Progress in research: Daratumumab improves treatment outcomes of patients with AL amyloidosis
Abstract
Outcomes for patients with systemic light-chain (AL) amyloidosis have improved over the last two decades with timely diagnosis, use of novel chemotherapeutic agents, risk stratification and better patient selection criteria before hematopoietic autologous stem cell transplant (ASCT). However, majority of patients have advanced stage disease at initial presentation and at relapse rendering them ineligible for intensive cytotoxic chemotherapy or ASCT. Daratumumab (Dara) with or without standard chemotherapy appears to be an excellent treatment option for newly diagnosed and relapsed refractory AL amyloidosis. This is largely due to its tolerable safety and remarkable efficacy as seen in multiple retrospective, small phase II studies as well as a phase III randomized controlled trial. Here we review published clinical trials and retrospective data of Dara in AL amyloidosis that explore its role as a valuable addition to the treatment armamentarium for this challenging disease.
1. Introduction
1.1. Epidemiology
Immunoglobulin light chain (AL) amyloidosis is a monoclonal plasma cell disorder characterized by extracellular deposition of insol- uble aggregates of β-pleated amyloid fibrils that lead to organ dysfunc- tion (Merlini and Bellotti, 2003). AL amyloidosis is a rare disease with an annual incidence of 9–14 cases per million person-years (Quock et al., 2018) and approximately 4000 new cases of AL amyloidosis are esti- mated every year in the United States by the National Organization for Rare Disorders (NORD). Estimated prevalence is reported 8–15 cases per million person-years before 2010 that has increased to 40–58 cases per million person-years since then (Quock et al., 2018; Duhamel et al., 2017). Most commonly affected organs include heart (75 %), kidneys (65 %), liver (17 %), soft tissues (17 %) and the peripheral and auto- nomic nervous system (15 %) (Sachchithanantham et al., 2016; Palla- dini and Merlini, 2016).
1.2. Risk factors
Risk factors for AL amyloidosis include a pre-existing monoclonal
gammopathy of undetermined significance (MGUS) with a relative risk of 8.8 as compared to patients who do not have MGUS (Kyle et al., 2018). Overt AL amyloidosis has also been reported to coexist in about 10–15 % of patients with multiple myeloma (MM) (Desikan et al., 1997). Affected patients may have AL amyloidosis alone or in association with other plasma cell dyscrasias besides MM like lymphoplasmacytic lym- phoma (LPL) and Waldenstro¨m macroglobulinemia (WM) (Kyle et al., 2002). Another risk factor includes genetic susceptibility as single nucleotide polymorphisms (SNPs) have been identified to have a sta- tistically significant association at 10 different loci. Among these, the variant rs9344 that promotes the translocation t (Muchtar et al., 2019; Kourelis et al., 2013a) within the splice site of CCND1 that encodes cyclin D1 and the variant rs79419269 that assists in chromatin remodeling have been found to have the highest significance (p = 7.80 × 10—11 and 5.2 × 10-8, respectively) (da Silva Filho et al., 2017).
1.3. Prognostic factors
Prognosis of AL amyloidosis depends on multiple factors including nature, number, extent of organ involvement and stage of disease. For some patients with significant degree of major organ impairment such as advanced cardiac failure, median survival is estimated to be less than six months (Kumar et al., 2011). Other major causes of mortality include hepatic failure and infections (Muchtar et al., 2019). However, for pa- tients without cardiac involvement median survival can be more than 5 years and current literature shows it is possible to achieve survival for more than 10 years even if they fail to respond to first-line therapy (Muchtar et al., 2019; Ravichandran et al., 2020). The presence and severity of cardiac involvement determined by Brain Natriuretic Peptide (BNP), N-Terminal ProBNP and troponin (Dispenzieri et al., 2004) along with bone marrow plasma cell (BMPC) infiltrate of >10 % are associated with poorer survival (Duhamel et al., 2017; Kourelis et al., 2013a).
