally or intravenously (IV), and dexamethasone 40 mg for 6 cycles of 28 days duration. SC daratumumab-hyaluronidase 1800 mg was given weekly for 8 doses, biweekly for 8 doses, and monthly thereafter. Dara was continued until disease progression, unacceptable toxicity, or a total of 24 cycles (Figure 1). A total of 388 patients were randomized to receive treatment and baseline patient characteristics were well balanced in the two arms. A total of 71% and 59% of the patients had cardiac and renal involvement, respectively. More than one-third of the patients had cardiac stage IIIa involvement. The primary end point of the trial was hematologic complete response rate (CR) and key secondary end points included major organ deterioration–progression-free survival (MOD-PFS), organ response rate, survival, and safety. MOD-PFS was defined as any one of the following events (whichever comes first): death; cardiac deterioration (requiring cardiac transplant, left ventricular assist device, or intra-aortic balloon pump); end stage renal disease requiring hemodialysis or renal transplant; or hematologic progression per consensus guidelines [3].

Figure 1. ANDROMEDA study design.

Fifty-three percent of patients in the D-VCd arm achieved a CR versus (vs) 18% in the VCd arm (95% CI, 2.1–4.1; p < .0001). MOD-PFS (HR, 0.58; 95% CI, 0.36–0.93; p = .02) and organ responses (cardiac: 42% vs 22%; renal: 54% vs 27%) were superior in the D-VCd arm. Hematological CR/VGPR at 1 and 3 months were superior in the D-VCd arm and were associated with reduced risk of death or MOD in the multivariate analysis. Median OS was not reached at the time of data cut off (Table 1) [3].

Table 1. Summary of efficacy outcomes

Outcome	Dara-VCd, N (%) (N = 195)	VCd, N (%) (N = 193)
CR	104 (53.3)	35 (18.1)
ORR	179 (91.8)	148 (76.7)
VGPR or better	153 (78.5)	95 (49.2)
MOD PFS Hematologic progression Major organ deterioration Death	8 (4.1) 1 (0.5) 25 (12.8)	25 (13) 7 (3.6) 21 (10.9)
Cardiac response at 6 months	41.5%	22.2%
Renal response at 6 months	53%	23.9%
Quality of life GHS Fatigue	MTTI/MTTW, months 7.82/4.7 9.3/8.84	MTTI/MTTW, months 16.79/2.89 NE/3.75

Dara: daratumumab; VCd: bortezomib-cyclophosphamide-dexamethasone; CR: complete response; mo: months, ORR: overall response rate; VGPR: very good partial response; MOD PFS: major organ deterioration–progression-free survival; GHS: global health status; MTTI: median time to improvement; MTTW: median time to worsening; NE: not estimable.

The trial also evaluated ‘deep hematological response’ defined as involved free light chain (iFLC) less than 20 mg/L regardless of free light chain ratio (FLCr) and the difference in involved and uninvolved light chains (dFLC) less than 10 mg/L regardless of FLCr. Regardless of the criteria used, the addition of Dara to VCd increased the rate of deep hematological responses that correlated with longer MOD-PFS [4]. Patients in both arms tolerated treatment, with the most reported adverse reactions (≥20%) being diarrhea, peripheral edema, constipation, fatigue, upper respiratory infection, and peripheral neuropathy. The rate of treatment discontinuation was 4% in both arms [3].

2. Expert opinion

The ANDROMEDA trial clearly demonstrated that the addition of Dara to VCd resulted in early and deep hematological responses in patients with newly diagnosed AL amyloidosis, which in turn, led to improvement in organ function and quality of life [5]. With remarkable efficacy and safety profiles, there are several important aspects of this trial and regimen with significant relevance in clinical practice. Moreover, it is important to highlight some of the unanswered questions and areas of unmet need before we determine if the ANDROMEDA trial and the addition of Dara represent a new standard of care for AL Amyloidosis or just a semblance of Earth’s closest galaxy, needing to be examined with an analytical telescope.

