Focus on the Treatment of Multiple Myeloma

Transcription

1 Focus on the Treatment of Multiple Myeloma PRINTER-FRIENDLY VERSION AT CLINICALONCOLOGY.COM SHAJI KUMAR, MD Associate Professor of Medicine Division of Hematology Mayo Clinic Rochester, Minnesota S. VINCENT RAJKUMAR, MD Professor of Medicine Division of Hematology Mayo Clinic Rochester, Minnesota KENNETH C. ANDERSON, MD Kraft Family Professor of Medicine Harvard Medical School Jerome Lipper Myeloma Center Dana-Farber Cancer Institute Boston, Massachusetts Multiple myeloma (MM) is the second most common hematologic malignancy, affecting more than 20,000 patients each year and contributing to more than 10,000 deaths. The disease remains incurable with current treatment approaches. The treatment of MM has undergone a significant change over the past decade, primarily due to the introduction of effective novel agents. In addition, a better understanding of the genetic heterogeneity in this disease has allowed investigators to begin developing risk-adapted therapies. As a result of these recent advances, survival rates for patients with MM have improved. This review summarizes recent findings from clinical trials of novel agents used to treat MM and also outlines a recommended treatment approach. CLINICAL ONCOLOGY NEWS SEPTEMBER/OCTOBER

2 Newly Diagnosed Myeloma Once a patient has been diagnosed with MM and the decision to initiate treatment has been made, clinicians should make every effort to enroll patients in clinical trials. For those not enrolled in a clinical trial, the first critical step is to determine whether the patient is eligible for autologous stem cell transplant (ASCT) and is willing to undergo the procedure trial (Figure). 1 Traditionally, eligibility has been based on age, reflecting the results of randomized clinical trials (RCTs); however, existing data support the use of ASCT in selected older patients. 2 Thus, the decision to undergo ASCT must be based on the patient s physiologic age and preferences. The criteria used for assessing response to treatment and likelihood for relapse after successful therapy has been revised to incorporate recent advances, such as the free light chain assay (Table 1). 3 INITIAL TREATMENT If the patient is considered a potential candidate for ASCT, initial therapy is aimed at maximizing disease control with the least toxicity. Traditionally, this has included 4 to 6 months of treatment with one or more commonly used regimens, followed by stem cell collection and high-dose therapy. 4-7 The long-term impact of initial therapy on the outcome of ASCT remains undefined, with individuals refractory to initial therapy obtaining as much benefit from ASCT as those who have responded to the initial regimen. 8 In this scenario, the 5 important attributes for initial therapy are as follows: 1. effectively controlling disease and minimizing early mortality, thereby providing the maximum possibility of reaching an ASCT; 2. minimizing possible toxicity; 3. administering therapy with the least negative impact on quality of life; 4. minimizing the impact on the ability to collect stem cells; and 5. continuing therapy with minimal modification given the lack of a survival advantage for early ASCT if a decision is made to delay ASCT. The introduction of newer agents has shifted the initial approach from the traditional regimens of singleagent dexamethasone or a combination of vincristine, doxorubicin, and dexamethasone (VAD) to 1 of 3 regimens: the combination of the thalidomide analogue lenalidomide (Revlimid, Celgene) and low-dose dexamethasone; thalidomide and dexamethasone (TD); or bortezomib (Velcade, Millennium Pharmaceuticals) and dexamethasone. Various clinical trials in patients newly diagnosed with MM provide support for this approach. In 2 Phase III trials, TD compared with dexamethasone alone was associated with increased response rates and longer time to progression (TTP), but toxicities, especially thrombotic events, were higher with the combination. 6,9 The combination also has been compared with the VAD regimen and has been found to have a superior response rate. 10 Several trials also examined the addition of thalidomide to chemotherapy regimens demonstrating attainment of deeper responses, at least prior to SCT. Lenalidomide in combination with dexamethasone was studied in Phase II and III trials, and long-term follow-up demonstrates a 2-year survival rate greater than 90%. In comparison with dexamethasone alone, the combination imparts a higher response rate and longer progression-free survival (PFS). Another Phase III trial compared lenalidomide and high-dose (standard) dexamethasone with lenalidomide and low-dose (weekly) dexamethasone. This study demonstrated improved survival, despite a lower response rate, for patients treated with lowerdose dexamethasone, effectively eliminating highdose dexamethasone treatment from the setting of newly diagnosed disease. 