Autologous Stem Cell Transplantation forMultiple Myeloma: Identification of
Prognostic FactorsLalit Kumar, Sunu L. Cyriac, Tilak VSVGK Tejomurtula, Ankur Bahl,
Bivas Biswas, Ranjit K. Sahoo, Anjali Mukherjee, Omdutt Sharma
AbstractCurrently, high dose chemotherapy supported by autologous stem cell transplantation (ASCT) is considereda standard treatment approach for multiple myeloma (MM) patients aged 65 years or younger. To evaluate thepredictors of outcome after ASCT, we analyzed results of 170 patients. Pretransplant chemosensitive diseaseand achievement of complete response (CR) were associated with improved outcome.Introduction: The purpose of this study was to evaluate the effect of prognostic factors on the outcome of patientswith MM after ASCT. Patients and Methods: We analyzed results of 170 consecutive patients (121 male and 49 female)of MM who underwent ASCT. Patients’ median age was 52 years (range, 26-68 years). High dose melphalan (200 mg/m2)was used for conditioning. One hundred thirty-two patients (77.6%) had evidence of chemosensitive disease beforetransplant. Response was assessed using European Group for Blood and Bone Marrow Transplantation criteria. Results:Post ASCT 44.7% of patients achieved CR, 24.7% had very good partial response (VGPR), and 21.2% had partialresponse (PR). Presence of pretransplant chemosensitive disease (CR, VGPR, and PR) and transplant within 12 monthsof diagnosis for years before 2006 were associated with higher response rates on multivariate analysis. At a medianfollow-up of 84 months, median overall (OS) and event-free survival (EFS) is 85.5 and 41 months, respectively. EstimatedOS and EFS at 60 months is 62 � 0.04% and 41 � 0.04%, respectively. Patients who responded to transplant (CR, VGPR,and PR) had a longer OS (P � .001) and EFS (P � .001). Additionally, patients who achieved CR post transplant had alonger OS (P � .001) and EFS (P � .001). Patients who received novel agents for induction pretransplant had a longer OS(P � .001) and EFS (P � .002). Conclusion: Outcome after ASCT is better for myeloma patients with pretransplantchemosensitive disease and those who achieve CR after transplant.
IntroductionHigh-dose chemotherapy followed by autologous peripheral
blood stem cell transplantation (ASCT) is currently a standard treat-ment approach for multiple myeloma (MM) patients aged 65 yearsor younger.1,2 A number of nonrandomized,3,4 randomized,5-9 and
opulation-based studies10 and metaanalyses11,12 have suggestedhat this approach is associated with improved response rates, and
Department of Medical Oncology, Laboratory Oncology, Institute Rotary CancerHospital, All India Institute of Medical Sciences, New Delhi, India
linical Lymphoma, Myeloma & Leukemia February 2013
vent-free survival (EFS) compared with conventional chemother-py. These studies were done before newer and more potent novelgents (eg, immune modulators: thalidomide and lenalidomide, pro-easome inhibitors—bortezomib) were routinely used. Higher re-ponse rates achieved with use of novel agents, followed by consoli-ation with ASCT13-15 has led to search for predictors of outcome
post ASCT. We started our autologous stem cell transplant programin 1990; our initial results with conventional chemotherapy for in-duction and ASCT have been reported earlier.16 We have now up-dated our experience and analyzed data on 170 patients of MMtreated with ASCT. This report describes the results.
Patients and MethodsBetween April 1990 and June 2010, 170 patients with MM
underwent ASCT. Patient characteristics are shown in Table 1.
Patients age ranged from 26 to 68 years (median 52 years). There
were 121 male and 49 female patients. The database was main-tained prospectively.
