High-dose chemotherapy and autologous stem cell transplantation of patients with multiple myeloma in an outpatient setting

High-dose (HD) chemotherapy and autologous blood stem cell transplantation (ABSCT) is a standard of care in transplant eligible patients with multiple myeloma (MM) and a variety of malignant diseases [1–4]. Initially established as a single ABSCT in newly diagnosed MM, subsequent trials have shown the benefit of a tandem ABSCT in overall survival, particularly in those patients who do not reach at least a very good partial remission after the first autograft [5–8]. Moreover, HD chemotherapy and ABSCT is also an effective treatment option for relapse MM patients [9–11].

MM patients undergoing HD chemotherapy and ABSCT have traditionally been admitted to the hospital for several weeks. With the increasing ABSCT experience of the transplanting centres, the patients’ wish for a shorter stay in the hospital, increasing number of nosocomial infections and growing economic pressure, particularly in view of increasing absolute numbers of ABSCTs in Europe during the last decade [12], there is a clear trend towards outpatient treatment. The experience from performing HD chemotherapy and ABSCT in an outpatient setting in the late 1990s has indicated a high degree of safety, feasibility, cost saving and patient satisfaction [13–16]. Although it has been well established in the United States of America [17–19] and Canada [20, 21], only single reports on outpatient HD chemotherapy and ABSCT in Europe are available [22, 23]. To the best of our knowledge, the outpatient treatment option has not been established as a routine in a transplant centre in Germany so far.

Since 2012, we have performed HD chemotherapy and ABSCT on an outpatient basis in individually selected MM patients within an elaborated program. Currently, this outpatient ABSCT program is being extended to a higher case number, and up to 2 patients undergo this treatment in parallel at a time. This report summarizes our experience of 21 ABSCTs performed on an outpatient basis. The aim of this retrospective study is to demonstrate our approach and analyse the safety and efficacy of the program.

In Europe, HD melphalan chemotherapy followed by ABSCT is performed almost always on an inpatient basis, and only scattered reports on outpatient HD chemotherapy exist [23]. In contrast, in the USA and Canada, outpatient HD chemotherapy and ABSCT in MM and lymphoma patients has been well established for decades [19] and is performed with a high degree of safety [16–18, 26], cost savings [14, 15, 20] and patient satisfaction [13]. As one of the first centres in Europe, we established an outpatient ABSCT program at our institution in 2012. Based on our inpatient HD melphalan chemotherapy and ABSCT treatment protocol, we developed a comprehensive treatment plan for an outpatient setting. Patients were carefully selected and criteria have been developed for hospital admission. Comprehensive patient education about how to behave during aplasia at home took place. Moreover, daily rounds of the outpatients, including vital parameter monitoring, and laboratory tests were performed. The outpatient ABSCT program also included the advanced management of side effects exceeding the standard inpatient care, including a triple anti-emetic regimen, strong recommendation to rinse the mouth with Caphosol® at least once an hour and administration of daily i.v. fluids. Furthermore, with regard to Kim et al., who showed that sequential prophylaxis with oral fluoroquinolone followed by i.v. ertapenem may effectively prevent episodes of bacteremia and hospitalizations in neutropenic MM outpatient ABSCT recipients [27], an empirical i.v. antibiotic therapy was initiated at subfebrile body temperatures when CRP elevation was detected.

Between 2012 and 2016, 21 MM patients underwent HD chemotherapy and ABSCT on an outpatient basis. No SAEs were observed. In our patient cohort, confirmed post-transplant infections were documented in 5 of the 21 patients (24%, positive blood cultures in 4 patients and 1 positive urine culture in 1 patient). This is comparable to the results of Paul et al., who reported an infection rate of 22% (18 of 82 patients) in an initial brief in-hospital stay of MM patients group receiving HD melphalan and ABSCT [17], and to Graff et al., who described an infection rate of 19% (19 of 95 patients) in MM and lymphoma patients undergoing this therapy as outpatients [18]. Less than 10% of patients (2 of 21) developed grade 3 stomatitis. No grade 4 or 5 stomatitis cases were observed. In contrast, Jagannath et al. reported a stomatitis grade ≥3 in 31% of 118 MM patients undergoing outpatient HD chemotherapy and ABSCT [15]. We attribute the low mucositis rate in our patient cohort to regular Caphosol® mouth rinse. Neutropenic fever was observed in two-thirds of the cases. However, the median fever duration was relatively short (2 and 4 days for outpatients and those who required a hospital admission, respectively), and the majority of patients with neutropenic fever (8 of 14) were not admitted for inpatient stay. The neutropenic fever rate is comparable to those observed by Jagannath et al. (50% of 118 outpatient MM auto-transplants [15]) and Leger et al. (56% of 60 outpatient ABSCTs in relapse follicular lymphoma [21]). Moreover, the observed neutropenic fever rate was relatively low compared to in-house historical patient cohorts undergoing HD chemotherapy and ABSCT, with rates of approximately 80% [28, 29]. Although Meisenberg et al. and Paul et al. reported a pulmonary infection rate of 4% (of 27 patients [16]) and 5% (of 82 MM patients [17]) in outpatient auto-transplantation cases, respectively, no pulmonary infections were documented in our patient cohort.

