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The Choice of Multiple Myeloma Induction Therapy Affects the Frequency and Severity of Oral Mucositis After Melphalan-Based Autologous Stem Cell Transplantation
Original Study
The Choice of Multiple Myeloma Induction Therapy Affects the Frequency and Severity of Oral Mucositis After Melphalan-Based Autologous Stem Cell Transplantation Shaun Fleming,1 Simon J. Harrison,2,3 Piers Blombery,2 Trish Joyce,2 Kerrie Stokes,2 John F. Seymour,2,3 H. Miles Prince,2,3 David Ritchie1,2,3 Abstract Mucositis is a significant complication of high dose melphalan autologous transplantation (AHSCT) for myeloma. We hypothesized that prior therapy received would impact on mucositis risk in AHSCT. We retrospectively analyzed 128 sequential 200mg/m2 melphalan AHSCT performed as part of primary. There was a significant reduction in mucositis risk in patients receiving immunomodulator based induction therapy compared to conventional chemotherapy. Introduction/Background: Mucositis is a common complication of high-dose melphalan (HDM) used before autologous stem cell transplantation (ASCT) for multiple myeloma (MM). Mucositis rates are influenced by previous chemotherapy (CT) exposure. We examined the effect of induction therapy before ASCT on ASCT mucositis rates. Patients and Methods: Patients undergoing first 200 mg/m2 HDM ASCT were assessed. Those receiving < 200 mg/ m2, or those with previous ASCT were excluded. Patients were evaluated depending on type of induction therapy (CT, immunomodulatory drug [IMiD], or proteasome inhibitor [PI]) before ASCT. A case record review was performed and data collected on response to induction, rates of Grade 3/4 mucositis, and days of total parenteral nutrition (TPN) or parenteral opiate analgesia. Results: One hundred twenty-eight patients with ASCT were assessed. Induction therapy was CT- (n ¼ 62), IMiD- (n ¼ 51), or PI-based (n ¼ 15) therapy. Patient characteristics were overall similar, including median age, MM stage, and CD34þ cell dose. IMiD-based therapy patients had lower rates of mucositis (33% vs. 53%; P ¼ .03) and less opiate requirements (10% vs. 31%; P ¼ .02) compared with those treated with CT. Rates of mucositis and opiate use in the PI group were not different to the CT cohorts (33% vs. 53%; P ¼ .6 and 13% vs. 31%; P ¼ .13), likely due to concurrent anthracycline exposure. TPN usage was similar (CT, 42%; IMiD, 35%; and PI, 20%), as was neutropenia duration and antibiotic usage. Conclusion: Patients treated with IMiD-based regimens before HDM ASCT had significantly lower rates of mucositis than those treated with CT-based therapy. There were too few patients who received PI therapy to evaluate the effect. Clinical Lymphoma, Myeloma & Leukemia, Vol. -, No. -, --- ª 2014 Elsevier Inc. All rights reserved. Keywords: Autologus transplantation, Mucositis, Myeloma, Novel therapy, Supportive Care
Introduction Oral mucositis is a common complication of autologous stem cell transplantation (ASCT), with rates of severe (Grade 3 or 4) 1
The Royal Melbourne Hospital, Victoria, Australia Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia 3 University of Melbourne, Victoria, Australia 2
Submitted: Sep 22, 2013; Revised: Feb 6, 2014; Accepted: Feb 11, 2014 Address for correspondence: Shaun Fleming, MBBS (Hons), Royal Melbourne Hospital, Grattan Street, Parkville, Victoria, Australia E-mail contact: fl[email protected]
2152-2650/$ - see frontmatter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clml.2014.02.001
mucositis according to the Common Terminology Criteria for Adverse Events (CTCAE) reported to be as high as 46%.1 In patients with multiple myeloma (MM) undergoing ASCT the overall rate of mucositis has been reported as 75%, with severe mucositis recorded in 21%, with melphalan dose and renal impairment before transplant identified as risk factors for mucositis severity.2 Preexisting oral pathology, the presence of oral appliances, dental hygiene, and previous oral lesions have also been identified as risk factors for mucositis.3 Patients with severe mucositis have a significantly greater rate and duration of neutropenic sepsis.1,4 Furthermore, more than 40% of
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Multiple Myeloma Induction Alters Transplant Mucositis patients undergoing ASCT will report mucositis as their most debilitating transplantation-related side effect.5 Severity of mucositis is identified as a major risk factor for transplant-associated mortality in autologous and allogeneic transplantation.4 Severe mucositis forms 1 of the major barriers to outpatientbased ASCT procedures in MM. Supportive care for severe mucositis including intravenous opiates, enteral feeding, and total parenteral nutrition (TPN) are difficult or impossible to administer in the outpatient setting, and mucositis-associated complications such as neutropenic sepsis also necessitate readmission. In a study of outpatient-based melphalan-conditioned ASCT in MM, a readmission rate of 36% (10 of 28 patients) was observed, of which half were for severe mucositis.6 In less well selected patients, the readmission rate might be significantly greater.7 Since the mid 1990s, high-dose chemotherapy (CT) with ASCT has been a key part of consolidation for patients with MM after conventional CT-based induction (CCT). ASCT delivers deeper MM responses and is associated with improved progression-free and overall survival.8-10 Historically, the most commonly used CT regimen was VAD (vincristine 1.6 mg, adriamycin 36 mg/m2, and dexamethasone 40 mg daily for 4 days).11,12 Novel therapy-based induction with either immunomodulatory drug (IMiD) or proteasome inhibitor (PI) therapy provide superior outcomes compared with CT-based induction.13-18 Although there is interest in therapeutic approaches that defer transplantation until first disease progression, with ongoing trials continuing in this area,19 current evidence supports ASCT after primary induction therapy as the standard of care among transplant-eligible patients.20 Because CT might be associated with subclinical mucosal lesions,21 we hypothesized that the type of previous induction therapy might influence the incidence and severity of ASCT-related mucositis. We investigated the effect of induction therapy before transplantation on mucositis in patients undergoing ASCT for MM at our institution.
Patients and Methods
2
-
We undertook a retrospective review of case records of patients who had received ASCT for MM at the Peter MacCallum Cancer Centre between May 2005 and August 2011. All data were collected in accordance with approval from an institutional ethics committee. Patients were considered evaluable if they were undergoing a first 200 mg/m2 melphalan ASCT for treatment of MM, with those receiving subsequent ASCT or salvage therapy excluded. Also excluded were patients who had not received any induction therapy or only steroids before ASCT. Data were collected on demographic information, previous therapies received, and MM status including stage at diagnosis.22 Treatment data including regimen received, steroid dose, and time from therapy to transplant were determined from clinical notes, pharmacy records, and treatment summaries. ASCT data were obtained on the conditioning regimen received, stem cell dose received, rates of mucositis, onset of fever, and day of discharge from day of stem cell infusion. Clinically significant mucositis was defined as Grade 3 or 4 clinical mucositis according to the CTCAE version 3.0.23 Surrogate measures of mucositis were also measured including parenteral opiate use and the use of TPN. Response to therapy was categorized according to the International Uniform Response Criteria.24
Clinical Lymphoma, Myeloma & Leukemia Month 2014
Patients were evaluated on the basis of induction therapy received; either CT-, IMiD-, or PI-based therapy. Any patient who had received a CT-based treatment was classified as having received CT irrespective of any subsequent novel agent exposure before transplantation, and those who received a single CT agent in combination with either IMiD or PI therapy were counted in their respective groups. Data analysis was performed using the R statistical platform version 2.14.1 (R Foundation for Statistical Computing, Vienna, Austria), using the c2 test and Fisher exact test for comparison of nominative data and the Kruskal-Wallis test for analysis of nonparametric data. Secondary evaluation was performed on the basis of steroid exposure, time between treatment, and ASCT and anthracycline exposure to establish which, if any, of these variables contributed to mucositis outcomes.