Before transplant, patients had received induction therapy eitherusing VAD (vincristine, doxorubicin, dexamethasone; n � 78),novel agents (thalidomide and dexamethasone, or lenalidomide anddexamethasone, or bortezomib and dexamethasone; n � 66), oralkylating agents (VMCP [vincristine, melphalan, cyclophospha-mide, and prednisolone] or MP [melphalan and prednisolone], n �
26); 42.4% of patients received more than 1 line of regimen. Onehundred thirty-two patients (77.6%) had chemosensitive disease (in-cluding complete response [CR], very good partial response[VGPR], and partial response [PR]) before ASCT. Thirty-nine pa-
Table 1 Patient Characteristics
Patients, N 170
Age (Years) Median (Range) 52 (26-68)
Sex, M:F 121:49 (71.2% vs. 28.8%)
Myeloma Subtype, n (%)
IgG � 83 (50)
IgG � 35 (21)
IgA � 09 (5.4)
IgA � 09 (5.4)
Kappa light chain only 11 (6.6)
Lambda light chain only 13 (7.8)
Nonsecretory 03 (1.8)
Subtype not known 03 (1.8)
Renal Function at Diagnosis, n (%)
Normal 131 (76.6)
Abnormal (serum creatinine � 2 mg) 39 (23.4)
Stage at Diagnosis (n � 168)
IA 3
IIA 4
IIIA 121 (72.6%)
IIIB 39 (23.2%)
First-Line Treatment BeforeTransplant, n (%)
Alkylating agents 26 (15.3)
VAD 78 (45.9)
Novel agents 66 (38.8)
Chemosensitive disease 132 (77.6)
Chemoresistant or refractory disease 38 (22.4)
Interval From Diagnosis toTransplant (Months)
Mean 15.2
Median 10
Range 3-128
Abbreviations: AL � amyloid light chain; CR � complete response; PR � partial response; VAD� vincristine, doxorubicin, dexamethasone; VGPR � very good partial response.Four patients had primary AL amyloidosis. Chemosensitive defined as CR, VGPR, and PR, com-bined; chemoresistant defined as stable and progressive disease combined.
tients (23.4%) had renal insufficiency at diagnosis and 16 (9.4%) m
had renal dysfunction at the time of transplant. Four patients hadprimary amyloid light chain (AL) amyloidosis (Table 1).
Transplant ProtocolBriefly, all patients were initially reviewed in the weekly ‘Bone
Marrow Transplant Clinic’ in which the procedure, potential risksand benefits were explained to patients and family members. Initialevaluation included: history, physical examination, staging accord-ing to Durie-Salmon, and International Staging System (ISS). De-tails of previous treatment were recorded. Investigations includinghemogram, differential count, renal and liver function tests, bonemarrow examination, skeletal survey, serum and urine electrophore-sis, immunofixation studies, serum �-2 microglobulin and immuno-lobulin levels (quantitative) were done in all patients. Written in-ormed consent was obtained.
During follow-up patients were seen in the ‘Transplant Clinic’nitially monthly, then bi-to tri-monthly for 3 years, then every 6
onths thereafter. Follow-up information is available for all patients.ransplant cost was met by the individuals, government support,edical insurance, and charitable organizations.
Stem Cells. The source of stem cell was bone marrow in the first 7atients; for the next 163 patients granulocyte colony-stimulatingactor (G-CSF) mobilized peripheral blood stem cells were harvested.median of 2 leukapheresis were done (range, 1-3). A sample of stem
ells was obtained and total cell counts were determined using anutomated cell counter and the differential cell count was done man-ally. For CD34 counts cells were labeled with florescence 4 conju-ated anti-CD34 and analyzed using a fluorescence-activated cellorter scan flow cytometer to yield an absolute CD34� counts. Stemells were kept at 4°C or were cryopreserved at �80°C using cryo-rotectant mixture of 7.5% dimethyl sulfoxide (DMSO), albumin,nd saline. Stem cells were transfused intravenously 24 hours afterigh dose melphalan. The viability of cells was determined by trypanlue dye exclusion test.
I.V.) push on day 1 followed by forced alkaline diuresis. Four pa-ients with AL amyloidosis, and 16 patients with renal insufficiencyt the time of transplant received melphalan 120-150 mg/m2. Au-
tologous blood stem cells were reinfused on day 0 through acentral venous catheter (Hickman) preceded by pheniramine mal-eate 50 mg I.V.
Supportive Care and Monitoring. All patients received growth fac-tors G-CSF 5 �g/kg daily subcutaneously on day �1 and onwards
ntil engraftment. Patients were admitted in an isolation room andeverse barrier nursing was practiced. All patients received antimicro-ial prophylaxis-ciprofloxacin, fluconazole/itraconazole and acyclo-ir. Packed red blood cells and platelet transfusions were adminis-ered to maintain a hemoglobin level �8 g/dL and a platelet count
10 � 109/L. All the blood products transfused during the post-ransplant period were irradiated with 25 Gy. Patients receivedroad-spectrum antibiotics for fever; amphotericin B was added,f patients had persistent fever after 4-5 days of intravenous anti-
icrobial therapy.
