Treatment of relapsed and refractory multiple myeloma

S. Lonial ABSTRACT

Department of Hematology and Treatment options and outcomes for patients with relapsed myeloma have dramatically changed Medical Oncology, Winship Cancer over the past ten years due in large part to the availability of novel agents such as , thalido- Institute, Emory University School of mide and lenalidomide. These have now been incorporated into the treatment approach for newly Medicine, Atlanta, GA, USA diagnosed patients and also raise questions about bow best to manage patients who relapse. In addi- tion to existing and approved agents, several others have recently been or are soon to be approved, as Correspondence: well as new classes of agents in phase III trials that are likely to not only improve long-term outcomes, Sagar Lonial but that will also complicate treatment algorithms. We will review data on the optimal use of existing E-mail: [email protected] approaches for relapsed disease, as well as new agents under development for relapsed and refractory myeloma. Acknowledgments Sagar Lonial is supported by funding Learning goals from the Richard and Annelly Deets At the conclusion of this activity, participants should understand: Fund for Multiple Myeloma. - when a patient needs therapy for relapsed myeloma; - how best to use available treatment options for managing relapsed myeloma; Hematology Education: - which are the new agents under development and how to use them for the management of relapsed the education program for the and refractory myeloma. annual congress of the European Hematology Association 2013;7:216-226 Introduction myeloma with the highest chance of response and good tolerance for any given patient. Multiple myeloma (MM) is a clonal plasma cell malignancy characterized by bone, renal, How to define relapse hematologic, and often neurological complica- tions.1 The overall survival for patients with symptomatic myeloma has dramatically Response criteria in myeloma represent an improved over the last decade due to the broad evolving work in progress. While the defini- use of high-dose therapy and autologous trans- tion of complete response (CR) continues to plant for suitable patients, as well as the avail- become more and more stringent, the defini- ability of novel agents whose mechanisms of tion of relapse or progression has been rela- action are distinctly different from alkylators tively constant. Relapse from a CR is defined or steroids. However, even with these as reappearance of the serum or urinary para- advances, most patients will eventually die of protein, of 5% or over bone marrow plasma complications associated with the develop- cells, new lytic bone lesions/soft tissue plas- ment of resistant disease.2 Plasma cells spend macytomas, an increase in size of residual their time in the marrow microenvironment bone lesions, and/or development of hypercal- supported by autocrine and paracrine secretion cemia (corrected serum calcium >11.5 mg/dL) of growth factors such as IL-6, TNFα, IGF-1 not attributable to another cause.5 Following and VEGF,3 as well as direct interaction of the the increased depth of response seen with new bone marrow microenvironment with plasma therapies, the ‘CR penalty’ was addressed by cells via integrins and cell adhesion molecules allowing patients who have achieved a CR to which promote growth and inhibit apoptosis.4 be defined as relapsed when they develop a However, the practical delivery of anti-myelo- protein of at least 0.5 gm/dL rather than the ma therapy in the context of relapsed or refrac- historical definition of immunofixation nega- tory disease is a constantly evolving area of tive to immunofixation positive.6 Criteria for research, and one which needs to take into progressive disease (PD) when a CR has not consideration factors of clinical importance. been achieved include new or expanding bone These include: i) which diseasevs setting the lesions, hypercalcemia, and a more than 25% patient comes to us in (early . late); ii) dis- increase in either serum monoclonal parapro- ease specific biology (standard- or high-risk); tein concentration, 24-h urinary light chain iii) prior therapies; and iv) prior toxicities excretion, or plasma cells within a bone mar- from therapy. Through clinical integration of row. Relapsed MM refers to the circumstance these factors, a treatment strategy can be wherein a patient treated to the point of maxi- defined for patients with relapsed or refractory mal response experiences PD, whereas refrac-