Results A total of 128 sequential patients treated with 200 mg/m2 melphalan ASCT after primary induction therapy were evaluated across the review period. An additional 120 episodes were not evaluated because they formed part of salvage therapy in relapsed or refractory MM (n ¼ 59), were a second ASCT as part of a tandem ASCT (n ¼ 10), received less than 200 mg/m2 of melphalan (n ¼ 40), steroid-only induction (n ¼ 5), nonemelphalan-based transplant (n ¼ 3), did not receive induction therapy before transplantation (n ¼ 3), received a delayed ASCT not as part of primary therapy (n ¼ 1), and insufficient information available (n ¼ 1). The median time to ASCT from initiation of systemic therapy was 181 (range, 79-628) days, with no significant difference in time to ASCT in any of the treatment groups or in relation to mucositis outcomes (P ¼ .98 for Grade 3 or 4 mucositis). Of the episodes evaluated, 51 occurred after an IMiD-based induction, 62 after a CT-based induction, and 15 after PI-based induction (Table 1). Ten of the CT patients had received some exposure to an IMiD in the lead-up to their ASCT. Patients across all 3 groups were similar in terms of age, renal function, stage of disease, and baseline paraprotein level (Table 2). All patients had received cyclophosphamide and granulocyte colony stimulating factor based stem cell mobilization, and the median CD34þ cell dose received was similar.
Primary Outcome Measures The overall rate of Grade 3 or greater mucositis was 43%, with 33 of 62 in the CT group (53%), 17 of 51 in the IMiD group (33%), and 5 in the PI group (33%). The difference of mucositis rates between the IMiD and CT groups was 20% (P ¼ .03). There was no statistically significant difference between the PI and CT groups or the IMiD and PI groups. Parenteral opiates were used for treatment of mucositis in 21% of patients, with 20 in the CT group (31%), 5 in the IMiD group (10%), and 2 in the PI group (13%). Statistical significance was observed in the difference between the IMiD and CT groups (P ¼ .02), but not between the PI and CT or PI and IMiD groups. The rate of TPN use (42% CT, 35% IMiD, 20% PI) was not significantly different between the groups (Table 3).
Secondary Outcome Measures Neutropenic sepsis was frequent (85%, n ¼ 109) after ASCT for the whole cohort, with no significant difference between any of
Shaun Fleming et al Table 1 Induction Therapy Induction Class
Table 2 Patient Characteristics Therapy
Conventional Chemotherapy
Number of Patients
CT (n [ 62)
IMiD (n [ 51)
PI (n [ 15)
Median age, years
57.5
58
60
Male Sex, n
35
34
11
IgG myeloma
27
26
7
IgA myeloma
18
12
5
1
0
0
13
10
3
Plasma cell leukemia
1
0
0
Plasmacytoma
0
2
0
1
POEMS
1
1
0
Amyloidosis
1
0
0
24
Stage (ISS) I
25
24
6
II
11
21
4
III
7
2
2
19
4
3
0-9
3
5
3
10-29
8
8
1
30-59
24
16
5
60-90
16
21
3
>90
2
0
1
Unknown
9
1
2
0-5
17
10
3
6-20
7
6
5
21-50
27
28
3
>50
6
7
4
Unknown
5
0
0
6.06
4.72
6.49
62 AD Cyclophosphamide (with or without dexamethasone) VAD Melphalan and prednisolone DT-PACE
IMiD-Based
29 5 25 1 2 51
Cyclophosphamide, thalidomide, and dexamethasone Cyclophosphamide, thalidomide, and prednisolone Lenalidomide and dexamethasone
20
Melphalan, thalidomide, and dexamethasone
1
Thalidomide and dexamethasone
4
Thalidomide and prednisolone
1
Proteasome Inhibitor-Based
15 Bortezomib, doxorubicin, and dexamethasone Bortezomib, cyclophosphamide, and dexamethasone
14 1
Abbreviations: AD ¼ adriamycin and dexamethasone; DT-PACE ¼ dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide; IMiD ¼ immunomodulatory drug; VAD ¼ vincristine, adriamycin, and dexamethasone.
Characteristic Demographic
Diagnosis
IgG/IgA myeloma LC myeloma
Unknown Marrow Plasma Cell Infiltrate at Diagnosis, %
Paraprotein Level, g/L
the treatment groups. Rates of neutropenic enterocolitis were low, occurring in 6 patients (5%) of the cohort without significant differences between treatment groups. A single treatment-related death was recorded in the CT-treated group, with no treatment-related deaths in either the IMiD or PI group. The median number of days of TPN use was similar across all groups (6.5 days in CT, 5 in IMiD and PI). There was a statistically significant difference in the median number of days of antibiotic usage between the CT- and PI-treated groups (7 vs. 5 days; P ¼ .02), but not the IMiD group (6 days; P ¼ .09). There was no statistically significant difference in median duration of admission between treatment groups (14 days for IMiD, 13 for PI and CT). Neutrophil engraftment (defined as an absolute neutrophil count of > 0.5 109/L) was a median of 10 days in the CT treated group, and it was at day 12 and 11 in the IMiD and PI treated groups, respectively (P < .001 CT vs. IMiD; P ¼ .26 CT vs. PI).
Median CD34D Cell Dose (3 106/kg) Renal Function at Time of Transplant Cr (mmol/L) median
71
71
63
Abbreviations: Cr ¼ serum creatinine; CT ¼ chemotherapy; IMiD ¼ immunomodulatory drug; ISS ¼ International Staging System; LC ¼ light chain; PI ¼ proteasome inhibitor; POEMS ¼ Polyneuropathy, Organomegaly, Endicrinopathy, Monoclonal Gammopathy and Skin Changes Syndrome.
received doxorubicin, preventing separation of the anthracycline effect in this group.
