Combined Submyeloablative and Myeloablative

Dose Intense Melphalan Results in Satisfactory

Responses with Acceptable Toxicity in Patients
with Multiple Myeloma
Nicolas Novitzky,1,2 Jaqueline Thomson,1 Valda Thomas,2 Cecile du Toit,1,2
Zainab Mohamed,3 Andrew McDonald1,2

We studied in patients with multiple myeloma (MM) the efficacy, cost-effectiveness, and toxicity of a strategy
of submyeloablative doses of Mel and stem cell support in the ambulatory setting, followed by a standard
myeloablative dose transplant. Patients with recently diagnosed symptomatic MM received dexamethazone
to induce clinical response. Cytokine mobilized peripheral blood progenitor cells (PBPC) were split into 2
aliquots and cryopreserved. Patients then received Mel 100 mg/m2 (Mel100) and infusion of the first
PBPC aliquot in an ambulatory facility. Individuals received standard neutropenia prophylaxis and no growth
factor support, but were seen regularly at the clinic until recovery. The cost of this step was calculated in
a cohort of 23 patients where information for the expenditure was available. Six months later patients
were conditioned in the hospital with Mel 200 mg/m2 (Mel 200) followed by nfusion of the second aliquot.
This study tested the cost, effectiveness, and the toxicity of out-patient-based transplantation, as well as the
rate of response (complete remission [CR], very good partial remission [VGPR], partial remission [PR], and
stable disease [SD]) and overall survival (OS) of this strategy. Twenty-six female and 16 male patients, with
a median age of 53 years (range: 33-68 years) and median Salmon & Durie clinical disease stage III (range: II-III)
were studied. The paraprotein was IgA in 17%, IgG in 52%, and light chains in 26%. The median harvested
CD341  106 cells/kg was 12.03 (2.25-55.4). The median interval between the 2 transplant procedures
was 239 (105-376) days. The median Karnofsky presentation score was 40%, but improved to 80% after
the Mel 100 and was 90% following Mel 200. Subsequent to MEL 100 response was complete (CR) in 7
and it was VGPR in 9. Mel 100 grade 3-4 toxicity was mainly hematologic, but 15 (36%) required hospital
admission for a median of 5 days. The median cost of MEL100 and corresponding supportive therapy was
U.S. $2,142.35. In addition, the total median cost of those who needed admission to hospital was
U.S. $6,042.78. Thus, pooling costs from patients who needed or did not need admissions the average
cost of this strategy was U.S. $3,546.50 per patient. Among Mel 200 patients, except for hematologic toxicity,
no patient had greater than grade 2 side effects. On completion of the program, 20 (48%) patients achieved
CR, a further 14 (33%) had VGPR, whereas 6 had PR. At a median follow-up of 659 days there were 8 deaths,
1 (2%) was related to the treatment procedures and 6 from disease progression; thus, the 1000 days OS was
73%. Significant adverse factors included older age, lower presentation Hb, and lower Karnofsky %. Non-
parametric testing confirmed that good performance scores and VGPR or CR were associated with more
favorable outcome. Importantly, these satisfactory results were obtained in the absence of the new biologic
cell modifiers. Mel 100 was well tolerated in the outpatient setting and the overall strategy seems to be ef-
fective in inducing durable responses with acceptable toxicity.
Biol Blood Marrow Transplant 16: 1402-1410 (2010) Ó 2010 American Society for Blood and Marrow Transplantation

KEY WORDS: Multiple myeloma, Autologous stem cell transplanation, Submyeloablative conditioning

From 1The University of Cape Town Leukaemia Centre and the Di- of Cape Town Medical School, Anzio Road, Observatory, 7925,
vision of Haematology, Department of Medicine; 2Clinical Lab- Western Cape, South Africa (e-mail: nicolas.novitzky@uct.
oratory Sciences, Faculty of Health Sciences, University of Cape ac.za).
Town; and 3Department of Radiation Medicine, Groote Schuur Received June 10, 2009; accepted April 2, 2010
Hospital, Observatory 7925, Cape Town, South Africa. Ó 2010 American Society for Blood and Marrow Transplantation
Financial disclosure: See Acknowledgments on page 1409. 1083-8791/$36.00
Correspondence and reprint requests: Nicolas Novitzky, Dip Med, doi:10.1016/j.bbmt.2010.04.002
FCP(SA), Ph.D(UCT), Department of Haematology, University

