research paper

Lenalidomide and vorinostat maintenance after autologous transplant in multiple myeloma

Douglas W. Sborov,1 Don M. Benson,2 Nita Williams,2 Ying Huang,2 Mindy A. Bowers,3 Kristina Humphries,3 Yvonne Efebera,2 Steven Devine2 and Craig C. Hofmeister2 1

Hematology/Oncology Fellowship, Department

of Internal Medicine, The Ohio State University, 2

Division of Hematology, Department of Internal

Medicine, The Ohio State University, and 3Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA Received 22 February 2015; accepted for publication 27 April 2015 Correspondence: Craig C. Hofmeister, Associate Professor of Clinical Medicine, M200G Starling Loving Hall, 320 West 10th Avenue, Columbus, OH 43210, USA. E-mail: [email protected]

Summary Single-agent post-autologous transplant maintenance therapy with lenalidomide is standard of care for patients with multiple myeloma. The tolerability and effectiveness of combination post-transplant maintenance therapy is unknown, so we investigated lenalidomide and vorinostat (suberoylanilide hydroxamic acid) in this setting, hypothesizing that the regimen would be well tolerated and associated with an improved post-transplant response. This trial followed a standard 3 9 3 dose escalation phase 1 design. Vorinostat was administered beginning day +90 post-haematopoietic stem cell transplantation for days 1–7 and 15–21, and lenalidomide was started at 10 mg days 1–21, both on a 28-d cycle. The primary endpoint was maximum tolerated dose and dose limiting toxicities were assessed during the first cycle. Treatment was well tolerated in 16 enrolled patients. During Cycle 1, the most common toxicities included cytopenias, gastrointestinal complaints and fatigue. Seven patients improved their transplant response after starting combination therapy. The median follow-up was 38
4 months, and the median progression-free survival and overall survival have yet to be reached. This oral post-transplant maintenance regimen was well tolerated. This is the first trial to publish results on the use of a histone deacetylase inhibitor in the maintenance setting, and it provides rationale for the ongoing randomized trial in maintenance (ISRCTN 49407852). Trial Registration: NCT00729118 Keywords: myeloma, autologous transplant, deacetylase inhibition, immunomodulatory agent.

In transplant-eligible multiple myeloma (MM) patients, maintenance therapy with lenalidomide following autologous haematopoietic stem cell transplantation (ASCT) is associated with increased time to disease progression and improved overall survival (OS), and is currently standard of care (McCarthy et al, 2012). Effective and tolerable maintenance drug combinations may further prolong the clinical response achieved from ASCT. Numerous studies are currently underway investigating the role of proteasome inhibitors and other novel agents in this therapeutic setting. Histone deacetylase inhibitors (HDAC-I) are associated with anti-myeloma activity, and represent a promising combination approach for maintenance therapy. In recent years, the importance of epigenetic modification in the initiation, proliferation, survival and progression of tumour cells has risen to the forefront (Herman & Baylin,

First published online 8 June 2015 doi: 10.1111/bjh.13527

2003). A novel class of agents, the HDAC-I’s, inhibit histone deacetylase (HDAC) enzymes, effectively targeting epigenetic silencing mechanism(s) that can reverse crucial steps involved in carcinogenesis. This drug class also renders tumour cells more susceptible to immune-mediated killing (Skov et al, 2005; Gialitakis et al, 2006), and induces an antiinflammatory effect via inhibition of cytokine release that may disrupt the tumour microenvironment (Leoni et al, 2002). Vorinostat (suberoylanilide hydroxamic acid, SAHA), a nonspecific oral HDAC-I, was approved by the US Food and Drug Administration (FDA) in 2006 for the treatment of cutaneous manifestations in patients with cutaneous Tcell lymphoma (Duvic et al, 2006, 2007). Vorinostat induces numerous anti-proliferative and pro-apoptotic effects in MM cells (Mitsiades et al, 2004), and has been investigated ª 2015 John Wiley & Sons Ltd British Journal of Haematology, 2015, 171, 74–83