Similarly, dFLC (difference between involved and uninvolved circu- lating free light chains) of 180 mg/Liter or more has been incorporated in Mayo Clinic’s revised staging system as it correlated to the severity of the disease (Kumar et al., 2012). Recent studies have shown that patients with a very low dFLC (<50 mg per liter) have better survival as an in- dependent good prognostic factor (Milani et al., 2017a). Other bio-
markers include an elevated von Willebrand factor (Kastritis et al., 2016) and growth differentiation factor-15 (Kastritis et al., 2018) that have been associated with early death and progression to dialysis respectively. Over the last two decades, early mortality has decreased and possibility of long-term survival has improved largely as a conse- quence of prompt diagnosis, risk stratification and early initiation of effective therapy aimed at achieving deep hematological remissions (Muchtar et al., 2017a; Dispenzieri et al., 2001).
1.4. Effective regimens with efficacy data
Current treatment strategy is directed at the control of plasma cell (PC) proliferation in the bone marrow (BM) to decrease the production of amyloidogenic proteins. This in turn limits further organ damage and may allow regression of tissue amyloid deposition, eventually leading to organ function recovery over months to years (Cibeira et al., 2011a). Effective treatment requires a multidisciplinary approach with collab- oration of experts in various fields including hematology, cardiology, nephrology, gastroenterology, neurology, pulmonary and stem cell transplantation. For patients who are newly diagnosed (ND) transplant eligible, high dose melphalan (HDM) and ASCT is very effective in inducing deep hematological remission (34 %–48 %) (Cibeira et al., 2011b; Minnema et al., 2019) which in turn prolongs survival with 5-year overall survival approaching 77 % (72 %–82 %) (Dispenzieri et al., 2001; D’Souza et al., 2015). Patients can typically proceed directly to ASCT without requiring 2–4 cycles of cyclophosphamide, bortezomib and dexamethasone (CyBorD) induction therapy unless they have con- current myeloma defining events as defined by International Myeloma Working Group criteria (Rajkumar et al., 2014), or BMPC percentage is
>10 %, or presence of high-risk genetics on fluorescence in situ hybridization (del 17p, t (Sachchithanantham et al., 2016; Kourelis et al., 2013a), or t(14;20)) or if there is an anticipated delay in ASCT beyond one month (Treatment Guidelines: Amyloidosis [Internet], 2019; Kourelis et al., 2013b). However, majority of patients (~75 %) at time of presentation are not candidates for transplant due to fraility, renal insufficiency, advanced heart failure, or multiorgan involvement that all contribute towards significant transplant-related mortality (Dispenzieri et al., 2013).
Patients with ND transplant-ineligible disease are now commonly offered upfront Dara in combination with CyBorD based on the results of ANDROMEDA study as reviewed underneath. Other potential thera- peutic regimens include melphalan-based combinations (Gertz, 2012) (melphalan-dexamethasone, melphalan-bortezomib-dexamethasone) with better hematological and organ responses seen with three- drug (bortezomib, melphalan and dexamethasone) combinations than two-drug combinations (melphalan and dexamethasone) (Kastritis and Dimopoulos, 2016). Reported hematological complete response (CR) for CyBorD (Palladini et al., 2015) and melphalan-dexamethasone (MDex) (Palladini et al., 2014) are 23 % and 12 %, respectively. Cardiac and renal response rates approximate 17 % & 25 % for CyBorD (Palladini et al., 2015), and 20 % & 17 % for MDex (Palladini et al., 2014). In the relapsed/refractory (RR) setting, treatment options depend on the risk stratification, previously used agents and the duration of previous remission. Potential options include Dara monotherapy or combination therapy (if not used upfront), low-dose immunomodulatory agents (lenalidomide, pomalidomide), proteasome inhibitors (ixazomib, car- filzomib), venetoclax, and melphalan-based combinations, none of which have been studied in randomized clinical trials in RR setting. Therefore whenever possible, clinical trials should be offered and referral to centers of excellence should be considered. This review fo- cuses on the efficacy of Dara in RR and ND AL amyloidosis and discusses the significant predictive and prognostic factors that will help direct future prospective studies and clinical trials.