11 Lenalidomide has been studied in combination with alkylators or anthracyclines, as well as other novel agents, in multiple Phase I and II studies The combination of bortezomib and dexamethasone has been examined in the setting of newly diagnosed MM in several clinical trials, with high response rates and excellent safety. 16 This combination has been compared with VAD as induction therapy prior to SCT in a Phase III trial, with deeper responses and reduced need for tandem ASCT, as well as improved PFS after SCT. 17 The exciting results seen with the novel agents raised the question of whether these agents in combination can further enhance the up-front treatment of myeloma. The combination of bortezomib, thalidomide, and dexamethasone (VTD) was compared with TD in a Phase III trial. VTD resulted in significantly higher response rates and deeper responses, which translated into an improved PFS following SCT. 18 Subsequently, lenalidomide has been combined with bortezomib and dexamethasone (VRD), resulting in a 100% response rate with very good partial response (VGPR) or better in nearly two-thirds of the patients. 19 To maximize the initial treatment, the EVOLUTION (Evaluation of VELCADE, dexamethasone, and Lenalidomide with or without cyclophosphamide Using Targeted Innovative ONcology strategies in the treatment of front-line multiple myeloma) trial added cyclophosphamide to the VRD combination and reported a 100% response rate with high 2

3 Transplant-Ineligible Transplant-Eligible MPT or MPV x 12 cycles Induction Therapy a Lenalidomide-Low-dose Dexamethasone Bortezomib-Dexamethasone Thalidomide-Dexamethasone Collect stem cells after 4 cycles of induction Option 1 Autologous stem cell transplant Option 2 Continue induction therapy Second transplant or maintenance thalidomide if not in complete response or very good partial response after first transplant Continue until maximum response or indefinite based on adverse effects Figure. Approach to patient with newly diagnosed MM. a Bortezomib-containing regimens preferred in patients with high-risk myeloma based on adverse cytogenetics, and in patients with renal failure. Combination regimens such as VRD and VTD may be considered outside a clinical trial in patients in whom rapid response is required due to disease-related complications or aggressive disease. MM, multiple myeloma; MPT, melphalan-prednisone-thalidomide; MPV, melphalan-prednisone-bortezomib; VRD, bortezomib-dexamethasone-lenalidomide; VTD, bortezomib-dexamethasone-thalidomide Based on reference 1. 3

4 VGPR rates after a median of 4 cycles of therapy. 20 Similarly, liposomal doxorubicin has been added to the VRD combination in the setting of newly diagnosed myeloma. 21 The overall response rate (ORR) was 97%, including 62% VGPRs. The long-term impact of these highly active regimens is not clear and longer follow-up will be required to delineate their effect on the natural history of the disease. ROLE OF ASCT Several RCTs have indicated that ASCT improves the outcome of patients with MM, whereas others have suggested no benefit for ASCT, especially in patients responsive to initial therapy In the IFM94 and Myeloma VII trials, previously untreated patients younger than age 65, were randomly assigned to receive either conventional chemotherapy (CCT) or ASCT. Patients receiving ASCT had a superior response rate, event-free survival (EFS), and overall survival (OS) compared with those receiving CCT. 22,23 In contrast, MAG91 demonstrated improved EFS and time without symptoms, treatment, and toxicity (TWiSTT) with ASCT, but no improvement in OS, in patients younger than age Similarly, the Intergroup study S9321 showed that patients with untreated MM randomly assigned to either ASCT or CCT, with further randomization of responding patients to interferon maintenance or no maintenance, did not reveal any OS benefit. 26 The Spanish cooperative group PETHEMA conducted a randomized trial comparing ASCT with CCT in patients who responded to initial therapy and demonstrated higher complete response (CR) rates with ASCT but no differences in PFS or OS. 24 In the MAG90 trial, patients were randomly assigned to receive ASCT after 3 to 4 cycles of initial therapy, or to continue CCT, with ASCT done at time of first relapse or if the patient became refractory to initial therapy. 