Lenalidomide and Vorinostat Following Transplant in Myeloma in myeloma patients in numerous clinical trials (Table SI). Phase 1 investigation of single agent vorinostat in relapsed/ refractory myeloma patients confirmed single agent tolerability (Richardson et al, 2008). Numerous other early phase trials have investigated vorinostat with bortezomib and have confirmed the tolerability of this combination, albeit at the cost of increased toxicity (Badros et al, 2009; Siegel et al, 2011; Weber et al, 2012; Dimopoulos et al, 2013; Wider et al, 2013). The randomized, placebo-controlled phase 3 VANTAGE (Vorinostat Clinical Trials in Haematological and Solid Malignancies) 088 trial demonstrated a significant increase in median progression-free survival (PFS) with this combination (Dimopoulos et al, 2013). When used in combination with lenalidomide and dexamethasone in relapsed patients, the addition of vorinostat was well tolerated and associated with stable disease (SD) in approximately 90% of patients (Siegel et al, 2014). Further, the three-drug regimen including bortezomib, lenalidomide and vorinostat in newly diagnosed patients was well tolerated and associated with complete response (CR) in three, very good partial response (VGPR) in one and partial response (PR) in four of the eight evaluable patients (Kaufman et al, 2010). In the relapsed/refractory setting, an overall response rate of 43% was noted and of the nine enrolled patients, 89% had a MR or better (Siegel et al, 2010). Collectively, these data indicate that vorinostat is relatively well tolerated and more efficacious when used in combination with other agents, including both proteasome inhibitors and immunomodulatory agents. Given two randomized studies investigating lenalidomide monotherapy following ASCT (Attal et al, 2012; McCarthy et al, 2012), we hypothesized that combining vorinostat with lenalidomide in the maintenance setting would be safe and augment clinical response. We are the first to describe the use of vorinostat with lenalidomide in the post-autologous transplant maintenance setting, and our data sets the stage for further evaluation of this combination in a randomized trial.

Methods

were required to have adequate organ function, including an absolute neutrophil count >1
0 9 109/l, platelet count >75 9 109/l, total bilirubin, aspartate transaminase and alanine transaminase 10 mg at 12 months. Half of the patients in this cohort were treated with 5 mg lenalidomide at 12 months.

Table II. 28-d cycle oral dosing regimen.

Dose level

Vorinostat Days 1–7, 15–21

Lenalidomide Days 1–21

1 2 3

200 mg/d 300 mg/d 400 mg/d

10 mg/d 10 mg/d 10 mg/d

All three doses levels included starting doses of lenalidomide at 10 mg by mouth daily. Dose level 1 included a starting dose of vorinostat 200 mg PO days 1–7 and 15–21. Dose levels 2 and 3 included vorinostat on the same schedule but with 300 and 400 mg daily, respectively.

3 (vorinostat 400 mg and lenalidomide 10 mg). Fifteen patients received more than one cycle of therapy. Five patients remain on study, five were removed from the study due to treatment-related toxicities, and six were removed from the study due to progressive disease, two of whom have since expired. Of the patients that discontinued the trial due to toxicities, four remain off treatment and without evidence of disease progression, while the fifth continues 5 mg lenalidomide on days 1–21 of a 28-d cycle.

