Multiple Myeloma: A Practical Guide to Current Management

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Multiple Myeloma: A Practical Guide to Current Management

Multiple Myeloma:

A Practical Guide to Current Management

November 2005 • Complimentary CME Monograph for 2.0 category 1 credits • Leading Experts ~ Leading Knowledge

A Roundtable Discussion of the Role of Thalidomide

by International Key Opinion Leaders

GUEST EDITOR

Keith Stewart, MB.ChB.

Mayo Clinic

Scottsdale, Arizona

Jointly sponsored by The American School of Oncology and The University of Alabama, School of Medicine Division of Continuing Medical Education

© Copyright, NMCR 2005.


Jointly Sponsored by The American School of Oncology and The University of Alabama, School of Medicine Division of

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Multiple Myeloma: A Practical Guide to Current Management” has been made possible by an unrestricted educational grant from

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Multiple Myeloma: A Practical Guide to Current Management is produced by The American School of Oncology. The American

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Introductory Letter

Multiple Myeloma: A Practical Guide to Current Management

Dear Colleague,

Options for management of newly diagnosed and relapsed multiple myeloma have increased

significantly in the recent past, and additional novel therapies will soon be added to our

armamentarium. Thalidomide and lenalidomide, the proteasome inhibitor bortezomib, autologous

and mini-allotransplantation, and the conventional agents dexamethasone and melphalan all have

roles to play in current therapeutic strategies. Appropriate sequencing of these therapies and skillful

management of associated toxicities is mandatory if outcomes are to be optimized for patients with

myeloma.

To provide a broad international perspective regarding the management of multiple myeloma,

a panel of experts was convened prior to the 10th International Myeloma Workshop held in Sydney,

Australia, in April 2005. As chairperson of a roundtable discussion, I charged the group with the task

of providing practical, evidence-based guidelines for management that would be useful for the

practicing oncologist and hematologist. In many cases a clear consensus of the participating experts

could be achieved, while in others there were defensible differences of opinion.

I hope you will find this monograph to be of value in the management of your patients with

multiple myeloma.

Sincerely,

A Roundtable Discussion of the Role of Thalidomide

by International Key Opinion Leaders

Keith Stewart, MB. CHB.

Mayo Clinic

Scottsdale, Arizona

This publication is designed to provide accurate and authoritative information in regard to the subject matter covered. The information contained

herein is based upon sources believed to be accurate and reliable. We have exercised reasonable care to assure the accuracy of the information.

However, no representation or warranty is made as to such accuracy. Readers should check primary sources where appropriate and use the

traditional research techniques to make sure that the information has not been affected or changed by recent developments.


Multiple Myeloma: A Practical Guide to

Current Management

Introduction 4

Optimal Therapy for Newly Diagnosed Patient 5

Starting Dosage in Combination Therapy 7

Assessing Response 8

Options for Non–Transplantation Candidates 8

Combinations as Induction Therapy 9

Relapse/Refractory Patients 10

Other Salvage Therapies 11

Posttransplantation Maintenance 12

Minimizing Toxicities 13

Future Directions 15

Lenalidomide 16

Goal of Therapy 18

Conclusions 19

Continuing Medical Education Registration, Test, and Evaluation 23


Monograph Overview

Target Audience:

Medical oncologists, hematologists

Program Overview:

This monograph will present a group of discussions from a roundtable meeting of world-renowned experts in the field of multiple myeloma research and

treatment. It contains a thorough overview of current treatment alternatives and focuses on immunomodulatory agents, their role in early and late treatment of

multiple myeloma as well as side effect management.

Educational Objectives:

After reading the publication the participant will be able to:

• Discuss the ultimate goals of therapy for multiple myeloma.

• Discuss current research results and new areas of study related to multiple myeloma therapy, specifically combination therapies and monotherapy utilizing

immunomodulatory agents (IMiDs).

• Compare treatment alternatives available in myeloma therapy today.

• Be able to discuss the role of immunomodulatory agents (IMiDs) in upfront therapy, relapsed disease, and maintenance therapy.

• Discuss the management and prophylaxis of DVT and peripheral neuropathy in the thalidomide patient.

• Discuss the role of bortezomib in the treatment of multiple myeloma, efficacy and side effect management.

Accreditation:

This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical

Education (ACCME) through the joint sponsorship of The University of Alabama School of Medicine and The American School of Oncology. The University

of Alabama School of Medicine is accredited by the ACCME to provide continuing medical education for physicians.

The University of Alabama School of Medicine designates this educational activity for a maximum of 2.0 Category 1 credits toward the AMA Physician’s

Recognition Award. Each physician should claim only those credits that he/she actually spent in the activity.

The University of Alabama is an equal opportunity/affirmative action institution.

The American Medical Association has determined that physicians not licensed in the US who participate in this CME activity are eligible for AMA PRA

Category 1 credit.

Disclaimer Statement:

Medical information is ever-changing, transformed frequently by new research and clinical experience. While the University of Alabama School of Medicine

Division of Continuing Medical Education makes every effort to present accurate information, no warranty, expressed or implied, is offered. Furthermore, the user

should also use his/her own judgment, knowledge, experience, and diagnostic decision-making before applying any information, whether provided the UASOM

Division of CME, other users, or third parties, to any professional or personal use.

The information contained and displayed within this enduring material is provided solely for educational and discussion purposes.

Support for this program has been provided by an unrestricted educational grant from Celgene.