27 Although the OS was similar in this study, TWiSTT was significantly better for the early ASCT group. SCT in MM involves collection of peripheral blood stem cells, using either granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor alone or following initial priming with cyclophosphamide, and collection during recovery. Purging of tumor cells from the stem cell collection, using various selection methods, has not translated into any improvement, likely reflecting the disease biology and the inability of the conditioning therapy to completely eradicate the tumor clone. The most widely used conditioning regimen is that of melphalan 200 mg/m 2, based on results of the IFM95-02 trial, in which patients were randomly assigned to receive either 8 Gy total body irradiation (TBI) plus 140 mg/m 2 melphalan, or 200 mg/m 2 melphalan alone. 28 Patients receiving only melphalan had a faster recovery of neutrophils and platelets, and milder mucositis, without any effect on EFS or OS. Ongoing trials are attempting to improve melphalan conditioning by increasing the melphalan dose (alone or in combination with cytoprotectants such as amifostine), adding skeletal targeted radioisotopes such as samarium or holmium, using skeletal targeted TBI, or adding novel agents such as bortezomib. The role of ASCT in the treatment of MM continues to evolve in the era of novel agents. The high response rates seen with the new combination regimens incorporating novel agents have brought the role of SCT into question once again. Recent studies have shown that even with the high response rates obtained with the novel agent combinations, SCT provides additional tumor reduction. Whether this can be replaced by additional cycles of novel agent combinations remains to be studied. However, MM remains an incurable disease and in the absence of randomized trials demonstrating lack of benefit with SCT, it still should be considered a part of the therapeutic armamentarium for MM. Ongoing trials are examining the best way to integrate these treatment modalities to provide maximum benefit to patients. ROLE OF SECOND ASCT The concept of a second transplant was introduced to examine if further consolidation can be achieved with additional cycles of ASCT. Three RCTs have assigned previously untreated patients to a single or double transplant. The IFM94 trial showed a slight improvement in the combined CR and VGPR rate with double transplant (50% vs 42%), but at 7 years, EFS (20% vs 10%) and OS (42% vs 21%) doubled with the second ASCT. 29 The benefit of a second transplant was, for the most part, restricted to individuals failing to achieve a VGPR after first transplant (OS at 7 years of 43%, vs 11%). This is particularly relevant, given that a significant proportion of patients undergoing induction therapy with novel agents achieve a VGPR state after the initial ASCT, thus negating the need for a second ASCT. In the Bologna 96 trial, the addition of a second ASCT prolonged EFS by 12 months and TTP by 17 months, with a projected OS at 6 years of 44% for single transplant and 63% for double transplant. 30 Again, patients who failed to achieve a CR or VGPR after the first ASCT obtained the maximum benefit from the second cycle of ASCT. In the MAG95 clinical trial, patients were randomly assigned to receive single or double ASCTs and then further randomized 4

5 Table 1. Response Criteria for MM Response Subcategory CR Response Criteria Negative immunofixation on the serum and urine and Disappearance of any soft tissue plasmacytomas and <5% plasma cells in bone marrow Stringent CR (CR as above plus) Normal FLC ratio and Absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescence VGPR PR Serum and urine M-component detectable by immunofixation but not on electrophoresis or 90% reduction in serum M-component plus urine M-component <100 mg/24 h 50% reduction of serum M-protein and reduction in 24-h urinary M-protein by 90% or to <200 mg per 24 h If the serum and urine M-protein are unmeasurable, a 50% decrease in the difference between involved and uninvolved FLC levels is required in place of the M-protein criteria If serum and urine M-protein are unmeasurable, and serum FLC assay is also unmeasurable, 50% reduction in bone marrow plasma cells is required in place of M-protein, provided baseline percentage was 30% In addition to the above criteria, if present at baseline, 50% reduction in the size of soft tissue plasmacytomas is also required SD PD Not meeting criteria for CR, VGPR, PR, or PD Increase of 25% from baseline in: Serum M-component (absolute increase must be 0.5 g/dl) and/or Urine M-component (absolute increase must be 200 mg/24 h) and/or Only in patients without measurable serum and urine M-protein levels: the difference between involved and uninvolved FLC levels (absolute increase must be >10 mg/dl) Bone marrow plasma cell percentage (absolute % must be 10%) Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas Development of hypercalcemia (corrected serum calcium >11.5 mg/dl) that can be attributed solely to the plasma cell proliferative disorder Relapse from CR Reappearance of serum or urine M-protein by immunofixation or electrophoresis or Development of 5% plasma cells in the bone marrow or Appearance of any other sign of progression (ie, new plasmacytoma, lytic bone lesion, or hypercalcemia) CR, complete response; FLC, free light chain; MM, multiple myeloma; PD, progressive disease; PR, partial response; SD, stable disease; VGPR, very good partial response Based on reference 3. 5