2. Daratumumab in the treatment of AL amyloidosis
Monoclonal antibody (mAb) based treatments have revolutionized the treatment of hematological malignancies due to their high specificity and minimal off target toxicity. Dara, a humanized IgG1K anti-CD38 mAb, targets cell surface antigen CD38 that is expressed in high con- centration on malignant BMPC and in low concentration on normal hematopoietic and non-hematopoietic cells (Lokhorst et al., 2015). This ensues induction of complement dependent cytotoxicity (CDC), anti- body dependent cell-mediated cytotoxicity (ADCC), antibody dependent cellular phagocytosis (ADCP), tumor cell apoptosis and modulation of enzymatic activity of the receptor.
2.1. Role of Daratumumab in relapsed and/or refractory AL amyloidosis
Since its successful use in the treatment of AL amyloidosis (Sher et al., 2016) in 2016, Dara has been used both as monotherapy and in combination with chemotherapy in RR disease setting. Initial report by (Sher et al., 2016) described the efficacy of Dara in two previously treated AL amyloidosis patients who had disease progression after pro- teasome inhibitors (PI) (bortezomib and carfilzomib), immunomodula- tory drugs (IMiDs), and ASCT. One of the patients had both cardiac and hepatic involvement while the other had disease limited to the kidneys. Both patients achieved CR and normalization of serum free light chains (sFLC). These results were encouraging as Dara monotherapy showed unexpected deep remissions in heavily pretreated disease. Since then, 2 phase II clinical trials have evaluated Dara’s efficacy and safety as a rescue therapy and many institutional retrospective series have been published in the last 4 years. Fig. 1 and Table 1 summarizes these studies highlighting the median age, lines of therapy, extent of organ involve- ment, hematologic & organ response rates and treatment toxicities.
Despite the limitations of borderline performance status in an elderly population (median age 66 & 67, respectively) and heavily pretreated disease (lines of therapy (LOT): 1–10), retrospective series by Kaufman et al. (2017) and Khouri et al. (2019) introduced the role of Dara monotherapy as a safe and effective treatment option. This was partic- ularly true in patients with disease relapse after ASCT (16 % and 65 %, respectively) or in patients with cardiac involvement (72 % and 50 %, respectively) where salvage therapy with IMiDs may be contraindicated. Even patients with suboptimal or poor response (15–60 % refractory) to previous LOT responded well to Dara monotherapy. Although data is not available on the timing of organ response, hematological responses were seen as early as 4 weeks, further highlighting the remarkable efficacy of Dara in this patient population.
At the International Symposium on Amyloidosis in 2018, Abeykoon et al. (2019) compared dara monotherapy (DMT) with dara combination therapy (DCT). The estimated 10-month overall survival (OS) was longer in the DMT as compared to DCT (100 % vs 89 %), however, DCT led to superior hematological [overall response OR: 78 % vs 88 %, CR / VGPR (very good partial response): 77 % vs 82 % in DMT vs DCT] and organ responses (cardiac 18 % vs 36 %). Nevertheless, a formal statis- tical analysis of the 2 groups was not done due to the non-randomized design of the retrospective study. The study reinforced the use of Dara, either as monotherapy or combination therapy, achieving deep hema- tologic responses (>80 %) in RR AL amyloidosis, without major grade 3 or higher treatment-related adverse events (TRAE) compared to other conventional chemotherapies (Mahmood et al., 2014).
In their retrospective series, Van de Wyngaert et al. (2020) reported higher rate of infectious complications with grade 3–5 infections seen in 30 % of the patients including one infection-related death (upper res- piratory tract infections in 8 patients, pneumonia in 7 patients and bacteremia in two patients). Most of the patients in this small study (n = 15) were frail with a median Eastern Cooperative Oncology Group (ECOG) score of 2 (range 0–3), a Cumulative Illness Rating Scale (CIRS) score ≥6 in all patients (median 14; range, 8–27), and a Charlson score ≥2 in 87 % (median 4; range 1–8). About 67 % of the patients had Mayo cardiac Stage IIIA/B disease. Despite this, early and deep hematologic and organ responses were seen in 86 % and 45 % of patients, respec- tively. Given the incidence of infections, authors suggested that infec- tious prophylactic measures are warranted in patients with high fraility scores (ECOG > 2, CIRS and Charlson score).
