myeloma committee agenda 2002/myeloma.pdfs0115 high risk, auto transplant dr. cruz s0231...

OCTOBER 25 - 28, 2002 SOUTHWEST ONCOLOGY GROUP MYELOMA 1

MYELOMA COMMITTEE

Chair: Bart Barlogie, M.D., Ph.D.

Statisticians: John J. Crowley, Ph.D. Joth L. Jacobson, M.S. Jason McCoy, M.S. Erik Rasmussen, M.S.

Data Coordinator: Remi Gallevo, M.D. Protocol Coordinator: Larissa Rios, B.A.

Basic Science: John Shaughnessy, Ph.D.

Cytogenetics Liaison: Sandra Wolman, M.D.

Nurses: Beth E. Getman, R.N., B.S.N. Kathy F. Young, R.N., B.S.N.

Clinical Research Associate:

Ellen Chase, B.S.

2 MYELOMA SOUTHWEST ONCOLOGY GROUP OCTOBER 25 - 28, 2002

CONTENTS Myeloma Committee Agenda . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

Initial Registrations to Therapeutic Studies. . . . . . . . . . . . . . . . . . . . . 4

Patient Registration by Study and Arm . . . . . . . . . . . . . . . . . . . . . . . 5

S9321 Phase III Intergroup (INT 0141) . . . . . . . . . . . . . . . . . . . . . . 6

S9628 Phase II . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

S0115 Phase II . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

S0120 Biologic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

S0204 Phase II . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24

S0231 Phase II . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

S0232 Phase III . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26


Myeloma Committee Agenda

Scientific Session S9321 Comparing S9321 with Previous Studies in Multiple Myeloma Dr. Barlogie, Arkansas

New Agents in Myeloma: Recent Experience with PS-341 and ImiD

Dr. Barlogie and Dr. Zangari, Arkansas

Gene Expression Comparisons of Waldenstrom's and Multiple Myeloma

Dr. Shaughnessy

Active Studies S9628 Amyloidosis Dr. Dhodapkar

S0120 MGUS Dr. Dhodapkar

S0204 DT Followed by Tandem Transplant Dr. Hussain

Proposed Studies S0115 High Risk, Auto Transplant Dr. Cruz

S0231 Asymptomatic Myeloma Dr. Mehta

S0232 ImiD Dr. Zonder

Biology


Initial Registrations to Therapeutic Studies

by 12 month Intervals MYELOMA COMMITTEE

0

50

100

150

200

250

Time of registration

JUL 1997JUN 1998

27

30

30

116

JUL 1998JUN 1999

32

35

41

98

JUL 1999JUN 2000

36

7

25

64

JUL 2000JUN 2001

5213

15

JUL 2001JUN 2002

13587

MEMBER AFFILIATES CCOP NON-SWOG


Patient Registration by Study and Arm

MYELOMA COMMITTEE

Jan-June

2002 July-Dec 2001 Jan-June

2001 All Patients

S9321 MMyel, Standard vs High Dose Priming, No Allo Match

HDCTX+PBSC prior to Autol BMT 0 0 3 290 HDCTX+PBSC prior to chemo 0 0 5 285 0 0 8 575 Transplant or VBMCP Allogeneic BMT 0 0 0 38 Autologous BMT 0 0 5 232 VBMCP 0 0 6 235 0 0 11 505 Maintenance/Observation Interferon 2 4 8 143 Observation 2 5 8 137 4 9 16 280 Autol BMT after PD on VBMCP Autologous BMT after VBMCP 4 5 6 50 S9628 Amyloidosis, Dex + Interferon Induction Therapy

Dexamethasone Induction 12 13 4 88 Maintenance Therapy Dexamethasone+Alpha Interferon 7 4 0 48 S9805 WM, Tandem HD Melph + PBSCT Stem Cell Collection

