Outpatient Autologous Hematopoietic Stem Cell Transplantation in Patients with Multiple Myeloma

Abstract

Autologous hematopoietic stem cell transplantation is still the standard of care in patients with multiple myeloma who are eligible for transplantation, despite the recent availability of several lines of novel therapies. Several studies have shown that autologous transplantation using non-cryopreserved stem cells is safe, cost-effective, and leads to outcomes that are equivalent to transplantation of cryopreserved autologous stem cells. With daily clinical evaluation and intensive supportive care, performance of autologous stem cell transplantation at outpatient setting is safe, feasible, and cost-effective. However, there are specific inclusion and exclusion criteria that should be taken into consideration to select the right candidates for this modality of transplantation. Recipients of outpatient transplantation may require hospitalization in case of certain complications, such as febrile neutropenia, sepsis, decrease in performance status, and severe mucositis. Following outpatient autologous transplantation, maintenance therapy is usually given till disease progression.

1. Introduction

Multiple myeloma (MM), the second most common hematologic malignancy (HM), is characterized by proliferation of monoclonal plasma cells in the bone marrow and production of monoclonal proteins as well as occurrence of secondary end-organ damage [1, 2, 3, 4, 5, 6, 7]. Over the last two decades, the utilization of various novel therapies, such as proteasome inhibitors, immunomodulatory agents, and monoclonal antibodies, in the treatment of patients with newly diagnosed MM and relapsed disease has improved the depth and duration of disease response and has eventually translated into improved overall survival (OS) in patients with MM [8, 9].

In patients with newly diagnosed MM, the triplet regimen: bortezomib, lenalidomide, and dexamethasone (VRd) is recommended as the standard first-line treatment [4, 7, 10]. However, in patients with high-risk (HR) MM, the addition of a fourth drug, such as daratumumab, has been shown to improve efficacy and prolong survival [4, 10, 11, 12, 13]. Despite the recent advances in the development of novel therapies, MM has remained an incurable disease [14, 15]. The development of novel targeting therapies with different mechanisms of action is needed to achieve deep and durable responses in an attempt to cure MM [14]. Additionally, identification of tumor intrinsic and extrinsic resistance mechanisms may direct the design of combinations of novel drugs that prevent or overcome drug resistance to improve patient survival [15].

2. Autologous HSCT in MM

Autologous hematopoietic stem cell transplantation (HSCT) is a widely accepted therapeutic strategy for the treatment of certain HMs and it is most frequently indicated for patients with MM and lymphoma [9, 16]. Despite the availability of several lines of novel agents, autologous HSCT is still considered the standard of care in the treatment of patients with MM who are eligible for transplantation [1, 7, 8, 13, 17]. Eligibility for autologous HSCT is determined by age, performance status, presence and severity of comorbid medical conditions, and frailty score as frailty has been shown to be a predictor of short survival and is considered an exclusion criterion for autologous HSCT [7, 8, 18, 19].

The standard conditioning regimen for patients with MM undergoing autologous HSCT is high-dose melphalan (200 mg/m²) given intravenously (IV) [5, 7, 8, 13, 20]. However, in patients with renal dysfunction or failure, dose reductions to 100−140 mg/m² are needed according to creatinine clearance [5, 7]. The following drugs are used in mobilization of stem cells: cyclophosphamide, granulocyte colony-stimulating factor (G-CSF), and plerixafor in case of poor mobilization [3, 13, 16]. After stem cell mobilization, peripheral blood stem cells are collected using apheresis machine aiming to collect at least 2.5 × 10⁶/kilogram body weight to guarantee a successful autologous graft [3, 16].

Cryopreservation using the cryopreservative dimethyl sulfoxide is routinely employed after stem cell collection prior to autologous HSCT [3, 7, 21]. However, several old and recent studies in addition to one systematic review have shown that autologous HSCT using non-cryopreserved stem cells is safe and cost effective and leads to short-term as well as long-term results that are at least equivalent to autologous HSCT using cryopreserved stem cells [7, 16, 21, 22, 23, 24, 25, 26]. One of the advantages of autologous HSCT without cryopreservation is the simplicity of its implementation. Hence, autologous HSCT can be performed entirely as outpatient [3, 7, 27].