Comparison on the Basis of Anthracycline Exposure One of the principle differences between the treatments received was anthracycline exposure. When evaluating those who received anthracycline (n ¼ 69) against those who did not (n ¼ 59), irrespective of whether they received CT only or in combination with a novel agent, there were significantly greater rates of mucositis (52% [36 of 69] vs. 32% [19 of 59]; P ¼ .02) and parenteral opiate use (27% [16 of 69] vs. 14% [8 of 59]; P < .01), however, rates of TPN usage were similar. All of the PI-treated patients
Steroid Exposure and Time to Therapy The median total dose of steroid received was 4266 mg prednisolone equivalent, which was similar across all treatment groups. Patients were stratified into high- and low-dose steroid exposure (defined as being less than [low-dose; n ¼ 48] or at or greater than [high-dose; n ¼ 79] the median dose of 4266 mg prednisolone equivalent). There was no significant difference in mucositis outcomes between each group with regard to the rate of Grade 3 or 4 mucositis
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Multiple Myeloma Induction Alters Transplant Mucositis Table 3 Mucositis According to Induction Regimen Outcome Grade ‡3 Mucositis Parenteral Opiate Use TPN Use
CT (n [ 62)
IMiD (n [ 51)
Pa
PI (n [ 15)
Pa
33 19 26
17 6 18
.03 .02 .47
5 2 3
.17 .18 .07
Abbreviations: CT ¼ chemotherapy; IMiD ¼ immunomodulatory drug; PI ¼ proteasome inhibitor; TPN ¼ total parenteral nutrition. a Compared with CT.
(44% [35] high-dose vs. 43% [21] low-dose; P ¼ .77), opiate requirement for mucositis (24% high-dose vs. 17% low-dose; P ¼ .32) or requirement for TPN (35% high-dose vs. 40% lowdose; P ¼ .64).
Stem Cell Dose and Mucositis There was no correlation between incidence of severe mucositis or requirement of parenteral opiates (P ¼ .42 and P ¼ .97, respectively).
Progression-Free Survival According to Induction Class There was no significant difference in progression-free survival identified with a median of 937 days in the CT group and 1179 days in the IMiD group, with insufficient follow-up data in the PI treated group (log-rank test P ¼ .64). The onset of severe mucositis during transplantation did not affect progression-free survival (logrank test P ¼ .83).
Discussion In this study, patients who were previously treated with IMiD based therapies had significantly lower rates of severe oral mucositis after ASCT compared with those treated with CT, which was further reflected by lower rates of parenteral opiate requirements. Our findings demonstrate that preexisting effects on the oral mucous membranes likely predispose for the subsequent development of transplant-associated mucositis. This effect has substantial patient care and resource allocation implications during ASCT for MM. Indeed, there was a significant difference in rates of severe oral mucositis and parenteral opiate use although there was not a significant difference in the use of TPN. This likely reflects the use of TPN for indications other than oral mucositis including poor oral intake due to lack of appetite or nausea, and a concurrent early intervention nutrition study running during the period of data collection (manuscript in preparation). We have identified that anthracycline exposure (Table 4), seen in the pre-novel therapy age (VAD and AD [adriamycin and dexamethasone]) and in combination with a PI (PAD [bortezomib, adriamycin, dexamethasone] regimen) to be a risk factor for subsequent development of mucositis. Anthracyclines are recognized to
Table 4 Mucositis According to Anthracycline Exposure Outcome Grade ‡3 Mucositis Parenteral Opiate Use TPN Use
4
-
Yes (n [ 69)
No (n [ 59)
P
36 19 26
19 8 21
.02 .05 .8
Abbreviations: CT ¼ chemotherapy; IMiD ¼ immunomodulatory drug; PI ¼ proteasome inhibitor; TPN ¼ total parenteral nutrition.
Clinical Lymphoma, Myeloma & Leukemia Month 2014
cause oral mucositis with conventional-dose CT, with rates that vary from 3% in patients receiving anthracyclines for treatment of Hodgkin lymphoma, to as high as 70% when administered in combination with fludarabine and cytarabine in acute leukemia.25 In patients receiving CT with either VAD or AD, rates of clinical mucositis are reported to be approximately 5%.26 Mucositis is a consequence of a CT-initiated pathway of reactive oxygen species production stimulating proinflammatory and tissue injury cytokines including interleukin (IL)-1b, IL-6, and tumour necrosis factor-a which is further stimulated by ulceration, which leads to exposure of the subepithelial layers to microorganisms and further secretion of proinflammatory cytokines. Activation of the cyclooxygenase and prostaglandin pathways along with adhesion molecules stimulates angiogenesis in the epithelial bed.27,28 Increased cytokine levels persist long after apparent healing of the mucosal injury with increased levels of prostaglandins, IL-1b, and cyclooxygenase-1 seen months after ASCT.29 Although the rates of clinical mucositis are low in VAD- and AD-treated patients, subclinical lesions and changes in the inflammatory cytokines might exist without the development of clinically apparent mucositis. This priming is evidenced by the increased risk of mucositis with cumulative anthracycline exposure.28 Subsequently, when exposed to high-dose CT the patient is at increased risk of developing mucositis. This effect might be compounded by other traditional risk factors for oral mucositis such as renal impairment, oral pathology, oral appliances, dental hygiene, and previous oral lesions, and by genetic changes in drug metabolism.30 We propose that novel agents in the absence of anthracycline exposure are not associated with clinical and subclinical mucositis lesions and thus less priming for the development of mucositis after melphalan exposure. Potential methods currently available to ameliorate the effect of mucositis during ASCT include the use of oral cryotherapy with melphalan administration, laser therapy, and the keratinocyte growth factor palifermin. Cryotherapy, the administration of ice during the melphalan infusion, has been recently shown in a metaanalysis to reduce the risk of oral mucositis in patients receiving high-dose melphalan.31 Laser therapy for reduction of mucositis in patients receiving hematopoietic stem cell transplantation has been investigated and found to be tolerable and efficacious,32 however, it has not entered routine practice. The keratinocyte growth factor palifermin has been studied in the prevention of oral mucositis in patients receiving an autologous stem cell transplant. The evidence for its efficacy is conflicted, with some studies showing a benefit to its administration,33,34 and others have failed to show a similar benefit.35 The use of palifermin is also limited by its substantial cost.36 Regimens using combinations of novel agents with corticosteroids and/or an alkylating agents such as cyclophosphamide have
Shaun Fleming et al shown results superior to that seen with conventional CT. Although the PAD regimen shows excellent response rates and survival outcomes,31 similar outcomes are seen with other novel therapy-based inductions such as CTD (cyclophosphamide, thalidomide, dexamethasone), CyBorD (cyclophosphamide, bortezomib, and dexamethasone), and RD (lenalidomide and dexamethasone).37-39 Oral mucositis confers an increased risk of treatment-related morbidity including neutropenic sepsis, need for nutritional support, and parenteral analgesia necessitating hospital admission and reducing the opportunity for outpatient-based transplant regimens, with consequent effect on bed utilization and cost.40 Current outpatient-based transplant regimens are safe and effective, but associated with a substantial readmission rate.7,41 Half of the readmissions after ASCT in MM are mucositis-related. Strategies, which reduce the occurrence of mucositis might not only reduce the symptom burden for patients but might also reduce readmission rates, thus making outpatient regimens significantly more viable. Our study is limited by the retrospective nature of the data obtained, and that a significant time period of patient accrual was necessary to acquire sufficient patients. The finding was also only shown as significant in univariate analysis, likely reflective of the numbers of patients accrued and also the strong links between steroid exposure, anthracycline usage, and a CCT-based regimen. CCT regimens not incorporating an IMiD or PI are almost completely superseded in myeloma induction. Combination regimens using lenalidomide and/or bortezomib now allow successful induction therapy without requiring CT. However, although AD and VAD are no longer used, anthracycline-containing regimens such as PAD are in common use. Our analysis of mucositis incidence in ASCT after previous treatment with CCT regimens vs. non-CCT regimens highlights that mucositis onset is largely determined by the effect of treatment before high-dose melphalan exposure. This is an important point for decision-making for resource allocation in which the costs associated with novel drug therapy in induction might largely offset the costs associated with a substantial reduction in ASCT-associated mucositis. Because all patients included in this analysis received cyclophosphamide mobilization, we cannot discount its possible contribution on mucositis onset. However, because we determined that risk of mucositis is largely determined by CT exposure before ASCT, this provides further impetus to move toward noneCTbased mobilization strategies. From our findings it is clear that cumulative CT exposure, and not just the melphalan conditioning regimen before ASCT, is responsible for mucositis induction. The widespread application of noneCT-containing induction regimens is likely to result in a lower incidence of significant mucositis after ASCT and allow for greater delivery in an ambulatory setting. To this end, the rates of mucositis should be included in all ASCT analyses and correlated with not only the conditioning regimen, but with previous induction therapy to ascertain whether these now historic findings translate into modern clinical practice.