Clinical Lymphoma, Myeloma & Leukemia February 2013 33
a
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Transplant for Multiple Myeloma: Prognostic Factors
34 C
Response. Response to transplant was assessed 6 weeks after trans-plant as per European Group for Blood and Bone Marrow Trans-plantation criteria.17
Toxicity. All cases of nonhematological dysfunction were consid-ered regimen-related toxicities unless they could be clearly explainedby another cause. A grading scale (Bearman et al, 1988)18 was used.
Maintenance TherapyUntil December 2001, patients received maintenance therapy
post-ASCT with interferon-� at a dose of 3 million units thrice aweek subcutaneously. From January 2002 and onward, all respond-ing patients received thalidomide 50 mg daily for 1 year or more.Maintenance therapy was initiated when engraftment was stable (ab-solute neutrophil count �2000/mm3, platelets �100,000/mm3).Therapy was continued for 12 months or more. Patients also receivedzoledronic acid 4 mg I.V. once in 3 months indefinitely.
Statistical AnalysisAnalysis has been done as intent to treat analysis. Descriptive sta-
tistics (median and range) were calculated for all variables. The prog-nostic factors for response to transplant were analyzed by Pearson �2
test and binary logistic regression analysis. Overall survival was de-fined as the time from date of transplant until death or date of censor.Event-free survival was calculated from date of transplant to diseaseprogression or death (regardless of cause of death). Survival curveswere plotted according to method of Kaplan and Meier and werecompared by the log rank test. The prognostic factors for survivalwere analyzed by Cox regression analysis. Analysis was carried outusing SPSS-16 statistical software. The median follow-up for thewhole group is 84 months (range, 18-220 months). The data wascensored on December 31, 2011.
ResultsEngraftment Characteristics
These are listed in Table 2. The mean number of mononuclearnd CD34� cells transfused was 4.5 � 108/kg (range, 1.5-11.8 �
108/kg) and 3.8 � 106/kg (range, 0.88-16.7 � 106/kg). The mediantime to engraftment (absolute neutrophil count 500/mm3 for 3 con-ecutive days) was 11 days (range, 9-24 days) and median time forlatelet transfusion independence was 12 days (range, 8-58 days).ngraftment failed in 6 patients (3.5%). After transplant, patients
eceived a mean of 1 unit of red cells and 3 units of single donorlatelet transfusion. Post transplant patients received G-CSF for aedian of 12 days (range, 9-30 days).
ToxicityGrade III-IV mucositis, grade II-III nausea or vomiting, grade II
diarrhea, and alopecia were the common nonhematologic toxicities.Other toxicities were liver dysfunction grade I-II (14.7%, includingveno-occlusive disease in 8.9%, and grade 3 renal in 3.6% of pa-tients). Twenty-one percent of patients had evidence of engraftmentsyndrome as evidenced by weight gain, fever, dyspnea, pleural effu-sion, skin rash, and impaired liver and renal functions. The mediantime for onset of engraftment syndrome was 11 days (range, 9-22
days) (Table 3).
linical Lymphoma, Myeloma & Leukemia February 2013
Febrile EpisodesA total of 214 febrile episodes (neutropenic � 97.6%) were re-
corded (mean, 1.25); infection could be documented clinically andradiologically in 27.2%, clinically, radiologically, and microbiologi-cally in 10.1%, and clinical and microbiologically in 5.3%, and mi-crobiologically alone in 4.7% of febrile episodes. The remaining46.7% episodes were defined as isolated febrile episodes. The mostcommon sites of infections were pulmonary infection (21.9%), gas-trointestinal (7.7%), skin and subcutaneous tissue (0.9%), urinarytract infection (UTI) (0.9%), and central line infection in 5.9% of
Table 2 Engraftment Characteristics
Mononuclear Cells Infused (� 108/kg)
Median 4.2 (1.5-11.8)
Mean 4.5
CD34� Mean (� 106/kg) 3.8 (0.88-16.70)
Median Days to Achieve ANC > 500/mm3 11 (9-24)
Median Days to Achieve Platelets (> 20,000/mm3) 12 (8-58)
Days of Fever, Median (Range) 6 (0- 24)
Days of Antibiotics, Median (Range) 9 (0-28)
Days of Hospitalization After Transplant (Range) 18 (8-43)
RBC Transfusion (Mean) 1 (0-10)
Platelet Transfusion, Mean Number of SingleDonor Platelets (Range) 3 (1-15)
Days of Growth Factors, Median (Range) 12 (9-30)
Response to Transplant, n (%)
Complete 76 (44.7)
Very good partial response 42 (24.7)
Partial response 36 (21.2)
Minimal and stable 10 (5.9)
Not evaluablea 6 (3.5)
Abbreviations: ANC � absolute neutrophil count; RBC � red blood cell.a Died of graft failure.
