Focus on the Treatment of Multiple Myeloma

(1)

ultiple 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 thera-pies. 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

Focus on the Treatment of

Multiple Myeloma

PRINTER-FRIENDLY VERSION AT CLINICALONCOLOGY.COM

S

HAJI

K

UMAR

, MD

Associate Professor of Medicine Division of Hematology Mayo Clinic Rochester, Minnesota

S. V

INCENT

R

AJKUMAR

, MD

Professor of Medicine Division of Hematology Mayo Clinic Rochester, Minnesota

K

ENNETH

C. A

NDERSON

, MD

Kraft Family Professor of Medicine Harvard Medical School

Jerome Lipper Myeloma Center Dana-Farber Cancer Institute Boston, Massachusetts

M

Copyright © 2009 McMahon Publishing Gr

oup unless otherwise noted.

All rights r

eserved. Repr

oduction in whole or in part without permission is pr

(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 tri-als (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

I

NITIAL

T

REATMENT

If the patient is considered a potential candidate for ASCT, initial therapy is aimed at maximizing dis-ease 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 ini-tial 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:

effectively controlling disease and minimizing early 1.

mortality, thereby providing the maximum possibil-ity of reaching an ASCT;

minimizing possible toxicity; 2.

administering therapy with the least negative impact 3.

on quality of life;

minimizing the impact on the ability to collect stem 4.

cells; and

continuing therapy with minimal modification—giv-5.

en 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 single-agent dexamethasone or a combination of vincristine, doxorubicin, and dexamethasone (VAD) to 1 of 3 regi-mens: the combination of the thalidomide analogue lenalidomide (Revlimid, Celgene) and low-dose dex-amethasone; 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 combina-tion.6,9_{The combination also has been compared with}

the VAD regimen and has been found to have a supe-rior 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 sur-vival rate greater than 90%. In comparison with dex-amethasone 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 lenali-domide and low-dose (weekly) dexamethasone. This study demonstrated improved survival, despite a lower response rate, for patients treated with lower-dose dexamethasone, effectively eliminating high-dose dexamethasone treatment from the setting of newly diagnosed disease.11_{Lenalidomide has been}

studied in combination with alkylators or anthracy-clines, as well as other novel agents, in multiple Phase I and II studies.12-15_{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

com-bination 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 com-bination can further enhance the up-front treatment of myeloma. The combination of bortezomib, tha-lidomide, and dexamethasone (VTD) was compared with TD in a Phase III trial. VTD resulted in signifi-cantly 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), result-ing 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, dexametha-sOne, and Lenalidomide with or without cyclophos-phamide Using Targeted Innovative ONcology strate-gies in the treatment of front-line multiple myeloma) trial added cyclophosphamide to the VRD combina-tion and reported a 100% response rate with high

Copyright © 2009 McMahon Publishing Gr

All rights r

eserved. Repr

(3)

Transplant-Ineligible

MPT or MPV x 12 cycles

Continue until maximum response or indefinite based on adverse effects

Option 2

Continue induction therapy

Second transplant or maintenance thalidomide if not in complete

response or very good partial response after first transplant

Option 1

Autologous stem cell transplant

Transplant-Eligible

Induction Therapya

Lenalidomide-Low-dose Dexamethasone Bortezomib-Dexamethasone Thalidomide-Dexamethasone

Collect stem cells after 4 cycles of induction

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.

Copyright © 2009 McMahon Publishing Gr

All rights r

eserved. Repr

(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 diag-nosed 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.