Given early and deep hematological responses seen with the quadruplet therapy, addition of Dara may allow for bortezomib to be dose reduced or eliminated in patients with underlying peripheral neuropathy. Similarly, volume overload issues commonly seen in patients on high-dose dexamethasone in VCd may be avoided by corticosteroids dose reduction, without compromising the regimen efficacy. Dara in SC formulation is not only associated with lower incidence of injection reactions but also smaller volumes and faster administration. SC Dara also helps avoid volume overload issues associated with infusional therapy, lessens chemotherapy chair time, and reduces resource utilization.

Time to best hematological response is around 2 months and these early responses translate into superior organ responses at 6 months. As the vast majority of the patients achieve VGPR, which is a desirable response, duration of chemotherapy in transplant eligible and ineligible patient populations remains unclear. In transplant eligible patients, 2–4 cycles of induction chemotherapy with Dara-VCd to minimize plasma cell burden and achieve VGPR prior to transplant appears to be a reasonable strategy. However, whether to continue Dara monotherapy as maintenance post-transplant remains unclear as the trial did not include transplant eligible patient population. Similarly, in the transplant ineligible patient population, whether to continue systemic chemotherapy beyond 6 cycles with Dara monotherapy, especially in patients who achieve deeper hematological remission, needs to be determined with long-term follow-up of the study. OS has not yet been reached and may take several years to report. Perhaps, attainment of minimal residual disease (MRD) negativity can be used as a surrogate marker of long-term remission and indicator of cessation of therapy [6]. This will have a meaningful impact on patients’ quality of life and the overall costs of therapy.

The costs of adding Dara to standard treatment should also be considered. An 1800 mg dose of SC Dara-hyaluronidase cost approximately $10,000 US dollars [7]. If a patient were to receive a full 24 months of treatment, this would amount to an additional $340,000 in medication costs alone. A costs-benefit analysis should be considered given the lack of OS data at this time, more so in resource limited settings including many European countries.

The trial showed that deep hematological remission with iFLC less than 20 mg/L and dFLC lower than 10 mg/L strongly correlates with organ responses and hence these two parameters may be increasingly used as the relevant endpoints in future clinical trials instead of historical endpoints of hematological CR/VGPR. This is particularly relevant as FLCr may continue to be abnormal at very low light chain levels and hence may not be an appropriate hematological response criterion. With a relatively short median follow-up of 11.3 months and with 61% of the patients in the control arm receiving Dara based therapy upon progression, it is not surprising that the trial has yet to show any difference in overall survival. While the overall number of deaths and deaths within the first 60 days of treatment were similar between the two arms, deaths attributed to cardiac adverse events were more frequent in the Dara-VCd arm (11.9% vs 7.4%) [3]. While deaths related to cardiac adverse events are not uncommon in patients with advanced stage cardiac disease (one third of the patients in this trial), higher incidence of cardiac deaths in the Dara-VCD arm may not be a statistically significant outcome from which to draw any meaningful conclusions. Although significant organ responses were seen in the Dara-VCd arm, patients with stage IIIb cardiac disease were excluded from the trial and continue to represent an area of unmet need for newly diagnosed AL amyloidosis. Whether to use Dara-VCd in patients with advanced stage cardiac amyloidosis remains a measure of physician gestalt and heuristic approach to decision-making. Combinations of Dara with novel immunomodulatory agents including pomalidomide [8] and proteasome inhibitors including ixazomib [9] in newly diagnosed and relapsed refractory AL amyloidosis are currently being investigated.

3. Conclusion

In summary, given the remarkable efficacy and safety profile, Dara-VCd should be considered as a new standard of care for treatment of newly diagnosed AL amyloidosis irrespective of transplant eligibility. Timely diagnosis, organ specific risk stratification at diagnosis, improvement in treatment strategies for both newly diagnosed and relapsed disease, and therapy change for poor responders are developments that will help change the natural history of the AL amyloidosis.

Declaration of interests

H Hashmi is on advisory boards of Sanofi, Janssen and Bristol-Myers Squibb. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

One of the peer reviewers on this manuscript is a named patent inventor on anti-CD38 antibodies. Two additional peer reviewers have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

The authors have no funding to report.