Stem Cell Collection 0 0 0 7 First Transplant HD Melph+PBSCT+G-CSF 0 0 0 6 Second Transplant Second HD Melph+PBSCT+G-CSF 0 0 2 4 Maintenance Therapy Maintenance Alpha Interferon 0 0 0 1 S9922 MMYEL, DCEP +/- Thalidomide DCEP 0 2 3 9 DCEP + Thalidomide 0 6 2 10 0 8 5 19


S9321/III

S9321 Phase III Intergroup (INT 0141) Coordinating Group: SWOG

Standard Dose Versus Myeloablative Therapy for Previously Untreated Symptomatic Multiple Myeloma

Intergroup Participants: SWOG, CALGB (9312), ECOG

Study Coordinators: B Barlogie, K Anderson (CALGB), R Kyle (ECOG)

Statisticians: J Crowley, J Jacobson

Data Coordinator: R Gallevo

Date Activated: 1/15/1994

Date Closed: 10/1/2000

Schema

Observation

CompleteresponseVAD

2-4cycles

REGISTER

RANDOMIZE

HDCTXMESNAG-CSF

HDCTXMESNAG-CSFPBSC

HDCTXMESNAG-CSFPBSC

REGISTRATION

REGISTRATION

Allogeneictransplant

Autologoustransplant

GVHD prophylaxisw/ methotrexate,cyclosporine

REGISTER

VBMCP

Progressivedisease

Autologoustransplant

RANDOMIZE

Interferon

*Patients not registering for an allogeneic transplant will be randomized to autologous transplant vs chemotherapy.

*

Objectives To perform a randomized trial, in newly diag-nosed patients with symptomatic multiple mye-loma (MM), of standard therapy versus myeloab-lative therapy, in order to examine whether the greater tumor cytoreduction effected by intensive therapy translates into extended event-free sur-vival and overall survival. Specifically, to com-pare, in untreated patients up to age 70, standard combination chemotherapy with VBMCP versus peripheral blood stem cell (PBSC) supported

myeloablative therapy with Melphalan (MEL) 140 mg/m² and total body irradiation (TBI) 1,200 cGY, following induction with VAD x 4 and high-dose cyclophosphamide (HDCTX) 4.5 g/m² plus G-CSF for patients with at least stable dis-ease.

To compare in responders (≥ 75% cytoreduction) to both VBMCP and autotransplant supported myeloablative therapy, the value of IFN versus no maintenance.


S9321/III

To offer to patients up to age 55, with an HLA-compatible MLC-non-reactive donor, allogeneic transplantation with the same myeloablative regimen of MEL 140 mg/m² plus TBI 1,200 cGY.

To evaluate the associated toxicities and possible long term side effects of these regimens, includ-ing the development of myelodysplastic disease and/or acute myeloblastic leukemia.

Patient Population Initially, patients must have newly diagnosed multiple myeloma requiring treatment (Durie-Salmon Stage ≥I). Patients with smoldering mye-loma will be eligible provided there is evidence of progressive disease. Protein criteria must be present, but patients with IgM myeloma or no quantifiable monoclonal proteins are not eligible. Pre-treatment bone marrow aspirate slides must be submitted.

Patients must have received no prior chemother-apy for this disease. Only prior local radiation is allowed, and it must have been given for isolated plasmacytomas.

Patients must be no older than 70 years. Patients must have a performance status of 2 or better. Pa-tients must not have uncontrolled diabetes, any significant co-morbid medical condition, any un-controlled life-threatening infection, unstable an-gina, difficult to control congestive heart failure, uncontrolled hypertension or cardiac arrhythmias, myocardial infarction in the last six months, a history of chronic obstructive or chronic restric-tive pulmonary disease, or a history of chronic cerebral vascular accident. Ejection fraction must be within the institutional normal range. Patients must be negative for both Hepatitis-B and HIV, and they must be evaluated for Hepatitis-C and CMV.

Prior to the second registration (HDCTX, Mesna, G-CSF) patients must have adequate renal, pul-monary, and cardiac function.