More recently, Kimmch et al. published the largest (n = 168) consecutive series comparing daratumumab/dexamethasone (DD) and daratumumab/bortezomib/dexamethasone (DVD). DVD group had a higher BMPC (13 % vs 19.5 %, p = .0014) and more patients in the DD versus (vs) the DVD group had significant previous IMiD exposure (73 % vs 5%, p = <.001), IMiD refractoriness (40 % vs 2%, p= <.001) and prior ASCT (23 % vs 8%, p = .019). Although OR was similar (64 % vs 66 %),median hematologic event free survival (hemEFS) was shorter with DD vs DVD group (11.8 vs 19.1 months). It is important to highlight that time from first therapy with DD was longer than DVD, 29 months (range 0–143) vs 5 months (0–104), p <.0001. DD was used as a median third line therapy while DVD was used as a second line therapy which could lead to some discrepancies in outcomes. Hence, no direct comparison for efficacy or survival could be made between the two groups. Trans- location t(11:14) was beneficial whereas gain of 1q21, hyperdiploidy, and nephrotic range albuminuria with an albumin/creatinine ratio (ACR) >220 mg/mmol were considered adverse prognostic factors for outcomes with Dara based therapy. Poor outcomes associated with traditional risk factors of dFLC >180 mg/dL, NT-ProBNP> 8500 ng/L could not be overcome with Dara salvage therapy.Chung et al. (2020) emphasized the significance of achieving strin- gent dFLC response (dFLC <1 mg/dL) at 3-months after initiation of therapy. More than 80 % of patients achieving this response were expected to be alive without disease progression or death at 3-year follow up. Among responders who did not achieve a stringent dFLC, the 3-year time-to-next-treatment (TTNT)-free survival was 25 % as compared to 82 % in those with the desired responses (p=<.01). Of note, 2 patients also had prior heart transplant and no rejection was reported. Based on the results of a multicenter retrospective study, Lecumberri et al. (2020) suggested that hematological responses were more likely to occur when Dara is used as a second-line therapy rather than in subsequent therapies (92 % vs 61 %, p = 0.06), emphasizing early use of Dara in the disease
course. However, this benefit can be because of less aggressive disease
that has not yet needed multiple LOT. In the subgroup of patients (n = 7) with NT-ProBNP >8500 ng/L,median OS remained poor at ~4 months even though 3 of these patients had achieved a hematological response (1PR, 1 VGPR, 1CR).
Milani et al. (2020) concluded that there was no significant differ- ence in CR/VGPR rates in patients that were treated with Dara mono- therapy as compared to combination regimens (CR/VGPR rates 59 % vs 60 %, p = .488). Responses were also not different when BMPC involvement was >20 % (85 % vs 81 %, p = .308), which has recently
been identified as a negative prognostic marker (Muchtar et al., 2020). However the sample size of DCT was small (n = 25). Dara showed deepening in responses if continued beyond 6 months; responses in 2 out of 4 patients improved from VGPR to CR (total CR% improved from 16 % to 30 %). The study also hypothesized that better cardiac responses maybe seen when Dara is used in combination with IMiDs like pomali- domide that is currently being evaluated in a phase II study at Pavia & the U.S. (NCT04270175).
In a phase II clinial trial, Sanchorawala et al. (2020) treated patients with Dara monotherapy until progression or unacceptable toxicity for up to 24 months. About 73 % of the patients had received PI, 41 % had received IMiDs, and 68 % had undergone ASCT. One-third of the pa- tients (3/10 patients) who had minimal residual disease (MRD) evalu- ation done by 10-color flow cytometry were MRD negative and interestingly 50 % of the patients who had hematologic CR (3/6 pa- tients) were MRD positive. The study showed the successful use of Dara in patients (3/22) with a prior solid organ transplant (SOT) without rejection or adjustment in immunosuppression. Atrial fibrillation (18 %) and congestive heart failure (14 %) appeared to be higher than what has been typically seen with Dara-based regimens in MM. This could be related to cardiac involvement with AL amyloidosis and sensitivity to hydration volume used with intravenous Dara. SC Dara is likely to ameliorate these adverse effects. Whether therapy should be dis- continued after 2 years of treatment will need to be answered with a randomized controlled trial in future.