1402
Biol Blood Marrow Transplant 16:1402-1410, 2010 Ambulatory Stem Cell Transplantation in Multiple Myeloma 1403

INTRODUCTION PATIENTS AND METHODS

Despite substantial progress in our understanding Definitions and Diagnostic Criteria
of the biology of multiple myeloma (MM) and the
Between 2003 and 2008, patients with Salmon &
availability of new treatment modalities, it still remains
Durie stage II or III [15] symptomatic MM, aged up
essentially an incurable disease. Over the last 20 years,
to 65 years and Karnovsky performance status .30%
a number of strategies have been developed that have
were eligible for the study. Consent for therapy was ob-
resulted in significant improvement in the control of
tained according to the directives of the University of
the malignancy, and even leading to complete remis-
Cape Town. Diagnosis of MM was made in line with
sions in a significant fraction of patients. These strate-
the criteria of the Chronic Leukemia-Myeloma Task
gies include the introduction of dose-escalated
force [16]. Entry conditions were symptomatic disease
melphalan (Mel) with autologous stem cell transplan-
in patients who had no contraindications for intensive
tation (SCT) [1-4], and more recently, disease
chemotherapy with high-dose Mel, as well as acceptable
modulation with biologic cell modifiers such as
vascular access to undergo apheresis. Exclusion factors
thalidomide [5], lenalidamide [6], and bortezomib
were cardiac ejection fraction of\45%, vital pulmonary
[7], alone or in combination with corticosteroids and
capacity of \45% of the predicted value, estimated
cytotoxic agents [8]. Thus, with these emerging
creatinine clearance of \30 mL/min, active hepatitis
options, the optimal management of symptomatic
B or C virus infection or HIV reactivity, as well as un-
patients still remains to be defined; however, because
controlled epithelial cancer or psychiatric disease. The
myeloma still constitutes an incurable disease, both
primary objective was to determine the efficacy and tox-
improvement in the length and the quality of life
icity of ambulatory conditioning with submyeloablative
must be equivalent goals. Yet, for those who do not
dose-intensified Mel followed by SCT. The secondary
have contraindications, autologous SCT remains the
end points were to quantitate the rate of complete
gold standard in the management of this condition.
remission (CR), disease free survival (DFS), and overall
Following high-dose therapy there is rapid control of
survival (OS) for this strategy of tandem transplantation.
the malignancy, and around 50% of patients may
We also attempted to calculate the costs of this
show no morphologic or chemical evidence of the
outpatient strategy in the South African setting. Study
disease, a state that has been associated with improve-
population included newly diagnosed patients with
ment in survival [3,8,9]. As for the older population,
MM who were treated with a steroid-based induction.
this procedure is still associated with substantial
morbidity. Palumbo and colleagues [10] tested lower
doses of dose-intense Mel (submyeloablative; 100 Supportive Measures
mg/m2) and also observed substantial responses with Groote Schuur Hospital is a state health institution
lower toxicities [10]. In addition, a number of investi- that serves mainly patients without medical insurance.
gators have shown that long-term survival was associ- Patients are often in need of financial assistance to be
ated with good response to this therapy, and that for able to attend hospital visits and have limited family
certain patients, 2 transplants, in tandem, increased support. To participate in the current program
the rates of such favorable responses [11-14]. patients underwent a psychosocial evaluation to deter-
We, therefore, describe a stepwise therapeutic mine their ability to care for themselves, their under-
approach where patients with symptomatic myeloma standing of the complexities of this protocol, to make
were offered induction therapy with dexamethasone, certain of their compliance, as well as to ensure that
followed by harvesting of sufficient stem cells for 2 they had adequate family support. Individuals were
autologous SCTs. The first conditioning was with required to have a care giver readily available, to test
intermediate dose melphalan (melphalan 100 mg/m2 their body temperatures every 8 hours, and have easy
[Mel 100]), followed by the infusion of the first ali- access to the hospital. For all patients receiving initial
quot of autologous stem cells. Patients were fully therapy, usual neutropenia prophylaxis applied. Fol-
managed in the ambulatory setting. We calculated lowing submyeloablative conditioning and graft infu-
the costs of this intervention to determine cost sion, patients were requested to attend the clinic
effectiveness compared to current modalities. Once 3 times a week to detect possible complications of
individuals recovered from the initial therapy, leukopenia and for evaluation of nausea and oropha-
approximately 6 months later, they received the sec- ryngeal mucosal damage (mucositis) by chemotherapy.
ond full dose conditioning (melphalan 200 mg/m2 Uncontrolled nausea and vomiting despite serotonin
[Mel 200]) in a high-care ward. We show here that inhibitor antiemetics, pyrexia higher than 38 C, or
this strategy was associated with good disease control, clinical manifestations of malnutrition/dehydration
was well tolerated, and has resulted in encouraging from mucositis were all indications for prompt
long-term outcome. admission to the hospital.
1404 N. Novitzky et al. Biol Blood Marrow Transplant 16:1402-1410, 2010