R

OLEOF

ASCT

Several RCTs have indicated that ASCT improves the outcome of patients with MM, whereas oth-ers have suggested no benefit for ASCT, especially in patients responsive to initial therapy.22-24_{In the}

IFM94 and Myeloma VII trials, previously untreat-ed patients younger than age 65, were randomly assigned to receive either conventional chemother-apy (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 65.25_{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 mainte-nance, did not reveal any OS benefit.26_{The Spanish}

cooperative group PETHEMA conducted a random-ized trial comparing ASCT with CCT in patients who responded to initial therapy and demonstrated higher complete response (CR) rates with ASCT but no dif-ferences 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-stimulat-ing factor or granulocyte-macrophage colony-stimu-lating 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/m2_{, 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/m2

melphalan, or 200 mg/m2_{melphalan alone.}28_Patients

receiving only melphalan had a faster recovery of neutrophils and platelets, and milder mucositis, with-out any effect on EFS or OS. Ongoing trials are attempting to improve melphalan conditioning by increasing the melphalan dose (alone or in combina-tion 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 contin-ues to evolve in the era of novel agents. The high response rates seen with the new combination regi-mens 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 thera-peutic armamentarium for MM. Ongoing trials are examining the best way to integrate these treatment modalities to provide maximum benefit to patients.

R

OLEOF

S

ECOND

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 induc-tion 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 clini-cal trial, patients were randomly assigned to receive single or double ASCTs and then further randomized

Copyright © 2009 McMahon Publishing Gr

All rights r

eserved. Repr

(5)

Table 1.

Response Criteria for MM

Response Subcategory

Response Criteria

CR • Negative immunofixation on the serum and urine and

Disappearance of any soft tissue plasmacytomas

• and

<5% plasma cells in bone marrow •

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.

Stringent CR

(CR as above plus)

Normal FLC ratio • and

Absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescence •

VGPR • Serum and urine M-component detectable by immunofixation but not on electrophoresis or ≥

• 90% reduction in serum M-component plus urine M-component <100mg/24h

PR • ≥50% reduction of serum M-protein and reduction in 24-h urinary M-protein by ≥90% or

to <200mg per 24h

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 • Not meeting criteria for CR, VGPR, PR, or PD

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)

PD Increase of 25% from baseline in:

Serum M-component (absolute increase must be

• ≥0.5g/dL)and/or

Urine M-component (absolute increase must be

• ≥200mg/24h) 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

Copyright © 2009 McMahon Publishing Gr

All rights r

eserved. Repr

(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 con-siderably 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.

M

AINTENANCE

T

HERAPY

A

FTER

ASCT

ASCT clearly improves response rates in patients with newly diagnosed MM compared with conven-tional 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/m2_{subcutaneously 3}

times weekly following initial ASCT suggested a mod-est 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 tan-dem 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 mainte-nance (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 con-trol 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 follow-ing 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 mainte-nance 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 strat-egies, such as dendritic cell vaccines. Long-term

results of these trials should be evaluated before this is adopted into routine practice.

A

LLOGENIC

S

TEM

C

ELL

T

RANSPLANT

Although allogeneic stem cell transplant (alloSCT) has been shown to mediate a potentially curative graft-versus-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 allo-geneic bone marrow transplant (allo-BMT) were com-pared 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 sur-vival 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 ini-tial cytoreduction achieved by the conditioning regi-men. 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 periph-eral blood SCT (median of 2-4 months from ASCT), then mycophenolate mofetil–cyclosporine graft-ver-sus-host disease prophylaxis, and finally a second ASCT.39_{At a median follow-up of}_{3 years,}

treatment-related mortality was 11% for the alloSCT group ver-sus 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=0.00008). This trial had several shortcomings, however, and the results can-not be generalized.

P

ATIENTS

N

OT

E

LIGIBLEFOR

T

RANSPLANT

Patients not eligible to receive a transplant consti-tute a sizable proportion of patients, given that nearly two-thirds of individuals with MM are older than age

Copyright © 2009 McMahon Publishing Gr

All rights r

eserved. Repr

(7)