In another phase II study, Roussel et al. (2020) reported outcomes of AL patients with dFLC>15 mg/L from 15 centers treated with DMT for a median of 6 months (16 infusions). Majority of the patients were refractory to bortezomib (32.4 %), IMiDs (58.8 %), and melphalan (47.4 %). Based on univariate analysis, authors concluded that response after first dose of Dara was the most important predictor of disease relapse. No meaningful response (absence of PR) after 4 doses of Dara was pre- dictive of absence of response at 6 months. Furthermore, the depth of response influenced duration of response (DOR) as patients who attained > VGPR (p = 0.039) had lower incidence of disease relapse at 16-month. Whether addition of another agent or complete change oF therapy in patients who failed to achieve a response after 4 weekly in- fusions, and whether Dara should be continued after 6 months of ther- apy in patients who have achieved at least a VGPR are some of the questions which remain unanswered.
Overall, all retrospective series and published trials suggest that Dara is highly effective in RR AL amyloidosis, with no apparent difference between single-agent and combination therapies.
2.2. Role of daratumumab in primary refractory AL amyloidosis
Use of Dara to induce deeper hematological responses was evaluated by Kastritis et al. 2018 (Kastritis et al., 2019) in 16 patients with pre- vious best response as VGPR and one patient in PR. A total of 15 patients with AL amyloidosis and 2 with light chain deposition disease after completing their primary bortezomib based therapy were given 4 weekly infusions of Dara as consolidation. At a follow up of 1 month, 41 % had improved their responses. For patients who achieved CR from VGPR (n = 6/16), 50 % were MRD negative by next-generation flow (NGF). The authors concluded that consolidation with a short course of achieved a hematological CR after their primary therapy with minimal to no additional toxicity. Whether the hematological responses seen with this consolidative therapy translate into an improvement in long-term survival or recovery of organ function remains to be seen. Moreover, this strategy may be useful for patients who are not ASCT candidates but the role of pre-ASCT consolidative therapy in patients who may be eligible for ASCT remains unclear.
2.3. Role of daratumumab in newly diagnosed AL amyloidosis
Role of SC Dara in combination with CyBorD in upfront treatment of amyloidosis compared with CyBorD alone is evaluated in recently completed randomized open-label phase III ANDROMEDA trial (Kas- tritis et al., 2021) [Table 2]. In this trial, treatment was discontinued after 6 cycles in the CyBorD arm, while Dara alone was administered monthly for 2 years or until progression in the experimental arm after 6 courses of dara-CyBorD arm. Second-line therapy was initiated in 42 % of patients in the CyBorD arm and in 10 % of subjects in the dara-CyBorD arm. Patients with advanced cardiac involvement (Stage IIIB-IV disease) were excluded from this trial. The hematological OR at 6 months (91 % vs. 77 %) as well as the rate of VGPR/CR (78 % vs. 49 %) were higher in the Dara-CyBorD arm as compared with CyBorD alone. Moreover, rates of cardiac and renal responses at 6 months were also significantly higher with Dara-CyBorD (42 % vs. 22 % and 54 % vs. 27 %, respectively). Systemic administration-related reactions to Dara occurred in 7.3 %(14 %); all such reactions were of grade 1 or 2. Results were consistent for patients with Stage III disease and t(11:14) translocation. Despite the longer 2 year maintainence of Dara, analysis without censoring for subsequent therapy still showed significantly longer survival free from major organ deterioration or hematologic progression in the Dara group. Grade 3 or 4 TRAE were reported in 43 %, notably lymphopenia (13 % vs 10 %), pneumonia (8% vs 4%), overall/congestive cardiac faiure (6% vs 5%) and diarrhea (6% vs 4%) [Table 2]. Overall, Dara in combination with CyBorD was well tolerated with manageable toxicities. This study led to the FDA’s accelerated approval of SC Dara in combination with CyBorD on January 15, 2021 in ND AL amyloidosis.