Release date: November 2005

Expiration date: November 2006

1


Multiple Myeloma: A Practical Guide to

Current Management

PROGRAM FACULTY

2

Ivan Borrello, MD

Assistant Professor of Oncology

Johns Hopkins University

Baltimore, Maryland

Philip Greipp, MD

Director, Hematologic Malignancies Program

Mayo Clinic

Rochester, Minnesota

Mohamad Hussein, MD

Director, Multiple Myeloma Research Program

Cleveland Clinic Foundation

Cleveland, Ohio

Jayesh Mehta, MD

Professor of Medicine

Feinberg School of Medicine

Northwestern University

Chicago, Illinois

Gareth Morgan, MB.ChB., PhD

Royal Marsden Hospital

London, United Kingdom

Robert Orlowski, MD

Associate Professor of Medicine

University of North Carolina

Chapel Hill, North Carolina

Miles Prince, MBBSMD, MRACMA,

FRACP, FRCPA

Peter MacCallum Cancer Centre

East Melbourne, Australia

Paul Richardson, MD

Assistant Professor of Medicine

Dana-Farber Cancer Institute

Boston, Massachusetts

Seema Singhal, MD

Director Myeloma Program; Professor of Medicine

Feinberg School of Medicine

Northwestern University

Chicago, Illinois

Keith Stewart, MB.ChB. (Guest Editor)

Mayo Clinic

Scottsdale, Arizona

Robert Vescio, MD

Director Multiple Myeloma and

Bone Metastases Program

Cedars-Sinai Medical Center

Los Angeles, California


Faculty Disclosures

Dr. Ivan Borrello

Johns Hopkins University

The discussant, Ivan Borello, MD, receives

grant/research support from Cell Genetics.

Dr. Philip Greipp

Mayo Clinic

The discussant, Philip Greipp, MD, to the best

of his knowledge has no conflict of interest.

Dr. Mohamad Hussein

Cleveland Clinic Foundation

The discussant, Mohamad Hussein, MD, receives

grant/research support from Alza, Ortho Biotech,

Celgene, and Amgen.

Dr. Jayesh Mehta

Northwestern University Medical School

The discussant, Jayesh Mehta, MD, receives

grant/research support from Celgene and Millennium.

Professor Gareth Morgan

Royal Marsden Hospital

The discussant, Gareth Morgan, PhD, to the best

of his knowledge has no conflict of interest.

Dr. Robert Orlowski

University of North Carolina at Chapel Hill

The discussant, Robert Orlowski, MD, to the best

of his knowledge has no conflict of interest.

Dr. Miles Prince

Peter MacCallum Cancer Centre

The discussant, Miles Prince, MBBS, is a consultant

for Amgen (Australia), Celgene, Janssen-Cilog

(Australia), and Novartis (Australia).

Dr. Paul Richardson

Dana-Farber Cancer Institute

The discussant, Paul Richardson, MD, is an educator

for Millennium and Celgene.

Dr. Seema Singhal

Northwestern University Medical School

The discussant, Seema Singhal, MD, is an educator

for Celgene and Millennium.

Dr. Keith Stewart

Mayo Clinic

The discussant, Keith Stewart, MD, is a consultant

for Ortho Biotech and has stock in Celgene.

Dr. Robert Vescio

Cedars-Sinai Medical Center

The discussant, Robert Vescio, MD, receives

grant/research support from Celgene and Millennium.

3


Multiple Myeloma: A Practical Guide to

Current Management

INTRODUCTION

4

Multiple myeloma is the second most common

hematologic malignancy after non-Hodgkin’s lymphoma.

It is estimated that 15,980 new cases of multiple myeloma

(approximately 8,600 men and 7,380 women) will be

diagnosed during 2005 in the United States, and

approximately 11,300 individuals (5,660 men and 5,640

women) will die of the disease. The 5-year survival rate

for patients with multiple myeloma is 30%, with younger

patients having outcomes superior to those seen in the

elderly. Although no cure exists for the disease, recent

improvements in the treatment of multiple myeloma are

expected to increase survival rates.

The response of multiple myeloma to treatment is

predominantly dependent on underlying genetic variation;

nevertheless, commonly employed staging systems use

more readily accessible clinical tools. Staging for multiple

myeloma is commonly based on two approaches: The

Durie-Salmon Staging (Appendix 1) and the recently

proposed International Staging System (Appendix 2).

Depending on the age of the patient and the disease stage,

several treatment modalities are available for treating

multiple myeloma, including:

• Conventional-dose chemotherapy.

• Steroid therapy.

• High-dose chemotherapy with stem cell rescue.

• Thalidomide-based regimens.

• Newer agents: bortezomib and lenalidomide.

Given the options available, treatment of multiple

myeloma is dependent on individual physician pattern of

practice, which is based on patient characteristics and

clinical trials data for available therapies. These practices

are reflected in these proceedings from a roundtable

meeting entitled Multiple Myeloma: A Practical Guide to

Current Management held on April 9, 2005, in

conjunction with the 10 th International Myeloma

Workshop in Sydney, Australia. Keith Stewart, MB.ChB.,

chaired the session and posed questions to experts in the

field of multiple myeloma. The opinions of the experts are

captured in this monograph.


Multiple Myeloma: A Practical Guide to

Current Management

OPTIMAL THERAPY FOR NEWLY DIAGNOSED PATIENT

What constitutes optimal therapy for a patient newly

diagnosed with multiple myeloma?

Clinical practices among the participating experts varied

with respect to the regimen of choice for treating multiple

myeloma in the newly diagnosed patient. There was

consensus that tumor burden and the perceived need for

rapid cytoreduction were major factors influencing choice

of initial therapy. Also, all agreed that candidates

(generally those less than 70 years of age in good health)

for consideration of auto-transplantation should not receive

induction therapy with stem cell damaging agents (e.g.,

melphalan), which might preclude subsequent successful

stem cell harvest. Traditionally, oncologists have used

combination VAD chemotherapy as induction, but recently

single-agent dexamethasone or dexamethasone with

thalidomide have become popular due to convenience and

avoidance of intravenous catheter use. Whether

combination therapy with dexamethasone and thalidomide

is now the “standard of care” for initial induction was

raised as a question. In response, several participants

indicated that single-agent dexamethasone induction

therapy might be very reasonable in low-risk, low–tumorburden

patients. In contrast, patients requiring rapid tumor

burden control should receive combination therapy

(dexamethasone and thalidomide or VAD).

All participants, however, emphasized that, when

combination therapy is chosen, careful attention to

toxicities is imperative. Among the reasonable options for

induction therapy given these caveats were single-agent

dexamethasone and combination approaches including

thalidomide plus dexamethasone, VAD (vincristine,

doxorubicin, dexamethasone) and DVd (pegylated

doxorubicin, vincristine and dexamethasone). For a

non–transplantation population melphalan and prednisone

remains the standard of care, although many clinicians are

adopting the use of thalidomide/dexamethasone in this

setting as well.

