Second Autologous Stem Cell Transplant: An Effective Therapy for Relapsed Multiple Myeloma

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Second Autologous Stem Cell Transplant: An Effective Therapy

for Relapsed Multiple Myeloma

Kamal Kant Singh Abbi

1,*

_{, Junting Zheng}

2

_{, Sean M. Devlin}

2

_{, Sergio Giralt}

3

_{, Heather Landau}

3 1_{Division of Hematology, Oncology and Bone Marrow Transplantation, University of Iowa Hospitals and Clinic, Iowa City, Iowa}

2_{Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York}

3_{Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York}

Article history: Received 21 July 2014 Accepted 13 November 2014 Key Words: Multiple myeloma Relapsed

Autologous stem cell transplant Melphalan

a b s t r a c t

Therapeutic options for patients with multiple myeloma (MM) whose disease has relapsed after a prior autologous stem cell transplant (ASCT) include an expanding armamentarium of novel agents, often com-bined with traditional chemotherapy, or a second ASCT, with no clear standard of care. We retrospectively analyzed the outcomes of 75 patients who underwent salvage melphalan-based ASCT for relapsed MM at Memorial Sloan-Kettering Cancer Center between 1995 and 2012. Conditioning was performed with melphalan 200 mg/m2(n¼ 43), 180 mg/m2_(n_{¼ 1), 140 mg/m}2_(n_{¼ 22), and 100 mg/m}2_(n_{¼ 9). The median}

age at second ASCT was 59 years (range, 36 to 75), and 58% (n¼ 35) were men. Of those with available data, 19% had high-risk cytogenetics (including t (4;14), p53 loss, or del 13q by karyotype) at the time of second ASCT. Median interval betweenfirst and salvage ASCT was 37.5 months (range, 6.9 to 111.4). Of 72 assessable patients, 57% had chemotherapy-sensitive disease before to salvage ASCT and 43% were chemoresistant. Four patients died within 100 days of ASCT. Response was assessed at 2 to 3 months post-ASCT, and of 71 assessable patients, 82% achieved at least a partial response, 15% had stable disease, and 3% progressed despite salvage ASCT. After salvage ASCT, 38 patients received maintenance therapy and 14 went on to allogeneic ASCT. The median progression-free survival (PFS) after second autograft was 10.1 months (95% confidence interval [CI], 7.6 to 13.4) and median overall survival (OS) 22.7 months (95% CI, 19.2 to 41.2). Patients with chemosensitive relapse had a trend toward better PFS (hazard ratio [HR], .60 [95% CI, .36 to 1.02]; P¼ .058) and significantly longer OS (HR, .49 [95% CI, .27 to .88]; P ¼ .017) than patients with resistant relapse. Those with high-risk cytogenetics at the time of second ASCT had higher risk of death (HR, 2.98 [95% CI, 1.28 to 6.97]; P¼ .012) compared with patients with standard-risk cytogenetics. Salvage ASCT is an effective strategy for relapsed MM with chemosensitive disease and results in comparable PFS and OS to other salvage strategies.

Ó 2015 American Society for Blood and Marrow Transplantation.

INTRODUCTION

An increase in available and effective therapies for patients with multiple myeloma (MM) has led to an improvement in overall survival (OS)[1]. High-dose therapy and autologous stem cell transplant (ASCT) as part of initial therapy is complementary to novel therapies and represents a standard for patients with MM younger than 65 years and selected cases older than this age[2,3]. However, almost all patients with MM will relapse after initial therapy, and most patients with MM still die of their disease. The median time

to progression after initial ASCT is 23 to 46 months and is longer for patients who receive post-transplant maintenance therapy[4-9]. At the time of disease recurrence, no 1 stan-dard salvage approach is used; instead, various therapeutic options are used, including retreatment with prior effective therapy, use of novel or experimental agents, and, in selected patients, allogeneic (allo-) SCT.

Theﬁrst report of the use of ASCT as salvage therapy was published in 1995 and demonstrated a signiﬁcantly prolonged survival compared with standard therapy[10]. Reported rates of progression-free survival (PFS) after second salvage ASCT have differed and have ranged from a median of 6.8 months to 4.2 years[11,12]. Here, we report the results of a retrospective analysis of salvage ASCT conducted at our center. Our goal was

to deﬁne the outcomes of patients with access to more

modern therapy who underwent salvage ASCT and to identify prognostic factors for prolonged PFS and OS.