Treatment of MM was defined following the IMF recommendations

Recently diagnosed patients with symptomatic [17,20]. CR required absence of plasmacytosis from the
MM were treated with dexamethasone 40 mg daily BM and of the serum praprotein on immunofixation.
on days 1-4, 8-11, and 18-21, every 28 days for 4 cycles. Disease progression implied at least a 25% increase in
After the completion of the fourth series of dexameth- tumor mass, BM plasmacytosis, or any new disease
asone and of the corresponding treatment response manifestation. Relapse was defined as recurrence of
evaluation, regardless of initial outcome, patients monoclonal protein or BM plasmacytosis or evidence
underwent stem cell mobilization as an ambulatory of extramedullary disease in case of CR, very good
procedure. Mobilization chemotherapy consisted of partial remission (VGPR), or partial response (PR),
etoposide 1 g/m2 on each of 2 consecutive days. including any new disease manifestation such as hyper
Patients were taught to inject and received filgrastim calcemia or new bone lesions. Treatment-related
(Neupogen, Roche Pharmaceuticals, Indianapolis, mortality (TRM) included any death within 30 days
IN, USA) 300 mg subcutaneously twice daily for 7-10 posttransplantation.
days, starting on day 5. On day 14 following mobiliza-
tion chemotherapy, peripheral blood progenitor cells Evaluation of Costs
(PBPCs) were enumerated according to ISHAGE rec- Most medication in the state hospital in South
ommendations [17] and apheresis was commenced Africa is procured at State Tender prices, which are
once CD341 cell count exceeded 5  106/mL. Apher- substantially lower than those charged to the general
esis was undertaken with continuous cell separator public by private pharmaceutical drug suppliers.
(Cobe Spectra, NJ, USA) and enough progenitor cells Biologic agents such as thalidomide or bortezomib
for 2 procedures were collected. The minimum target are not available at state hospitals, but may be pur-
CD341 was 2  106/kg, per graft. chased from pharmacies privately, or once approval
After premedication with allopurinol 300 mg, par- from insurance companies has been obtained. Patients
enteral prehydration and antiemetics, patients had a sin- who have health insurance pay for the cost of the med-
gle intravenous infusion of Mel 100 in the clinic. ication at a single exit price (SEP), which is negotiated
Twenty-four hours later cryopreserved PBPC were between the pharmaceutical companies and the Health
thawed in a 37 C water bath and the first aliquot of Department. We retrospectively determined the cost
stem cells was rapidly transfused in the outpatient for the induction phase with the Mel 100 program
section. Oral neutropenia prophylaxis consisted of (inclusive of value added tax) by calculating the costs
ofloxacin 200 mg twice a day and daily fluconazole of the reagents to store the stem cells, conditioning,
(400 mg); antiemetic agents were continued for 72 and of supportive drugs applying the SEP for all phar-
hours or while patient remained symptomatic. Individ- maceuticals used and added the costs of consultations
uals receiving the first graft were then requested to at the hospital. We calculated the cost of consultations
attend the clinic on alternate days until recovery of neu- and hospital admission tariffs according to the Depart-
tropenia. Hematopoietic growth factors were not ment of Health National Reference Price List
offered. Approximately 6 months following the initial (www.doh.gov.za/docs/nhrpl-f.html) tariffs charged
transplant, patients with MM were admitted to the pro- by medical insurance as well as the cost of blood prod-
tected environment unit at Groote Schuur Hospital and uct support as per Western Province Blood Transfu-
a siliconized double lumen indwelling catheter [18] was sion Service price list (www.wpbtsmedical.org.za/
inserted percutaneously into the internal jugular images/Private09.pdf; year 2010).
vein. Patients were prescribed similar protective
measures and neutropenia prophylaxis as for the initial Statistical Methods
conditioning chemotherapy. For the second transplant,
patients received Mel 100 mg/m2 on each of 2 consecu- Standard population statistics were employed to
tive days (total dose 200 mg/m2;; MEL 200), as define the patient population. Median cost of
a 30-minute infusion. outpatient and in hospital therapies for Mel 100 were
calculated. Final costs were estimated by adding the
expenses generated by hospital admissions of 15
Evaluation of Response patients to the outpatient expenses. Survival analyses
Evaluation of response required review of the bone were performed using the product limit estimate of
marrow (BM) plasmacytosis, protein electrophoresis the Kaplan-Meier method. Significance in the
with immunofixation, as well as determinations of b2 difference of survival curves from various groups
microglobulin and of serum chemistry, which were was compared by the log-rank test. To predict
performed at 8-12 weeks after the first and second outcome, pretransplant variables analyzed were lactate
autologous transplants [19]. Part of this evaluation dehydrogenase (LDH), albumin, BM plasmacytosis,
included determination of the changes in the perfor- time to second transplant, and response to salvage che-
mance status using Karnovsky scale. Response type motherapy by nonparametric statistics. Patients were
Biol Blood Marrow Transplant 16:1402-1410, 2010 Ambulatory Stem Cell Transplantation in Multiple Myeloma 1405