The rate of positive blood cultures in our patient cohort (19%, 4 of 21 patients) is in line with the observation of Graff et al. (10%, 9 of 95 MM and lymphoma ABSCT receiving outpatients [18]) and Paul et al. (16%, 13 of 82 MM patients with an initial in-hospital stay post ABSCT [17]). Moreover, Graff et al. reported 1 central venous line infection among 95 MM/lymphoma patients treated on an outpatient basis (4%) [18]. In our patient group, port explantation was performed in 3 cases (14%) due to a clinical suspicion of port infection upon persisting fever, but without definitive prove of infection by bacterial culture. 90% (19 of 21) of transplanted patients received i.v. antibiotics. Compared to Jagannath et al. who reported a use of i.v. antibiotics in 78% (of 118 MM patients) transplanted in an outpatient setting [15] the higher relative number of patients with i.v. antibiotics in our group can be attributed to an early intervention strategy with initiation of ertapenem infusion at subfebrile temperatures and elevated CRP levels.

Graff et al. observed a neutrophil ≥0.5 × 10⁹/L recovery and platelet ≥20 × 10⁹/L after a median of 10 and 19 days, respectively, in a cohort of MM and lymphoma patients undergoing outpatient ABSCT. We observed neutrophil ≥0.5 × 10⁹/L recovery and platelet recovery after a median of 14 days in both groups, which is almost identical with study data of two historical in-house patient cohorts undergoing HD chemotherapy and ASCT at our institution, with the time to leukocyte increase ≥1 × 10⁹/L and time to platelet increase ≥50 × 10⁹/L being a median of 14 days [28, 29]. Pack red cell and platelet transfusion was necessary in 6 (29%) and 15 (71%) patients. This corresponds to the findings of Jagannath et al. (57% and 97%) [15].

On average, the median treatment duration was 21 and 22 days for outpatients and those who were intermittently admitted to the hospital, respectively. This is in line with the treatment duration of a completely in-hospital-treated MM patient undergoing HD chemotherapy and ABSCT at our institution [29]. Hospital admission was indicated in one-third (7 of 21) of the auto-transplanted MM patients in our cohort. In a comparable MM patient group described by Jagannath et al., 21% of the 118 outpatient transplant procedures required hospital admission [15]. However, in a cohort of 82 MM patients who had an initial brief hospital stay and were followed as outpatients, as described by Paul et al., 67% required hospital re-admission [17]. In our MM patient group, patients who were admitted to the hospital had a relatively short median inpatient treatment of 5 days, and the necessity of hospital admission did not lead to prolonged overall treatment duration. Thus, the temporary inpatient treatment-duration in our cohort was even shorter compared to the cohort of outpatient ABSCTs performed in patients with different hematologic malignancies reported by McDiarmid et al. (median total length of stay 21 d, median inpatient 7 d and median outpatient 14 d) [30].

Overall, approximately 90% (391 days) of the overall cumulative treatment days for 21 patients were spent on an outpatient basis and 10% (53 days) on an inpatient basis. With increasing numbers of outpatient ABSCTs at our centre, the relatively short inpatient stay will represent a significant cost saving option. The magnitude of this effect depends on a number of factors, including reimbursement for in-/outpatient ABSCT, occupancy rate of hospital beds, staff availability etc., and should be addressed in detail in future studies.

Limitations of the presented data result from the relatively small number of outpatients. In addition, this patient cohort was carefully selected and represented only about 5% of all transplanted myeloma-patients at our center during that time period. It therefore represents a pilot-study aiming to proof the feasibility and to describe the necessary preconditions.

According to the results of the structured questionnaire, the patient’s satisfaction with outpatient medical care provided by physicians and nurses as well as their treatment in the outpatient clinic as a whole was very high. In addition, all of the patients indicated willingness to undergo further HD chemotherapy and ABSCT within the outpatient program again, if indicated. This was actually the case in three patients. Further continuation and expansion of the program is intended.

Carefully selected MM patients undergoing HD chemotherapy and ABSCT can successfully be treated on an outpatient basis with low morbidity and infectious complications and very high patient satisfaction. Although dependent on a number of variables, including the individual compensation agreement with the health-insurance providers, such an approach may also have a significant economic impact on the performing transplant centre.