3. Outpatient autologous HSCT in MM

There are several models for autologous HSCT in patients with MM and these include (1) entirely inpatient model; (2) entirely outpatient model; (3) at-home model; and (4) mixed inpatient outpatient model, that is, inpatient model with early discharge after HSCT [28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43]. Unfortunately, there is a lack of randomized studies that clearly indicate which model is better than the other; there are no studies that have analyzed long-term survival outcomes and real costs of these models or HSCT programs, and there are no stringent guidelines for selection of patients and clinical management for each model [28, 44]. However, one randomized study compared the model of early hospital discharge with that of entirely inpatient model of HSCT and it showed safety and feasibility of early discharge model provided that caregivers are available and that the distance between home and hospital is relatively short [43].

While historically, due to logistic issues and concerns regarding toxicities and infections, most of the autologous HSCTs were performed at inpatient setting, the swift recovery after peripheral autologous HSCT and improvements in supportive care have enabled patients to receive autologous HSCT at outpatient [32, 45]. It has been reported that outpatient autologous HSCT is safe and feasible in patients with lymphoma, central nervous system tumors, and breast cancer [32, 46, 47, 48]. Early discharge after intensive chemotherapy has been done successfully in patients with acute myeloid leukemia receiving induction and consolidation cycles of chemotherapy, and in patients with lymphoma receiving BCNU, etoposide, cytarabine, and melphalan (BEAM) conditioning therapy [49, 50, 51, 52]. Additionally, allogeneic HSCT with reduced intensity conditioning therapy as well as haploidentical allogeneic HSCT has been performed in outpatient settings in the following diseases: MM; relapsed and refractory (R/R) lymphoma; Sezary syndrome; and other R/R HMs [53, 54, 55, 56, 57, 58, 59]. Even total body irradiation has been given successfully in outpatient settings [59].

In carefully selected patients with MM and lymphoma, outpatient autologous HSCT has been shown to be safe, feasible, and cost-effective, provided the following measures are applied: frequent clinical evaluation, administration of the needed supportive care, adopting a multidisciplinary approach, and close follow-up at the designated outpatient clinics and treatment areas. Additionally, it can lead to improvement in quality of life as well as excellent short-term and long-term patient outcomes [28, 30, 31, 32, 40, 44, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70]. It is vital to have HSCT-specific supportive interventions that address the multidisciplinary and complex needs of both patients and their caregivers by optimizing the involvement of the key stakeholders throughout the entire process from stem cell mobilization to passing the first 100 days post-HSCT [71]. A multidisciplinary approach with close follow-up is required to guarantee successful outcome of the autologous outpatient HSCT program [60, 61, 68, 72]. Due to the ease of administration of high-dose melphalan, the relatively low extra-hematological toxicity and the short period of neutropenia, patients with MM are ideal candidates for outpatient autologous HSCT [29, 44, 70].

Several studies have clearly indicated that outpatient HSCT has certain inclusion criteria, including (1) availability of full-time caregiver; (2) residence within 20- to 30-minute drive from the hospital; (3) good performance status; (4) favorable comorbidity profile; (5) stable psychology; (6) expected compliance; (7) patient preference; and (8) signed written consent [28, 30, 32, 62, 69, 70]. On the other hand, the exclusion criteria of outpatient HSCT include (1) age more than 65 years; (2) performance status > 1; (3) severe comorbid medical conditions; (4) severe impairment of organ functions; (5) severe infection either encountered recently or not completely eradicated; (6) colonization with multidrug-resistant bacteria or fungus; (7) lack of caregiver; (8) > 1-hour drive distance between home and hospital; (9) no guaranteed availability of quick readmission to hospital once hospitalization is needed; and (10) advanced disease, such as MM or lymphoma [44, 45, 64, 73].