Hematology Education: the education program for the annual congress of the European Hematology Association | 2013; 7(1) | 216 | Stockholm, Sweden, June 13-16, 2013 tory MM refers to a clinical scenario in which a patient is patients who did not have a transplant as part of their ini- either unresponsive to current therapy or progresses within tial treatment, or for patients with long duration of remis- 60 days of last treatment. It is important to recall that sion following transplant, salvage autologous transplant ‘patients with refractory disease’ has historically referred could be considered. Incorporation of patient- or treat- to patients who were resistant to dexamethasone and alky- ment-related AEs (existing cytopenias, neuropathy, or lators and, given the short duration of response to both thrombosis) should also play a part in the choice of agents alone, patients often developed refractory disease. More in the relapsed disease setting. For patients with more recently, the availability of different classes of agents advanced relapse, or with aggressive disease biology, the including proteasome inhibitors and immunomodulatory use of combinations of agents or novel agents in combina- agents, the generic term ‘refractory’ requires more speci- tion with cytotoxic agents may be a more appropriate ficity. Currently, the term ‘refractory’ requires a descrip- approach. Even among patients with aggressive relapse, tion of what the patient is refractory to, i.e. steroids, borte- the use of salvage transplant has a role if cytopenias are zomib or lenalidomide. In addition, there may be biologi- limiting treatment options, as long as some form of main- cal differences between patients who areversus defined as refrac- tenance therapy is used afterwards in an effort to stave off tory by progression on treatment those who early or rapid relapse. Disease biology can also influence progress within 60 days of stopping therapy and, as such, the choice of therapy for relapsed/refractory MM, and reg- they should be specified when base-line patients’ charac- imens including bortezomib or lenalidomide are preferred teristics are described in clinical trials. Patients who fail to in individuals with the higher risk t(4;14) disease as well achieve any response to induction therapy (< minimal as the use of some form of maintenance therapy, which response, MR) and then progress on therapy are an espe- appears to be of greater importance among patients with cially challenging category of patients with primary biologically defined high-risk disease. Importantly, the refractory myeloma.7 optimal therapy of patients with deletion of 17p (p53), As we now have more tools with which to approach who usually derived short benefit from available therapies relapsed disease, the decision as to when to treat this con- outcomes, is not known at this time and thus for these tinues to be an issue. The current International Myeloma patients aggressive combination therapy with aggressive Working Group guidelines (IMWG) state that patients maintenance treatment may be warranted.9,10 More sophis- should be observed until they develop symptomatic ticated biological correlatives for the selection of treat- relapse (the same criteria used to differentiate smoldering ment are obviously desirable but are not currently avail- myeloma from symptomatic myeloma). This raises the able for routine clinical practice. issue of differences between patientsversus with biochemical Interestingly, most of the novel combination approaches relapse (blood or urine protein only) those patients in MM explored to date have reliably produced response with symptomatic relapse (new evidence of end organ in the majority of patients, and CR/nCR is not uncommon. damage according to the CRAB criteria). Most clinical tri- One unresolved question in MM therapy is whether use of als require patients to have symptomatic relapse prior to combinations of novel agents to achieve high response study entry, and it is clear that there are patients who can rates is better than the sequential use of these agents alone have long-term low-level disease burden and who do not or with corticosteroids. Emerging data from large phase III require therapy. Early initiation of salvage therapy in those studies suggest that progression-free survival is superior patients would not necessarily offer benefit, while there with a 3-drug combination compared with a doublet, but may be others with high risk or aggressive relapse for so far no survival improvement has been noted.11 Several whom waiting till there is evidence of end organ damage currently ongoing phase III trials are evaluating a similar may ultimately limit the efficacy of therapy. At this point, comparison (lenalidomide/dexamethasone +/- carfil- it remains prudent to observe patients who have ‘biochem- zomib, lenalidomide/dexamethasone +/- elotuzumab, ical relapse’ only, unless there are other factors (prior his- bortezomib/dexamethasone +/- ) and these tory of rapid relapse, high-risk genetics, etc.) that suggest data are critically important as we begin to evaluate the to the clinician that delaying therapy may cause the patient benefit of inducing deeper responses and their impact on harm. long-term outcomes in the relapsed disease setting.

How to systematically approach a relapsed Second autologous transplant patient For over 20 years, conventional and high- While there is no clear simple algorithm to define how dose therapy (HDT) with either autologous stem cell sup- a patient should be treated in the relapsed setting, there are port has been utilized in the management of relapsed some general principles that can guide the choice of ther- and/or refractory MM. Regimens based on conventional apy.8 For patients with indolent or relapse early in their chemotherapy have included: high-dose dexametha- disease course, the use of single agents, depending upon sone;12,13 , , and dexamethasone what was used in their initial therapy as well as treatment- (VAD);14-18 vincristine, , , related toxicity, is a reasonable approach. For patients who prednisone, vincristine, , doxorubicin, and received thalidomide or lenalidomide-based induction prednisone (VMPC/VBAP);19 and doxorubicin, vin- therapy, switching to bortezomib-based salvage makes cristine, dexamethasone, , and cyclophos- sense in order to switch drug class at the time of relapse. phamide (CEVAD).20 The use of melphalan as high-dose Similarly, patients who received bortezomib-based induc- therapy (HDT) in relapsed and/or refractory myeloma was tion may gain benefit from switching to an immunomodu- introduced by McElwain and colleagues21 and subsequent- latory agent in the relapsed setting. In addition, for ly by Barlogie and colleagues, who demonstrated that