The initial use of the thalidomide/dexamethasone

combination in this setting is supported by data from two

key studies that reported a favorable clinical outcome. The

first study was from the Mayo Clinic [Rajkumar 2002],

where 50 patients with newly diagnosed multiple

myeloma were treated with thalidomide/dexamethasone.

Thalidomide 200 mg/day was administered orally.

Dexamethasone 40 mg/day was administered orally on

days 1 to 4, 9 to 12, and 17 to 20 (odd cycles) and

40 mg/day on days 1 to 4 (even cycles), repeated monthly.

A confirmed response rate of 64% (95% confidence

interval [CI], 49% to 77%) was reported in 32 patients.

The second study was from the M. D. Anderson Cancer

Center [Weber 2003], where 40 consecutive patients with

symptomatic multiple myeloma were given thalidomide

100 to 200 mg orally at bedtime, with serial increments

of 50 to 100 mg at weekly intervals. Thalidomide was

administered to a maximum tolerated dose of 400 mg.

Dexamethasone 20 mg/m 2 was given for four days

beginning on days 1, 9, and 17. Each cycle of treatment

was considered to be 30 days. Both groups of patients

were treated for at least three months. In this study also,

28 newly diagnosed patients were treated with

thalidomide alone to a maximum tolerated dose

of 600 mg. Of patients treated with thalidomide/

dexamethasone, 72% showed response to therapy

(including complete response in 16% of patients), and the

median time to remission was 0.7 months. Patients treated

with thalidomide alone showed a 36% response rate and

a median time to remission of 4.2 months. A recent update

from the M.D. Anderson Cancer Center [Weber 2005]

indicates a response rate of 69% in 130 patients who

received thalidomide/dexamethasone. Median time to

remission was 1.1 months and the median duration of

remission had not yet been reached.

Although the general consensus favors the combination

of thalidomide and dexamethasone in cases of high tumor

burden that merit a need for rapid cytoreduction, some

participants supported the use of dexamethasone alone in

patients with low disease burden. In such instances,

addition of thalidomide is advocated in subsequent cycles

of treatment if a suboptimal response is seen after one

cycle of treatment with dexamethasone alone.

5


Multiple Myeloma: A Practical Guide to Current Management

6

The most commonly cited reason for not using

thalidomide in combination with dexamethasone for frontline

therapy is risk of deep vein thrombosis (DVT), which

is significantly higher with the combination than with

thalidomide alone. DVT was seen in both the initial Mayo

Clinic trial of combination thalidomide/dexamethasone

therapy (19%) and in the M.D. Anderson trial (15%).

These toxicities have prompted recommendations that

DVT prophylaxis with either therapeutic doses of warfarin,

a low molecular weight heparin, or aspirin be considered

when using this combination.

The role of thalidomide in newly diagnosed patients was

discussed in the context of the results of Eastern

Cooperative Oncology Group (ECOG) Study E1A00

[Rajkumar 2004]. In this study, 207 patients were

randomly assigned to receive dexamethasone with or

without the addition of thalidomide. Thalidomide was

administered orally at 200 mg/day. Dexamethasone 40 mg

daily was administered on days 1 to 4, 9 to 12, and 17 to

20 of a 30-day cycle. Responses were assessed after four

cycles of treatment. In the intent-to-treat patients, best

responses were defined as 50% reduction in serum and

urine M protein as measured by SPEP (serum protein

electrophoresis) and UPEP (urine protein electrophoresis),

respectively, and 90% reduction in urine M protein as

measured by UPEP, if only urinary protein was evaluable

for response. The efficacy and safety data for the study

Table 1: Eastern Cooperative Oncology Group Study E1A00: Efficacy and Safety

Efficacy

are summarized in Table 1. Patients treated with

dexamethasone alone showed response rates of 41%,

compared to 63% for those treated with thalidomide/

dexamethasone. In addition, DVT was seen in only 3% of

patients receiving dexamethasone, compared to18% in

patients receiving thalidomide/dexamethasone. The study

concluded that although response rates with thalidomide/

dexamethasone are superior to response rates with

dexamethasone alone, additional significant toxicity is

seen in patients receiving thalidomide/dexamethasone.

Some participants were of the opinion that there is still

a need for intense induction therapy with VAD (or similar

regimen) in patients who are candidates for stem cell

transplantation, particularly patients with hypercalcemia

and renal insufficiency, who require very rapid disease

control. Patients administered VAD typically receive

vincristine 0.4 mg, doxorubicin 9 mg/m 2 (by continuous

infusion every four hours for four days), and

dexamethasone 40 mg (orally on days 1 to 4, 9 to 12, and

17 to 20), administered every 30 days. However, VAD is

cumbersome to administer, with the need for central

venous access, and has the potential to cause

doxorubicin-associated cardiotoxicity as well as

neurotoxicity secondary to vincristine. In addition,

reported response rates of 55% are similar to response

rates of 41% seen in ECOG E1A00 patients administered

dexamethasone alone.

Thalidomide/Dexamethasone Dexamethasone

Patients 103 107

Best response within 4 cycles 73% 50%

p=0.002

Progressed at 4 months 3% 5%

Safety

Patients 102 101

Deep vein thrombosis (grade ≥ 3) 18% 3%

Grade 4 or higher toxicity 34% 17%

Grade ≥ 3 non-heme toxicity 68% 43%

Deaths 7% 11%

*Allowing for using serum M protein levels (or Q1 levels, in 2 patients) in patients in whom measurable urine M protein was unavailable at follow up.


Multiple Myeloma: A Practical Guide to Current Management

Although no randomized trials exist, one recent

retrospective study attempted to put the question of

VAD versus the combination of thalidomide and

dexamethasone to the test. The two regimens were

analyzed as induction therapy prior to autologous

peripheral blood stem cell transplantation [Cavo 2005].

The study was a case-control analysis of 200 patients

who entered two consecutive studies from 1996 to 2004

and received thalidomide and dexamethasone (n=100)

or VAD (n=100) for four cycles. Patients receiving

thalidomide were given initial oral doses of 100 mg/day.

After 14 days, the thalidomide dose was escalated to

200 mg/day. Patients were matched for age, clinical

stage of disease, and serum β 2 -microglobulin.

Significantly higher response rates were reported for

STARTING DOSAGE IN COMBINATION THERAPY

What is the starting dosage of thalidomide

recommended in combination therapy?