Conclusion In our study, patients treated with IMiD-based therapy had significantly lower rates of mucositis than those treated with conventional CT during induction for MM. Patients in this group are
at lower risk of mucositis, and might be more appropriate for outpatient-based care.
Clinical Practice Points Mucositis is a major toxicity associated with autologous stem cell
transplantaiton for myeloma. Previously there was limited research about the potential impact
of prior therapy on mucositis risk. Conventional chemotherapy regimens were associated with a
higher risk of mucositis that regimens consisting of immunomodulators such as Lenalidomide or Thalidomide. While conventional chemotherapy regimens such as AD and VAD are no longer in routine clinical use, chemotherapy combinations with novel agents remain commonplace. In assessing risk of transplant associated side effects such as mucositis prior therapy should be considered as a potential risk factor. This risk of transplant associated mucositis may factor into decisions regarding outpatient autologous transplantation in determining readmission risk. Future studies into upfront myeloma therapy should incorporate information on later transplant associated toxicities.
Disclosure Simon J. Harrison has received study funding and honoraria from Celgene and Janssen-Cilag. All other authors state that they have no conflicts of interest.
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29. Lalla RV, Pilbeam CC, Walsh SJ, Sonis ST, Keefe DM, Peterson DE. Role of the cyclooxygenase pathway in chemotherapy-induced oral mucositis: a pilot study. Support Care Cancer 2009; 18:95-103. 30. Dumontet C, Landi S, Reiman T, et al. Genetic polymorphisms associated with outcome in multiple myeloma patients receiving high-dose melphalan. Bone Marrow Transplant 2010; 45:1316-24. 31. Peterson DE, Ohrn K, Bowen J, et al. Systematic review of oral cryotherapy for management of oral mucositis caused by cancer therapy. Support Care Cancer 2013; 21:327-32. 32. Cowen D, Tardieu C, Schubert M, et al. Low energy Helium-Neon laser in the prevention of oral mucositis in patients undergoing bone marrow transplant: results of a double blind randomized trial. Int J Radiat Oncol Biol Phys 1997; 38:697-703. 33. Tsirigotis P, Triantafyllou K, Girkas K, et al. Keratinocyte growth factor is effective in the prevention of intestinal mucositis in patients with hematological malignancies treated with high-dose chemotherapy and autologous hematopoietic SCT: a video-capsule endoscopy study. Bone Marrow Transplant 2008; 42:337-43. 34. Kobbe G, Bruns I, Schroeder T, et al. A 3-day short course of palifermin before HDT reduces toxicity and need for supportive care after autologous blood stem-cell transplantation in patients with multiple myeloma. Ann Oncol 2010; 21:1898-904. 35. Blijlevens N, de Château M, Krivan G, et al. In a high-dose melphalan setting, palifermin compared with placebo had no effect on oral mucositis or related patient’s burden. Bone Marrow Transplant 2013; 48:966-71. 36. Elting LS, Shih YC, Stiff PJ, et al. Economic impact of palifermin on the costs of hospitalization for autologous hematopoietic stem cell transplant: analysis of phase 3 trial results. Biol Blood Marrow Transplant 2007; 13:806-13. 37. Gay F, Magarotto V, Crippa C, et al. Bortezomib induction, reduced-intensity transplantation and lenalidomide consolidation-maintenance for myeloma: updated results. Blood 2013; 122:1376-83. 38. Srivastava G, Rana V, Lacy MQ, et al. Long-term outcome with lenalidomide and dexamethasone therapy for newly diagnosed multiple myeloma. Leukemia 2013; 27:2062-6. 39. Rabin N, Percy L, Khan I, Quinn J, D’Sa S, Yong KL. Improved response with post-ASCT consolidation by low dose thalidomide, cyclophosphamide and dexamethasone as first line treatment for multiple myeloma. Br J Haematol 2012; 158: 499-505. 40. Vera-Llonch M, Oster G, Ford CM, Lu J, Sonis S. Oral mucositis and outcomes of allogeneic hematopoietic stem-cell transplantation in patients with hematologic malignancies. Support Care Cancer 2007; 15:491-6. 41. Holbro A, Ahmad I, Cohen S, et al. Safety and cost-effectiveness of outpatient autologous stem cell transplantation in patients with multiple myeloma. Biol Blood Marrow Transplant 2013; 19:547-51.