Toxicities Of the adverse events that were possibly, probably or definitely related to therapy that occurred during the first year of trial participation, the most common toxicities were neutropenia (14
4% of total patients), fatigue (13
5%), leucopenia (12
7%), thrombocytopenia (11
9%), lymphopenia (11
0%) diarrhoea (9
3%), anaemia (8
5%), hypokalaemia (7
6%), rash (5
9%) and nausea (5
1%). In total, only two patients (12
5%) had grade 2 or lower adverse events, while all others had one or more grade 3 toxicity throughout their treatment course. Grade 4 toxicities include one patient each with neutropenia and thrombocytopenia. Grade 3 toxicities included neutropenia (n = 7), thrombocytopenia (n = 4), leucopenia

Dose modifications Twelve months after starting study treatment, the median dose of lenalidomide was 5 mg and vorinostat was 200 mg (Table III). Approximately 6 months after starting the study treatment, eight patients were treated with lenalidomide doses higher than the 10 mg starting dose (range 15–25). At 12 months, five of these patients remained on lenalidomide doses >10 mg. In total, five patients had lenalidomide dose

Table III. Vorinostat and lenalidomide dosing in evaluable patients. Vorinostat dose (mg)

Lenalidomide dose (mg)

Time to first dose reduction (cycle)

ID

Starting

Ending

Starting

Max

Ending

Vorinostat

Lenalidomide

A B C D E F G H I J K L M N O P

200 200 200 300 300 300 400 400 400 400 400 400 400 400 400 400

200 200 200 300 100 100 300 400 300 300 400 400 100 400 300 200

10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10

25 10 20 10 20 10 15 25 25 10 25 25 10 20 20 15

5 5 10 10 5 5 5 20 5 5 25 15 5 5 15 5

NA NA NA NA 3 6 9 NA 17 1 NA NA 1 NA 2 3

6 7 4 NA 3 1 5 7 5 1 NA 5 1 3 12 2

Vorinostat and lenalidomide dose escalations and reductions are listed by patient. ID, patient identification; Max, maximum; NA, not applicable. ª 2015 John Wiley & Sons Ltd British Journal of Haematology, 2015, 171, 74–83

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D. W. Sborov et al (n = 2), fatigue (n = 1), diarrhoea (n = 1) and hypokalaemia (n = 1). As shown in, the median time to the first grade 3 or higher event was 172 d (Fig S1). During Cycle 1, cytopenias (n = 20), gastrointestinal complaints (n = 9) and fatigue (n = 4) were the most common toxicities. Of note, there were no grade 4 events during Cycle 1. Grade 3 adverse events included one patient each with neutropenia, fatigue and hypokalaemia, grade 2 events included nausea (n = 2), emesis (n = 2), lymphopenia (n = 2) and one patient each with neutropenia, diarrhoea and fatigue. All other Cycle 1 events were grade 1 (Fig 1).

Patient report outcomes Analysis of the QoL from the start of therapy through the first three cycles found no significant change in the BFI, FACT-G and CES-D (P = 0
425, P = 0
140, P = 0
897, respectively) (Table IV). CES-D indicated that patients did not have significantly worse depressive scores between the start of therapy (day +90) and the end of the trial. Likewise, the FACT-G functional well-being tool revealed relatively stable functional status, and patients did not have significant changes in fatigue over the course of treatment. Additionally, descriptive statistics showed that fatigue, functional wellbeing, and the CES-D depression scale did not appear to differ significantly between dose levels, however, we recognize the limitations of strict comparisons between dose levels given the limited numbers of patients involved.

Flow cytometry At days +56–60 post-transplant (n = 16), prior to starting combination vorinostat and lenalidomide maintenance ther-

apy, the median percentage of leucocyte subsets was quantified. These patients were generally CD19+ B cell depleted (17
9%). The majority of leucocytes were CD4+ and CD8+ T cells (67
9%) of which most were CD8+ T cells (43
4%). The other predominant cell subset was NK cells (CD3 /CD16+/ CD56+), which made up 15
1% of the total cell population. Flow cytometric analyses were then obtained on posttransplant days +120 and +150, corresponding to the beginning of Cycles 2 and 3 following treatment with vorinostat and lenalidomide. There was a significant increase in NKand CD4+ T-cells, and significant decrease in CD19+ B-cells between days +54–66 and +150 (P = 0
03, 0
0001 and 0
003, respectively) (Table SII; Fig S2). There was no significant change between these same time points for CD8+ T-cells.