When using thalidomide in combination therapy, several

roundtable participants recommend the use of 50 mg

thalidomide per day as the starting dose while others begin

at 100 mg per day. Patients can be dose-escalated every

one to two weeks. Starting doses of 200 mg are generally

recommended for high-risk patients where the need for

cytoreduction is urgent. Clinical experience suggests that

this approach allows for maximum tolerability. In elderly

patients and patients with poor performance status, it is

particularly important to start with thalidomide at a dose of

50 or 100 mg. Clinicians who start at thalidomide doses of

50 mg and 100 mg will typically dose-escalate to doses of

200 to 400 mg per day based on tolerance. The most

common target dose level is 200 mg.

Does a lower starting dose of thalidomide adversely

impact response rate?

The consensus of this panel of experts was that it does

not. It was felt that finding a tolerable maximum dose and

patients receiving thalidomide and dexamethasone (76%

versus 52% for VAD; p200 mg/day recommended

with aggressive disease and high

tumor burden and risk factors

Special populations (e.g., the elderly, 50 mg/day starting dose.

poor performance status) Escalate by 50mg/day

q 2 weeks

7


Multiple Myeloma: A Practical Guide to

Current Management

ASSESSING RESPONSE

8

How many cycles of thalidomide should be given

before assessing response?

Most of the roundtable experts agree that for induction

therapy three to four monthly cycles of therapy should be

adequate for assessing a response. An inadequate response

to therapy is defined as less than a 25% decrease in

measurable paraprotein levels. Again, maximum

thalidomide dose must be titrated to achieve response

within the bounds of acceptable toxicity. Regarding the use

OPTIONS FOR NON–TRANSPLANTATION CANDIDATES

Which regimens are reasonable options for newly

diagnosed patients with myeloma who are not transplant

candidates?

This panel of experts felt there were numerous reasonable

options for use as induction therapy in patients deemed not

to be candidates for stem cell transplantation. Among these

were melphalan/prednisone, thalidomide alone or with

dexamethasone, dexamethasone alone, and possibly VAD

or DVd. Choice of regimen would be based on the same

factors as previously mentioned, including tumor burden,

need for rapid response, toxicity, and ease of administration.

Interesting data comparing the efficacy and safety of MPT

(melphalan, prednisone, thalidomide) with MP have come

from the Italian Myeloma Network, which carried out a

prospective, randomized trial in newly diagnosed patients

with a median age of 72 years (range 56-85). An interim

analysis of this study was presented at the annual meeting of

the American Society of Hematology in 2004 [Palumbo

2004] and updated at the 10 th Congress of the European

Hematology Association in June 2005 [Palumbo 2005]. The

overall endpoints of the study were response, event-free

survival, overall survival, and toxicity. In the study, patients

of thalidomide/dexamethasone in combination, there was

consensus that full-dose dexamethasone as per published

schedules should be used for cycle #1. If dexamethasone

toxicity is encountered, participating experts felt that the

drug could be administered only on days 1 to 4 of the

second and subsequent cycles or a 50% dose reduction of

total dexamethasone dose considered. It was felt that a

minimum of two cycles of thalidomide-based therapy

would be necessary to declare a lack of response based

upon the usual parameter of disease progression.

received both melphalan 4 mg/m 2 and prednisone 40 mg/m 2

on days 1 to 7. The thalidomide dosage was 100 mg/day.

The cycle of treatment was repeated every four weeks. In

the trial, partial remission was defined as an M protein

reduction of 50% to 99% measured by immunofixation. An

M protein reduction of 0% to 49% was defined as stable

disease. Based on updated results from June 2005, median

overall survival has not been reached. However, patients in

the MPT arm of the trial had higher partial, complete, and

near complete responses than did patients treated with MP

(MPT: 22.2% CR; 5.5% near CR; and 49.4%PR. MP: 4.2%

CR; 1.2% near CR; and 41.3% PR). The median EFS was

25.2 months after MPT and 13.7 after MP (P


Multiple Myeloma: A Practical Guide to

Current Management

COMBINATIONS AS INDUCTION THERAPY

Apart from thalidomide/dexamethasone, is there a

role for use of thalidomide in combination with other

agents as induction therapy in newly diagnosed

patients?

A number of thalidomide-based combination regimens

are being evaluated in clinical trials and these include the

following:

BTD (Biaxin, thalidomide, dexamethasone). Patients

with untreated multiple myeloma were administered

clarithromycin (Biaxin) 500 mg twice daily, thalidomide

50 to 200 mg daily, and dexamethasone 40 mg weekly

until disease progression. Minimum response was defined

as greater than 50% reduction in monoclonal

immunoglobulin or light chain levels (serum or urine). Of

50 evaluable patients, response was seen in 93% of

patients (13% CR, 40% near CR, 13% major responses,

and 27% partial responses). The regimen was considered

highly effective, with neurotoxicity that was mild to

moderate in nature. Median duration of treatment was

seven months. Four patients died, including three patients

with severe cardiopulmonary disease [Coleman 2002].

VTD (bortezomib, thalidomide, dexamethasone).

Patients with untreated multiple myeloma were assigned

to receive either TD (thalidomide/dexamethasone; n=130)

or VTD (n=30). Thalidomide was administered at a

dose of 200 mg/day; dexamethasone 20 mg/m 2 was

administered orally on days 1-4, 9-12, and 17-20,

and bortezomib was administered at several dose levels

(1.1 mg/m 2 ,1.3 mg/m 2 ,1.5 mg/m 2 ,1.7 mg/m 2 , and

1.9 mg/m 2 ). Overall response rates of 68% (TD) and 80%

(VTD) were observed and were not statistically

significantly different (p=0.18). However, among patients

who received VTD, the overall response was significantly

higher for patients receiving bortezomib ≥1.5 mg/m 2

(94% vs. 64% for patients receiving bortezomib


Multiple Myeloma: A Practical Guide to

Current Management

RELAPSE/REFRACTORY PATIENTS

10

What is appropriate therapy for patients who relapse

or are refractory to front-line therapy?

Choice of salvage therapy for relapse or for disease

refractory to induction therapy is dictated by the initial

regimen utilized. Considerations would include thalidomide

with or without dexamethasone, bortezomib, VAD, or stem

cell transplantation.