Prior to the third registration (VBMCP or trans-plant) patients must have stable or better disease. Patients must have a performance status of 0-1 and adequate renal function. There must be evi-dence of financial coverage for transplant. Pa-tients who had previously been randomized to mandatory stem cell collection (second registra-tion) must now have at least 6 x 108 peripheral blood mononuclear cells per kilogram to be eligi-ble to continue.

Prior to the fourth registration (IFN maintenance or observation) patients must have ≥ 75% re-sponse and adequate hematologic counts. At least five weeks, but no more than 12 weeks must have elapsed since the patient received autologous

BMT or since the end of the last cycle of treat-ment with VBMCP.

Stratification/Descriptive Factors There will be no descriptive or stratification fac-tors for the initial registration.

At the second registration patients will be strati-fied by (1) stage at diagnosis: I-II vs IIIa vs IIIb, (2) serum beta-2 microglobulin (SB2M) at diag-nosis: < 6 ug/ml vs ≥ 6 ug/ml, (3) response to VAD induction: ≥ 75% vs 50-74 vs < 50% re-gression, and (4) an allogeneic transplant planned for this patient: yes vs no.

At the third registration patients will be stratified by (1) treatment patient will be receiving: VBMCP (optional prior stem cell collection) vs autologous transplant (mandatory prior stem cell collection) vs allogeneic transplant (no prior stem cell collection required), and (2) SB2M at this registration: < 3ug/ml vs ≥ 3 ug/ml.

At the fourth registration patients will be strati-fied by (1) response to treatment: ≥ 75% regres-sion but no CR vs CR and (2) last treatment pa-tient received: autologous transplant vs VBMCP.

Accrual Goals We expect to accrue a total of 500 eligible ran-domized patients and 60 patients eligible for al-logeneic transplantation. The first interim analy-sis is planned after the randomization of 333 eli-gible patients. Additional interim analyses are planned when ½ and ¾ of the total expected deaths have occurred. The final analysis will be performed after three years of follow-up from the close of the initial randomization.

Summary Statement This study accrued a total of 899 patients, 99 of whom are currently listed as ineligible (13 due to insufficient documentation that when submitted could make the patient eligible). Two eligible pa-tients received no protocol treatment, and are not analyzable. During initial VAD treatment, one major deviation involved an improper dosing of vincristine, one patient discontinued VAD after one day of treatment due to myocardial infarction and another patient received radiotherapy along with VAD; these patients are evaluable for toxic-ity. Twenty-three patients have had fatal toxici-ties, of which fifteen were due to infection, two to cardiac failure, one to pneumonitis, one to diver-ticulitis, one to a secondary AML/MDS malig-nancy and three who died of as yet unknown but possibly treatment-related causes. In addition, 150 other patients have had Grade 4 toxicities.

Five hundred fifty-four eligible patients have been randomized to autologous transplant or


S9321/III

VBMCP chemotherapy after stem cell collection. During priming, one patient died due to infection.

Thirty-seven eligible patients were registered to the allogeneic transplant step. Thirteen patients died of possibly treatment-related causes. The al-logeneic transplant arm has been closed for rea-sons of patient safety.

Two hundred twenty-two eligible patients have undergone autologous transplantation, three of whom died of pneumonitis, one of whom died of cardiac failure, and two of whom died of infec-tion. One hundred eighty-nine other patients have had Grade 4 toxicities. Two hundred twenty-

seven eligible patients have been started on VBMCP, with one death due to cardiac edema and 27 other patients with Grade 4 toxicities re-corded to date.

Forty-five eligible patients have been registered to autologous transplant after progression on VBMCP.

Two hundred fifty-nine eligible patients have gone on to the maintenance randomization to in-terferon versus observation. One patient on inter-feron died of respiratory infection and 14 other patients have experienced Grade 4 toxicities to date.