followed up at the clinic or telephonically. Patients Table 1. Clinical and Laboratory Parameters of the Study
were studied for response TRM, OS, and event-free Population
survival (EFS) according to IMWG criteria. OS was Parameter Value
calculated from time of first dose of dexamethasone.
Age, years median (range) 53 (33-68)
Sex distribution, F/M 26/16
Parapotein type, patient No. (%)
IgA 7 (17)
RESULTS IgG 22 (52)
Light chain 11 (26)
Non secretor 2 (10)
Patients’ Demographic and Clinical Data b2 microglobulin mmol/L median, (range) 2.4 (1.4-8.1)
Abnormal No. (%) 12 (29)
The characteristics of the patient population at en- Salmon & Durie clinical stage, median (range) III (II-III)
try are shown in Table 1. All patients had symptomatic ISS median, range 1 (0-2)
disease. On presentation the renal function was abnor-
ISS indicates International Scoring System;19.
mal in 10 patients, and it normalized with treatment in
all except 1. The median Karnofsky score at diagnosis All patients showed some improvement of MM
was 40% but improved to 80% after the Mel 100 and after stem cell mobilization with etoposide (and
was 90% following Mel 200 (Figure 1). As patients filgrastim), conditioning with Mel 100 and infusion
progressed through the treatment sequence, improve- of the first graft. CR was now observed in 7 patients
ment of paraprotein level, BM plasmacytosis, Hb, (5 additional), whereas 9 (6 additional) had achieved
serum albumin, b2MG, and Karnofsky status can be VGPR (38% CR 1 VGPR). One patient in CR died
observed in Figure 1. during the insertion of Hickman line before the Mel
Following dexamethasone-based induction, evi- 200 treatment. Two individuals who had progressed
dence of response (CR 1 VGPR 1 PR) was observed after dexamethasone now achieved PR and VGPR.
in 25 (61%) individuals. In this group, 2 patients After the second graft, a stringent evaluation showed
achieved CR and another 3 VGPR, whereas 20 were that 20 (48%) patients achieved CR, a total of 14
in PR. Disease parameters decreased by less than 50% (33%) had achieved VGPR, whereas another 6 were
or remained stable in another 13 individuals; MM in PR. Disease progressed in 1 subject. Compared to
progressed in 2 patients. Response data was not avail- the outcome of the lower intensity schedule, Mel 200
able in 2 individuals. Regardless of type of response, improved the response of most initially responsive pa-
all patients proceeded to the transplantation stage. tients and resulted in 81% achieving CR or VGPR.
One patient who had responded to Mel 100 progressed
rapidly after Mel 200. At relapse patients were treated
Stem Cell Transplantation Parameters and with various alkylators, biologicals, or anthracycline-
Treatment Outcomes based combinations. One patient died following motor
After stem cell mobilization with etoposide, the vehicle accident. At the time of the analysis, 5 had
median harvested CD341 cells/kg was 12.3 (range: progressed but had stable disease on further therapies
2.25-55.4; Table 2). The median number of apheresis and 6 patients had died of progressive multiple
procedures was 1 (1-3). However, in 1 individual the myeloma. At 8-12 weeks following Mel 200, plasmacy-
circulating CD341 cell number decreased rapidly tosis .10% was detected in 5% (n 5 40; Figure 1A).
and PBPC available allowed only 1 transplant, which At a median follow-up of 648 days, there were
followed a single Mel 200 conditioning. Thus, suffi- 8 deaths: 1 (2%) was directly related to the treatment
cient CD341 cells for the 2 procedures were collected procedures, 1 from a motor vehicle accident, and
in 40 subjects and it was with a single apheresis in 35 6 from disease progression (Table 2). Median survival
(87.5%) patients. There was no significant difference has not been reached. For the complete cohort, the
in the CD341 cell number infused between the 2 trans- 1000-day survival is 73% (Figure 2A). Figure 2 shows
plants. The median interval between the 2 transplant that there was significant difference in survival
procedures was 212 (105-376) days, the delay being between the 3 response groups, with CR or VGPR
mainly because of logistic and operational reason resulting in better outcome compared to the PR group
(availability of a bed for admission). One patient failed (Figure 2B; P 5 .01). On multivariate analysis,
to receive the second graft because of a vascular access significant adverse factors for survival included lower
catastrophe that led to the patient’s death in VGPR. (than median) Hb on presentation (P \ .01), lower
Thus, a total of 41 patients received the first graft Karnofsky % (P \ .01), and older age (P 5 .04).
and 40 individuals completed the full program.
Respectively, the median time to neutrophil and plate-
let recovery was 14 and 18 days for the first procedure Toxicity (Table 3)
and 13 and 17 days for the second. No maintenance Toxicity of dexamethasone was predictable, of
therapy was prescribed until disease recurrence. mild nature, and was well controlled with standard
1406 N. Novitzky et al. Biol Blood Marrow Transplant 16:1402-1410, 2010