Table 3 Regimen-Related Toxicity
Toxicity Grade1-2, %
Grade3-4, %
Nausea/Vomiting (n � 165) 74.2 24.8
Diarrhea (n � 167) 69.5 28.1
Mucositis (n � 168) 28.6 71.4
Hepatic (n � 168) 14.7 —
VOD (n � 168) 8.9 —
Renal (n � 169) 35.5 3.6
Cardiac (n � 169) 1.2
Pulmonary (n � 168) 3.6 1.2
Cystitis (n � 168) 0.6 —
Engraftment Syndrome (n � 161) 21.1 —
Abbreviation: VOD � veno–occlusive disease.
patients. Microbiologically, organisms were isolated in 27.8% of pa-
(
sa
ponse.
Lalit Kumar et al
tients, these included gram-negative organisms: 14.2% (E. coli, En-terobacter, Acinetobacter, Klebsiella, and Pseudomonas aeruginosa) andgram-positive: 7.1% (Staphylococcus aureus, Staphylococcus epidermi-dis, and Streptococcus viridans), both gram-negative and gram-posi-tive in 2.4% of patients, and fungi in 4.2% of patients. Amongcentral line infections isolates were gram-positive in 7.7%, gram-negative in 6.5%, polymicrobial in 1.2%, and fungi in 0.6% ofpatients. Sixty-eight patients (40.2%) received amphotericin B eitherempirically (34.9%), or for suspected fungal infection (4.1%), orbecause of definite fungal isolates (1.2%). Two patients had Clostridiumdifficile enterocolitis.
MortalitySixteen patients (9.4%) died; this included 6 cases (3.5%) of graft
failure; of these 5 had progressive disease and 1 had stable diseasebefore transplant. Another 8 patients died before day 30; 4 because ofsepsis with multi-organ failure, 1 because of pulmonary embolism, 1because of pneumocystis pneumonia (PCP) pneumonia, 1 because ofhemophagocytosis with pulmonary mucormycosis, and 1 because ofpulmonary alveolar hemorrhage. Two patients died between day 30and 100, 1 because of ventilator-associated complications and an-other because of bleeding diathesis. Higher morbidity and mortalityin the present series might have been because of poor case selection(higher number of patients with chemo-resistant disease, previousheavy treatment with alkylating agents in 8 of 16 patients, and pro-
Table 4 Factors Predicting Outcome According to Year of Tran
Factors< 2000 (n �
Disease Status; Chemosensitive vs. Chemoresistantor Refractory Disease (n � 132 vs. 38) 23 vs. 17
Mean CD34 Counts (� 106/kg) 6.01 (n � 1
Graft Failure (n � 6) 5
Day 30 Mortality (n � 14), n (%) 6 (15)
Engraftment Syndrome 17.5%
Pretransplant: First-Line Induction TherapyAlkylating Agents vs. VAD vs. Novel Agents 14 vs. 26 vs
Abbreviation: VAD � vincristine, doxorubicin, dexamethasone.
Table 5 Pretransplant Disease Status Versus Response to Tran
Pretransplant Status Patients, nCR
CR 23 23
VGPR 50 28
PR 59 22
Stable or Minimal 17 2
Progressive Disease 21 1
Total (%) 170 76 (44.7)
Abbreviations: CR � complete response; PR � partial response; VGPR � very good partial res
gressive disease at time of transplant, paraparesis in 2, end-stage renal
failure in 4, and rheumatoid arthritis in 2 patients), and use of alky-lating agents in the initial years (Table 4).
Response to TransplantThe overall response rate was 90.6%; CR, 76 (44.7%), VGPR, 42
(24.7%), and PR, 36 (21.2%). Ten patients (5.9%) had stable orprogressive disease. Among 132 patients with pretransplant chemo-sensitive disease, 73 achieved CR (55.3%) compared with 3 of 38patients (7.9%) with stable (n � 17) and progressive (n � 21) diseaseTable 5).
Factors Affecting Response to TransplantPatients with Durie-Salmon stage III B at diagnosis (P � .002),
hemoglobin �10 g/dL (P � .03), and those who underwent trans-plant beyond 12 months of diagnosis for years before 2006 (P �
.004) had lower response to transplant. Patients with pretransplantchemosensitive disease (P � .001), serum M protein �1 g/dL (P �
.001) and those who received novel agents for induction (P � .001)had a significantly higher response to transplant. Response rate wasnot significantly different for patients with ISS I and II versus III.