6 to selected or unselected CD34-positive cells. 31 The study again confirmed an OS advantage for this approach. However, the proportion of patients not achieving VGPR with the first SCT has decreased considerably in the current era, given the high response rates with novel agents prior to the SCT. As a result, it is not clear how beneficial a second SCT is in the era of effective novel agents. MAINTENANCE THERAPY AFTER ASCT ASCT clearly improves response rates in patients with newly diagnosed MM compared with conventional therapy, but patients invariably relapse. Various trials have attempted to maintain the ASCT response through maintenance approaches. A small RCT of interferon alfa 3 x 106 units/m 2 subcutaneously 3 times weekly following initial ASCT suggested a modest improvement in EFS. 32 In IFM99-02, patients with standard-risk MM (β2-microglobulin [B2M] <3 mg/l, and no chromosome 13 deletion) were randomly assigned to receive no maintenance, pamidronate, or pamidronate plus thalidomide 2 months after tandem ASCT. 33 The response rates were significantly higher for the thalidomide arm; this translated into an improved EFS of 52%, compared with 36% with no maintenance and 37% with pamidronate alone. The 4-year estimated survival from diagnosis was higher with thalidomide (87%) compared with no maintenance (77%). In an Australian trial, patients were randomized to receive prednisolone with or without thalidomide. 34 After a median follow-up of 3 years, the 3-year PFS rates were 42% and 23%, and the OS rates were 86% and 75% in the thalidomide and control groups, respectively. More importantly, there was no difference in survival between the groups when followed after disease progression (79% vs 77%), negating concern that maintenance therapy may alter natural history of disease. Additional studies have examined the role of thalidomide maintenance; a PFS advantage has been noted for thalidomide following SCT in all studies, with survival advantage seen in 4 of 5 studies. An ongoing large study (Cancer and Leukemia Group B) is evaluating lenalidomide as maintenance after single ASCT. Maintenance approaches have been attempted with bortezomib; however, long-term data are lacking. The HOVON 65 trial randomized patients to bortezomib, doxorubicin, dexamethasone (PAD) or VAD followed by maintenance with bortezomib or thalidomide, respectively. Early data show improvement in the response rates with PAD. 35 Other approaches for post-transplant maintenance have included immunotherapeutic strategies, such as dendritic cell vaccines. Long-term results of these trials should be evaluated before this is adopted into routine practice. ALLOGENIC STEM CELL TRANSPLANT Although allogeneic stem cell transplant (allosct) has been shown to mediate a potentially curative graftversus-myeloma effect, it also is associated with a high level of toxicity. 36 Most of the initial reports on the use of allogeneic approaches have come from small studies or from transplant registries. In a retrospective case-matched analysis from the European Blood and Marrow Transplant Registry, patients treated with allogeneic bone marrow transplant (allo-bmt) were compared with a similar group of patients who received ASCT. 37 The OS was significantly better for the ASCT arm than for the allo-bmt arm, with median survival of 34 and 18 months, respectively. The poorer survival in allo-bmt patients could be attributed mostly to the higher treatment related mortality (41% vs 13%). Among patients surviving the first year, there was a trend for better OS and EFS for allo-bmt. The use of nonmyeloablative SCT is intended to curb treatment related mortality by depending more on the anti-tumor effect of the graft than on the initial cytoreduction achieved by the conditioning regimen. The IFM99-03/99-04 trials included patients with high-risk myeloma (B2M level >3 mg/l and chromosome 13 deletion at diagnosis). 38 In IFM99-03, 65 patients with an HLA-identical sibling donor were assigned to receive reduced-intensity conditioning (RIC) allosct; in IFM99-04, 219 patients without an HLA-identical sibling donor were assigned to undergo a second ASCT. The investigators found that RIC-alloSCT was associated with an inferior outcome compared with tandem ASCT. In an Italian trial, 108 patients younger than age 65 with newly diagnosed MM received standard ASCT, followed by low-dose TBI conditioning and HLA-matched sibling peripheral blood SCT (median of 2-4 months from ASCT), then mycophenolate mofetil cyclosporine graft-versus-host disease prophylaxis, and finally a second ASCT. 39 At a median follow-up of 3 years, treatmentrelated mortality was 11% for the allosct group versus 4% for the double ASCT group; CR rate was 46% versus 16%; OS was 84% versus 62% (P=0.003); and PFS was 75% versus 41% (P= ). This trial had several shortcomings, however, and the results cannot be generalized. PATIENTS NOT ELIGIBLE FOR TRANSPLANT Patients not eligible to receive a transplant constitute a sizable proportion of patients, given that nearly two-thirds of individuals with MM are older than age 6