Hematology Education: the education program for the annual congress of the European Hematology Association | 2013; 7(1) | 217 | 18th Congress of the European Hematology Association high-dose melphalan with stem cell support could over- lenalidomide, and pomalidomide, as well as the protea- come resistance to conventional-dose chemotherapy.22 some inhibitors bortezomib and , to overcome Available data on second autologous transplants for drug resistance was clearly demonstrated in pre-clinical relapsed patients suggest that these procedures are rela- models and confirmed in the context of clinical trials lead- tively well-tolerated, with a 100-day mortality of less than ing to US Food and Drug Administration (FDA) approval 10%.23-26 The overall response rates (ORR) in more recent of these compounds in the treatment of MM. This review studies, in which most patients have received novel will elaborate on the role of novel agents in the treatment agents, range from 55%-69%.23,24,26,27 A recent analysis of relapsed and refractory MM, with discussion of other suggests that a relapse-free survival of more than 18 emerging compounds that may yet have a further impact months after the first auto-SCT is the most reliable predic- on the field. tor of clinical outcome after a second auto-SCT,28,29 though the impact of planned post-transplant maintenance therapy Specific therapeutic agents on the duration of first response post-auto transplant is currently unknown. Thalidomide As such, for patients who experienced an initial duration of remission of more than 24 months following their initial Thalidomide was one of the first novel agents to be eval- 30,31 autologous transplant, the use of a second autologous uated in relapsed and refractoryet al. patients. A recent transplant can potentially offer clinical benefit following a review from Glasmacher demonstrated that thalido- short course of salvage therapy to re-induce some level of mide alone produced a partial response or better in 30% of a response. Additionally, for patients who have significant relapsed patients, with a 1-year survival of 60% and medi- cytopenias as a consequence of salvage therapy, the use of an survival of 14 months.31 While the depth and duration a salvage autologous transplant may provide a method by of response may seem short by current standards, at the which more normal hematopoiesis can be re-established time this represented a major step forward for patients even in the setting of short duration of remission from pre- with few other options. Toxicities of thalidomide included vious autologous transplants. This may allow patients to sedation, constipation, and increased risk of venous receive additional salvage therapy that would ultimately thromboembolism (VTE), as well as peripheral neuropa- be limited by low blood counts. thy. It was noted later on that the incidence of peripheral neuropathy (PN) increased if the daily dose of thalidomide exceeded 200 mg or if administered for six months or Novel agents in relapse 32,33 more. It was subsequently noted that the addition of steroids to thalidomide increases the overall response rate The emergence of novel therapies over the past decade to 50%, typically with prolonged remission duration, as is has dramatically altered the therapeutic landscape and nat- now known to be the case for all the immunomodulatory ural history of relapsed and refractory myeloma. The abil- agents.34 ity of the immunomodulatory drugs (IMiDs) thalidomide, Thalidomide has also been combined with conventional

Table 1. Selected thalidomide combinations in relapsed or refractory MM.

Author/year N. Regimen Overall response rate CR/nCR rate Median PFS Median OS (%) (%) (mos) (mos) Kropff 200335 60 Hyper CDT 72 11.0 (EFS) 19.0 Garcia-Sanz 200436 71 TCD 57 Offidan 200638 50 T/PLD/D 76 22.0 NYR Palumbo 200637 24 MPT 42 9.0 14.0

T: thalidomide; C: cyclophosphamide; D: dexamethasone; PLD: pegylated liposomal doxorubicin; P: prednisone; M: melphalan; CR: complete remission; nCR: near CR; PFS: progression-free survival; OS: overall sur- vival; EFS: event-free survival; NYR: not yet reached; mos: months.

Table 2. Selected bortezomib combinations in relapsed or refractory MM.

Author/year N. Regimen Overall response rate CR/nCR rate Median PFS Median OS (%) (%) (mos) (mos) Pineda-Romané 200839 85 VTD 63 22 -- 22 Biehn 200740 22 V + PLD 63 36 9.3 (TTP) 38.3 Terpos 200541 60 VMPT 59 11 9.5 -- Reece 200842 13 V+C+P 85 54 >12 >12 T: thalidomide; C: cyclophosphamide; D: dexamethasone; PLD: pegylated liposomal doxorubicin; P: prednisone; M: melphalan; CR: complete remission; nCR: near CR; PFS: progression-free survival; OS: overall sur- vival; EFS: event-free survival; NYR: not yet reached; mos: months.