On multivariate analysis pretransplant disease status, chemosensi-tive disease, and interval �12 months from diagnosis to transplantwere significant factors. Factors, eg, patient age (�52 vs. �52 years),ex (male vs. female), myeloma subtype (IgG vs. IgA vs. light chain),nd BM plasma cells (�40% vs. �40%) did not affect response to
t
Year
2001-2005 (n � 54) 2006-2010 (n � 76) P
40 vs. 17 69 vs. 7 � .001
4.38 (n � 52) 3.05 (n � 74) .48
1 1 � .004
4 (7.4) 4 (5.3) .34
18.5% 13.1% .88
7 vs. 41 vs. 6 5 vs. 11 vs. 60 � .001
nt
Response to Transplant
VGPR PR Stable Died
0 0 0 0
20 2 0 0
17 20 0 0
2 8 4 1
3 6 6 5
42 (24.7) 36 (21.2) 10 (5.9) 6 (3.5)
splan
40)
2)
. 0
spla
transplant (Table 6).
Clinical Lymphoma, Myeloma & Leukemia February 2013 35
tt
u
l agent2006-2
Transplant for Multiple Myeloma: Prognostic Factors
36 C
SurvivalAt a median follow-up of 84 months, the median OS and EFS
for the whole group is 85.50 � 17.85 (95% confidence interval[CI], 50.52-120.48) and 41 � 7.35 (95% CI, 26.59-55.41)months, respectively. Estimated OS at 5 and 10 years is 62.1 �
0.04% and 45.10 � 0.05%, respectively (Figure 1). Correspond-ing figures for EFS are 41 � 0.04% and 37.1 � 0.04%, respec-ively (Figure 2). Patients who achieved CR and VGPR afterransplant had a significantly better survival.
Prognostic FactorsOverall Survival. On univariate analysis Durie-Salmon stage IIIB
(P � .008), ISS III (P � .06), serum albumin � 3.4 g/dL (P � .02),se of alkylating agent-based therapy pretransplant (P � .001), year
of transplant (prior to year 2000, P � .004) were predictors of infe-
Table 6 Response to Transplant: Analysis of Prognostic Factor
Factor Patients, n
Age (years)
� 52 vs. � 52 87 vs. 83
Sex
Male vs. female 121 vs. 49
Interval From Diagnosis to Transplant
� 12 vs. � 12 months 107 vs. 63
Durie-Salmon Stage
� IIIA vs. IIIB 129 vs. 39
ISS Stage
I and II vs. III 133 vs. 32
Hemoglobin (g/dL)
� 10 vs. � 10 92 vs. 77
Serum Albumin (g/dL)
� 3.5 vs. � 3.5 69 vs. 98
� 3.4 vs. � 3.4 57 vs. 110
BM Plasma Cells (%)
� 40 vs. � 40 87 vs. 77
Myeloma Subtype
IgG vs. IgA vs. light chain 118 vs. 18 vs. 24
Pretransplant M Protein (n � 159)
0-1 g/dL vs. � 1.0 g/dL 93 vs. 66
Pretransplant Disease Status
Chemosensitive vs. chemoresistant disease 132 vs. 38
First-Line Induction Regimen
Novel agents vs. VAD vs. alkylating agents 66 vs. 78 vs. 26
Year of Transplant
� 2000 vs. 2001-2005 vs. 2006-2010 40 vs. 54 vs. 76
Abbreviations: BM � bone marrow; ISS � International Staging System; VAD � vincristine, adIgG versus IgA, P � .06; IgG versus light chains, P � .27; IgA versus light chain, P � .32; noveagents, P � .01; year of transplant � 2000 versus 2001-2005, P � .44; 2001-2005 versus
rior OS. Patients with pretransplant chemosensitive disease (P �
linical Lymphoma, Myeloma & Leukemia February 2013
.001), pretransplant CR (P � .02), pretransplant serum M protein �
1 g/dL (P � .001) had a significantly longer OS. Patients who re-sponded to transplant (CR, VGPR, and PR combined, P � .001) orpost transplant CR (P � .001) and those who underwent transplantwithin 12 months of diagnosis had a superior survival (P � .04)(Table 7).