Figure 1. Graphical representation of the laboratory parameters and of Karnofsky scores at the different stages of the described therapeutic strategy.
All the values are significantly different from the presentation parameters. (Dexa: dexamethasone; SCT 1 and 2: stem cell transplant 1 and 2).
Biol Blood Marrow Transplant 16:1402-1410, 2010 Ambulatory Stem Cell Transplantation in Multiple Myeloma 1407

Table 2. Autologous Stem Cell Transplantation in Tandem: was available was calculated. The median cost of Mel
Cause of Death and Overall Survival 100 and corresponding supportive therapy was
Treatment Outcome (No. 42) R 16,281.80 (range: 15,441.14-3278.60) or U.S.
$2,142.35 (1Rand: 7.60 U.S. $). In addition, the total
All deaths: 8
TRM 1 median cost of those who needed admission to hospital
Other 1 (in a private facility) for the typical complications was
Progression of myeloma 6 R 45,925.10 (U.S. $6.042,28). Thus, because 36%
Follow up, median days 648 (111-1824)
% surviving 75% required admission for complications of dose intense
% in response 41% Mel 100 for a median of 5 days, the average cost until
TRM indicates treatment-related mortality; OS, overall survival. recovery of this strategy pooled from 10 patients who
needed or did not need admissions was R 26,953.40
supportive measures. Mobilization of CD341 cells (U.S. $3,546.50).
with etoposide at 2 g/m2 gave mainly hematologic
and gastrointestinal toxicities. All patients developed
severe (grade 3-4) neutropenia; 5 patients were admit- DISCUSSION
ted with neutropenic fever and all responded to antibi- The combination of oral Mel and prednisone has
otics. Grade 2 mucositis occurred in 18 individuals, been the mainstay in the treatment for patients with
but none showed grade 3 or 4 toxicities. All underwent MM for 4 decades. Other cytotoxic combinations
stem cell harvest without delays. such as infusional vincristine, adriamycin, and high-
The toxicity of Mel 100 was manageable in the out- dose dexamethasone (VAD) [21], etc., have also been
patient setting (Table 3). All patient developed grade explored but in a meta-analysis, these more complex
4 hematologic toxicities and 10 individuals required schedules did not significantly improve survival [22].
transfusion of red cells (median 2 units) and, in 6 cases, Moreover, dexamethasone appears to be the most active
of platelets (median 1 single donor unit). Fifteen patients ingredient in the VAD combination leading to similar
required admission to hospital, mainly for neutropenic outcomes as the substantially more complex and
fever, for a median of 5 days. One patient in VGPR toxic 3-drug combination. Nevertheless, most patients
and normal blood parameters died of bleeding during will experience disease recurrence and then further
the insertion of a Hickman line before the second trans- management remains unsatisfactory. For this reason,
plant. Mel 200 was associated with the usual side effects, in a prospective randomized study, the Intergroup
but except for hematologic toxicity, no patient had Francophone pour l’etude du Myelome (IFM) showed
greater than grade 2 side effects. There was no mortality that in myeloablative doses Mel followed by autologous
after conditioning with Mel 100 and Mel 200. stem cell infusions was associated with significantly
better responses and more extended survival than
Cost of Therapy standard dose salvage therapy [3]. Thereafter, these
The expenditure of Mel 100 induction therapy and other investigators suggested that 2 autologous
received by 23 individuals where detailed drug usage transplants in tandem led to superior DFS and OS,

Figure 2. OS of the study population. (A) Shows the overall outcome. (B) Shows the outcome according to type of response to the therapeutic strat-
egy. Patients who failed to achieve at least VGPR had significantly worse outcome.
1408 N. Novitzky et al. Biol Blood Marrow Transplant 16:1402-1410, 2010