Response Following transplant (day +90) and before starting the study maintenance regimen, three patients had SD, two had PR, seven had VGPR, two had CR and two had stringent CR (sCR) (Fig 2). Seven patients had improved response following the initiation of study treatment, and this improvement was noted in ≤5 cycles in four of these patients. The best improvement in response was SD to sCR, but two patients were noted to improve from PR to CR. The changes in the dominant monoclonal protein for each patient are displayed in Fig 3. Of note, in those patients with IgA disease, the total IgA was followed for response and progression. The median follow-up was 38
4 months (range 31
6– 43
1 months). The median PFS and OS have not yet been met (Fig 4). Six patients remain on trial and have been treated for an average of 36 cycles. Two patients have died due to disease progression, and both patients (G and J) had

Fig 1. Ten worst grade adverse events occurring during Cycle 1. Treatment was generally well tolerated and no grade 4 events were experienced by any patient. Grade 3 events included neutropenia, fatigue and hypokalaemia. Grade 2 events included neutropenia, nausea, diarrhoea, fatigue, lymphopenia and emesis. The most frequently experienced grade 1 events included cytopenias (neutropenia, leucopenia and thrombocytopenia), nausea, diarrhoea and hypokalaemia.

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ª 2015 John Wiley & Sons Ltd British Journal of Haematology, 2015, 171, 74–83

Lenalidomide and Vorinostat Following Transplant in Myeloma Table IV. Quality of life indices. BFI

FACT-G FWB

Quality of life (Timepoint)

 (SE) X

C1D1 (+90) C1D15 (+105) C2D1 (+120) C3D1 (+150) C4D1 (+180) EOT

2
7 3
2 2
4 3
0 2
5 3
2

(0
54) (0
62) (0
58) (0
66) (0
52) (1
70)

P

 (SE) X

0
425

2
3 2
5 2
6 2
5 2
6 2
7

(0
20) (0
20) (0
20) (0
21) (0
18) (0
52)

CES-D P

 (SE) X

P

0
140

7
6 7
5 7
4 7
9 6
8 9
5

0
(897)

(1
22) (1
64) (1
84) (1
55) (1
39) (4
17)

Quality of life was measured by the Brief Fatigue Inventory (BFI), Functional Assessment of Cancer Therapy-General (FACT-G), and the Center for Epidemiologic Studies Depression Scale (CES-D) at the initiation of study treatment (Cycle 1, Day 1; C1D1), Day 15 of Cycle 1 (C1D15), Day 1 of each successive cycle from Cycles 2 to 4, and at the end of the trial (EOT). Though there was variation in all three quality of life indices over the course of treatment, there were no significant changes in the quality of life for patients over the course of treatment.

Fig 2. Changes in response from transplant to trial discontinuation. Seven of the evaluable 16 patients had an improvement of response following treatment. Two patients improved from stable disease (SD) to partial response (PR), one patient improved from SD to stringent complete response (sCR), two patients improved from PR to very good partial response (VGPR), one patient improved from VGPR to complete response and one patient improved from VGPR to sCR. The remaining nine patients did not have an improvement in response, but all had VGPR or better following autologous stem cell transplantation. *Deceased patients.

evidence in improvement in response following the initiation of combination maintenance therapy (SD to PR and PR to VGPR). Three patients discontinued the trial due to progressive disease and remain alive (Patients A, N, P). One patient was taken off treatment due to toxic megacolon that was not attributable the study treatment, but rather to transplant. Four other patients were taken off treatment for gastrointestinal intolerance (n = 2) and cytopenias (n = 2); all but one of these remain off-treatment without disease progression.