| 218 | Hematology Education: the education program for the annual congress of the European Hematology Association | 2013; 7(1) Stockholm, Sweden, June 13-16, 2013 cytotoxic drugs (Table 1)35-37 and ,38 as well results of the two trials were identical, with overall as with novel agents such as bortezomib,39 in response rates of 60% and 61% for lenalidomide + dexam- relapsed/refractory MM (Table 2).39-42 Combination thera- ethasone compared with 20% and 24% with high-dose py with thalidomide improves the overall response rate dexamethasone as a single agent. The median TTP was and CR rates inet several al., phase I-II studies. In a recent series approximately 11 months in both trials, while the OS with from Garderet the 3-drug combination of VTD was the combination had not yet been reached in the North superior to TD in the relapsed setting with a PFS of nearly American trial (MM-090) at the time of the last report;46 20 months (the longest reported in a phase III OS was 29.6 months in the European trial (MM-010).47 in relapsed myeloma) compared with 12 months for TD Moreover, the benefit of lenalidomide + dexamethasone alone. These data suggest that the combination of novel was apparent despite extensive crossover of patients from agents can be administered, and result in a very prolonged the dexamethasone arm to lenalidomide-based therapy. duration of remission, far superior to what is seen when The main toxicity of lenalidomide avoids some of the single agents are administered separately. While there was more common toxicities of thalidomide, such as somno- no difference in overall survival, there is a trend favoring lence, constipation and significant peripheral neuropathy. the group that received VTD salvage therapy.11 However, it is associated with an increased risk of VTE, Thalidomide combinations carry an increased risk of similar to thalidomide, and thromboprophylaxiset al is venous thromboembolism (VTE) that requires some form required.43,44 A retrospective analysis from Nooka . of prophylaxis. Individuals with a prior history of VTE sought to validate the IMWG guidelines for lenalidomide should be fully anti-coagulated, as should patients with thromboprophylaxis.48 In this series, all patients being other risk factors for the development of VTE. The use of treated with lenalidomide in the relapsed or refractory set- aspirin, low molecular weight heparin (LMWH) and war- ting were evaluated, and the incidence of VTE, with ASA farin have all been evaluated,43 and the International prophylaxis, was low. Among patients who did develop Myeloma Working Group has published guidelines based VTE, each of them had more than 1 risk factor suggesting on a risk assessment model, with LMWH for patients with that their VTE episode was predicted by the International more than one risk factor, while aspirin (ASA) can be con- Myeloma Working Group (IMWG) guidelines. sidered for those with lower risk profiles.44 In a random- Different to thalidomide, the most common adverse ized trial from Palumbo and colleagues, patients who were event associated with lenalidomide therapy is neutropenia receiving IMiD-based therapy (including thalidomide) and thrombocytopenia.46.47.49 though these events do not were randomized to receive either LMWH, warfarin, or typically limit the duration of therapy. If significant neu- ASA. In this trial, patients received bortezomib containing tropenia occurs, either the dose of lenalidomide can be regimens were used as a ‘low risk’ group for comparison. reduced, or intermittent dosing of granulocyte-colony There was no statistically significant difference in inci- stimulating factor (G-CSF) can be administered. In the dence in VTE among the 3 randomized arms, and all 3 experience reported at Princess Margaret Hospital, arms had a low incidence of VTE, supporting the equiva- Toronto, Canada, an average of four doses of G-CSF per lence and utility of ASA as a convenient oral antithrom- cycle is usually sufficient, and is typically given twice botic agent in this setting.45 weekly starting Day 15 of each cycle.50 Interestingly, at Lenalidomide least when used as initial therapy, more neutropenia was observed in patients given a low-dose weekly, rather than Lenalidomide is a 2nd generation immunomodulatory full-dose pulse dexamethasone.51 agent that is more potent than thalidomide, and has a very Lenalidomide combinations have also been studied, different safety profile. Similar to thalidomide, the effica- mostly in phase I and II studies, but have also documented cy of lenalidomide can be significantly enhanced through improved overall and depth of response when combina- the co-administration of steroids. The primary registration tions are used. These include combinations with doxoru- trials for lenalidomide in the relapsed setting were the bicin or pegylated liposomal doxorubicin52,53 and MM-009 and MM-010 trials. The dose of lenalidomide cyclophosphamide54 (Table 3). Lenalidomide + borte- administered was 25 mg Days 1-21 of a 28-day schedule, zomib +/- dexamethasone has shown especially encourag- with pulse dexamethasone given Days 1-4, 9-12 and 17-20 ing activity and excellent tolerability in this context.56 The for the first 4 cycles; subsequently, the dose of dexametha- maximum tolerated doses of this regimen were borte- sone was decreased to only Days 1-4 per cycle.46,47 The zomib 1.0 mg/m2 on Days 1, 4, 8 and 11 and lenalidomide

Table 3. Selected lenalidomide combinations in relapsed or refractory MM.

Author/year N. Regimen Overall response rate CR/nCR rate Median PFS Median OS (%) (%) (mos) (mos) Knop 200953 66 LDoD 73 15 8 88% (1year) Reece 200954 15 LCP 74 45 (VGPR) -- -- Baz 200652 52 L/PLD/Vi/D 75 29 (nCR) 61% (1year) 84% (1year) Anderson 200955 62 LVD Ph II 69 26 12 29 CR: complete remission; nCR: near CR; TTP: time to progression; OS: overall survival; L: lenalidomide; Do: doxorubicin; D: dexamethasone; C: cyclophosphamide; P: prednisone; PLD: pegylated liposomal doxorubicin; Vi: vincristine; V: bortezomib; VGPR: very good partial remission; Ph: phase; mos: months.

Hematology Education: the education program for the annual congress of the European Hematology Association | 2013; 7(1) | 219 | 18th Congress of the European Hematology Association