7 65 at diagnosis. 40 For decades, melphalan and prednisone (MP) have been the mainstays of therapy for patients not eligible for SCT. A meta-analysis of multiple randomized trials failed to demonstrate any benefit for combination regimens compared with MP. In a Phase III clinical trial, Italian investigators examined the addition of thalidomide to MP. 41 Patients older than 65 years with newly diagnosed MM, or younger than age 65 and ineligible for SCT, were randomly assigned to receive MP (melphalan 4 mg/m 2, days 1-7, and prednisone 40 mg/m 2, days 1-7) or MP plus thalidomide 100 mg daily (MPT) for 6 cycles. Patients in the MPT arm continued on maintenance thalidomide after the 6 cycles until relapse. At 6 months from initiation of therapy, 76% of patients in the MPT arm had a response (CR or partial), compared with 47.6% in the MP arm. With comparable follow-up, the EFS at 2 years doubled with the addition of thalidomide to MP (54% vs 27%), with those older than age 70 deriving similar benefit as the younger patients. Grade 3 and 4 adverse events (AEs), however, nearly doubled with the addition of thalidomide (48% for MPT vs 25% for MP) and 11 patients had toxicity-related deaths in the MPT group, compared with 6 patients in the MP group. Deep vein thrombosis was the most common grade 3/4 AE in the MPT group, with 13 of the first 65 patients developing the condition. After introduction of enoxaparin prophylaxis, however, 2 of the remaining 64 patients developed thrombosis. A second clinical trial, conducted in France (IFM99-06) randomly assigned patients aged 65 to 75 to receive MP (12 cycles at 6-week intervals), MPT (maximum tolerated thalidomide dose, up to 400 mg/d), or MEL100 (induction therapy with VAD x 2, cyclophosphamide 3 g/m 2 -based mobilization, and 2 courses of melphalan 100 mg/m 2 with stem cell support). 42 A CR or VGPR was seen in 9%, 64%, and 58% of patients in the MP, MPT, and MEL100 groups, respectively; at a median follow-up of 32.2 months, the corresponding PFS rates were 17.2, 29.5, and 19 months. The median OS rates were 30.3 months, not reached at 56 months, and 38.6 months in the MP, MPT, and MEL100 groups, respectively. Another French trial specifically examined this question in a group of older patients (>75 years) and was able to demonstrate improved PFS and OS with addition of thalidomide. 43 There have been 5 randomized studies comparing MPT with MP, including the 3 mentioned above. The trials have consistently demonstrated a PFS advantage for addition of thalidomide, with 2 of the 5 showing an improvement in OS as well. Based on these results, the recommendation for patients ineligible for SCT is to add 100 mg per day of thalidomide to the MP regimen and limit the therapy to 12 months. Patients should be given daily aspirin for thromboprophylaxis, and clinicians should limit the use of low molecularweight heparin or warfarin anticoagulation to patients at higher risk for thrombosis. The role of bortezomib in combination with MP was examined in the large Phase III VISTA (VELCADE as Initial Standard Therapy in multiple myeloma: Assessment with melphalan and prednisone) trial, in which patients with previously untreated MM who were not candidates for ASCT were randomly assigned to receive bortezomib plus MP (VMP) or MP alone. 44 Patients in the VMP arm received IV bortezomib 1.3 mg/m 2 twice per week (weeks 1, 2, 4, and 5) for 4 cycles of 6 weeks (8 doses per cycle), followed by once per week (weeks 1, 2, 4, and 5) for 5 cycles of 6 weeks (4 doses per cycle) in combination with oral melphalan 9 mg/m 2 and prednisone 60 mg/m 2 once daily on days 1 to 4 of each cycle. Patients in the MP arm received MP once daily on days 1 through 4 for 9 cycles of 6 weeks. Both the median TTP and OS at 2 years were significantly better in the VMP group: TTP, 24 months with VMP versus 16.6 months with MP; OS at 2 years, 82.6% with VMP versus 69.5% with MP. MP also has been studied in combination with lenalidomide; Phase II results are promising, and a Phase III trial comparing this regimen with MPT is ongoing. 