Event-Free Survival. Patients with pretransplant chemosensitivedisease (P � .001), serum M protein �1 g/dL (P � .001), re-sponse to transplant (CR, VGPR, and PR combined, P � .001)and those who achieved CR (P � .001) had a significantly longerEFS. Use of novel agents for induction before ASCT (P � .002)and transplant within 12 months of diagnosis for years before2006 (P � .01) was associated with longer EFS (Table 7).
On multivariate analysis serum albumin �3.4 g/dL, response
Patients Responding to Transplant,n P
76 vs. 78 .65
114 vs. 40 .13
104 vs. 50 .004
121 vs. 26 .002
126 vs. 26 .07
80 vs. 73 .03
62 vs. 91 .25
50 vs. 103 .15
76 vs. 64 .44
106 vs. 18 vs. 23 .41
91 vs. 52 .001
132 vs. 22 .001
64 vs. 73 vs. 17 .001
33 vs. 49 vs. 72 .35
n and dexamethasone.s versus VAD, P � .33; novel agents versus alkylating agents, P � .005; VAD versus alkylating010, P � .22; � 2000 versus 2006-2010, P � .13.
s
riamyci
to transplant, and achievement of CR post ASCT was associated
earpwroai4
Hbbir
ponse.
Lalit Kumar et al
with superior overall and EFS. Additionally, use of novel agentsfor induction therapy was associated with better OS (Table 8).
Current StatusOne hundred fifty-four patients were alive, from day �100 and on-
ward. Of these, 52 have died because of relapse or progressive disease(n � 46), acute cardiac event (n � 2), stroke (n � 1), pulmonarymbolism (n � 1), myelodysplastic syndrome (n � 1), and amyloidosisnd congestive heart failure in 1 patient. Of 46 patients who died ofelapse, 10 had evidence of chest infection, renal failure (n � 8), andlasma cell leukemia (n � 8), and 2 patients relapsed with neurologicaleakness at the time of death. Of the remaining 102 patients, 42 had
eceived salvage therapy for relapse and are currently alive either in sec-nd CR (n � 7), VGPR (n � 7), or PR (n � 6), with stable disease in 1,nd 21 are alive with active disease. The remaining 60 patients are aliven continuous CR; 19 (10.11%) �60 months, 10 (5.9%) �8 years, and(2.3%) beyond 10 years in continuous CR.
DiscussionIn the present study, an objective response rate of 90.6% including
CR in 44.7% of patients was achieved after transplant. These resultsare similar to recent reports13,15 but are higher than those obtained in
Figure 1 Overall Survival
1.0
0.8
0.6
0.4
0.2
0.0
0.00 24.00 48.00 72.00 96.00 12
Ov
CR versus others, P < .001
VPR
Stable
Abbreviations: CR � complete response; PR � partial response; VGPR � very good partial resCR versus others, P � .001.
earlier studies5-9 using conventional chemotherapy for induction.
ere, pretransplant induction therapy varied from alkylating agent-ased treatment to VAD to novel agents thalidomide/lenalidomide/ortezomib-based combination. Superiority of novel agents-basednduction therapy both in terms of mobilization of stem cells andesponse rates to ASCT has been established.1 Recently, a combina-
tion of bortezomib, lenalidomide or thalidomide and dexametha-sone and/or cyclophosphamide has been reported to be associatedwith higher CR and VGPR rates pretransplant.13-15 Our finding thatpretransplant chemosensitive disease is associated with improvedpost transplant response is in line with these observations. Reducedlevels of M protein pretransplant (� 1 g/dL) reflect good response toinduction therapy19 and are a predictor of response to transplant, asseen in our study too. It has been suggested that serial serum free lightchain levels along with intact M protein levels might be more pre-dictive of response.20 We also observed higher response rates forpatients who underwent transplant within 12 months of diagnosis(P � .004) for the years before 2006 but not for those who under-went transplant in recent years (2006-2010) (P � .15). The latterwas because of increasing use of novel agents compared with earlieryears; 2006-2010 versus 2001-2005 versus earlier than 2000: 60versus 6 versus 0 (P � .001). Lower responses in patients who re-
ths
urvival
144.00 168.00 192.00 216.00 240.00
CR
0.00Mon
erall S
GPR
ceived transplant beyond 12 months are possibly indicative of
Clinical Lymphoma, Myeloma & Leukemia February 2013 37
s
o
tt
pwa(c
twAtwoiSsnttR
ponse.
Transplant for Multiple Myeloma: Prognostic Factors
38 C
chemoresistance. This is reflected by the fact that in the presentstudy, only 57.6% of patients had received only 1 line of inductiontherapy, 33.5% received 2 lines, 5.9% received 3 lines, and 2.9% �
3 lines of therapy pretransplant. Response rate was higher for thosereceiving only 1 line of therapy (P � .001) (data not shown).