65 at diagnosis.40_{For decades, melphalan and}

pred-nisone (MP) have been the mainstays of therapy for patients not eligible for SCT. A meta-analysis of mul-tiple randomized trials failed to demonstrate any ben-efit 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/m2_{, days 1-7,}

and prednisone 40 mg/m2_{, days 1-7) or MP plus}

tha-lidomide 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 deriv-ing 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 remain-ing 64 patients developed thrombosis. A second clini-cal trial, conducted in France (IFM99-06) randomly assigned patients aged 65 to 75 to receive MP (12 cycles at 6-week intervals), MPT (maximum toler-ated thalidomide dose, up to 400 mg/d), or MEL100 (induction therapy with VAD x 2, cyclophosphamide 3 g/m2_{-based mobilization, and 2 courses of}

mel-phalan 100 mg/m2_{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 correspond-ing 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

regimen and limit the therapy to 12 months. Patients should be given daily aspirin for thromboprophylaxis, and clinicians should limit the use of low–molecular-weight 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}

borte-zomib 1.3 mg/m2_{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/m2_{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 lenalido-mide; Phase II results are promising, and a Phase III trial comparing this regimen with MPT is ongoing.45

Both thalidomide and bortezomib have been com-bined 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 (bort-ezomib 1.3 mg/m2_{, days 1, 8, 15, and 22; melphalan}

9 mg/m2_{, 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 administra-tion schedule. Addiadministra-tion 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 cytoge-netic 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

All rights r

eserved. Repr

(8)

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 recommend-ed for patients with relapsrecommend-ed 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 decreas-ing response duration, with each relapse reflectdecreas-ing increasingly acquired drug resistance.47

Two of the most promising drugs undergoing clini-cal 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 dexametha-sone 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 clini-cal 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) inhibi-tors and the heat-shock protein (Hsp) inhibiinhibi-tors. The HDAC inhibitor vorinostat is in a Phase III trial in com-bination 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 combi-nation 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

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

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 Dexamethasone (pulse dose) DT-PACE (± bortezomib)

DT-PACE, dexamethasone, thalidomide, cisplatin, adriamycin, cyclophosphamide, etoposide; MM, multiple myeloma

Copyright © 2009 McMahon Publishing Gr

All rights r

eserved. Repr

(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 heterogene-ity of the disease.56_{Selected patients also may be}

can-didates for clinical trials with nonmyeloablative SCT.

Supportive Care

B

ISPHOSPHONATES

The widespread use of bisphosphonates stems from early trials demonstrating a benefit for pamidronate in reducing skeletal events in patients with MM. The dura-tion of therapy with bisphosphonates and the frequen-cy 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 zole-dronic 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

A

NEMIA

Anemia is common in patients with MM and is multifactorial in origin. Typically, effective thera-py 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 erythropoi-etin in patients with MM, unless hemoglobin does not improve with effective therapy. The target for hemo-globin is 10 to 11 g/dL.

H

YPERCALCEMIA

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.

R

ENAL

F

AILURE

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, includ-ing cast nephropathy, hypercalcemia, hyperuricemia, dehydration, hyperviscosity, medications such as

non-steroidal anti-inflammatory drugs and, rarely, coexis-tent amyloidosis or light chain deposition disease. Renal insufficiency in MM should be managed aggres-sively 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 impor-tant to prevent further deterioration of, and possibly ensure improvement of, renal function. Patients with advanced renal failure will require dialysis support.

V

ERTEBRAL

C

OMPRESSION

F

RACTURES

Vertebral compression fractures contribute to sig-nificant morbidity in patients with MM, and verte-broplasty 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.

Table 3.

Novel Drugs Undergoing

Clinical Trials in Myeloma

IMiD—pomalidomide (Celgene)

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)

Copyright © 2009 McMahon Publishing Gr

All rights r

eserved. Repr

(10)

References

Dispenzieri A, Rajkumar SV, Gertz MA, et al. Treatment of newly 1.

diagnosed multiple myeloma based on Mayo Stratification of Myeloma and Risk-adapted Therapy (mSMART): consensus statement. Mayo Clin Proc. 2007;82(3):323-341, PMID: 17352369. Siegel DS, Desikan KR, Mehta J, et al. Age is not a prognos-2.

tic variable with autotransplants for multiple myeloma. Blood. 1999;93(1):51-54, PMID: 9864145.