Indications for admission in recipients of outpatient HSCT include (1) febrile neutropenia; (2) severe mucositis requiring narcotic analgesia or total parenteral nutrition (TPN); (3) inability of family or caregiver to cope; (4) poor oral intake or uncontrolled nausea, vomiting, or diarrhea requiring TPN or intensive hydration; (5) the presence of any other serious complication, such as pneumonia, sepsis or arrhythmia; and (6) declining performance status of the patient [43, 45, 61, 64, 65, 66, 67]. Percentage of recipients of outpatient autologous HSCT who require hospitalization in the first 100 days post-HSCT ranges between 8% and 84% [31, 45, 61, 64, 65, 66, 67, 68, 74]. Duration of hospitalization ranges between 4 and 9 days and the most frequent day of unexpected hospitalization is day 7 after autologous HSCT [31, 60, 61, 65, 67]. The median time to engraftment in patients with MM receiving autologous HSCT at outpatient is 9−14 days for neutrophils and 12–19 days for platelets [61, 63, 64, 65, 66, 67]. The reported transplant-related mortality in recipients of autologous transplantation performed at outpatient is 0.0−1.1% [28, 31, 44, 61, 66, 67, 68, 69, 72]. Outpatient autologous HSCT has several advantages that include the following: (1) significant reduction in costs; (2) alleviation of constraints of chronic bed shortage; (3) significantly lower overall resource utilization; (4) patient convenience and high patient satisfaction; (5) lower rate of infectious complications; (6) lower morbidity; and (7) lower treatment-related mortality [30, 42, 44, 60, 64, 68, 72, 75].

4. Maintenance and continuous therapy in MM

In patients with MM, maintenance therapy after autologous HSCT has been shown to deepen and prolong responses and increase OS and progression-free survival (PFS) [76]. The use of lenalidomide as a maintenance treatment after autologous HSCT in patients with MM had been investigated in 4 phase III randomized control studies, which demonstrated a benefit in PFS [77, 78, 79]. Lenalidomide is the only drug that has been approved for maintenance therapy in patients with MMM [76]. Lenalidomide maintenance given after autologous HSCT till disease progression had become the standard of care in patients with newly diagnosed MM as it has been shown to prolong PFS and event-free survival [78, 80, 81, 82].

Bortezomib maintenance therapy after autologous HSCT in MM patients has been shown to be safe, well tolerated, and efficacious, particularly in patients with HR cytogenetics including deletion 17p, renal insufficiency, inability to tolerate lenalidomide, and previous history of another cancer [83, 84, 85]. Additional benefits of bortezomib maintenance are upgrading of post autologous HSCT responses, achievement of superior OS and PFS, and absence of peripheral neuropathy [84, 86].

In maintenance therapy, a single agent or double treatment is used while in continuous therapy a doublet or triplet regimen is administered till disease progression [87]. Compared to the traditional fixed-duration approaches, the evolving paradigm of continuous therapy and maintenance treatment offers prolonged disease control and improved outcomes in patients with MM. For example, continuous therapy has been shown to significantly improve OS and PFS [87, 88]. Hence, continuous therapy has become a key strategy in the treatment of patients with MM as it has been shown to improve duration of remission [89]. Currently, continuous therapy till disease progression represents the standard approach for patients with MM both at diagnosis and at relapse [90].

5. Conclusions

Outpatient autologous HSCT has specific inclusion and exclusion criteria. With daily clinical evaluation, and intensive supportive care including correction of electrolytic disturbances, and administration of blood products and antimicrobials as needed, autologous HSCT performed at outpatient can lead to short-term as well as long-term outcomes that are at least equivalent to autologous HSCT performed at an inpatient setting. Additional advantages of outpatient autologous HSCT include reduction in costs, saving hospital beds, and lower rates of infectious complications as well as transplant-related morbidity and mortality.