3. Expert opinion and future directions
Patients with RR AL as well as ND advanced stage AL amyloidosis have limited treatment options, especially with significant cardiac involvement. Traditional chemotherapeutic agents may be associated with significant toxicity and limited efficacy in this frail patient popu- lation. Based on the highlighted data, Dara appears to be highly effective and safe option for RR AL amyloidosis either as monotherapy or in combination. When used in combination therapy, there does not appear to be an increased risk of toxicities. This becomes even more important given the deep responses seen with addition of Dara to chemotherapy in ND AL amyloidosis patients. Patients that are deemed transplant ineli- gible due to multiple/major organ impairment can achieve a similar hematological CR (53 %) (Efstathios Kastritis et al., 2020) as compared to those treated with transplant (34 %–48 %) without exposing them to significant adverse effects from chemotherapy (Cibeira et al., 2011b; Minnema et al., 2019). Lower rates of infusion related reactions, reduced administration times and smaller administration volumes with SC formulation will pave the way for Dara-CyBorD to be the new standard-of-care irrespective of transplant eligibility in ND AL amyloidosis.
Preliminary observations can be made about safety of Dara in SOT patients based on the data by Boston University (n = 3) and Stanford group. This data is consistent with other small case series (n = 4) reinforcing that daratumumab-based salvage regimens were not associated with worsening organ/graft function but did bring forward an increased risk of infectious complications (Chaulagain et al., 2020). However, several questions remain unanswered and will help guide future clinical trials. It will be of interest if normalization of dFLC or involved FLC at 1 month (Roussel et al., 2020) or 3 months (Chung et al.,2020) can guide change to subsequent therapies or can predict early relapses. Currently there is no consensus on the criteria to initiate salvage therapy in patients with relapsed disease (Milani et al., 2017b). Some of the factors that should be taken into consideration before initiating therapy include; dFLC at time of diagnosis, time to FLC rise, depth of response after upfront therapy, clinical presentation and severity of organ dysfunction at the time of diagnosis. There remains an unmet need of a robust, validated clinical and biomarker driver criterion for hematologic progression before over organ-deterioration. A nascent concept of ‘high-risk dFLC progression’ (defined as dFLC of >20 mg/L, a level >20 % of baseline value, and a >50 % increase from the value reached at best response) has been proposed as a trigger for rescue treatment before cardiac progression based on a retrospective study of non-transplanted patients (Palladini et al., 2018). Therefore, the role of a short course of consolidative Dara for patients who fail to achieve adequate response before or after ASCT needs to be further elucidated. Similarly, given the heterogeneity in the duration of therapy in the above studies, the optimal duration of therapy for patients with RR disease is yet to be determined and practices vary from center to center. This is even more relevant for patients who fail to achieve meaningful recovery of organ function despite achieving hematological response. Perhaps, MRD assays may be able to address duration of therapy in future [NCT03346135].
Furthermore, it appears that Dara may not be able to overcome the effect of poor prognostic markers (dFLC >180 mg/dL, NT-ProBNP> 8500 ng/L), especially in the absence of early responses. Long-term validity of BMPC infiltrate >20 %, hyperdiploidy, +1q21, ACR > 220 (Kimmich et al., 2020) as a predictive marker of poor survival/outcome warrant further studies and more effective combination regimens of Dara need to be elucidated. Similarly, the favorable hematological impact of t(11:14) with Dara will need further exploration with the increasing use of (B-cell lymphoma) Bcl-2 inhibitors like venetoclax especially when t(11:14) overexpression is reportedly present in 50 % of the cases in AL amyloidosis (Muchtar et al., 2017b).
Role of Dara in patients with secondary AL amyloidosis is being actively pursued in several clinical trials. Lastly, combination of Dara with novel IMiDs including pomalidomide [NCT04270175] and PI including ixazomib [NCT03283917] are also being explored for possible improved organ responses, especially cardiac responses, that may confer a survival benefit (Table 3).
4. Conclusions
With earlier diagnosis, better risk stratification at diagnosis, enhanced biomarker-driven response evaluation, early therapy change for poor responders and improvement in treatment strategies for both newly diagnosed & relapsed disease, the prognosis of AL amyloidosis has improved significantly over the last few years. Daratumumab use, either as monotherapy or in combination therapy, leads to early and deep hematological responses with acceptable TRAE in patients with AL amyloidosis. This eventually leads to improvement in organ function and reversal of organ failure that major causes of morbidity and mor- tality in patients with AL amyloidosis. Given its efficacy and toxicity profile, Dara should be considered standard of care treatment for both ND and RR AL amyloidosis irrespective of transplant eligibility.