Achievement of CR is an important event in myeloma and repre-ents the major surrogate marker for long-term OS and EFS.21-27 It
has been suggested that achievement of CR might be associated withimproved survival in poor-risk patients.28,29 Harousseau et al for theFrench Group identified achievement of ‘at least VGPR’ as an im-portant predictor of outcome in an analysis of 802 patients.30 In thepresent study, EFS was better for complete responders comparedwith those achieving VGPR. Probability to achieve CR post trans-plant, is related to pretransplant disease status. This is supported byour observation that among 132 patients with pretransplant chemo-sensitive disease, 73 (55.3%) achieved CR compared with 3 of 38(8%) with stable or progressive disease pretransplant (Table 5). Wedid not find difference in OS and EFS for 23 patients who were inCR pretransplant and continued to be in CR post transplant versus55 patients who achieved CR post transplant (induced CR frompretransplant VGPR, PR, or stable disease status) as reported by Kimet al.31 Additional predictors of extended OS and EFS were presence
Figure 2 Event-Free Survival
1.0
0.8
0.6
0.4
0.2
0.0
0.00 24.00 48.00 72.00 96.00 1
Cum
Sur
viva
l
Ev
CR versus others, P < .001
VGPR
PRStable
Abbreviations: CR � complete response; PR � partial response; VGPR � very good partial resCR versus others, P � .001.
f pretransplant chemosensitive disease, pretransplant serum M pro- t
linical Lymphoma, Myeloma & Leukemia February 2013
ein � 1 g/dL, induction therapy with novel agents, and response toransplant (CR, VGPR, and PR combined) (Table 7).
Higher morbidity and day 30 mortality in the present series isossibly a result of poor case selection; higher number of patientsith chemoresistant disease (38 of 170; 22.4%), and use of alkylating
gents (15.3%), in the initial years compared with novel agents38.8%) in the recent years (Tables 4 and 5). As the initial learningurve has passed, mortality rate has also decreased (Table 4).
When to do transplant in myeloma has been a subject of debate. Inhe current study, response rate to transplant, median OS and EFSas significantly higher for patients (whole group) who underwentSCT within 12 months of diagnosis (Tables 6 and 7). We analyzed
he effect of interval (� 12 vs. � 12 months) on patients (n � 66)ho received transplant between 2006 and 2010 when the majorityf them had received novel agents for induction therapy. Interest-ngly, this difference in response rate is no longer present (P � .15).imilarly, mean OS (P � .98) and median EFS (P � .18) are notignificantly different in 2 groups. Whether this is because of a smallumber of patients or therapy with novel agents is able to overridehe effect of interval remain speculative and needs further study. Inhe CIBMTR (Center for International Bone Marrow Transplantegistry study) OS at 3 years was better for patients who received
nths
ee Survival
144.00 168.00 192.00 216.00 240.00
CR
20.00Mo
ent-fr
ransplant within 18 months of diagnosis; 55 � 4% versus 43 � 5%;
impcm
ns
dIE 000 veP
Lalit Kumar et al
P � .08.32 However, OS was not significantly different in a random-zed French study of 200 patients who underwent ASCT either im-
ediately after induction therapy or after they had relapsed; butatients who received transplant earlier had a higher median EFSompared with those who received transplant later (39 vs. 13
Table 7 Overall and Event-free Survival: Analysis of Prognostic
Factor Patients, n
Age (years)
� 52 vs. � 52 87 vs. 83
Sex
Male vs. female 121 vs. 49
Interval From Diagnosis to Transplant (months)
� 12 vs. � 12 107 vs. 63
Durie-Salmon Stage
IIIA vs. IIIB 129 vs. 39
ISS Stage
I and II vs. III 133 vs. 32
Hemoglobin (g/dL)
� 10 vs. � 10 92 vs. 77
Serum Albumin (g/dL)
� 3.5 vs. � 3.5 69 vs. 98
� 3.4 vs. � 3.4 57 vs. 110
BM Plasma Cells (%)
� 40 vs. � 40 87 vs. 77
Myeloma Subtype
IgG vs. IgA vs. light chain 118 vs. 18 vs.
Pretransplant M Protein (n � 159) (g/dL)
0-1 vs. � 1.0 93 vs. 66
Pretransplant Disease Status
Chemosensitive vs. chemoresistant disease 132 vs. 38
First-Line Induction Regimen
Novel agents vs. VAD vs. alkylating agents 66 vs. 78 vs.