Financial disclosure: See Acknowledgments on page 472.

* Correspondence and reprint requests: Kamal Kant Singh Abbi, MD, Division of Hematology, Oncology and Bone Marrow Transplantation, University of Iowa Hospitals and Clinics, Iowa City, IA 52242.

E-mail address:kabbi101@hotmail.com(K.K. Singh Abbi).

http://dx.doi.org/10.1016/j.bbmt.2014.11.677

1083-8791/Ó 2015 American Society for Blood and Marrow Transplantation.

Biology of Blood and

Marrow Transplantation

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METHODS Patients

With institutional review board approval, we performed a systematic, retrospective review of medical charts of all patients who received salvage ASCT for MM at Memorial Sloan-Kettering Cancer Center between 1995 and December 2012. In total, 75 patients were identiﬁed.

Deﬁnitions

A transplant was defined as salvage if the patient had already received a prior ASCT and underwent a second ASCT after evidence of disease pro-gression, regardless of the number of lines of treatment administered after thefirst ASCT. Patients who received a planned tandem ASCT were excluded from this study. PFS was defined as the time from date of the second ASCT to disease progression or death, whereas OS was defined from the date of the second ASCT to the date of death from any cause. Patients with high-risk cytogenetics were defined by the presence of t (4;14), del p53, and del13q by karyotype only. Chemotherapy-sensitive disease was defined by having achieved at least a minimal response (25% reduction in serum M-protein level or 50% reduction in urine M-protein) to salvage chemotherapy before second ASCT.

Response

Response and progression were defined according to the International Myeloma Working Group criteria[13,14]. A complete response was defined as negative immunofixation of serum and urine, disappearance of soft tissue plasmacytoma, and<5% plasma cells in the bone marrow. Very good partial response was defined as serum and urine M-protein detectable only by immunofixation or as a 90% or greater reduction in serum M-protein plus a urine M-protein level<100 mg per 24 hours. Partial response was defined as a reduction in serum M-protein of at least 50% and by a reduction of at least 90% or an absolute value<200 mg per 24 hours in urine M-protein. Minimal response was defined by reduction in the serum M-protein by at least 25% but less than 50% and reduction in the urine M-protein by 50% to 89%. Stable disease was defined as not meeting any response criteria, and progressive disease was defined as a confirmed increase >25% of M-protein from baseline. Relapse was defined as the reappearance of serum or urine

M-protein or the development of new bone lesions, plasmacytoma, or hy-percalcemia. Response post-ASCT was assessed at a maximum of 80 to 100 days post-transplantation, and patients were followed approximately every 3 months thereafter.

Statistical Analysis

Cox proportional hazard model was used to assess the associations between the following variables collected before second ASCT with OS and PFS: time to relapse afterfirst ASCT, time between first and second ASCT (18 months versus <18 months), the presence of high-risk cytogenetics, and chemosensitive disease. Time-dependent Cox regression was used to evaluate the post-second ASCT factors of maintenance therapy and allo-ASCT after second allo-ASCT. Univariate factors significant at the .05 level were included in multivariate models for OS and PFS. Survival curves of patients were prepared using the Kaplan-Meier method.

RESULTS

Patient Characteristics

Patient characteristics at time of second transplants are

shown in Table 1. In total, 75 patients (45 men and 30

women) received second ASCT for relapsed MM at our center from January 1998 to December 2012. Median age at second transplant was 59 years (range, 36 to 75). The median time to relapse after_{ﬁrst ASCT was 21.9 months. The median number}

of months between ﬁrst and second transplant was 37.7

(range, 6.9 to 111.4). Median number of chemotherapies before second transplant was 1 (range, 1 to 4). Sixteen pa-tients had 2 lines of therapies before transplant, 12 papa-tients had 3 lines, and 5 patients had 4 lines of therapies before transplant. The most likely explanation for this could be physician’s discretion to take the patient to transplant even if they were not responding to salvage therapy.

In total, 31 patients had resistant/refractory disease going into the transplant. Of these 31, 12 patients were treated with a single line of therapy before transplant consisting of agents either alone or in combination (eg, thalidomide, Decadron, velcade, Cytoxan, cisplatin, etoposide, and revlimid). Eight patients had 2 lines of treatment, 7 patients had 3 lines of treatment, and 4 patients had 4 lines of treatment. Of pa-tients with available data, 19% had high-risk disease at time of second transplant. Thirty-eight patients (51%) received thalidomide, lenalidomide, or bortezomib maintenance therapy after the second transplant. Fourteen patients (19%) received allo-ASCT after their second autologous transplant.