45 Both thalidomide and bortezomib have been combined with MP in this population (VMPT). Palumbo et al randomized 450 newly diagnosed MM patients aged 65 or older to VMPT (n=221) or VMP (n=229). Patients were treated with nine 5-week cycles of VMPT (bortezomib 1.3 mg/m 2, days 1, 8, 15, and 22; melphalan 9 mg/m 2, days 1-4; prednisone 60 mg/m 2, days 1-4 and thalidomide 50 mg, days 1-35) or VMP. The weekly administration of bortezomib resulted in significantly less neuropathy compared with standard administration schedule. Addition of thalidomide resulted in a higher response rate (84% vs 78%) and increased depth of response (CR + VGPR 51% vs 42%). 46 Management of Relapsed MM The key determinants of the approach to the patient with relapsed disease depend on types of previous therapy and response, duration of response to previous therapy, and presence of high-risk cytogenetic features. Patients relapsing on initial therapy or within 12 months of ASCT, and those with the high-risk genetic abnormalities should be considered at high risk for early mortality. Patients without any of these high-risk features have several options for treatment at first relapse. ASCT remains an option for those with or without previous ASCT, as long as they are considered 7

8 Table 2. Options for Relapsed MM Bortezomib ± dexamethasone Lenalidomide ± dexamethasone Melphalan, prednisone (± thalidomide, lenalidomide, or bortezomib) Cyclophosphamide, prednisone Vincristine, adriamycin, dexamethasone Thalidomide ± dexamethasone Bortezomib, doxorubicin HCl liposome injection (± dexamethasone) Bortezomib, thalidomide (or lenalidomide), dexamethasone Cyclophosphamide, thalidomide (or lenalidomide), dexamethasone eligible for transplant. Retrospective studies support the use of a second ASCT in patients with relapsed disease. Nontransplant approaches can involve the use of a single active agent or combinations of active agents that have been studied in different clinical trials. A compilation of the regimens that have been evaluated in different clinical trials is presented in Table 2. As with newly diagnosed MM, inclusion of patients in clinical trials of new agents is recommended for patients with relapsed MM. Outside of a clinical trial, repeating the initial therapy is favored, as long it was tolerated without significant toxicity. Studies into the natural history of MM point toward decreasing response duration, with each relapse reflecting increasingly acquired drug resistance. 47 Two of the most promising drugs undergoing clinical trials in this setting include the IMiD pomalidomide, in development by Celgene, and the proteosome inhibitor carfilzomib, in development by Proteolix. The Phase II trial of pomalidomide and dexamethasone enrolled 60 patients with relapsed MM who had received 1 to 3 prior regimens. The ORR was 58%, including a 25% VGPR, and the regimen was very well tolerated, with a manageable toxicity profile. The response rate among patients who were previously refractory to lenalidomide was 29%, demonstrating nonoverlapping mechanisms of action. 48 The Phase II trial of carfilzomib, a proteasome inhibitor, enrolled 31 patients with relapsed MM, who had had 3 or fewer prior therapies. The responses were relatively rapid, occurring within 2 cycles; the ORR was 36%, and response was higher among those without previous exposure to bortezomib. 49 Other agents being evaluated in ongoing clinical trials are listed in Table 3. Two classes of drugs are of particular interest and are being explored in Phase III trials in combination with novel agents. These include the histone deacetylase (HDAC) inhibitors and the heat-shock protein (Hsp) inhibitors. The HDAC inhibitor vorinostat is in a Phase III trial in combination with bortezomib based on in vitro synergy and encouraging results from Phase II trials of the combination. Similarly, the Hsp inhibitor tanespimycin (Kosan Biosciences) is in a Phase III trial in combination with bortezomib based on promising results from a Phase II trial. 50 The HDAC inhibitors are also undergoing Phase I/II testing in combination with lenalidomide. 14,15 Dexamethasone (pulse dose) DT-PACE (± bortezomib) DT-PACE, dexamethasone, thalidomide, cisplatin, adriamycin, cyclophosphamide, etoposide; MM, multiple myeloma Patients With High-Risk Features at Diagnosis Patients with cytogenetic deletions 13 and 17p and translocations (t)4;14 or 14;16 on fluorescence in situ hybridization tests; cytogenetic hypodiploidy, plasma cell labeling index greater than 3%; and B2M greater than 5.5 tend to have very short response duration with ASCT and should be considered for clinical trials evaluating novel drug combinations. 