Discussion In this phase 1 dose escalation trial of maintenance oral lenalidomide and vorinostat, the maximum administered doses were 400 mg vorinostat, days 1–7 and 15–21 and 25 mg lenalidomide, days 1–21, each of a 28-d cycle. No dose limiting toxicities occurred, however, 60% of the patients in the final cohort required dose reduction of vorinostat and lenalidomide due to onset of adverse events. Of those patients that required dose reductions, the median time to regimen augmentation was 3 (range 1–17) and 4
5 (range 1–12) cycles ª 2015 John Wiley & Sons Ltd British Journal of Haematology, 2015, 171, 74–83

for vorinostat and lenalidomide, respectively. While most patients (73%) tolerated dose escalation of lenalidomide over their course of treatment, 36% reached the 25 mg dose, but 91% required dose reduction primarily due to neutropenia. Considering that the majority of patients required dose reductions and that the median dose of vorinostat and lenalidomide at 1 year were 200 mg and 5 mg, respectively, it is likely that the most well tolerated dose of vorinostat includes vorinostat 200 mg days 1–7 and 15–21 of a 28-d cycle. In fact, in those patients treated at the 200 mg dose (Cohort 1), all three patients had an improvement in their post-transplant response, two of whom achieved sCR. The most common observed adverse events over the course of the trial included cytopenias, fatigue, diarrhoea and hypokalaemia. During Cycle 1, no grade 4 events were experienced. Grade 2 and 3 events were minimal and included neutropenia, nausea, diarrhoea, fatigue, hypokalaemia, emesis and lymphopenia (Fig 1). In parallel with prior experience describing common vorinostat side effects when used as single agent (Richardson et al, 2008) and in combination regimens (Badros et al, 2009; Siegel et al, 2014), diarrhoea and 79

D. W. Sborov et al

Fig 3. Changes in monoclonal protein from before transplant to the end of treatment. The predominant clone for each patient is depicted over time from prior to transplant to screening and through the duration of treatment. 100% represents the pre-transplant baseline and each subsequent data point is the monoclonal protein at a specific time point divided by this baseline value. For example, if a patient had a 50% decrease of the monoclonal protein from the pre-transplant baseline, this would be represented as a monoclonal protein of 50%, and if a patient had evidence of no monoclonal spike, then this would be depicted as 0%. Six patients continue therapy as of 1 September 2014 (dark solid lines). Four patients discontinued study treatment due to toxicities (light solid line) and six patients were found to have disease progression (dotted line). Although patient M’s monoclonal protein more than doubled by Cycle 14, the patient did not meet criteria for progressive disease. C, cycle; D, day (e.g., C1D1 = Cycle 1, Day 1)

Fig 4. Progression-free and overall survival. At the time of analysis (1 September 2014), median progression-free survival (PFS) and overall survival (OS) had not been reached (median days on treatment = 965).

hypokalaemia occurred, but the majority of these events were grade 1 or 2 in severity. Interestingly, though fatigue was the third most common adverse event recorded (12
4% of patients), the Global Fatigue Score did not significantly increase over the course of the trial (P = 0
425) (Table IV). Additionally, patient functionality and depression indices did not significantly change (P = 0
140 and P = 0
897, respectively). Collectively, our data confirm tolerability. Of the 16 patients enrolled, seven improved their response after starting lenalidomide/vorinostat. These patients achieved SD (n = 3), PR (n = 2) and VGPR (n = 2) following transplant, and all but two improved their response to 80