Registration by Institution Initial Registration

Institutions Total Reg Institutions

Total Reg

ECOG 383 Loyola University 5

CALGB 190 LSU-New Orleans CCOP 5 Arkansas, U of 35 Michigan, U of 5 Wichita CCOP 23 St Francis/Stormont/Kansas, U of 5 Columbia River CCOP 21 Colorado, U of 4 Toronto Hospital/Henry Ford Hosp 18 Hawaii CCOP, Univ of 4 Michael Reese Hosp/Oklahoma, Univ of 17 LSU-Shreveport 4 Utah, U of 11 Mansfield Gen Hosp/Cleveland Clinic OH 4 Columbus CCOP 10 Ozarks Reg CCOP 4 Sutter Hlth Western/Davis, U of CA 10 San Antonio, U of TX 4 Cleveland Clinic OH 8 St Louis University 4 Oregon Hlth Sci Univ 8 Wayne State Univ 4 Salem Hospital/Oregon Hlth Sci Univ 8 Bay Medical Center/Michigan, U of 3 Tulane University 7 Columbia University 3 Virginia Mason CCOP 7 Davis, U of CA 3 Atlanta Reg CCOP 6 Dayton CCOP 3 Tulane Univ/San Antonio, U of TX 6 Mt Sinai Med Ctr/Cleveland Clinic OH 3 BAMC/WHMC 5 Puget Sound 3 Cincinnati, U of/Cincinnati MC, U of 5 Upstate Carolina 3 Good Samaritan Hosp/Loyola University 5 All Other Institutions 38 Harris Methodist/San Antonio, U of TX 5 Total (67 Institutions) 899

Registration, Eligibility, and Evaluability Initial Registration

Data as of July 15, 2002

VAD Induction VAD Induction NUMBER REGISTERED 899 RESPONSE ASSESSMENT 798

INELIGIBLE 99 Determinable 705 Insufficient Documentation 70 Not Determinable 90 Irreversible 57 Too Early 1 Reversible 13 Not Applicable 2 ELIGIBLE 800 Not Analyzable 2 TOXICITY ASSESSMENT Evaluable 795 Not Evaluable 3


S9321/III

Patient Characteristics Initial Registration


VAD Induction

(n=798) VAD Induction

(n=798) AGE RACE Median 54 .0 White (Non-Hispanic) 626 78% Minimum 25 Black (Non-Hispanic) 136 17% Maximum 70 Hispanic 21 3% Asian 13 2% SEX Native 1 0% Males 474 59% Unknown 1 0% Females 324 41%

Treatment Summary Initial Registration


VAD Induction NUMBER ON PROTOCOL TREATMENT 0

NUMBER OFF PROTOCOL TREATMENT 798 REASON OFF TREATMENT Treatment completed as planned 614 Toxicity or side effects 33 Refusal unrelated to toxicity 21 Progression/relapse 19 Death 26 Other - not protocol specified 52 Reason under review 33 MAJOR PROTOCOL DEVIATIONS 3

Number of Patients with a Given Type and Degree of Toxicity Initial Registration


VAD Induction VAD Induction (n=795) (n=795)

Grade

Grade

TOXICITY Unk 0 1 2 3 4 5 TOXICITY Unk 0 1 2 3 4 5 ADR 0 792 0 0 0 0 3 Lung 5 595 59 91 31 12 2 Cardiovascular 6 519 81 96 71 20 2 Metabolic 0 543 61 67 88 36 0 Clotting 2 791 2 0 0 0 0 Miscellaneous 0 784 8 1 2 0 0 Dermatologic 6 341 165 277 4 2 0 Musculoskeletal 1 767 9 13 5 0 0 Ear 1 788 2 2 1 1 0 Neurologic 9 318 241 140 73 14 0 Endocrine 1 750 4 38 1 1 0 Pain 9 346 159 204 73 4 0 Eye 4 732 19 37 3 0 0 Renal/Bladder 5 688 44 32 11 13 2 Flu-like Symptoms 0 352 184 201 54 4 0 Secondary Malignancy 0 793 0 0 0 1 1 Gastrointestinal 14 218 261 209 80 12 1 Sexual/Reproductive Function 1 787 4 2 1 0 0 Hematologic 0 81 125 251 252 86 0 Hemorrhage 4 743 28 12 7 1 0 MAXIMUM GRADE Immunological 3 783 4 4 0 1 0 ANY TOXICITY Infection 7 600 19 47 101 6 15 Number 0 13 33 201 375 150 23 Liver 4 711 55 17 8 0 0