Figure 1. OS for MM patients undergoing a second ASCT. Table 1

Patient Characteristics/Clinical Factors at Second ASCT and Management after Second ASCT

Characteristics at Second ASCT n % Risk (27 missing)

High risk 9 19

None high risk 39 81 ISS stage (8 missing)

I 34 51 II 20 30 III 13 19 Melphalan dosing 100 9 12 140 22 29 180 1 1 200 43 57

Neoadjuvant chemotherapy (3 N/A)

Resistant 31 43

Sensitive 41 57

Time to relapse afterﬁrst ASCT

Within 1 yr 12 16 1 yr 62 84 Median Range Age, yr 59 36-75 Albumin 3.7 2.0-4.6 b2-micro 2.3 0-28.8 LDH 176 96-1893

Months betweenﬁrst and second ASCT 37.5 6.9-111.4 Time to relapse afterﬁrst ASCT, mo 21.9 2.7-136.2 Management post salvage ASCT n % Maintenance therapy (5 N/A)

Yes 38 51

No 37 49

Allo-ASCT (nonmaintenance)

Yes 14 19

No 61 81

ISS indicates International Staging System; N/A, not available;b2-micro,

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Response and Survival

Response was assessed between 2 and 3 months post-transplant. Four patients died within 100 days of ASCT, accounting for 5% transplant-related mortality. Of 71

assessable patients, 17% (n ¼ 12) achieved complete

response, 34% (n ¼ 24) achieved partial response, 31%

(n¼ 22) achieved very good partial response, 15% (n ¼ 11) had stable disease, and 3% (n¼ 2) had progression of disease. The overall response to second ASCT was 77% (at least partial response). With a median follow-up of 33.3 months (range, 3.2 to 92.9) for survivors, the median OS was 22.7 months (95% conﬁdence interval [CI], 19.2 to 41.2) and the median PFS was 10.1 months (95% CI, 7.6 to 13.4) (Figures 1 and 2). At the time of last follow up, 53 patients had progressed, 48 died, and 12 remained event-free.

Prognostic Factors

Conventional karyotype analysis was available in 43 pa-tients and ﬂuorescent in situ hybridization in 38. Of those

with available data, 19% had high-risk cytogenetics at the time of second ASCT. Compared with patients who had standard-risk cytogenetics at the time of second ASCT, pa-tients with high-risk abnormalities had signiﬁcantly worse PFS (P¼ .005) and OS (P ¼ .012) (Table 2).

It has been shown in previous studies that the duration of response to initial therapy may predict response to subse-quent therapy [15,16]. Indeed, when time to relapse after initial ASCT was evaluated as a continuous variable, it was significantly associated with both PFS (P ¼ .002) and OS (P¼.013). However, there was no significant difference in PFS and OS when comparing patients who received a second ASCT within 18 months of thefirst transplant with those who had a longer interval between transplants.

Response to therapy before second ASCT was determined. Chemosensitivity (deﬁned as at least minimal response) at time of second transplant was associated with better OS (P¼ .017) and a trend toward better PFS (P ¼ .058). Other factors evaluated for impact on outcomes are shown in

Table 2. In multivariate analysis, high-risk cytogenetic at the time of second ASCT remained signiﬁcant for both PFS and

OS. Chemosensitivity and time from ﬁrst transplant to

relapse were no longer statistically signi_{ﬁcant in the PFS} model (Table 3). Univariate and multivariate analysis were

Figure 2. PFS for MM patients undergoing a second ASCT.