51 The outcome of these patients with newer induction therapy regimens, however, is not well studied; there are emerging data that bortezomib and lenalidomide may overcome some of these poor prognostic features. In the newly diagnosed setting, bortezomib appears to overcome the adverse impact of del 13 and t(4;14) translocation, based on the results from Phase II and III studies. 52,53 In the context of lenalidomide therapy, newly diagnosed patients with high-risk cytogenetic abnormalities had inferior outcome compared with standard-risk patients in one study, 54 but this finding was not replicated in another study with a relapsed population. 55 In most of the studies that have been conducted, the adverse effect of 17p deletion did not appear to be affected by the novel agents. Patients with these abnormalities should consider novel approaches with lenalidomide and/or bortezomib-containing regimens, and should delay the use of ASCT until relapse. However, recent 8

9 data have suggested that patients with t(4;14) with low B2M and normal hemoglobin may have a better than expected outcome, again highlighting the heterogeneity of the disease. 56 Selected patients also may be candidates for clinical trials with nonmyeloablative SCT. Table 3. Novel Drugs Undergoing Clinical Trials in Myeloma IMiD pomalidomide (Celgene) Supportive Care BISPHOSPHONATES The widespread use of bisphosphonates stems from early trials demonstrating a benefit for pamidronate in reducing skeletal events in patients with MM. The duration of therapy with bisphosphonates and the frequency of administration have been revisited as a result of the increasing recognition of osteonecrosis of the jaw (ONJ) as a complication of the therapy. Although zoledronic acid has been associated with a higher risk for ONJ, pamidronate also can lead to this side effect, with the risk correlating to the duration of therapy. Mayo Clinic has developed a consensus statement regarding the use of bisphosphonates in MM, and the American Society of Clinical Oncology has revised its guidelines to reflect the concerns regarding ONJ. 57,58 ANEMIA Anemia is common in patients with MM and is multifactorial in origin. Typically, effective therapy is associated with improvement in hemoglobin. Although clinicians have used erythropoietic agents in a limited manner, the most recent guidelines have placed increasing restrictions on their use. Concurrent use of erythropoietin in patients taking lenalidomide or thalidomide increases the risk for thrombosis. Mayo Clinic s approach is to avoid using erythropoietin in patients with MM, unless hemoglobin does not improve with effective therapy. The target for hemoglobin is 10 to 11 g/dl. HYPERCALCEMIA Usually seen in the setting of uncontrolled MM, hypercalcemia can be managed with conservative measures, including aggressive hydration and use of loop diuretics. Bisphosphonates can allow for the long-term stable control of hypercalcemia. New proteasome inhibitor carfilzomib (Proteolix) Histone deacetylase inhibitors vorinostat (Zolinza, Merck); panabinostat (Novartis) Monoclonal antibodies neural cell adhesion molecule (CD56), interleukin-6 Hsp-90 inhibitors tanespimycin (Kosan); retaspimycin (Infinity Pharmaceuticals) PI3k/Akt pathway inhibitor perifosine (Keryx Biopharmaceuticals) Farnesytransferase inhibitor tipifarnib (Zarnestra, Johnson & Johnson) Bcl2 inhibitors ABT737, obatoclax Anti-VEGF agents sorafenib (Nexavar, Bayer); sunitinib (Sutent, Pfizer) mtor inhibitors everolimus (Afinitor, Novartis); temsirolimus (Toricel, Wyeth) RENAL FAILURE Renal impairment of varying degrees is present in nearly 20% of patients diagnosed with MM. Renal insufficiency in MM is multifactorial in etiology and may be the result of one or more factors, including cast nephropathy, hypercalcemia, hyperuricemia, dehydration, hyperviscosity, medications such as nonsteroidal anti-inflammatory drugs and, rarely, coexistent amyloidosis or light chain deposition disease. Renal insufficiency in MM should be managed aggressively because renal function can either completely recover or improve significantly in some patients. Aggressive hydration as well as management of hypercalcemia and hyperuricemia is imperative. The role of plasmapheresis is controversial, but it is likely to benefit patients with high levels of free light chains. Prompt institution of antimyeloma therapy is important to prevent further deterioration of, and possibly ensure improvement of, renal function. Patients with advanced renal failure will require dialysis support. VERTEBRAL COMPRESSION FRACTURES Vertebral compression fractures contribute to significant morbidity in patients with MM, and vertebroplasty and kyphoplasty have a definite role in its management. These procedures decrease the pain and improve the spinal deformities associated with compression fractures. However, RCTs are required to define the precise role of these interventions. 9

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