S9321/III

Registration, Eligibility, and Evaluability Priming, No Allo Match


TOTAL

HDCTX+ PBSC prior

to Autol BMT

HDCTX+ PBSC prior

to chemo NUMBER REGISTERED 575 290 285

INELIGIBLE 21 15 6 ELIGIBLE 554 275 279 Analyzable, Pend. Elig. 1 1 0 RESPONSE ASSESSMENT Determinable 344 171 173 Not Determinable 83 43 40 Too Early 1 1 0 Not Applicable 126 60 66 TOXICITY ASSESSMENT Evaluable 522 263 259 Not Evaluable 26 11 15 Too Early 6 1 5

Patient Characteristics Priming, No Allo Match


HDCTX+PBSC prior to Autol BMT

(n=275)

HDCTX+PBSC prior to chemo

(n=279) AGE Median

54 .0

54 .0

Minimum 30 28 Maximum 70 70 SEX Males

159

58%

168

60%

Females 116 42% 111 40% RACE White (Non-Hispanic)

214

78%

218

78%

Black (Non-Hispanic) 49 18% 48 17% Hispanic 8 3% 9 3% Asian 3 1% 3 1% Native 0 0% 1 0% Unknown 1 0% 0 0% STAGE I-II

118

43%

124

44%

IIIa 128 47% 130 47% IIIb 29 11% 25 9% SERUM BETA-2 M < 6ug/ml

198

72%

196

70%

≥ 6ug/ml 77 28% 83 30% RESPONSE ≥ 75%

133

48%

144

52%

50-74% 58 21% 59 21% < 50% 60 22% 64 23% N/A 24 9% 12 4%


S9321/III

Treatment Summary Priming, No Allo Match


TOTAL

HDCTX+ PBSC prior

to Autol BMT

HDCTX+ PBSC prior

to chemo NUMBER ON PROTOCOL TREATMENT 5 1 4

NUMBER OFF PROTOCOL TREATMENT 549 274 275 REASON OFF TREATMENT Treatment completed as planned 484 244 240 Toxicity or side effects 1 1 0 Refusal unrelated to toxicity 12 2 10 Progression/relapse 0 0 0 Death 2 2 0 Other - not protocol specified 22 12 10 Reason under review 28 13 15 MAJOR PROTOCOL DEVIATIONS 17 5 12

Number of Patients with a Given Type and Degree of Toxicity Priming, No Allo Match Data as of July 15, 2002

HDCTX+ PBSC prior to Autol BMT HDCTX+PBSC prior to chemo

(n=263) (n=259)