The Choice of Multiple Myeloma Induction Therapy Affects the Frequency and Severity of Oral Mucositis After Melphalan-Based Autologous Stem Cell Transplantation Shaun Fleming,1 Simon J. Harrison,2,3 Piers Blombery,2 Trish Joyce,2 Kerrie Stokes,2 John F. Seymour,2,3 H. Miles Prince,2,3 David Ritchie1,2,3 Abstract Mucositis is a significant complication of high dose melphalan autologous transplantation (AHSCT) for myeloma. We hypothesized that prior therapy received would impact on mucositis risk in AHSCT. We retrospectively analyzed 128 sequential 200mg/m2 melphalan AHSCT performed as part of primary. There was a significant reduction in mucositis risk in patients receiving immunomodulator based induction therapy compared to conventional chemotherapy. Introduction/Background: Mucositis is a common complication of high-dose melphalan (HDM) used before autologous stem cell transplantation (ASCT) for multiple myeloma (MM). Mucositis rates are influenced by previous chemotherapy (CT) exposure. We examined the effect of induction therapy before ASCT on ASCT mucositis rates. Patients and Methods: Patients undergoing first 200 mg/m2 HDM ASCT were assessed. Those receiving < 200 mg/ m2, or those with previous ASCT were excluded. Patients were evaluated depending on type of induction therapy (CT, immunomodulatory drug [IMiD], or proteasome inhibitor [PI]) before ASCT. A case record review was performed and data collected on response to induction, rates of Grade 3/4 mucositis, and days of total parenteral nutrition (TPN) or parenteral opiate analgesia. Results: One hundred twenty-eight patients with ASCT were assessed. Induction therapy was CT- (n ¼ 62), IMiD- (n ¼ 51), or PI-based (n ¼ 15) therapy. Patient characteristics were overall similar, including median age, MM stage, and CD34þ cell dose. IMiD-based therapy patients had lower rates of mucositis (33% vs. 53%; P ¼ .03) and less opiate requirements (10% vs. 31%; P ¼ .02) compared with those treated with CT. Rates of mucositis and opiate use in the PI group were not different to the CT cohorts (33% vs. 53%; P ¼ .6 and 13% vs. 31%; P ¼ .13), likely due to concurrent anthracycline exposure. TPN usage was similar (CT, 42%; IMiD, 35%; and PI, 20%), as was neutropenia duration and antibiotic usage. Conclusion: Patients treated with IMiD-based regimens before HDM ASCT had significantly lower rates of mucositis than those treated with CT-based therapy. There were too few patients who received PI therapy to evaluate the effect. Clinical Lymphoma, Myeloma & Leukemia, Vol. -, No. -, --- ª 2014 Elsevier Inc. All rights reserved. Keywords: Autologus transplantation, Mucositis, Myeloma, Novel therapy, Supportive Care
Introduction Oral mucositis is a common complication of autologous stem cell transplantation (ASCT), with rates of severe (Grade 3 or 4) 1
The Royal Melbourne Hospital, Victoria, Australia Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia 3 University of Melbourne, Victoria, Australia 2
Submitted: Sep 22, 2013; Revised: Feb 6, 2014; Accepted: Feb 11, 2014 Address for correspondence: Shaun Fleming, MBBS (Hons), Royal Melbourne Hospital, Grattan Street, Parkville, Victoria, Australia E-mail contact: fl[email protected]
2152-2650/$ - see frontmatter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clml.2014.02.001
mucositis according to the Common Terminology Criteria for Adverse Events (CTCAE) reported to be as high as 46%.1 In patients with multiple myeloma (MM) undergoing ASCT the overall rate of mucositis has been reported as 75%, with severe mucositis recorded in 21%, with melphalan dose and renal impairment before transplant identified as risk factors for mucositis severity.2 Preexisting oral pathology, the presence of oral appliances, dental hygiene, and previous oral lesions have also been identified as risk factors for mucositis.3 Patients with severe mucositis have a significantly greater rate and duration of neutropenic sepsis.1,4 Furthermore, more than 40% of
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Multiple Myeloma Induction Alters Transplant Mucositis patients undergoing ASCT will report mucositis as their most debilitating transplantation-related side effect.5 Severity of mucositis is identified as a major risk factor for transplant-associated mortality in autologous and allogeneic transplantation.4 Severe mucositis forms 1 of the major barriers to outpatientbased ASCT procedures in MM. Supportive care for severe mucositis including intravenous opiates, enteral feeding, and total parenteral nutrition (TPN) are difficult or impossible to administer in the outpatient setting, and mucositis-associated complications such as neutropenic sepsis also necessitate readmission. In a study of outpatient-based melphalan-conditioned ASCT in MM, a readmission rate of 36% (10 of 28 patients) was observed, of which half were for severe mucositis.6 In less well selected patients, the readmission rate might be significantly greater.7 Since the mid 1990s, high-dose chemotherapy (CT) with ASCT has been a key part of consolidation for patients with MM after conventional CT-based induction (CCT). ASCT delivers deeper MM responses and is associated with improved progression-free and overall survival.8-10 Historically, the most commonly used CT regimen was VAD (vincristine 1.6 mg, adriamycin 36 mg/m2, and dexamethasone 40 mg daily for 4 days).11,12 Novel therapy-based induction with either immunomodulatory drug (IMiD) or proteasome inhibitor (PI) therapy provide superior outcomes compared with CT-based induction.13-18 Although there is interest in therapeutic approaches that defer transplantation until first disease progression, with ongoing trials continuing in this area,19 current evidence supports ASCT after primary induction therapy as the standard of care among transplant-eligible patients.20 Because CT might be associated with subclinical mucosal lesions,21 we hypothesized that the type of previous induction therapy might influence the incidence and severity of ASCT-related mucositis. We investigated the effect of induction therapy before transplantation on mucositis in patients undergoing ASCT for MM at our institution.
Patients and Methods
2
-
We undertook a retrospective review of case records of patients who had received ASCT for MM at the Peter MacCallum Cancer Centre between May 2005 and August 2011. All data were collected in accordance with approval from an institutional ethics committee. Patients were considered evaluable if they were undergoing a first 200 mg/m2 melphalan ASCT for treatment of MM, with those receiving subsequent ASCT or salvage therapy excluded. Also excluded were patients who had not received any induction therapy or only steroids before ASCT. Data were collected on demographic information, previous therapies received, and MM status including stage at diagnosis.22 Treatment data including regimen received, steroid dose, and time from therapy to transplant were determined from clinical notes, pharmacy records, and treatment summaries. ASCT data were obtained on the conditioning regimen received, stem cell dose received, rates of mucositis, onset of fever, and day of discharge from day of stem cell infusion. Clinically significant mucositis was defined as Grade 3 or 4 clinical mucositis according to the CTCAE version 3.0.23 Surrogate measures of mucositis were also measured including parenteral opiate use and the use of TPN. Response to therapy was categorized according to the International Uniform Response Criteria.24
Clinical Lymphoma, Myeloma & Leukemia Month 2014
Patients were evaluated on the basis of induction therapy received; either CT-, IMiD-, or PI-based therapy. Any patient who had received a CT-based treatment was classified as having received CT irrespective of any subsequent novel agent exposure before transplantation, and those who received a single CT agent in combination with either IMiD or PI therapy were counted in their respective groups. Data analysis was performed using the R statistical platform version 2.14.1 (R Foundation for Statistical Computing, Vienna, Austria), using the c2 test and Fisher exact test for comparison of nominative data and the Kruskal-Wallis test for analysis of nonparametric data. Secondary evaluation was performed on the basis of steroid exposure, time between treatment, and ASCT and anthracycline exposure to establish which, if any, of these variables contributed to mucositis outcomes.
Results A total of 128 sequential patients treated with 200 mg/m2 melphalan ASCT after primary induction therapy were evaluated across the review period. An additional 120 episodes were not evaluated because they formed part of salvage therapy in relapsed or refractory MM (n ¼ 59), were a second ASCT as part of a tandem ASCT (n ¼ 10), received less than 200 mg/m2 of melphalan (n ¼ 40), steroid-only induction (n ¼ 5), nonemelphalan-based transplant (n ¼ 3), did not receive induction therapy before transplantation (n ¼ 3), received a delayed ASCT not as part of primary therapy (n ¼ 1), and insufficient information available (n ¼ 1). The median time to ASCT from initiation of systemic therapy was 181 (range, 79-628) days, with no significant difference in time to ASCT in any of the treatment groups or in relation to mucositis outcomes (P ¼ .98 for Grade 3 or 4 mucositis). Of the episodes evaluated, 51 occurred after an IMiD-based induction, 62 after a CT-based induction, and 15 after PI-based induction (Table 1). Ten of the CT patients had received some exposure to an IMiD in the lead-up to their ASCT. Patients across all 3 groups were similar in terms of age, renal function, stage of disease, and baseline paraprotein level (Table 2). All patients had received cyclophosphamide and granulocyte colony stimulating factor based stem cell mobilization, and the median CD34þ cell dose received was similar.