15 mg on Days 1-14 of a 21-day cycle with an overall These combinations generally produce high overall response rate (ORR) of 60% and an encouraging median response rates, in the range of 50%-80%, with encourag- OS of 37 months. This combination has been evaluated ing duration of response and OS. The best example of with dexamethasone 20 mg on the day of and the day after bortezomib + chemotherapy in the relapsed setting is the bortezomib for the first 4 cycles and 10 mg on the same trial comparing bortezomib alone with bortezomib + pegy- days after cycle 4, with the phase II trial of this regimen lated liposomal doxorubicin. This trial demonstratedvs. the reporting at least a partial remission (PR) in 54%, includ- superiority of the combination in terms of TTP (9.3 6.5 ing near CR in 6%, very good PR (>90% reduction in months), and also overall survival.71 serum monoclonal protein) in 30%, and minimal response 55 (MR) in 18%. New agents Bortezomib HDAC inhibitors Bortezomib is a with potent anti- myeloma activity as a single agent.57-59 The randomized Histone deactylase inhibitors are known to be effective APEX trial demonstrated the superiority of bortezomib on targets in several cancers and are thought to work primari- Days 1, 4, 8 and 11 of a 21-day cycle over pulse dexam- ly through epigenetic modification of gene expression. In ethasone in MM patients with relapsed/refractory disease the context of plasma cell disorders, the potential mecha- who had early relapse (1-3 prior lines of therapy). The nism is thought to be related to the effects of HDAC overall response rate was 38% with a median time to pro- inhibitors on HDAC 6, which is critical to the function of gression (TTP) of 6.2 months, compared with only 18% an alternative pathway of protein catabolism, the aggre- and 3.5 months with high-dose dexamethasone.60 Further some/autophagy pathway.72 Inhibition of proteasome follow up yielded a response rate of 43% with bortezomib,versus function results in activation of the alternative pathway, and a longer median overall survival of 29.8 23.7 the aggresome pathway, and protein catabolism occurs via months for the high-dose dexamethasone-treated patients. this. The combination of proteasome inhibition and This improvement in OS occurred despite the fact that HDAC 6 inhibition (accomplished using HDAC over 60% of patients in the dexamethasone arm were inhibitors, or tipifarnib73) results in pre-clinical synergy allowed to cross-over to receive bortezomib.61 Among a that has been demonstrated clinically. Preliminary data subset of patients treated in first relapse, the ORR for the from phase I studies combining with borte- bortezomib group was 51%.61 zomib demonstrated responses particularly among the In the initial phase II studies, dexamethasone, was patients who were defined as bortezomib resistant, with an added for a suboptimal response or progression, with a overall response rate of 30%.74,75 When this was tested in resultant improvement in the degree of response in 18%- large phase II randomized trials, the use of vorinostat with 39% of patients.62 Two smaller single arm phase II trials in bortezomib was found to be no different from bortezomib relapsed and refractory patients have described the use of alone in terms of progression-free and overall survival, but bortezomib +/- dexamethasone from the onset of therapy, there was significant toxicity associated with vorinostat with overall response rates ranging from 54%-74%, with a administration at the dose and schedule used for the study CR rate of 7% in both.63,64 that likely limited the ultimate durability of what was The toxicity profile of bortezomib has been well-charac- noted to be a higher overall response rate.76,77 In a similar terized, and includes nausea, diarrhea, cyclic reversible series of clinical trials, panobinostat (LBH589) was also thrombocytopenia, and peripheral neuropathy.57-60,65 tested alone and in combination with bortezomib.78,79 Peripheral neuropathy occurs in approximately one-third While the single agent activity was limited, the activity in of patients, and can be painful; however, with early inter- phase I and II studies combining panobinostat with borte- vention this can be reversible. Dose modification or dis- zomib demonstrated encouraging response rates with what continuation of bortezomib is required for moderate or appears to be an improved safety profile when compared severe neuropathy, especially if associated with pain; the with vorinostat. The results of the randomized phase III neuropathy usually improves or resolves in a high propor- Panorama 1 study are currentlyversus pending; this is testing tion of affected individuals, although often over several bortezomib/dexamethasone panobinostat/borte- months.66 The use of subcutaneous and/or weekly dosing zomib/dexamethasone in an early relapsed myeloma has changed the intensity and severity of bortezomib- patient population, and should shed some light on the true induced PN. When used in combinations, weekly therapy efficacy of this approach in relapsed myeloma. results in a much lower incidence of grade 3/4 PN and also Antibodies overall incidence of PN. In a randomized trial comparing intravenous (iv) and subcutaneous (sq) dosing of borte- The effects of thalidomide and lenalidomide on immune zomib in the relapsed disease setting, the overall response function have been demonstrated in a number of animal rate, time to progression (TTP) and OS were similar and pre-clinical models, and include enhancement of NK between each dosing method with a significant reduction cell function, CD8+ T-cell activation, and increased secre- in severity and overall incidence of PN. These data have tion of IL2 and interferon-g.23,80,81 Data with antibodies led to a wholesale change in the route of administration of directed against plasma cell and B-cell antigens such as bortezomib with a resultant improvement in related toxic- CD40 and CS1 were evaluated in pre-clinical models with ity.67,68 lenalidomide and demonstrated significant synergy.82,83 Bortezomib is an attractive agent to use in combination Experience with the potent CS1 antibody elotuzumab with other drugs and can safely be used in the setting of (known as Huluc63) demonstrates that this target is rela- renal insufficiency.69,70 Many bortezomib combinations tively plasma cell specific, and that the functional activity have been evaluated in phase I-II trials (Table 2).39-42 of the CS1 antibody requires NK cells to be present for