Grade Grade

TOXICITY Unk 0 1 2 3 4 5 Unk 0 1 2 3 4 5 Cardiovascular 2 210 26 19 5 0 1 4 210 19 19 6 1 0 Dermatologic 0 182 27 53 1 0 0 0 180 22 55 1 1 0 Ear 0 262 0 1 0 0 0 0 258 0 1 0 0 0 Endocrine 0 261 0 2 0 0 0 0 256 0 3 0 0 0 Eye 0 260 1 2 0 0 0 0 256 1 2 0 0 0 Flu-like Symptoms 2 166 36 53 6 0 0 1 172 35 41 9 1 0 Gastrointestinal 3 100 81 57 20 2 0 1 113 68 59 16 2 0 Hematologic 0 20 7 20 26 190 0 0 18 13 13 26 189 0 Hemorrhage 1 232 14 7 9 0 0 1 235 16 2 4 1 0 Immunological 0 258 5 0 0 0 0 0 257 2 0 0 0 0 Infection 2 204 3 5 44 4 1 1 194 1 5 56 2 0 Liver 0 246 13 2 1 1 0 0 245 12 1 1 0 0 Lung 4 222 10 16 7 4 0 3 226 7 18 4 1 0 Metabolic 0 208 21 17 13 4 0 1 200 28 18 10 2 0 Miscellaneous 0 262 1 0 0 0 0 0 257 1 1 0 0 0 Musculoskeletal 0 259 0 4 0 0 0 0 257 1 1 0 0 0 Neurologic 1 210 29 21 2 0 0 0 201 31 22 5 0 0 Pain 5 169 49 29 11 0 0 0 176 37 36 9 1 0 Renal/Bladder 1 245 8 6 2 0 1 0 240 10 8 1 0 0 Sexual/Reproductive Function 0 262 0 0 1 0 0 0 259 0 0 0 0 0 MAXIMUM GRADE ANY TOXICITY Number

0 4 12 22 34 190 1

0 5 15 20 28 191 0


S9321/III

Registration, Eligibility, and Evaluability Transplant or VBMCP


TOTAL Allogeneic

BMT Autologous

BMT VBMCP NUMBER REGISTERED 505 38 232 235

INELIGIBLE 19 1 10 8 ELIGIBLE 486 37 222 227 RESPONSE ASSESSMENT Determinable 314 16 145 153 Not Determinable 52 13 19 20 Too Early 1 0 1 0 Not Applicable 119 8 57 54 TOXICITY ASSESSMENT Evaluable 466 36 214 216 Not Evaluable 11 1 5 5 Too Early 9 0 3 6

Patient Characteristics Transplant or VBMCP


Allogeneic BMT

(n=37) Autologous BMT

(n=222) VBMCP (n=227)

AGE Median

47 .0

54 .0

55 .0

Minimum 31 31 28 Maximum 55 70 70 SEX Males

25

68%

127

57%

139

61%

Females 12 32% 95 43% 88 39% RACE White (Non-Hispanic)

27

73%

170

77%

177

78%

Black (Non-Hispanic) 8 22% 42 19% 37 16% Hispanic 0 0% 6 3% 9 4% Asian 2 5% 3 1% 3 1% Native 0 0% 0 0% 1 0% Unknown 0 0% 1 0% 0 0%


S9321/III

Treatment Summary Transplant or VBMCP


TOTAL Allogeneic

BMT Autologous

BMT VBMCP NUMBER ON PROTOCOL TREATMENT 8 0 2 6

NUMBER OFF PROTOCOL TREATMENT 478 37 220 221 REASON OFF TREATMENT Treatment completed as planned 358 23 194 141 Toxicity or side effects 7 0 0 7 Refusal unrelated to toxicity 3 0 2 1 Progression/relapse 38 0 0 38 Death 14 9 1 4 Other - not protocol specified 29 5 7 17 Reason under review 29 0 16 13 MAJOR PROTOCOL DEVIATIONS 10 5 2 3

Number of Patients with a Given Type and Degree of Toxicity Transplant or VBMCP


Allogeneic BMT Autologous BMT (n=36) (n=214)