Primary Outcome Measures The overall rate of Grade 3 or greater mucositis was 43%, with 33 of 62 in the CT group (53%), 17 of 51 in the IMiD group (33%), and 5 in the PI group (33%). The difference of mucositis rates between the IMiD and CT groups was 20% (P ¼ .03). There was no statistically significant difference between the PI and CT groups or the IMiD and PI groups. Parenteral opiates were used for treatment of mucositis in 21% of patients, with 20 in the CT group (31%), 5 in the IMiD group (10%), and 2 in the PI group (13%). Statistical significance was observed in the difference between the IMiD and CT groups (P ¼ .02), but not between the PI and CT or PI and IMiD groups. The rate of TPN use (42% CT, 35% IMiD, 20% PI) was not significantly different between the groups (Table 3).
Secondary Outcome Measures Neutropenic sepsis was frequent (85%, n ¼ 109) after ASCT for the whole cohort, with no significant difference between any of
Shaun Fleming et al Table 1 Induction Therapy Induction Class
Table 2 Patient Characteristics Therapy
Conventional Chemotherapy
Number of Patients
CT (n [ 62)
IMiD (n [ 51)
PI (n [ 15)
Median age, years
57.5
58
60
Male Sex, n
35
34
11
IgG myeloma
27
26
7
IgA myeloma
18
12
5
1
0
0
13
10
3
Plasma cell leukemia
1
0
0
Plasmacytoma
0
2
0
1
POEMS
1
1
0
Amyloidosis
1
0
0
24
Stage (ISS) I
25
24
6
II
11
21
4
III
7
2
2
19
4
3
0-9
3
5
3
10-29
8
8
1
30-59
24
16
5
60-90
16
21
3
>90
2
0
1
Unknown
9
1
2
0-5
17
10
3
6-20
7
6
5
21-50
27
28
3
>50
6
7
4
Unknown
5
0
0
6.06
4.72
6.49
62 AD Cyclophosphamide (with or without dexamethasone) VAD Melphalan and prednisolone DT-PACE
IMiD-Based
29 5 25 1 2 51
Cyclophosphamide, thalidomide, and dexamethasone Cyclophosphamide, thalidomide, and prednisolone Lenalidomide and dexamethasone
20
Melphalan, thalidomide, and dexamethasone
1
Thalidomide and dexamethasone
4
Thalidomide and prednisolone
1
Proteasome Inhibitor-Based
15 Bortezomib, doxorubicin, and dexamethasone Bortezomib, cyclophosphamide, and dexamethasone
14 1
Abbreviations: AD ¼ adriamycin and dexamethasone; DT-PACE ¼ dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide; IMiD ¼ immunomodulatory drug; VAD ¼ vincristine, adriamycin, and dexamethasone.
Characteristic Demographic
Diagnosis
IgG/IgA myeloma LC myeloma
Unknown Marrow Plasma Cell Infiltrate at Diagnosis, %
Paraprotein Level, g/L
the treatment groups. Rates of neutropenic enterocolitis were low, occurring in 6 patients (5%) of the cohort without significant differences between treatment groups. A single treatment-related death was recorded in the CT-treated group, with no treatment-related deaths in either the IMiD or PI group. The median number of days of TPN use was similar across all groups (6.5 days in CT, 5 in IMiD and PI). There was a statistically significant difference in the median number of days of antibiotic usage between the CT- and PI-treated groups (7 vs. 5 days; P ¼ .02), but not the IMiD group (6 days; P ¼ .09). There was no statistically significant difference in median duration of admission between treatment groups (14 days for IMiD, 13 for PI and CT). Neutrophil engraftment (defined as an absolute neutrophil count of > 0.5 109/L) was a median of 10 days in the CT treated group, and it was at day 12 and 11 in the IMiD and PI treated groups, respectively (P < .001 CT vs. IMiD; P ¼ .26 CT vs. PI).
Median CD34D Cell Dose (3 106/kg) Renal Function at Time of Transplant Cr (mmol/L) median
71
71
63
Abbreviations: Cr ¼ serum creatinine; CT ¼ chemotherapy; IMiD ¼ immunomodulatory drug; ISS ¼ International Staging System; LC ¼ light chain; PI ¼ proteasome inhibitor; POEMS ¼ Polyneuropathy, Organomegaly, Endicrinopathy, Monoclonal Gammopathy and Skin Changes Syndrome.
received doxorubicin, preventing separation of the anthracycline effect in this group.
Comparison on the Basis of Anthracycline Exposure One of the principle differences between the treatments received was anthracycline exposure. When evaluating those who received anthracycline (n ¼ 69) against those who did not (n ¼ 59), irrespective of whether they received CT only or in combination with a novel agent, there were significantly greater rates of mucositis (52% [36 of 69] vs. 32% [19 of 59]; P ¼ .02) and parenteral opiate use (27% [16 of 69] vs. 14% [8 of 59]; P < .01), however, rates of TPN usage were similar. All of the PI-treated patients
Steroid Exposure and Time to Therapy The median total dose of steroid received was 4266 mg prednisolone equivalent, which was similar across all treatment groups. Patients were stratified into high- and low-dose steroid exposure (defined as being less than [low-dose; n ¼ 48] or at or greater than [high-dose; n ¼ 79] the median dose of 4266 mg prednisolone equivalent). There was no significant difference in mucositis outcomes between each group with regard to the rate of Grade 3 or 4 mucositis
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Multiple Myeloma Induction Alters Transplant Mucositis Table 3 Mucositis According to Induction Regimen Outcome Grade ‡3 Mucositis Parenteral Opiate Use TPN Use
CT (n [ 62)
IMiD (n [ 51)
Pa
PI (n [ 15)
Pa
33 19 26
17 6 18
.03 .02 .47
5 2 3
.17 .18 .07
Abbreviations: CT ¼ chemotherapy; IMiD ¼ immunomodulatory drug; PI ¼ proteasome inhibitor; TPN ¼ total parenteral nutrition. a Compared with CT.
(44% [35] high-dose vs. 43% [21] low-dose; P ¼ .77), opiate requirement for mucositis (24% high-dose vs. 17% low-dose; P ¼ .32) or requirement for TPN (35% high-dose vs. 40% lowdose; P ¼ .64).
Stem Cell Dose and Mucositis There was no correlation between incidence of severe mucositis or requirement of parenteral opiates (P ¼ .42 and P ¼ .97, respectively).
Progression-Free Survival According to Induction Class There was no significant difference in progression-free survival identified with a median of 937 days in the CT group and 1179 days in the IMiD group, with insufficient follow-up data in the PI treated group (log-rank test P ¼ .64). The onset of severe mucositis during transplantation did not affect progression-free survival (logrank test P ¼ .83).