Durie BG, Harousseau JL, Miguel JS, et al. International 3.

uniform response criteria for multiple myeloma. Leukemia. 2006;20(9):1467-1473, PMID: 16855634.

Barlogie B, Smith L, Alexanian R. Effective treatment of advanced 4.

multiple myeloma refractory to alkylating agents. N Engl J Med. 1984;310(21):1353-1356, PMID: 6546971.

Kumar S, Lacy MQ, Dispenzieri A, et al. Single agent dexametha-5.

sone for pre-stem cell transplant induction therapy for multiple myeloma. Bone Marrow Transplant. 2004;34(6):485-490, PMID: 15286691.

Rajkumar SV, Blood E, Vesole D, Fonseca R, Greipp PR; Eastern 6.

Cooperative Oncology Group. Phase III clinical trial of thalido-mide plus dexamethasone compared with dexamethasone alone in newly diagnosed multiple myeloma: a clinical trial coordi-nated by the Eastern Cooperative Oncology Group. J Clin Oncol. 2006;24(3):431-436, PMID: 16365178.

Rajkumar SV, Hayman SR, Lacy MQ, et al. Combination therapy 7.

with lenalidomide plus dexamethasone (Rev/Dex) for newly diag-nosed myeloma. Blood. 2005;106(13):4050-4053, PMID: 16118317. Kumar S, Lacy MQ, Dispenzieri A, et al. High-dose therapy and 8.

autologous stem cell transplantation for multiple myeloma poorly responsive to initial therapy. Bone Marrow Transplant. 2004;34(2):161-167, PMID: 15133489.

Rajkumar SV, Rosinol L, Hussein M, et al. Multicenter, randomized, 9.

double-blind, placebo-controlled study of thalidomide plus dex-amethasone compared with dexdex-amethasone as initial therapy for newly diagnosed multiple myeloma. J Clin Oncol. 26(13):2171-2177, PMID: 18362366.

Cavo M, Zamagni E, Tosi P, et al. Superiority of thalidomide 10.

and dexamethasone over vincristine-doxorubicin-dexamethasone (VAD) as primary therapy in preparation for autologous

transplantation for multiple myeloma. Blood. 2005;106:35-39, PMID: 15761019.

Rajkumar SV, Jacobus S, Callander N, et al. Phase III trial of 11.

lenalidomide plus high-dose dexamethasone versus lenali-domide plus low-dose dexamethasone in newly diagnosed multiple myeloma (E4A03): a trial coordinated by the Eastern Cooperative Oncology Group. ASH Annual Meeting Abstracts.

Blood. 2007;110:74.

Kumar S, Hayman S, Buadi F, et al. Phase II trial of lenalidomide 12.

(Revlimid™) with cyclophosphamide and dexamethasone (RCd) for newly diagnosed myeloma. ASH Annual Meeting Abstracts.

Blood. 2008;112:91.

Baz R, Hussein MA, Sullivan D, et al. Phase II study of pegylated 13.

liposomal doxorubicin (PLD), low-dose dexamethasone (DEX), and lenalidomide (LEN) in patients with newly diagnosed (ND) multiple myeloma (MM). J Clin Oncol. 2009;27:

(15 suppl):Abstract 8518.

Spencer A, Taylor K, Lonial S, et al. Panobinostat plus lenalido-14.

mide and dexamethasone phase I trial in multiple myeloma (MM).

J Clin Oncol. 2009;27:(15 suppl):Abstract 8542.

Siegel DS, Weber DM, Mitsiades CS, et al. Vorinostat in combi-15.

nation with lenalidomide and dexamethasone in patients with relapsed/refractory multiple myeloma: A phase I study. J Clin Oncol. 2009;27:(15 suppl):Abstract 8586.

Jagannath S, Durie BG, Wolf J, et al. Bortezomib therapy alone 16.

and in combination with dexamethasone for previously untreated symptomatic multiple myeloma. Br J Haematol. 2005;129(6): 776-783, PMID: 15953004.