Table 2

Univariate Analysis of OS and PFS

HR (95% CI) P OS

High risk vs. not high risk (ref) 2.98 (1.28, 6.97) .012 Interval betweenﬁrst ASCT and second

ASCT 18 months vs. <18 months (ref)

.66 (.30, 1.49) .318 Chemosensitive vs. resistance (ref) .49 (.27, .88) .017 Melphalan 200 vs.<200 (ref) 1.04 (.59, 1.85) .888 Afterﬁrst ASCT relapse 1

year vs.<1 year (ref)

.67 (.33, 1.35) .261 Maintenance yes vs. no (ref)* 1.00 (.55, 1.83) .996 Allo-SCTyes vs. no (ref)* .98 (.45, 2.12) .978 PFS

.74 (.36, 1.51) .407 Chemosensitive vs. resistance (ref) .60 (.36, 1.02) .058 Melphalan 200 vs.<200 (ref) .95 (.57, 1.57) .831 Afterﬁrst ASCT relapse 1

.61 (.32, 1.14) .120 Maintenance yes vs. no (ref)* 1.06 (.63, 1.78) .831 Allo-SCT yes vs. no (ref)* .81 (.38, 1.72) .577 ref indicates reference group.

*Time-dependent variable Cox model analysis.

Table 4

Univariate Analysis of OS and PFS in Patients Who Received a Second ASCT Between 2007 and 2012 (n¼ 40)

HR (95% CI) P OS

.04 (0, .64) .023 Chemosensitive vs. resistance (ref) .26 (.10, .71) .009 Melphalan 200 vs.<200 (ref) 1.09 (.41, 2.92) .860 Afterﬁrst ASCT relapse 1

.30 (.10, .91) .034 Maintenance yes vs. no (ref)* .98 (.38, 2.57) .973 Allo-SCT yes vs. no (ref)* 2.52 (.92, 6.95) .073 PFS

.05 (0, .85) .038 Chemosensitive vs. resistance (ref) .34 (.14, .82) .017 Melphalan 200 vs.<200 (ref) 1.14 (.48, 2.68) .766 Afterﬁrst ASCT relapse 1

.23 (.07, .72) .012 Maintenance yes vs. no (ref)* 1.44 (.64, 3.26) .381 Allo-SCT yes vs. no (ref)* 2.10 (.83, 5.33) .119

*Time-dependent variable Cox model analysis. Table 3

Multivariate Analysis of OS and PFS (n¼ 47)

HR (95% CI) P OS

High risk vs. standard risk (ref) at second ASCT

2.85 (1.15, 7.11) .024 Chemosensitive vs. resistance (ref) .48 (.21, 1.09) .081 Time to relapse afterﬁrst ASCT

(unit increment¼ 1 month)

.99 (.97, 1.02) .583 PFS

High risk vs. not high risk (ref) at second ASCT

2.69 (1.09, 6.64) .031 Time to relapse afterﬁrst ASCT

(unit increment¼ 1 month)

.98 (.96, 1.00) .024 Univariate variables signiﬁcant at the level of .05, and patients with infor-mation available for these variables were included in the multivariate analysis.

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also done speci_{ﬁcally for patients who had second ASCT} between 2007e2012 as shown inTables 4 and 5.

DISCUSSION

Despite many advances in the treatment of MM, a cure has been elusive, and patients typically require sequential regimens to control the disease for as long as possible.

High-dose melphalan supported by ASCT in ﬁrst remission is

currently accepted as gold standard consolidation for

pa-tients with MM deemedﬁt. However, prolonged PFS

post-ASCT is uncommon, and selection of optimal treatment for disease relapse is the major decision for patients and treating clinicians[6,15].

This retrospective analysis indicates that patients with

relapsed MM can bene_{ﬁt from a second ASCT with median}

PFS of 10.3 months and OS of almost 2 years, which is comparable with salvage therapy with currently available novel agents [17-21]. Five percent of patients died from transplant-related complications. Most of our patients (90%) had received either proteasome inhibitors or immune-modulating (IMID) therapies as part of initial induction or as salvage before second ASCT. Similar to others, we found that a longer disease remission after initial ASCT and an inherent response of the disease to salvage therapy were significantly associated with better outcomes. In our study, patients who were cytogenetically defined as “standard risk” rather than those with high-risk abnormalities derived the most bene_{fit from this approach. On the other hand, the dose} of melphalan and receiving post-ASCT maintenance or allo-ASCT as consolidation after salvage autologous transplant did not impact outcomes.

It is important to recognize the limitations of this retro-spective study. First, the sample size was small and distrib-uted over more than 10 years. Yet, most patients received proteasome inhibitors and IMIDs as part of their reinduction

regimen, but these were most often ﬁrst- or

second-generation agents. Second, the induction regimens were heterogeneous, as were the number of prior lines of therapy. Therefore, these data do not guide decision making as to when to perform a second ASCT. Finally, the denominator of how many patients could have been eligible for salvage transplant is unknown because of the retrospective nature of the data. Although patients who die of relapsing disease quickly were not eligible for salvage transplant, which selects for more favorable patients, this study was performed when we and other centers were participating in early phase trials studying second- and third-generation IMIDs and protea-some inhibitors. Perhaps only patients presumed to be at

high risk of disease progression were offered second transplants.