| 220 | Hematology Education: the education program for the annual congress of the European Hematology Association | 2013; 7(1) Stockholm, Sweden, June 13-16, 2013 activity.84,85 A phase I/II study was designed to test the relapsed myeloma. Additional data are needed to under- clinical efficacy of this approach combining lenalidomide stand more fully the extent of response in relapsed and with elotuzumab (HuLuc63) and low-dose dexametha- refractory myeloma. 86 sone. In the phase I portion of the trial, patients received Carfilzomib up to 20 mg/kg without experiencing DLT. The ORR for the phase I study was 82% with 95% of lenalidomide Carfilzomib is a 2nd generation proteasome inhibitor that naïve patients achieving PR or better.86 In a more recent has been studied in a number of different clinical settings, phase II expansion of this study in which patients were and was recently approved for use by the FDA in the setting randomized to receive either 10 or 20 mg/kg of elotu- of relapsed myeloma. The approval was based in part on zomab in combination with lenalidomide and low-dose clinical experience from several phase II studies evaluating dexamethasone, a recent update of the data suggests not the efficacy of carfilzomib in relapsed myeloma (Table 4).89- only does the high response rate hold up, but that the dura- 94 Two phase II clinical studies evaluated carfilzomib in tion of response is very long as well. With a median follow MM patients, the 003-A0 trial (n=46) in relapsed and 89 up of nearly 21 months, the median PFS was 18 monthsversus refractory MM and 004 trial (n=129) in an earlier relapsed for the group that received 20 mg/kg of elotuzomab myeloma patient population.90 In both studies, patients ‘still not reached’ for the group that received 10 mg/kg.87 received carfilzomib 20 mg/m2 iv on Days 1, 2, 8, 9, 15 and When compared with historical cohorts of patients who 16 every 28 days for up to 12 cycles. The most common were treated with lenalidomide and high-dose dexametha- AEs were fatigue, anemia, thrombocytopenia, nausea, sone, there is the suggestion that the addition of elotu- upper respiratory infections, increased creatinine, and diar- zomab enhanced the ORR and PFS in the context of rhea. PN occurred in fewer than 10% of patients with 1 relapsed myeloma. Follow up from the randomized phase grade 3 in a patient with pre-existing grade 2 PN. The treat- III study (Eloquent 2) is clearly needed to better under- ment-emergent PN rate was low with grade 3/4 2.2%, stand the clinical benefit for patients in the relapsed dis- despite the fact that 78% of patients had grade 1/2 PN at ease setting, but trends to date are very exciting. enrollment. The response rate in 003-A0 was 18% PR, 7% While there are several other exciting antibody targets in MR, and 41% stable disease (SD) in this cohort of refracto- myeloma with early data (including CD138, CD56, anti- ry patients. Subsequently, a ‘stepped-up’ dosing schedule BAFF, and anti-DKK-1), the antibody which does appear incorporated a higher dose of 20/27 mg/m2 in order to max- to provide very early and exciting response data is the imize the clinical benefit of carfilzomib. Additional patients anti-CD38 antibody daratumomab.88 This was initially were enrolled to a ‘stepped-up’ dosing in the 003-A1 study presented in 2012 in the context of a phase 1 single agent and received 20 mg/m2 for the first cycle and 27 mg/m2 study; an encouraging overall response rate and complete thereafter.91 In the 003-A1 study, in which the increased remission rate was noted, suggesting that this may be the dose was used in a refractory myeloma population, a total first antibody with single agent activity in the context of of 266 patients were enrolled and 257 were response-evalu-

Table 4. Carfilzomib trials.

Trials Type/disease N Dose and schedule Results Serious adverse event (every 28 days) PX-171-002 Phase I 37 1.2-27 mg/m2 on Days 1,2, 8,9,15,16 PR 11% (MM) MR 3% (MM) Hypoxia, thrombocytopenia; Alsina, et al.94 (hematologic SD 16% (6% MM; 10% NHL) elevated creatinine malignancies) PX-171-003-A0 Phase II 46 CFZ: 20 mg/m2 on Days 1,2,8,9,15,16 >PR 18%; MR 26%; 5.1 Anemia, thrombocytopenia Jagannath, et al.89 (R/R myeloma) SD 41% median TTP neutropenia, fatigue, mos; median DOR 7.4 mos URTI; dyspnea

PX-171-003-A1 Phase IIb 257 CFZ: Days 1,2,8,9,15,16 >PR 24%; median DOR-7.4 mos Anemia, Siegel, et al.91 (R/R myeloma) (20 mg/m2 cohort 1; >PR in pts with CTG abnormalities: 28%; thrombocytopenia 27 mg/m2 cohort 2-12) median DOR-7.0m; median OS 15.5m neutropenia PX-171-004 Phase II 129 Cohort 1: 20/20 mg/m2 Cohort 1:ORR 42%; CR 3%; VGPR 14%. Anemia, thrombocytopenia Vij, et al.90 (R or R myeloma; Cohort 2 : 20/27 mg/m2 Cohort 2: ORR 52%; CR 2%; VGPR 27% neutropenia, pneumonia, bortezomib naïve) fatigue, dyspnea PX-171-005 Phase II 39 CFZ: 15/20 mg/m2 escalation CBR 37% (PR 23%; MR 14%); SD 37% Fatigue, anemia, diarrhea, Badros, et al.92 (R/R myeloma with to 27 mg/m2 nausea, thrombocytopenia, renal impairment) on Days 1,2,8,9,15,16 constipation PX-171-006 Phase Ib/II 52 CFZ: 20/27 mg/m2 on Days 1,2,8,9, 15, 16; ORR 78% (PR 38%; VGPR 22%, Neutropenia, anemia Wang, et al.93 (R/R myeloma) L 25 mg Days 1-21; D 40 mg Days 1,8,15,22 CR/sCR 18%) thrombocytopenia

CFZ: carfilzomib; L: lenalidomide D: dexamethasone; PR: partial response; MR: minimal response; SD: stable disease; TTP: time to progression; DOR: duration of response; CR: complete response; nCR: near CR; sCR: stringent complete response; OS: overall survival; ORR: overall response rate; VGPR: very good partial response; CBR: clinical benefit response; MM: multiple myeloma; NHL: non-Hodgkin’s lymphoma; CTG: clini- cal trials group; URTI: upper respiratory tract infection; mos: months.