Harousseau JL, Mathiot C, Attal M, et al. Bortezomib/dexametha-17.

sone versus VAD as induction prior to autologous stem cell transplantation (ASCT) in previously untreated multiple myeloma (MM): updated data from IFM 2005/01 Trial. J Clin Oncol. 2008;26(suppl):Abstract 8505.

Cavo M, Tacchetti P, Patriarca F, et al. Superior complete response 18.

rate and progression-free survival after autologous transplanta-tion with up-front Velcade-thalidomide-dexamethasone compared with thalidomide-dexamethasone in newly diagnosed multiple myeloma. ASH Annual Meeting Abstracts. Blood. 2008;112:158. Richardson PG, Lonial S, Jakubowiak A, et al. Safety and efficacy 19.

of lenalidomide (Len), bortezomib (Bz), and dexamethasone (Dex) in patients (pts) with newly diagnosed multiple myeloma (MM): a phase I/II study. J Clin Oncol. 2008;26(suppl):Abstract 852. Kumar S, Flinn IW, Noga SJ, et al. Safety and efficacy of 20.

novel combination therapy with bortezomib, dexamethasone,

All rights r

eserved. Repr

(11)

cyclophosphamide, and lenalidomide in newly diagnosed mul-tiple myeloma: initial results from the Phase I/II multicenter EVOLUTION trial. ASH Annual Meeting Abstracts. Blood.

2008;112:93.

Jakubowiak AJ, Hofmeister CC, Campagnaro EL, et al. 21.

Lenalidomide, bortezomib, pegylated liposomal doxorubicin hydrochloride, and dexamethasone in newly diagnosed multiple myeloma: Initial results of phase I/II MMRC trial. J Clin Oncol. 2009;27:(15 suppl):Abstract 8517.

Attal M, Harousseau JL, Stoppa AM, et al. A prospective, ran-22.

domized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Francais du Myelome. N Engl J Med. 1996;335(2):91-97, PMID: 8649495. Child JA, Morgan GJ, Davies FE, et al. High-dose chemotherapy 23.

with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med. 2003;348(19):1875-1883, PMID: 12736280.

Blade J, Rosinol L, Sureda A, et al. High-dose therapy intensifica-24.

tion compared with continued standard chemotherapy in multiple myeloma patients responding to the initial chemotherapy: long-term results from a prospective randomized trial from the Spanish cooperative group PETHEMA. Blood. 2005;106(12):3755-3759, PMID: 16105975.

Fermand JP, Katsahian S, Divine M, et al. High-dose therapy and 25.

autologous blood stem-cell transplantation compared with con-ventional treatment in myeloma patients aged 55 to 65 years: long-term results of a randomized control trial from the Group Myelome-Autogreffe. J Clin Oncol. 2005;23(36):9227-9233, PMID: 16275936.

Barlogie B, Kyle RA, Anderson KC, et al. Standard chemotherapy 26.

compared with high-dose chemoradiotherapy for multiple myeloma: final results of phase III US Intergroup Trial S9321.

J Clin Oncol. 2006;24(6):929-936, PMID: 16432076.

Fermand JP, Ravaud P, Chevret S, et al. High-dose therapy and 27.

autologous peripheral blood stem cell transplantation in multiple myeloma: up-front or rescue treatment? Results of a multicenter sequential randomized clinical trial. Blood. 1998;92(9):3131-3136, PMID: 9787148.

Moreau P, Facon T, Attal M, et al. Comparison of 200 mg/m

28. 2

mel-phalan and 8 Gy total body irradiation plus 140 mg/m2_melphalan

as conditioning regimens for peripheral blood stem cell transplan-tation in patients with newly diagnosed multiple myeloma: final analysis of the Intergroupe Francophone du Myelome 9502 ran-domized trial. Blood. 2002;99(3):731-735, PMID: 11806971.

Attal M, Harousseau JL, Facon T, et al. Single versus double autol-29.

ogous stem-cell transplantation for multiple myeloma. N Engl J Med. 2003;349(26):2495-2502, PMID: 14695409.