The roundtable faculty all agreed that thalidomide alone

or in combination with dexamethasone is reasonable and

effective salvage therapy for patients who relapse after

stem cell transplantation or who are refractory to initial

(non–thalidomide-containing) treatment. Published studies

suggest that salvage therapy with thalidomide alone yields

a response rate of 26% [Singhal 1999]; the addition of

dexamethasone, however, increases the response rate to

46% [Palumbo 2004].

The optimal dose of thalidomide when used in the

relapsed or refractory setting is debated. In high-risk

patients, it has been shown that a higher thalidomide dose

may offer clinical benefits to patients. In a phase II study,

169 patients with advanced multiple myeloma were treated

with thalidomide 200 mg/day [Barlogie 2001]. Doses were

escalated every two weeks in 200 mg increments to a

maximum of 800 mg. Of the patients who enrolled in

the study, 67% showed abnormal cytogenetics, 76% had

prior autologous transplants, 50% had β 2 -microglobulin

>3 mg/L, and 40% were 60 years or older. Response rates

Table 3: Thalidomide/Dexamethasone for Relapsed/Refractory Multiple Myeloma

were higher (43% versus 13% for patients who received

less than 42 g of thalidomide over three months; p=0.01)

and 2-year survival was longer (42% versus 20% for

patients who received less than 42 g of thalidomide over

three months; p=0.01) for high-risk patients who received

higher doses (more than 42 g) of thalidomide over

3 months of treatment rather than lower doses. Table 3

summarizes data from several trials that assessed various

doses of dexamethasone in combination with thalidomide.

Data from this table indicate that the regimen of

dexamethasone 20 mg/m 2 in combination with thalidomide

100-300 mg/day was associated in M protein decreases of

greater than 75% in 57% of patients with relapsed/

refractory multiple myeloma.

Although higher doses of thalidomide were administered

in the studies reported, the panel of experts recommended

a dosage schedule of 50 to 100 mg/day, with dose

escalation up to 200 mg/day, except in high-risk disease

states where higher doses might be appropriate for a

rapid response. These recommendations are supported by

published reports. In a 2004 study published in the Mayo

Clinic Proceedings [Richardson 2004], 30 patients with

relapsed/refractory multiple myeloma after stem cell

transplantation were treated with thalidomide doses of

200 to 600 mg/day. Patients had received an average

of five prior therapies for their disease. In this study,

responses were observed in patients receiving doses

of 200 to 400 mg/day, obviating the need for dose

escalation. Indeed, at thalidomide doses of ≥400 mg/day,

Thalidomide

M Protein Decrease (%)

Study Dose (mg/day) Dexamethasone Dose 75%-100% 50%-75% 25%-50%

Palumbo et al [2001] 100 40 mg/day 14/77 (18%) 18/77 (23%) 19/77 (25%)

Dimopoulos et al [2001] 200-400 20 mg/m 2 13/44 (30%) 11/44 (25%) 1/44 (2%)

Alexanian et al [2002] 100-300 20 mg/m 2 12/21 (57%) 1/21 (5%) N/A

Anagnostopoulos et al [2003] 200-600 20 mg/m 2 22/47 47%) — —

days 1-5 q 15 d


Multiple Myeloma: A Practical Guide to Current Management

dose-limiting toxicities in approximately 50% of patients

were observed.

There was much debate among the faculty about

duration of therapy with thalidomide when treating

relapsed or refractory myeloma. A minority opinion

was to treat with thalidomide with or without

dexamethasone until a response plateau was reached,

and then allow a treatment holiday. Paraprotein levels

OTHER SALVAGE THERAPIES

Is there a role for other agents in relapsed/refractory

patients with multiple myeloma?

Many possible alternative salvage regimens exist,

including cyclophosphamide-containing regimens, and

other combination chemotherapies. Nevertheless, while

several agents in combinations have been evaluated

in clinical studies, including combinations with

thalidomide, novel agents such as bortezomib or

lenalidomide hold most promise in this disease. One

key study has evaluated the role of bortezomib, a

proteasome inhibitor, in patients with relapsed multiple

myeloma. In the APEX (Assessment of Proteasome

Inhibition for Extending Remissions) study [Richardson

2005], 669 patients with relapsed multiple myeloma

were randomly assigned to receive either bortezomib

(1.3 mg/m 2 on days 1, 4, 8, and 11 for eight three-week

cycles followed by treatment on days 1, 8, 15, and 22

for three five-week cycles) or high-dose dexamethasone

would be monitored closely during time off therapy and

treatment reinstituted at time of disease progression.

However, the majority opinion was that indefinite

therapy with thalidomide at a well-tolerated dose level

was important. It was concluded that there is no

evidence to guide duration of therapy in this setting.

Therefore, the faculty suggested that for the responding

patient thalidomide therapy be continued indefinitely

with dose minimization to control toxicity.

(40 mg orally on days 1-4, 9-12, 17-20 for four fiveweek

cycles followed by treatment on days 1-4 for five

four-week cycles). The combined response rates were

38% and 18% for the bortezomib and dexamethasone

arms of the study, respectively (p


Multiple Myeloma: A Practical Guide to

Current Management

POSTTRANSPLANTATION MAINTENANCE

12

Is posttransplantation maintenance therapy of value

in multiple myeloma?

There were divergent opinions on maintenance therapy

for patients with multiple myeloma. Therapy in this

setting is being actively investigated, and the panel did not

arrive at any consensus regarding the agent(s) of choice

in this setting. In one study [Berenson 2002], alternateday

oral prednisone was evaluated at two dose levels (10

mg or 50 mg) in 250 patients with previously untreated

multiple myeloma following induction chemotherapy

with the VAD regimen. Although treatment-related

adverse events were similar in patients receiving either

10 or 50 mg alternate-day prednisone, the 50-mg dose was

associated with significantly longer progression-free

survival compared to the 10 mg dose (14 months vs. 5

months p=0.003) and median survival (37 months vs.

26 months p=0.05).

The National Cancer Institute of Canada (NCIC):MY-9

was a multi-center, randomized phase II trial that

evaluated the tolerability of combined thalidomide and

prednisone maintenance in multiple myeloma [Stewart

2004]. Patients were eligible if they had received

melphalan 200 mg/m 2 with autologous stem cell

transplants within one year of treatment onset.