Discussion In this study, patients who were previously treated with IMiD based therapies had significantly lower rates of severe oral mucositis after ASCT compared with those treated with CT, which was further reflected by lower rates of parenteral opiate requirements. Our findings demonstrate that preexisting effects on the oral mucous membranes likely predispose for the subsequent development of transplant-associated mucositis. This effect has substantial patient care and resource allocation implications during ASCT for MM. Indeed, there was a significant difference in rates of severe oral mucositis and parenteral opiate use although there was not a significant difference in the use of TPN. This likely reflects the use of TPN for indications other than oral mucositis including poor oral intake due to lack of appetite or nausea, and a concurrent early intervention nutrition study running during the period of data collection (manuscript in preparation). We have identified that anthracycline exposure (Table 4), seen in the pre-novel therapy age (VAD and AD [adriamycin and dexamethasone]) and in combination with a PI (PAD [bortezomib, adriamycin, dexamethasone] regimen) to be a risk factor for subsequent development of mucositis. Anthracyclines are recognized to
Table 4 Mucositis According to Anthracycline Exposure Outcome Grade ‡3 Mucositis Parenteral Opiate Use TPN Use
4
-
Yes (n [ 69)
No (n [ 59)
P
36 19 26
19 8 21
.02 .05 .8
Abbreviations: CT ¼ chemotherapy; IMiD ¼ immunomodulatory drug; PI ¼ proteasome inhibitor; TPN ¼ total parenteral nutrition.
Clinical Lymphoma, Myeloma & Leukemia Month 2014
cause oral mucositis with conventional-dose CT, with rates that vary from 3% in patients receiving anthracyclines for treatment of Hodgkin lymphoma, to as high as 70% when administered in combination with fludarabine and cytarabine in acute leukemia.25 In patients receiving CT with either VAD or AD, rates of clinical mucositis are reported to be approximately 5%.26 Mucositis is a consequence of a CT-initiated pathway of reactive oxygen species production stimulating proinflammatory and tissue injury cytokines including interleukin (IL)-1b, IL-6, and tumour necrosis factor-a which is further stimulated by ulceration, which leads to exposure of the subepithelial layers to microorganisms and further secretion of proinflammatory cytokines. Activation of the cyclooxygenase and prostaglandin pathways along with adhesion molecules stimulates angiogenesis in the epithelial bed.27,28 Increased cytokine levels persist long after apparent healing of the mucosal injury with increased levels of prostaglandins, IL-1b, and cyclooxygenase-1 seen months after ASCT.29 Although the rates of clinical mucositis are low in VAD- and AD-treated patients, subclinical lesions and changes in the inflammatory cytokines might exist without the development of clinically apparent mucositis. This priming is evidenced by the increased risk of mucositis with cumulative anthracycline exposure.28 Subsequently, when exposed to high-dose CT the patient is at increased risk of developing mucositis. This effect might be compounded by other traditional risk factors for oral mucositis such as renal impairment, oral pathology, oral appliances, dental hygiene, and previous oral lesions, and by genetic changes in drug metabolism.30 We propose that novel agents in the absence of anthracycline exposure are not associated with clinical and subclinical mucositis lesions and thus less priming for the development of mucositis after melphalan exposure. Potential methods currently available to ameliorate the effect of mucositis during ASCT include the use of oral cryotherapy with melphalan administration, laser therapy, and the keratinocyte growth factor palifermin. Cryotherapy, the administration of ice during the melphalan infusion, has been recently shown in a metaanalysis to reduce the risk of oral mucositis in patients receiving high-dose melphalan.31 Laser therapy for reduction of mucositis in patients receiving hematopoietic stem cell transplantation has been investigated and found to be tolerable and efficacious,32 however, it has not entered routine practice. The keratinocyte growth factor palifermin has been studied in the prevention of oral mucositis in patients receiving an autologous stem cell transplant. The evidence for its efficacy is conflicted, with some studies showing a benefit to its administration,33,34 and others have failed to show a similar benefit.35 The use of palifermin is also limited by its substantial cost.36 Regimens using combinations of novel agents with corticosteroids and/or an alkylating agents such as cyclophosphamide have
Shaun Fleming et al shown results superior to that seen with conventional CT. Although the PAD regimen shows excellent response rates and survival outcomes,31 similar outcomes are seen with other novel therapy-based inductions such as CTD (cyclophosphamide, thalidomide, dexamethasone), CyBorD (cyclophosphamide, bortezomib, and dexamethasone), and RD (lenalidomide and dexamethasone).37-39 Oral mucositis confers an increased risk of treatment-related morbidity including neutropenic sepsis, need for nutritional support, and parenteral analgesia necessitating hospital admission and reducing the opportunity for outpatient-based transplant regimens, with consequent effect on bed utilization and cost.40 Current outpatient-based transplant regimens are safe and effective, but associated with a substantial readmission rate.7,41 Half of the readmissions after ASCT in MM are mucositis-related. Strategies, which reduce the occurrence of mucositis might not only reduce the symptom burden for patients but might also reduce readmission rates, thus making outpatient regimens significantly more viable. Our study is limited by the retrospective nature of the data obtained, and that a significant time period of patient accrual was necessary to acquire sufficient patients. The finding was also only shown as significant in univariate analysis, likely reflective of the numbers of patients accrued and also the strong links between steroid exposure, anthracycline usage, and a CCT-based regimen. CCT regimens not incorporating an IMiD or PI are almost completely superseded in myeloma induction. Combination regimens using lenalidomide and/or bortezomib now allow successful induction therapy without requiring CT. However, although AD and VAD are no longer used, anthracycline-containing regimens such as PAD are in common use. Our analysis of mucositis incidence in ASCT after previous treatment with CCT regimens vs. non-CCT regimens highlights that mucositis onset is largely determined by the effect of treatment before high-dose melphalan exposure. This is an important point for decision-making for resource allocation in which the costs associated with novel drug therapy in induction might largely offset the costs associated with a substantial reduction in ASCT-associated mucositis. Because all patients included in this analysis received cyclophosphamide mobilization, we cannot discount its possible contribution on mucositis onset. However, because we determined that risk of mucositis is largely determined by CT exposure before ASCT, this provides further impetus to move toward noneCTbased mobilization strategies. From our findings it is clear that cumulative CT exposure, and not just the melphalan conditioning regimen before ASCT, is responsible for mucositis induction. The widespread application of noneCT-containing induction regimens is likely to result in a lower incidence of significant mucositis after ASCT and allow for greater delivery in an ambulatory setting. To this end, the rates of mucositis should be included in all ASCT analyses and correlated with not only the conditioning regimen, but with previous induction therapy to ascertain whether these now historic findings translate into modern clinical practice.
Conclusion In our study, patients treated with IMiD-based therapy had significantly lower rates of mucositis than those treated with conventional CT during induction for MM. Patients in this group are
at lower risk of mucositis, and might be more appropriate for outpatient-based care.