Cavo M, Tosi P, Zamagni E, et al. Prospective, randomized study 30.

of single compared with double autologous stem-cell transplanta-tion for multiple myeloma: Bologna 96 Clinical Study. J Clin Oncol. 2007;25(17):2434-2441, PMID: 17485707.

Fermand JP. MAG studies (1985-2005), 10th International 31.

Myeloma Workshop, Sydney, April 2005. http://myeloma.org/pdfs/ Sydney2005_Fermand_P8.pdf. Accessed September 23, 2009.

Cunningham D, Powles R, Malpas J, et al. A randomized trial of 32.

maintenance interferon following high-dose chemotherapy in multiple myeloma: long-term follow-up results. Br J Haematol. 1998;102(2):495-502, PMID: 9695964.

Attal M, Harousseau JL, Leyvraz S, et al. Maintenance therapy with 33.

thalidomide improves survival in patients with multiple myeloma.

Blood. 2006;108(10):3289-3294, PMID: 16873668.

Spencer A, Prince HM, Roberts AW. Consolidation therapy with 34.

low-dose thalidomide and prednisolone prolongs the survival of multiple myeloma patients undergoing a single autologous stem-cell transplantation procedure. J Clin Oncol. 2009;27:1788-1793, PMID: 19273705.

Sonneveld P, van der Holt B, Schmidt-Wolf IGH, et al. Analysis 35.

of HOVON-65/GMMG-HD4 randomized Phase III trial comparing bortezomib, adriamycin, dexamethasone (PAD) vs VAD as induc-tion treatment prior to high dose melphalan (HDM) in patients with newly diagnosed multiple myeloma (MM). ASH Annual Meeting Abstracts. Blood. 2008;112:653.

Tricot G, Vesole DH, Jagannath S, Hilton J, Munshi N, Barlogie 36.

B. Graft-versus-myeloma effect: proof of principle. Blood. 1996;87(3):1196-1198, PMID: 8562947.

Bjorkstrand BB, Ljungman P, Svensson H, et al. Allogeneic bone 37.

marrow transplantation versus autologous stem cell transplanta-tion in multiple myeloma: a retrospective case-matched study from the European Group for Blood and Marrow Transplantation.

Blood. 1996;88(12):4711-4718, PMID: 8977265.

Garban F, Attal M, Michallet M, et al. Prospective comparison of 38.

autologous stem cell transplantation followed by dose-reduced allograft (IFM99-03 trial) with tandem autologous stem cell trans-plantation (IFM99-04 trial) in high-risk de novo multiple myeloma.

Blood. 2006;107(9):3474-3480, PMID: 16397129.

All rights r

eserved. Repr

(12)

Bruno B, Rotta M, Patriarca F, et al. A comparison of allografting 39.

with autografting for newly diagnosed myeloma. N Engl J Med. 2007;356(11):1110-1120, PMID: 17360989.

Kyle RA, Rajkumar SV. Multiple myeloma.

40. N Engl J Med.

2004;351(18):1860-1873, PMID: 15509819.

Palumbo A, Bringhen S, Caravita T, et al. Oral melphalan and 41.

prednisone chemotherapy plus thalidomide compared with melphalan and prednisone alone in elderly patients with multiple myeloma: a randomised controlled trial. Lancet. 2006;367(9513):825-831, PMID: 16530576.

Facon T, Mary JY, Hulin C, et al. Melphalan and prednisone 42.

plus thalidomide versus melphalan and prednisone alone or reduced intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99-06). Lancet. 2007;370(9594):1209-1218, PMID: 17920916.

Hulin C, Facon T, Rodon P, et al. Efficacy of melphalan and pred-43.

nisone plus thalidomide in patients older than 75 years with newly diagnosed multiple myeloma: IFM 01/01 trial. J Clin Oncol. 2009;27(22):3664-3670, PMID: 19451428.