Maintenance therapy was initiated within 60 to 100 days

after stem cell transplantation. In the maintenance arms

of the trial, patients were randomized to receive

prednisone 50 mg/day on alternate days and thalidomide

at a dose of either 200 mg/day or 400 mg/day. Therapy

discontinuation or toxicity-associated dose reductions in

thalidomide or prednisone within six months of therapy

initiation were endpoints of the trial. With 67 patients

enrolled and a median follow-up of 36.8 months, the

primary endpoint of the trial was observed in 31% and

64% of patients receiving thalidomide 200 mg/day and

400 mg/day, respectively. After allowing for dose

reduction, 76% and 41% of patients receiving

thalidomide 200 mg/day and 400 mg/day, respectively,

remained on any maintenance therapy 18 months after

registration. Dose reductions in thalidomide and

prednisone were observed in 88% and 72% of patients,

respectively, within two years of initiating maintenance

therapy. This trial established an appropriate dosing

schedule for phase III trials, utilizing the thalidomide

200 mg/day.

The Intergroupe Francophone du Myelome (IFM) 99 02

[Attal 2005] is the first trial evaluating the impact

of maintenance treatment with thalidomide on the

duration of response obtained after high-dose therapy.

Multiple myeloma patients (under 65 years at diagnosis)

with no or with only one adverse prognostic factor

(β 2 -microglobulin >3 mg/L or deletion of chromosome

13) were enrolled in the trial. Patients were treated with

the following:

• Three to four cycles of the VAD regimen;

• A first autologous transplantation after preparation with

melphalan 140 mg/m 2 ;

• A second autologous transplantation after preparation

with melphalan 200 mg/m 2 .

Patients without progressive disease three months

after the second transplantation were randomized to Arm

A (no maintenance treatment), Arm B (maintenance

treatment with pamidronate 90 mg/month), or Arm C

(maintenance treatment with thalidomide 100 mg/day

and pamidronate 90 mg/month). Updated data as of April

2005 are summarized in Table 4. The mean follow-up

from diagnosis was 36 months. Conclusions from this

trial are that thalidomide is an effective maintenance

therapy that prolongs duration of response after high

dose therapy and that pamidronate is effective

maintenance to decrease the incidence of bone events in

these patients.

Because there are no definitive data from phase III

clinical trials, routine maintenance therapy is not

currently recommended until current clinical studies

mature.


Multiple Myeloma: A Practical Guide to Current Management

Table 4: Interim Data From Intergroupe Francophone du Myelome 99 02: Maintenance Therapy with

Thalidomide* (IMW–April 2005)

Arm A Arm B (Pamidronate Arm C (Thalidomide 100 mg/day

Clinical Parameter Evaluated (No Maintenance) 90 mg/month) and Pamidronate 90 mg/month) p

3-yr Progression-free survival 34% 37% 56%


Multiple Myeloma: A Practical Guide to Current Management

14

Table 5: Management of Toxicities Associated with Thalidomide Therapy

Toxicity Management

Deep vein thrombosis prophylaxis High-risk patient: warfarin or low molecular weight heparin

Low-risk patient: aspirin

Peripheral neuropathy Poor history underestimates pre-existing neuropathy. Management must be individualized.

• Grade 1—reduce thalidomide dosage by 50%

• Grade 2— withhold thalidomide until toxicity resolves to baseline or decreases to below grade 1

and then restart at a 50% lower dose

• Grade 3 or 4—discontinue thalidomide permanently

Somnolence Instruct patients to take their total daily dose at bedtime or to split the dose, one half taken at dinner

and the other half at bedtime

Patients should avoid performing hazardous tasks

Advise patients to avoid the use of concurrent medications that may cause drowsiness

If obtundation, stupor, or coma occurs, withhold thalidomide until toxicity resolves to baseline then

restart the drug at a 50% lower dose

Constipation Advise patients about prophylactic measures, such as diet and exercise

Prescribe a low-dose stool softener and/or laxative

In case of obstipation requiring manual extraction or an enema, or in case of obstruction and toxic

megacolon, withhold thalidomide until condition resolves; then restart thalidomide therapy with the

addition of prophylactic laxatives and/or a 50% dose reduction

Skin rash For mild to moderate skin rash, withhold thalidomide until toxicity resolves to baseline or decreases to

below grade 1; then restart treatment with a 50% dose reduction

Ghobrial IM, Rajkumar SV. Management of thalidomide toxicity. J Support Oncol. 2003;1:194-205.

Incidence of DVT based on aspirin use is seen in

Figure 1, and the significance of DVT incidence analyzed

by groups is as follows:

• Not significant when Group 1 was compared with

Group 2 (p=0.5576).

• Significant when Group 1 was compared with Group 3

(p=0.0009).

• Significant when Group 2 was compared with Group 3

(p=0.0025).

• Significant when Groups 1 and 2 were compared with

Group 3 (p=0.0001).

Thus, this retrospective uncontrolled singleinstitution

study suggests that aspirin prophylaxis

initiated at the start of DVd-T chemotherapy may be of

Stevens-Johnson syndrome: discontinue thalidomide indefinitely

value in preventing deep vein thrombosis. It was

suggested that this effect of aspirin may be due to

attenuation of the increase in von Willebrand factor and

platelet aggregation which occurs after administration

of DVd-T. However, it was emphasized that aspirin has

not generally been effective in other studies of venous

thrombosis, and this observation needs to be analyzed

in a prospectively designed clinical trial. The optimal

dose of aspirin has not been determined. In the

Cleveland Clinic experience, 81 mg has been used,

whereas in the current ECOG trial 325 mg is being

evaluated.

Similarly, in other nonrandomized studies, enoxaparin

and nadroparine were effective in significantly reducing

the incidence of DVT.


Multiple Myeloma: A Practical Guide to Current Management

FUTURE DIRECTIONS

The panel of experts agreed that data regarding

lenalidomide, an agent that belongs to the immunomodulatory

class of drugs, were important to discuss in

the context of future directions in myeloma therapy.