In all reports, chemosensitivity and remission afterﬁrst autograft emerge as the most important prognostic factors for subsequent long-term disease control [10,16,22,23].

However, whether patients with remissions beyond

12 months [24], 18 months [22], 24 months [25], or

36 months[26]should be offered this therapy remains un-clear. Other reports identiﬁed the number of lines of prior therapy had a signiﬁcant impact on outcomes and suggested that salvage ASCT should not be relegated to a“last-ditch effort” in patients who have failed all prior therapies but should be considered an integral component of initial salvage strategies[27].

The ﬁrst prospective randomized trial studying ASCT

versus less intensive alkylating agent consolidation (weekly cyclophosphamide) afterﬁrst relapse and reinduction with a bortezomib-containing regimen has been published[28]. This trial showed a clear advantage in terms of time to progression, 19 versus 11 months (P < .0001), for the transplant arm compared with the chemotherapy arm; in fact, the trial was stopped early because it met its pre-deﬁned endpoint. However, with limited follow-up, an OS difference was not shown. One could argue, however, that cyclophosphamide alone is not an effective agent and continuing combination treatment may have comparable outcomes. A PFS of 17.9 months was demonstrated in a study where a combination of bortezomib, thalidomide, and dexamethasone was used for 1 year in patients with relapsed/progressing disease post-transplant [29]. Taken

together, a prospective, randomized, controlled trial

comparing second ASCT versus continuing new treatment regimens is now warranted.

The role of second salvage ASCT in the context of the current treatment landscape that often includes mainte-nance after initial ASCT remains unknown. One can speculate that the longer duration of remission after initial transplant when maintenance is used may translate into improved outcomes after a second transplant. Alternately, mainte-nance therapy may select for more resistant clones and lead to shorter remission duration after a second transplant. Interestingly, 1 group reported longer time to progression after the second rather than thefirst ASCT, suggesting the persistence of more sensitive subclones in the absence of maintenance[23]. The availability of second- and even third-generation proteasome inhibitors and IMIDs may also limit the applicability of our data. Importantly, prospective studies that include pomalidomide and/or car_{filzomib-based} rein-duction and randomization to transplant or no transplant are ongoing or planned and are critical. Within this context, it will be essential to collect symptom burden and other quality of life data to have a broader understanding of the results of these studies. However, it is reassuring that to date most groups found the frequency and intensity of toxicities after thefirst and second transplantation to be similar[30].

Identiﬁcation of biological parameters that can predict

response to a given treatment, including high-dose

melphalan, would be help with selection of the most appropriate salvage therapy for individual patients. In our study, patients with high-risk cytogenetics were less likely to

beneﬁt from a second salvage ASCT; however, this is in

contrast to others who reported that adverse cytogenetics had no signiﬁcant impact on outcomes after salvage ASCT

[24]. This will best be assessed in the context of the afore-mentioned prospective, randomized clinical trials.

Table 5

Multivariate Analysis of OS and PFS in Patients Who Received Second ASCT Between 2007 and 2012 (n¼ 34)

HR (95% CI) P OS

.03 (0, .53) .016 PFS

.04 (0, .64) .023 Univariate variables signiﬁcant at the level of .05, and patients with infor-mation available for these variables were initially included in the multi-variate analysis. Backward selection method was used and only signiﬁcant variables were kept in the model.

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In summary, despite the development of very active novel therapies for the treatment of MM, patients eventually die from their disease. With a limited armamentarium of effec-tive treatment options, a second ASCT at the time of relapse is an option that has been associated with reasonable response rates and PFS. Patients with refractory disease and limited remissions after initial transplant to date have had limited beneﬁt with this approach and may be reasonable candidates for experimental therapies and/or allo-ASCT. However, next-generation reinduction and the routine use of post-transplant/consolidation maintenance may considerably change the outcomes with this approach.

ACKNOWLEDGMENTS

Financial disclosure: The authors have nothing to disclose. Conﬂict of interest statement: There are no conﬂicts of in-terest to report.

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