Table 3. Toxicity Scores of the Mel 100 and Mel 200 Condi- to another study [10,30]. Other reasons could be the
tioning Programs younger age of our population and possible patient
Mel 100 Mel 200 selection bias.
(n 5 41) (n 5 40) Including a vascular access complication (not
Mucositis (WHO) patient No. directly related to the study protocol), the overall pro-
I 7 6 cedure mortality was 2%, which is not different from
II 12 25 that of therapy with VAD like combinations or the
III-IV 0 9
Fever >38  C 15 38 experience in other high dose programs. However,
Number of hospital admissions 15 40 individuals entering such programs must be carefully
Days in hospital, median (range) 5 (4-9) 17 (14-28) evaluated and informed of the possible toxicities
Blood component support median, (range)
Platelets 1 (0-6) 4 (1-11) associated with dose intense chemotherapy; 36% of
Red cells 2 (0-2) 3 (0-7) patients undergoing submyeloablative conditioning
Time to engraftment required admission to hospital for the treatment of
Days of granulocytes <0 .5  109/L 6 (4-7) 7 (3-16)
Days of platelets <50  109/L 2 (2-4) 13 (4-19) intractable nausea, mucositis or neutropenic fever
(Table 3). Provided patients are compliant and closely
monitored, this strategy is feasible in the outpatient
particularly for patients who failed to achieve at least setting; it can considerably reduce the number of
VGPR after the first procedure [11,12,14,23]. This patients who may need to be admitted to hospital
observation was not universal, however [24]. and thus reduce the costs of this program.
Recently, a number of biologic cell modifiers Moreover, the outcome after Mel 200 and SCT is
(thalidomide, bortezomib, or lenalidomide) have been closely related to performance status, which was poor
shown to improve disease control in patients with recur- in most patients presenting to our clinic (median pre-
rent MM or in the upfront setting [25-27]. Nonetheless, sentation Karnofsky score of 40%; Figure 1). This,
intensified dose melphalan still remains the gold together with the substantial pressure on our high
standard in the treatment of younger patients, care beds, led us to prescribe the first Mel 100 [10] in
although its place in the therapeutic sequence in the the ambulatory setting as a treatment induction step.
context of these newer agents is currently being At this lower dose nausea and vomiting as well as ‘‘mu-
debated. However, state hospitals in South Africa do cositis’’ were less problematic, with minimal treatment
not receive funding for these new agents. related toxicities and no direct mortality (Figure 1). Of
Consequently, we prospectively studied patients with interest, we noted that responses to Mel 100 appeared
symptomatic myeloma to determine the effectiveness similar to those described with the new biologic agents.
of this strategy and establish their outcome after the To determine the cost effectiveness of this strategy, we
combination of Mel 100 and Mel 200 in tandem, each calculated the costs for the conditioning with MEL100,
supported by infusion of autologous stem cells. As our together with outpatient therapy with antiemetic
induction agent we chose dexamethazone, which, agents, neutropenia prophylaxis, and 3 weekly visits
regardless of response, was followed by stem cell to the clinic with the corresponding laboratory moni-