Lenalidomide is an analog of thalidomide and has been

shown to inhibit multiple pathways that are implicated in

Incidence of Deep Vein Thrombosis

Figure 1: Incidence of deep vein thrombosis based on aspirin use in a 10-year retrospective study at the Cleveland

Clinic. Presented by MA Hussein at IMW, Sydney, Australia, April 2005.

multiple myeloma cells interacting with the bone marrow

microenvironment. However, its toxicity profile is more

favorable than the toxicity profile of thalidomide. Its use

in front-line therapy and in the treatment of relapsed and

refractory disease has been the subject of several clinical

studies.

Figure 1

15


Multiple Myeloma: A Practical Guide to

Current Management

LENALIDOMIDE

16

Is the combination of lenalidomide and dexamethasone

appropriate as front-line therapy for multiple myeloma?

And what about the use of lenalidomide in patients with

relapsed and refractory disease?

The combination of lenalidomide and dexamethasone

as induction therapy in the newly diagnosed patient was

first evaluated in a phase II trial at the Mayo Clinic

[Rajkumar 2004], where the regimen was used as

induction therapy for potential transplantation candidates.

Lenalidomide was administered orally at a daily dose of

25 mg on days 1 to 21. Dexamethasone 40 mg was

administered on days 1 to 4, 9 to 12, and 17 to 20. All

patients received aspirin once a day as DVT prophylaxis.

Four cycles (28 days each) of therapy were to be provided

for patients who were candidates for stem cell

transplantation. Responding patients who were not

candidates for stem cell transplantation were allowed to

continue therapy at the discretion of the study investigator.

In the study, the following were criteria for partial

response:

• At least 50% reduction in serum M protein;

• At least 90% reduction in urinary M protein or a

reduction to


Multiple Myeloma: A Practical Guide to Current Management

Lenalidomide with Standard Dexamethasone

Figure 3: Schema of the Southwest Oncology Group study, S0232, a phase III study that will evaluate the efficacy

and safety of lenalidomide with standard dexamethasone given for three cycles in newly diagnosed patients with

multiple myeloma. Patients in the control arm will receive standard-dose dexamethasone and placebo. MM indicates

multiple myeloma; PD, progressive disease. Presented by P. Greipp at IMW, Sydney, Australia, April 2005.

Exciting new data for relapsed/refractory multiple

myeloma has been reported from two randomized, doubleblind,

placebo-controlled, phase III trials of lenalidomide/

dexamethasone versus dexamethasone at the 2005 annual

meeting of the American Society of Clinical Oncology

[Weber 2005] and updated at the 10 th Congress of

the European Hematology Association meeting in June

2005.[Dimopoulous 2005] The MM-009 trial was a multicenter

trial conducted in 48 centers in North America; the

MM-010 trial was an international trial conducted in 51

centers. Most recent updated results from both studies

show that complete and partial responses were significantly

improved for patients receiving combination therapy with

lenalidomide/dexamethasone (MM-009: 61.2% versus

22.8% for dexamethasone, p


Multiple Myeloma: A Practical Guide to

Current Management

GOAL OF THERAPY

18

What should the goal of therapy be in multiple

myeloma?

Traditionally, therapy has been utilized to achieve

response (generally partial [PR]) and to ameliorate

symptoms. The value of achieving a complete (CR) or near

complete response has been much less clear. However,

with the availability of thalidomide, bortezomib, and soon

lenalidomide, the possibility of achieving CR will

increase, and goals of therapy may well change.

Roundtable participants felt that for the present, judicious

Table 6: Ongoing and Completed Trials in Multiple Myeloma

sequential use of available agents to maximize response

and duration of response should be the goal of the treating

physician. However, all were quick to add that with

improved tools for initial therapy and for management of

relapsed/refractory disease, the importance of attempting

to achieve a complete response may change dramatically.

Ongoing clinical trials and those recently completed are

listed in Table 6. It is hoped and anticipated that in the

near future oncologists/hematologists and their patients

will have many new and improved therapeutic options.

Total

Study Site Study Number Patients

Currently Enrolling

Multicenter, open-label phase IV study of Lenalidomide plus Dex

in previously treated subjects with MM

USA 12,000

Randomized phase III study of CC-5013 + Dex vs. CC-5013 vs. low dose Dex in MM,

with Thal/Dex salvage therapy for non-responders

USA ECOG E4A03 412

Randomized phase III double-blind study of maintenance therapy with CC-5013 or

placebo following autologous SCT for MM patients

USA CALGB 100104 544

Double-blind placebo-controlled phase III trial comparing Dex to Dex + CC-5013 in

newly diagnosed MM patients

USA SWOG S0232 500

Open-label phase I study of safety and efficacy of bortezomib combined with CC-5013

in relapsed and relapsed/refractory MM patients

USA 58

Phase II study of Biaxin, Lenalidomide, and Decadron for newly diagnosed MM patients USA 35

Multicenter phase I/II trial of Lenalidomide, Doxorubicin and Dex (RAD) in relapsed

or refractory MM patients

Germany 59

Multicenter, open-label study of oral Melphalan, Prednisone, and CC-5013 (MPR) as

induction treatment in elderly newly diagnosed MM patients

Italy 51

Phase I study of DVd + CC-5013 in relapsed/refractory MM USA CC-5013-MM-011 50

Completed and Awaiting Results

Phase II trial of CC-5013 + Dex in newly diagnosed MM patients USA 34

Open-label study of safety and efficacy of CC-5013 for relapsed MM patients USA CC-5013-MM-001 27

Multicenter, controlled, parallel group open-label study to evaluate efficacy and safety

of two CC-5013 dose regimens alone or in combo with Dex for relapsed or refractory

MM patients

USA CC-5013-MM-007 100

Phase II study of continuous vs syncopated dosing of CC-5013 for refractory MM patients USA CC-5013-MM-008 100

Multicenter, controlled, parallel group open-label double-blind study of CC-5013 + Dex

vs Dex alone for previously treated MM patientss

USA CC-5013-MM-009 302

Multicenter, controlled, parallel group open-label double-blind study of CC-5013 + Dex

vs Dex alone for previously treated MM patients

Europe CC-5013-MM-010 302

Open-label study of safety and efficacy of single agent CC-5013 for relapsed and

refractory MM

USA CC-5013-MM-014 200


Multiple Myeloma: A Practical Guide to

Current Management

CONCLUSIONS

Several consensus opinions arose from the roundtable

convened to discuss the management of multiple

myeloma.