San Miguel JF, Schlag R, Khuageva NK, et al. Bortezomib plus mel-44.

phalan and prednisone for initial treatment of multiple myeloma.

N Engl J Med. 2008;359(9):906-917, PMID: 18753647.

Palumbo A, Falco P, Corradini P, et al. Melphalan, prednisone, and 45.

lenalidomide treatment for newly diagnosed myeloma: a report from the GIMEMA Italian Multiple Myeloma Network. J Clin Oncol. 2007;25(28):4459-4465, PMID: 17785703.

Palumbo AP, Bringhen S, Rossi D, et al. A phase III study of VMPT 46.

versus VMP in newly diagnosed elderly myeloma patients. J Clin Oncol. 2009;27(15 suppl):Abstract 8515.

Kumar SK, Therneau TM, Gertz MA, et al. Clinical course of 47.

patients with relapsed multiple myeloma. Mayo Clin Proc. 2004;79(7):867-874, PMID: 15244382.

Lacy MQ, Hayman SR, Gertz MA, et al. Pomalidomide (CC4047) 48.

plus low-dose dexamethasone (pom/dex) is highly effective therapy in relapsed multiple myeloma. ASH Annual Meeting Abstracts. Blood. 2008;112(11):866.

Jagannath S, Vij R, Stewart KA, et al. Initial results of PX-171-003, 49.

an open-label, single arm, Phase II study of carfilzomib (CFZ) in

patients with relapsed and refractory multiple myeloma (MM). ASH Annual Meeting Abstracts. Blood. 2008;112(11):864.

Richardson PG, Chanan-Khan A, Lonial S, et al. Tanespimycin 50.

plus bortezomib in patients with relapsed and refractory mul-tiple myeloma: final results of a phase I/II study. J Clin Oncol.

2009;27(15 suppl):Abstract 8503.

Gertz MA, Lacy MQ, Dispenzieri A, et al. Clinical implications 51.

of t(11;14)(q13;q32), t(4;14)(p16.3;q32), and -17p13 in myeloma patients treated with high-dose therapy. Blood. 2005;106(8): 2837-2840, PMID: 15976175.

Jagannath S, Richardson PG, Sonneveld P, et al. Bortezomib 52.

appears to overcome the poor prognosis conferred by chromosome 13 deletion in phase 2 and 3 trials. Leukemia. 2007;21(1):151-157, PMID: 17096017.

San Miguel JF, Schlag R, Khuageva NK, et al. Bortezomib plus mel-53.

phalan and prednisone for initial treatment of multiple myeloma.

N Engl J Med. 2008;359(9):906-917, PMID: 18753647.

Kapoor P, Kumar S, Fonseca R, et al. Impact of risk stratification 54.

on outcome among patients with multiple myeloma receiving initial therapy with lenalidomide and dexamethasone. Blood. 2009;114(3):518-521, PMID: 19324902.

Reece D, Song KW, Fu T, et al. Influence of cytogenetics in 55.

patients with relapsed or refractory multiple myeloma treated with lenalidomide plus dexamethasone: adverse effect of deletion 17p13. Blood. 2009;114(3):522-525, PMID: 19332768.

Moreau P, Attal M, Garban F, et al. Heterogeneity of t(4;14) in 56.

multiple myeloma. Long-term follow-up of 100 cases treat-ed with tandem transplantation in IFM99 trials. Leukemia. 2007;21(9):2020-2024, PMID: 17625611.

Kyle RA, Yee GC, Somerfield MR, et al. American Society of 57.

Clinical Oncology 2007 clinical practice guideline update on the role of bisphosphonates in multiple myeloma. J Clin Oncol. 2007;25(17):2464-2472, PMID: 17515569.

Lacy MQ, Dispenzieri A, Gertz MA, et al. Mayo Clinic consensus 58.

statement for the use of bisphosphonates in multiple myeloma.

Mayo Clinic Proc. 2006;81(8):1047-1053, PMID: 16901028.

All rights r

eserved. Repr