mobilization, stem cell harvest, and then the toring tests until recovery. We determined that the
ambulatory transplant procedure. median outpatient expenditure from 23 patients was
For the mobilization of stem cells, we elected to U.S. $2142.35 (range: 15,441.14-3278.60). The
use high-dose etoposide as in previous studies it had median admission costs from 11 patients was U.S.
been particularly effective in ‘‘poor mobilizers’’ com- $6042.78 (range: 3900.98-9,786.34), leading to an
pared to cyclophosphamide [28,29]. This was of overall estimated total expenditure of U.S. $3546.50,
significant relevance, as because of cost constraints, if the average of 10 patients was considered. This would
we wanted to harvest the required progenitor cells compare favorably with the cost of induction therapy
for the 2 transplants with 1 apheresis procedure only. with thalidomide (Thalomid; Key Oncologics, South
Additionally, etoposide has potent cytotoxic effects Africa; R: 10407.12 or U.S. $1387.61per 28 day course
against malignant plasma cells either in vitro or in at a dose of 200 mg/day) or bortezomib (Velcade,
clinical studies and has been included in various Janssen-Ceilag Pharmaceuticals, Johannesburg; R
chemotherapeutic schedules [13]. Indeed, sequential 55,346.92 (U.S. $7379.59) for 3 week cycle), even
monitoring of some of the disease parameters showed without considering other drug additions, the costs of
that after infusion of etoposide, even before the first screening visits and corresponding monitoring labora-
treatment of dose intensified Mel, a significant reduc- tory investigations. Thus, the cost for the collection of
tion in the serum paraprotein level was observed, with the additional grafts and outpatient transplantation
consequent improvement of the serum albumin and after the Mel 100 procedure, inclusive of 36% of possi-
blood hemoglobin levels (data not shown). This may ble admissions to hospital, was lower than the single
be one of the reasons that after the Mel 100 evaluation exit price of 3 months of thalidomide or 1 cycle of
the complete response rate and VGPR were superior boterzomib. Approximately 4-6 cycles of each strategy
Biol Blood Marrow Transplant 16:1402-1410, 2010 Ambulatory Stem Cell Transplantation in Multiple Myeloma 1409

are recommended. Mel 100 was well tolerated with no 4. Child JA, Morgan GJ, Davies FE, et al. High-dose chemother-
grade IV (except hematologic) toxicities reported. apy with hematopoietic stem-cell rescue for multiple myeloma.
N Engl J Med. 2003;348:1875-1883.
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ACKNOWLEDGMENTS 20. Durie BGM, Harousseau J-L, Miguel JS, et al. International
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We acknowledge the contributions by the staff at 2006;20:1467-1473.
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22. The Myeloma Trialists’ Collaborative Group. Combination
assistance and all the participating patients.
chemotherapy versus melphalan plus prednisone as treatment
Financial disclosure: The authors have nothing to for multiple myeloma: an overview of 6,633 patients from 27
disclose. randomized trials. J Clin Oncol. 1998;16:3832-3842.
23. Cavo M, Tosi P, Zamagni E, et al. Prospective, randomized
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