Hematology Education: the education program for the annual congress of the European Hematology Association | 2013; 7(1) | 221 | 18th Congress of the European Hematology Association able. ORR was 24% with median duration of response of Patients were enrolled on the basis of base-line renal func- 7.4 months. The most common treatment-related AEs were tion broken down into normal (CrCl 80 mL/min), mild predominately hematologic events with a very low inci- (50-79), moderate (30-49), and severe (<30) renal func- dence of neuropathy. tion. Patients received iv carfilzomib at a dose of 15 As a consequence of the higher response rate seen with mg/m2 on Days 1, 2, 8, 9, 15 and 16 every 28 days for the ‘stepped-up’ dosing in the 003 trial, the 004 trial was cycle 1, escalating to 20 mg/m2 in cycle 2 and to 27 mg/m2 also modified to increase the dose and assess responses.90 in cycle 3. Grade 3/4 AEs include anemia, thrombocytope- A subsequent cohort of patients were treated with nia, fatigue, increased creatinine, and mental status ‘stepped-up’ dosing with 20 mg/m2 for the first cycle and changes. Dose adjustments were not required suggesting 27 mg/m2 thereafter in cohort 2 (n=70). The study includ- manageable toxicity in renal failure patients. ed patients who were naïve to bortezomib treatment Finally, as single agent activity was defined, combina- (n=129) and patients who had received prior bortezomib tion therapy represented the next step. In this process, one (n=35). The subset of patients who were bortezomib-treat- of the first combinations to be used was the phase I/II trial ed patients had an ORR of 18%. The overall response rate combining carfilzomib with lenalidomide and dexametha- for cohorts 1 and 2 were ORR 42% and 52%, with VGPR sone.93 Dosing consisted of carfilzomib 20 mg/m2 on Days rates of 17% and 29% or over, and CR rates of 3% and 2%, 1-2 of cycle 1; 27 mg/m2 thereafter is administered on respectively. The median PFS was 8.3 months for all Days 1, 2, 8, 9, 15 and 16, oral (PO) lenalidomide 25 mg patients, and the most common grade 3/4 toxicities were Days 1-21, and 40 mg dexamethasone PO (Days 1, 8, 15, lymphopenia 14% and 19%, anemia 12% and 17%, throm- 22) in a 28-day cycle. Among the 52 patients enrolled, no bocytopenia 15% and 11%, neutropenia 12% and 14%, DLTs were reported and 11.5% of patients had serious AEs pneumonia 14% and 11%, fatigue 12% and 1%, and dys- (6 of 52). Hematologic AEs, including grade 3/4 neutrope- pnea 5% and 6%, respectively. Interestingly, grade 1/2 PN nia (n=12), anemia (n=8), and thrombocytopenia (n=8), was seen in only 14% and 19% patients and grade 3/4 in were manageable. The ORR was 78% (Cr/sCR 18%, only 2% and 0%, respectively. VGPR 22%, PR 38%, MR 2%, SD 8%) and toxicities with An additional area of exploration for carfilzomib was prolonged administration of this regimen were manage- the efficacy and safety in the context of renal dysfunction. able (14-23 months). This trial was used as the basis for Badros and colleagues performed a phase II trial to assess the recently completed phase III ASPIRE trial in which the safety and efficacy of carfilzomib in relapsed myeloma patients were randomized to receiveversus either CRd (carfil- patients with varying degrees of renal insufficiency.92 zomib/lenalidomide/dexamethasone) Rd (lenalido-

Table 5. Pomalidomide trials.

Trials Type/disease N Dose and schedule (every 28 days) Median prior therapy Overall response, ≥PR Schey95 Phase I 24 POM 1,2,5,10 mg 3 (1-6) 54% Days 1-28 q 28 Richardson96 Phase I 38 POM 2,3,4,5 mg 6 (2-17) 25% Days 1-21 q 28 D 40 mg weekly Richardson97 Phase II 221 POM 4 mg 5 (2-13) 13% Days 1-21 q 28 POM 4mg + Days 40 mg/wk 34% Days 1-21 q 28 Leleu98 Phase II 84 POM 4 mg + D 40 mg/wk 5 (1-13) 35% Days 1-28 q 28 POM 4 mg + D 40 mg/wk 34% Days 1-21 q 28 Lacy99 Phase II 35 POM 4mg + D 40 mg/wk 6 29% Days 1-28 q 28 Shah103 Phase I 30 POM 4mg + D 40 mg/wk 6 (1-15) 50% Days 1-28 q 28 CFZ escalating dose Richardson101 Phase I 15 POM 1-4 mg Days 1-14 q 21 2 (1-4) 73% D 20 mg day of and after V V 1-1.3 mg/m2 Days 1,4,8,11 Palumbo102 Phase 1 55 POM 1-2.5 mg continuous 3 (1-3) 51% P 50 mg qod C 50 mg qod PR: partial response; POM: pomalidomide; D: dexamethasone; CFZ: carfilzomib; V: bortezomib; P: prednisone; C: cyclophosphamide;