• Optimum therapy for newly diagnosed transplantationcandidate

patients. Single-agent induction therapy

with dexamethasone is reasonable in low-risk,

low–tumor-burden patients, thalidomide can be added

in nonresponders after 6-8 weeks. In high-risk patients

and when there is need for rapid cytoreduction,

combination therapy is appropriate. Reasonable

combination therapy options for induction include

thalidomide plus dexamethasone, VAD and DVd, with

choice dependent in part on the patient’s candidacy for

subsequent stem cell transplantation. DVT prohylaxis

with full-dose anticoagulation is required for the

dexamethasone-thalidommide combination.

• Optimum therapy for newly diagnosed non–transplantation

candidate patients. Melphalan and prednisone remain the

gold standard, but the combination of melphalanprednisone

and thalidomide looks very promising.

• Starting dose of thalidomide. Finding a tolerable

maximum dose and accomplishing consistent dosing over

time was more important than the dose chosen to initiate

therapy. Starting doses of 50-100 mg are recommended.

However, in elderly patients and in patients with poor

performance status, thalidomide 50 mg/day was an

appropriate starting dose. Dose escalations were

recommended two weeks following initiation of therapy.

• Cycles of therapy. For induction therapy, three to four

cycles of therapy were adequate for assessing a response.

When using thalidomide and dexamethasone in

combination, full-dose dexamethasone should be used for

cycle 1. In the event of dexamethasone toxicity, the drug

could be administered at reduced-dose subsequent cycles.

• Regimens for non–transplantation candidates. Melphalan

and prednisone, thalidomide alone or with dexamethasone,

dexamethasone alone, and possibly VAD or DVd were

regimens that could be considered, based on factors such

as tumor burden, need for rapid response, toxicity and ease

of administration.

• Role of thalidomide-combinations in induction therapy.

Apart from studies on the combination of thalidomide

and dexamethasone, there are studies showing other

thalidomide combinations, which demonstrate favorable

responses. These include VTD (bortezomib, thalidomide,

dexamethasone), DVd-T (Liposomal doxorubicin,

vincristine, dexamethasone, thalidomide), and VT

(bortezomib, thalidomide). However, the roundtable

faculty’s only recommendation for a thalidomide-based

combination regimen was the combination of thalidomide

and dexamethasone.

• Thalidomide for relapsed/refractory disease. Thalidomide

alone or in combination with dexamethasone is reasonable

and effective salvage therapy for patients who relapse

after induction with an alternative regimen or after stem

cell transplantation or who are refractory to initial

treatment. For responding patients, thalidomide therapy

should be continued indefinitely with dose minimization

to control toxicity.

• Other agents in relapse/refractory disease. The recently

reported APEX study showed that bortezomib (compared

with high-dose dexamethasone) is effective in patients

with relapsed multiple myeloma.

• Posttransplantation maintenance therapy for multiple

myeloma. Maintenance therapy should be explored in the

clinical trial setting; however, published studies suggest

that alternate-day therapy with prednisone 50 mg,

thalidomide alone, or thalidomide in combination with

either prednisone or dexamethasone might be appropriate.

Management of toxicities. Thalidomide toxicities are

predictable and manageable with appropriate dose

modifications and with attention to DVT prophylaxis and

bowel regimens to avoid severe constipation (Table 5).

19


Multiple Myeloma: A Practical Guide to

Current Management

20

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21


Multiple Myeloma: A Practical Guide to

Current Management

APPENDICES

22

Appendix 1: The Durie-Salmon Staging for Multiple Myeloma

Stage Criteria Myeloma Mass (×10 12 cells/m 2 )

I All of the following: 10 g/dL

• Serum calcium 12 g/24hr)

Sub-classification criteria:

A: Normal renal function (serum creatinine level 2.0 mg/dL)

Appendix 2: The International Staging for Multiple Myeloma

Stage Criteria

I β 2 -microglobulin 5.5


Multiple Myeloma: A Practical Guide to

Current Management

CME Registration & Evaluation

Return to: University of Alabama School of Medicine

Division of Continuing Medical Education

500 22nd Street South

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Birmingham, AL 35233

Course Code: EJ1105-3354

Phone: 205-934-2687 Fax: 205-975-6902

Please complete the following evaluation in order to receive 2 Category 1 credits toward the AMA Physician’s Recognition Award. All evaluation

forms must be received by the Expiration Date of November 2006 in order to earn credit.

First Name: MI Last Name:

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Please CIRCLE your answer for each of the following Questions:

1. Treatment regimens currently considered appropriate for use in the newly diagnosed multiple myeloma patient

who may be considered for stem cell transplantation in the future include:

A. Thalidomide/ dexamethasone

B. Dexamethasone alone

C. VAD

D. All of the above

2. The APEX trial demonstrated superior clinical benefit for use of bortezomib compared to high-dose

dexamethasone in patients who had relapsed multiple myeloma.

A. True

B. False

3. Which of the following has NOT been demonstrated to be effective prophylaxis for deep venous thrombosis

in patients receiving thalidomide-based therapy for multiple myeloma?

A. Warfarin—therapeutic dose

B. Warfarin—low dose (1-2 mg/day)

C. Low molecular weight heparin

D. Aspirin

4. The toxicity profiles for thalidomide and lenalidomide are very similar.

A. True

B. False

23


Multiple Myeloma: A Practical Guide to

Current Management

CME Registration & Evaluation

24

5. The role of maintenance therapy in the management of multiple myeloma has been clearly established by

controlled clinical trials.

A. True

B. False

6. Currently, which of the following is most accurate regarding the goal of therapy for patients with multiple

myeloma?

A. Judicious use of available agents in tolerable doses to maximize response and duration of response.

B. Treat aggressively to attempt to achieve a complete response (CR) since this has been conclusively shown to be

associated with superior outcomes.

7. Was the content objective and balanced?

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8. Was the content evidence-based?

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9. Was the type of evidence identified?

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B. No

10. Was the source of evidence identified?

A. Yes

B. No

11. Was the content commercially biased?

A. Yes

B. No

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