VGPR or better. Of those patients that did not improve on maintenance, the best responses included five VGPR, two CR, and two sCR (Fig 2). Interestingly, this data suggests that those patients that benefited least from transplant derived the most benefit from this maintenance regimen. In total, 14/16 (87
5%) of the enrolled patients remain alive with a median follow-up of 38
4 months. The median PFS and OS have not yet been reached (Fig 4), limiting our ability to make conclusions regarding the clinical benefit gained by the addition of vorinostat to lenalidomide monotherapy. The biological mechanism underlying the lenalidomide and vorinostat combination has not been elucidated, but it has been previously shown that various HDAC-Is show synergism when combined with immunomodulatory agents and/ or proteasome inhibitors (Mitsiades et al, 2004; Pei et al, 2004; Campbell et al, 2010; Kikuchi et al, 2010). HDAC-Is can modulate the immune response via increased expression of major histocompatibility complex class I-related chain A and B (MICA/B) (Skov et al, 2005) to enhance NK-cell mediated killing (Carbone et al, 2005). Additionally, it is known that lenalidomide stimulates T-cells, improves dendritic cell function and inhibits regulatory T-cell expansion (Quach et al, 2010). The resulting increase in production of interferon-c and interleukin-2 can reverse the impaired innate immune response by indirectly enhancing NK cell proliferation, cytolytic activity and antibody-dependent cell-mediated cytotoxicity (Davies et al, 2001; Hayashi et al, 2005). In the early post-transplant setting, it has been shown that patients with early NK cell recovery after autologous transplant have prolonged OS and PFS (Porrata et al, 2008). ª 2015 John Wiley & Sons Ltd British Journal of Haematology, 2015, 171, 74–83

Lenalidomide and Vorinostat Following Transplant in Myeloma Though conclusions are limited by the sample size, our correlative flow cytometric analyses indicate that the percentage of NK cells (CD3 /CD16+/CD56+) increased following combination therapy, potentially explaining at least in part the improvement in response of nearly half of our patients. Ultimately, data regarding immune constitution following autologous transplantation and the effects of maintenance therapy on NK-, T- and B-cellular subsets in myeloma patients remains limited, and further investigation is warranted to define the significance of these changes over the course of treatment. Combination with novel therapeutics, such as lenalidomide and bortezomib, in patients with MM is associated with improved clinical response; findings that continue to drive the pursuit to define optimal combination strategies. Ongoing trials have suggested in the phase 2 setting that multi-drug maintenance may be more effective in patients with higher risk disease (Nooka et al, 2014). Our trial is the first to investigate HDAC-Is in the maintenance setting, but this phase 1 study only sets the stage to compare multidrug regimens in the randomized setting against lenalidomide monotherapy. Additionally, pan HDAC-Is may not be the most effective therapy, and more selective HDAC-Is are being actively investigated. For example, ACY-1215 (HDAC-6-I) has been well-tolerated in the phase 1 setting in combination with both IMiDs (Vorhees et al, 2013) and proteasome inhibitors (Vogl et al, 2013), and preclinical investigation highlights that BG45 (HDAC-3-I) effectively induces MM cell apoptosis and increases the cytotoxic effects of bortezomib (Minami et al, 2014); promising findings that could lead to the eventual incorporation of these agents into effective and well tolerated MM treatment regimens.

U01CA076576 (PI Michael Grever). DWS is supported under Award Number T32CA165998 (PI Miguel Villalona and Steven Devine). The content is solely the responsibility of the authors and does not represent the official views of the National Cancer Institute or the National Institutes of Health.

Disclosures CCH reports personal fees and non-financial support from Celgene, personal fees from Millenium, personal fees from Onyx, outside the submitted work. SD reports personal fees from Amgen, Celgene, and GlaxoSmithKline. DWS, DMB, NW, YH, MAB, KH and YE have no disclosures to report.

Authorship CCH designed the study, analysed the data and wrote the manuscript. YH, DWS analysed data, wrote the manuscript. CCH, YE, DMB and SD enrolled patients. All authors revised the manuscript for intellectual content and approved the final version.

Supporting Information Additional Supporting Information may be found in the online version of this article: Fig S1. Number of days to first grade >3 adverse event. Fig S2. Box plot representation of cellular subset changes over the course of two cycles. Table SI. Clinical trials investigating vorinostat in patients with multiple myeloma. Table SII. Cell population subsets over time.

Acknowledgements This research is supported by the National Cancer Institute of the National Institutes of Health under Award Number

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