Clinical Practice Points Mucositis is a major toxicity associated with autologous stem cell
transplantaiton for myeloma. Previously there was limited research about the potential impact
of prior therapy on mucositis risk. Conventional chemotherapy regimens were associated with a
higher risk of mucositis that regimens consisting of immunomodulators such as Lenalidomide or Thalidomide. While conventional chemotherapy regimens such as AD and VAD are no longer in routine clinical use, chemotherapy combinations with novel agents remain commonplace. In assessing risk of transplant associated side effects such as mucositis prior therapy should be considered as a potential risk factor. This risk of transplant associated mucositis may factor into decisions regarding outpatient autologous transplantation in determining readmission risk. Future studies into upfront myeloma therapy should incorporate information on later transplant associated toxicities.
Disclosure Simon J. Harrison has received study funding and honoraria from Celgene and Janssen-Cilag. All other authors state that they have no conflicts of interest.
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Multiple Myeloma Induction Alters Transplant Mucositis 15. Harousseau JL, Attal M, Leleu X, et al. Bortezomib plus dexamethasone as induction treatment prior to autologous stem cell transplantation in patients with newly diagnosed multiple myeloma: results of an IFM phase II study. Haematologica 2006; 91:1498-505. 16. Jagannath S, Durie BG, Wolf J, et al. Bortezomib therapy alone and in combination with dexamethasone for previously untreated symptomatic multiple myeloma. Br J Haematol 2005; 129:776-83. 17. Avet-Loiseau H, Leleu X, Roussel M, et al. Bortezomib plus dexamethasone induction improves outcome of patients with t(4;14) myeloma but not outcome of patients with del(17p). J Clin Oncol 2010; 28:4630-4. 18. Cavo M, Zamagni E, Tosi P, et al. First-line therapy with thalidomide and dexamethasone in preparation for autologous stem cell transplantation for multiple myeloma. Haematologica 2004; 89:826-31. 19. Kumar SK, Lacy MQ, Dispenzieri A, et al. Early versus delayed autologous transplantation after immunomodulatory agents-based induction therapy in patients with newly diagnosed multiple myeloma. Cancer 2012; 118:1585-92. 20. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Multiple Myeloma version 2. Available at: http://www.nccn.org/ professionals/physician_gls/pdf/myeloma.pdf. Accessed: March 8, 2013. 21. Logan RM, Stringer AM, Bowen JM, Gibson RJ, Sonis ST, Keefe DM. Serum levels of NF-kB and pro-inflammatory cytokines following administration of mucotoxic drugs. Cancer Biol Ther 2008; 7:1139-45. 22. Greipp P, Miguel J, Durie B. International staging system for multiple myeloma. J Clin Oncol 2005; 23:3412-20. 23. Trotti A, Colevas A, Setser A, et al. CTCAE v3.0: development of a comprehensive grading system for the adverse effects of cancer treatment. Semin Radiat Oncol 2003; 13:176-81. 24. Durie BG, Harousseau JL, Miguel JS, et al. International uniform response criteria for multiple myeloma. Leukemia 2006; 20:1467-73. 25. Niscola P, Scaramucci L, Romani C, et al. Mucositis in the treatment of haematological malignancies. Ann Oncol 2008; 19(suppl 7):vii141-5. 26. Sonneveld P, Suciu S, Weijermans P, et al. Cyclosporin A combined with vincristine, doxorubicin and dexamethasone (VAD) compared with VAD alone in patients with advanced refractory multiple myeloma: an EORTC-HOVON randomized phase III study (06914). Br J Haematol 2001; 115:895-902. 27. Sonis ST, Elting LS, Keefe D, et al. Perspectives on cancer therapy-induced mucosal injury: pathogenesis, measurement, epidemiology, and consequences for patients. Cancer 2004; 100(suppl 9):1995-2025. 28. Niscola P, Romani C, Cupelli L, et al. Mucositis in patients with hematologic malignancies: an overview. Haematologica 2007; 92:222-31.
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Clinical Lymphoma, Myeloma & Leukemia Month 2014
29. Lalla RV, Pilbeam CC, Walsh SJ, Sonis ST, Keefe DM, Peterson DE. Role of the cyclooxygenase pathway in chemotherapy-induced oral mucositis: a pilot study. Support Care Cancer 2009; 18:95-103. 30. Dumontet C, Landi S, Reiman T, et al. Genetic polymorphisms associated with outcome in multiple myeloma patients receiving high-dose melphalan. Bone Marrow Transplant 2010; 45:1316-24. 31. Peterson DE, Ohrn K, Bowen J, et al. Systematic review of oral cryotherapy for management of oral mucositis caused by cancer therapy. Support Care Cancer 2013; 21:327-32. 32. Cowen D, Tardieu C, Schubert M, et al. Low energy Helium-Neon laser in the prevention of oral mucositis in patients undergoing bone marrow transplant: results of a double blind randomized trial. Int J Radiat Oncol Biol Phys 1997; 38:697-703. 33. Tsirigotis P, Triantafyllou K, Girkas K, et al. Keratinocyte growth factor is effective in the prevention of intestinal mucositis in patients with hematological malignancies treated with high-dose chemotherapy and autologous hematopoietic SCT: a video-capsule endoscopy study. Bone Marrow Transplant 2008; 42:337-43. 34. Kobbe G, Bruns I, Schroeder T, et al. A 3-day short course of palifermin before HDT reduces toxicity and need for supportive care after autologous blood stem-cell transplantation in patients with multiple myeloma. Ann Oncol 2010; 21:1898-904. 35. Blijlevens N, de Château M, Krivan G, et al. In a high-dose melphalan setting, palifermin compared with placebo had no effect on oral mucositis or related patient’s burden. Bone Marrow Transplant 2013; 48:966-71. 36. Elting LS, Shih YC, Stiff PJ, et al. Economic impact of palifermin on the costs of hospitalization for autologous hematopoietic stem cell transplant: analysis of phase 3 trial results. Biol Blood Marrow Transplant 2007; 13:806-13. 37. Gay F, Magarotto V, Crippa C, et al. Bortezomib induction, reduced-intensity transplantation and lenalidomide consolidation-maintenance for myeloma: updated results. Blood 2013; 122:1376-83. 38. Srivastava G, Rana V, Lacy MQ, et al. Long-term outcome with lenalidomide and dexamethasone therapy for newly diagnosed multiple myeloma. Leukemia 2013; 27:2062-6. 39. Rabin N, Percy L, Khan I, Quinn J, D’Sa S, Yong KL. Improved response with post-ASCT consolidation by low dose thalidomide, cyclophosphamide and dexamethasone as first line treatment for multiple myeloma. Br J Haematol 2012; 158: 499-505. 40. Vera-Llonch M, Oster G, Ford CM, Lu J, Sonis S. Oral mucositis and outcomes of allogeneic hematopoietic stem-cell transplantation in patients with hematologic malignancies. Support Care Cancer 2007; 15:491-6. 41. Holbro A, Ahmad I, Cohen S, et al. Safety and cost-effectiveness of outpatient autologous stem cell transplantation in patients with multiple myeloma. Biol Blood Marrow Transplant 2013; 19:547-51.