Year of Transplant
�2000 vs. 2001-2005 vs. 2006-2010 40 vs. 54 vs.
Response to Transplant
CR and VGPR and PR vs. others (landmark at day 100) 154 vs. 16
Post Transplant CR vs. Other Response
CR vs. VGPR and PR and stable (landmark at day 100) 76 vs. 94
Pretransplant CR vs. Others
CR vs. VGPR and PR and stable and PD 23 vs. 147
Abbreviations: BM � bone marrow; CR � complete response; EFS � event-free survival; ISS �isease; PR � partial response; VAD � vincristine, adriamycin and dexamethasone; VGPR � v
gG versus IgA, P � .28; IgG versus light chain, P � .68; IgA versus light chain, P � .42; noveFS P � .002; VAD versus alkylating agents, OS P � .01, EFS P � .007; year of transplant � 2� .2; � 2000 versus 2006-2010, OS P � .005, EFS P � .03.
onths, P � .01).33 Thus, our findings suggest that in the era of
ovel agents an early ASCT is not necessarily better and needs to betudied in a prospective, randomized trial.
ConclusionThe present study confirms that high dose chemotherapy sup-
tors
OS (Months) P EFS (Months) P
103 vs. 85 .89 30 vs. 28 .32
85 vs. 102 .72 32 vs. 24 .23
125 vs. 58 .04 37 vs. 22 .01
125.5 vs. 71.50 .008 30 vs. 22 .02
102 vs. 43 .06 32 vs. 20 .23
79 vs. 103 .34 28 vs. 33 .87
85.5 vs. 102 .36 23 vs. 32 .11
79 vs. 140 .02 20 vs. 36 .002
125.5 vs. 79 .18 29 vs. 24 .47
85.5 vs. 140 vs. MNR .55 28 vs. 51 vs. 22 .28
140 vs. 58 .001 51 vs. 18 .001
125.5 vs. 37 .001 41 vs. 15 .001
MNR vs. 85.5 vs. 32 .001 50 vs. 28 vs. 16 .002
48 vs. MNR vs. MNR .004 21 vs. 24 vs. 36 .07
103 vs. 8.0 .001 34 vs. 4 .001
125 vs. 9.0 .001 37 vs. 5.0 .001
204 vs. 42 .001 126 vs. 16 .001
204 vs. 48 .001 89 vs. 18 .001
140 vs. 85 .35 89 vs. 22 .001
ational Staging System; MNR � median not reached; OS � overall survival; PD � progressived partial response.versus VAD, OS P � .13, EFS P � .15; novel agents versus alkylating agents, OS P � .001,
rsus 2001-2005, OS P � .01, EFS P � 0.2; 2001-2005 versus 2006-2010, OS P �.28, EFS
Fac
24
26
76
Internery gool agents
ported by autologous peripheral blood stem cell transplant in pa-
Clinical Lymphoma, Myeloma & Leukemia February 2013 39
2
2
2
d dexam
Transplant for Multiple Myeloma: Prognostic Factors
40 C
tients with advanced myeloma is safe, effective, and is associated witha high CR rate. Patients who achieve CR post transplant have longerOS and EFS. Timing of transplant (early vs. late), identification ofpatients at higher risk of relapse by more sensitive techniques such asreverse transcription polymerase chain reaction and/or flow cytom-etry34 are likely to be areas of active research in future studies.
Clinical Practice Points● Currently for all patients of myeloma, novel agents and dexameth-
asone-based combinations are used for induction.● More than two-thirds of patients achieve significant response; this
includes VGPR and CR in � 50% of patients.● Further consolidation with high dose melphalan and ASCT results
in high CR rates.● In the present study, patients with pretransplant chemosensitive
disease and those who underwent ASCT within 12 months ofdiagnosis before 2006 had higher responses. The latter needs fur-ther evaluation.
● Serum albumin � 3.4 g/dL at diagnosis, response to transplant(CR, VGPR, and PR combined), and achievement of CR weresignificant predictors of improved OS and EFS.
● Further achievement of CR was associated with superior OS andEFS.
● Our results support the concept of using effective regimens orstrategies to achieve CR or VGPR pretransplant so this could betranslated to higher CR rates post transplant.
DisclosureAll authors have no conflicts of interest.
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Factor HR
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Response to transplant 0.352
Novel agents vs. VAD vs. alkylating agents 0.388
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