| 222 | Hematology Education: the education program for the annual congress of the European Hematology Association | 2013; 7(1) Stockholm, Sweden, June 13-16, 2013 mide/dexamethasone) in the setting of relapsed myeloma. develop more and more resistant disease, the sensitivity to Results are currently not available from the trial but any agent begins to decline. This supports the use of com- enrollment has been completed. bination therapy in the context of initial diagnosis, and this Pomalidomide is now also being tested in the relapsed setting. In the bal- ance is the concept that sequential therapy may be associ- Pomalidomide is the newest of the immunomodulatory ated with less toxicity than is seen with combination ther- class of agents that is now being evaluated in larger phase apy, and since few (if any) of these patients are cured of clinical trials. Data initially presented by Schey and col- their disease, whether to treat a patient with single agents leagues demonstrated favorable tolerability and activity of in sequence rather than combinations is an area of active this agent in myeloma patients with early relapse (Table study and ongoing debate. It is also clear that there are 95-102 5). Trials initially from the Mayo Clinic group demon- many new tools to use at our disposal and many more will strated a good overall response rate in the context of be developed. As such, the use of genomics and whole relapsed myeloma, and this has now been tested in a num- genome sequencing will be critically important as we seek 103,104 ber of different dosages and schedules. It appears to tailor therapy to a given patient’s disease, and to maxi- that, across the board, the response rate among patients mize duration of response while minimizing treatment- with lenalidomide-resistant disease using pomalidomide related toxicity. and dexamethasone is 30%. This was seen in trials from the US99,105 as well as in Europe.98 In recently reported data from a European study comparing pomalidomide/dexam- ethasone with high-dose dexamethasone alone among References refractory myeloma patients, not only was the overall response rate and progression-free survival superior for pomalidomide/dexamethasone, the overall survival also 1. Kyle RA, Rajkumar SV. Multiple myeloma. N Engl J Med. favored the use of pomalidomide/dexamethasone.106 Trials 2004;351:1860-73. 2. Harousseau JL, Shaughnessy J Jr, Richardson P. Multiple have varied the starting dose of pomalidomidevs (2-4 mg) as myeloma. 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Determine the Maximum Tolerated Dose, Safety, and Efficacy 2012;120:727. of Pomalidomide Alone or In Combination with Low-Dose 102. Palumbo A, Larocca A, Montefusco V, et al. Pomalidomide Dexamethasone In Patients with Relapsed and Refractory Cyclophosphamide and Prednisone (PCP) Treatment for Multiple Myeloma Who Have Received Prior Treatment That Relapsed/Refractory Multiple Myeloma. ASH Annual Includes Lenalidomide and Bortezomib. ASH Annual Meeting Meeting Abstracts. 2012;120:446. Abstracts. 2010;116:864. 103. Lacy MQ, Gertz MA, Hayman SR, et al. Pomalidomide 97. Richardson PG, Siegel DS, Vij R, et al. Randomized, Open (CC4047) Plus Low Dose Dexamethasone (Pom/dex) Is Label Phase 1/2 Study of Pomalidomide (POM) Alone or in Active and Well Tolerated in Lenalidomide Refractory Combination with Low-Dose Dexamethasone (LoDex) in Multiple Myeloma (MM). ASH Annual Meeting Abstracts. Patients (Pts) with Relapsed and Refractory Multiple 2009;114:429. Myeloma Who Have Received Prior Treatment That Includes 104. Richardson P, Siegel D, Baz R, et al. A Phase 1/2 Multi- Lenalidomide (LEN) and Bortezomib (BORT): Phase 2 Center, Randomized, Open Label Dose Escalation Study to Results. ASH Annual Meeting Abstracts. 2011;118:634. Determine the Maximum Tolerated Dose, Safety, and Efficacy 98. Leleu X, Attal M, Arnulf B, et al. High Response Rates to of Pomalidomide Alone or in Combination with Low-Dose Pomalidomide and Dexamethasone in Patients with Dexamethasone in Patients with Relapsed and Refractory Refractory Myeloma, Final Analysis of IFM 2009-02. ASH Annual Meeting Abstracts. 2011;118:812. Multiple Myeloma Who Have Received Prior Treatment That 99. Lacy MQ, Kumar SK, LaPlant BR, et al. Pomalidomide Plus Includes Lenalidomide and Bortezomib. ASH Annual Meeting Low-Dose Dexamethasone (Pom/Dex) in Relapsed Myeloma: Abstracts. 2009;114:301. Long Term Follow up and Factors Predicing Outcome in 345 105. Jagannath S, Hofmeister CC, Siegel DS, et al. Pomalidomide Patients. ASH Annual Meeting Abstracts. 2012;120:201. (POM) with Low-Dose Dexamethasone (LoDex) in Patients 100. Shah JJ, Stadtmauer EA, Abonour R, et al. A Multi-Center (Pts) with Relapsed and Refractory Multiple Myeloma Who Phase I/II Trial of Carfilzomib and Pomalidomide with Have Received Prior Therapy with Lenalidomide (LEN) and Dexamethasone (Car-Pom-d) in Patients with Bortezomib (BORT): Updated Phase 2 Results and Age Relapsed/Refractory Multiple Myeloma. ASH Annual Subgroup Analysis. ASH Annual Meeting Abstracts. Meeting Abstracts. 2012;120:74. 2012;120:450. 101. Richardson PG, Hofmeister CC, Siegel D, et al. MM-005: A 106. Dimopoulos MA, Lacy MQ, Moreau P, et al. Pomalidomide in Phase 1, Multicenter, Open-Label, Dose-Escalation Study to Combination with Low-Dose Dexamethasone: Demonstrates Determine the Maximum Tolerated Dose for the Combination a Significant Progression Free Survival and Overall Survival of Pomalidomide, Bortezomib, and Low-Dose Advantage, in Relapsed/Refractory MM: A Phase 3, Dexamethasone in Subjects with Relapsed or Refractory Multicenter, Randomized, Open-Label Study. ASH Annual Multiple Myeloma. ASH Annual Meeting Abstracts. Meeting Abstracts. 2012;120:LBA-6.

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