Grade Grade

TOXICITY Unk 0 1 2 3 4 5 Unk 0 1 2 3 4 5 ADR 0 36 0 0 0 0 0 0 214 0 0 0 0 0 Cardiovascular 1 9 4 9 8 4 1 1 118 43 29 18 4 1 Clotting 0 36 0 0 0 0 0 1 213 0 0 0 0 0 Dermatologic 0 4 8 20 3 1 0 2 68 46 91 7 0 0 Ear 0 36 0 0 0 0 0 0 211 1 1 1 0 0 Endocrine 0 35 0 1 0 0 0 1 212 1 0 0 0 0 Eye 0 30 2 3 1 0 0 0 203 2 8 1 0 0 Flu-like Symptoms 0 13 4 13 6 0 0 2 59 32 88 30 3 0 Gastrointestinal 0 1 2 0 20 13 0 2 12 19 47 84 50 0 Hematologic 0 2 0 1 0 33 0 0 11 1 2 12 188 0 Hemorrhage 0 24 3 1 4 2 2 0 185 22 3 4 0 0 Immunological 0 34 1 0 1 0 0 1 207 5 1 0 0 0 Infection 0 18 0 0 9 1 8 2 128 3 6 67 6 2 Liver 0 14 4 5 11 2 0 1 179 18 11 4 1 0 Lung 0 17 1 4 4 8 2 3 149 21 18 16 4 3 Lymphatics 0 36 0 0 0 0 0 0 213 1 0 0 0 0 Metabolic 0 24 3 3 5 1 0 0 131 23 21 35 4 0 Miscellaneous 0 35 0 0 0 1 0 1 210 3 0 0 0 0 Musculoskeletal 0 36 0 0 0 0 0 0 208 3 2 1 0 0 Neurologic 0 17 7 6 5 1 0 1 124 37 37 14 1 0 Pain 0 13 11 3 9 0 0 1 114 40 30 28 1 0 Renal/Bladder 0 21 5 4 0 5 1 1 188 9 12 3 1 0 Sexual/Reproductive Function 0 36 0 0 0 0 0 0 213 0 0 1 0 0 Syndromes 0 16 7 3 7 1 2 0 212 0 0 1 1 0 MAXIMUM GRADE ANY TOXICITY Number

0 1 0 0 2 20 13

0 2 1 4 12 189 6


S9321/III

Number of Patients with a Given Type and Degree of Toxicity (continued)

Transplant or VBMCP Data as of July 15, 2002

VBMCP (n=216)

Grade

TOXICITY Unk 0 1 2 3 4 5 ADR 0 215 0 0 1 0 0 Cardiovascular 4 170 29 6 6 0 1 Clotting 0 216 0 0 0 0 0 Dermatologic 5 120 34 56 0 1 0 Ear 0 213 1 1 1 0 0 Endocrine 0 209 6 1 0 0 0 Eye 4 198 6 5 3 0 0 Flu-like Symptoms 3 99 60 51 3 0 0 Gastrointestinal 2 113 59 30 11 1 0 Hematologic 0 15 18 46 111 26 0 Hemorrhage 3 201 7 2 3 0 0 Immunological 0 212 2 2 0 0 0 Infection 10 146 12 21 26 1 0 Liver 0 203 8 4 1 0 0 Lung 1 176 6 28 4 0 1 Lymphatics 1 215 0 0 0 0 0 Metabolic 0 169 25 14 8 0 0 Miscellaneous 1 215 0 0 0 0 0 Musculoskeletal 0 209 3 2 2 0 0 Neurologic 2 100 64 39 11 0 0 Pain 3 104 49 50 10 0 0 Renal/Bladder 1 195 11 7 1 1 0 Sexual/Reproductive Function 0 210 1 3 2 0 0 Syndromes 0 216 0 0 0 0 0 MAXIMUM GRADE ANY TOXICITY Number

0 4 3 51 130 27 1

Registration, Eligibility, and Evaluability Autol BMT after PD on VBMC


Autologous BMT

after VBMCP

Autologous BMT

after VBMCP NUMBER REGISTERED 50 TOXICITY ASSESSMENT 45

INELIGIBLE 5 Evaluable 37 ELIGIBLE 45 Not Evaluable 2 Analyzable, Pend. Elig. 3 Too Early 6 RESPONSE ASSESSMENT Determinable 23 Not Determinable 8 Too Early 11 Not Applicable 3


S9321/III

Registration, Eligibility, and Evaluability Maintenance/Observation


TOTAL Interferon Observation NUMBER REGISTERED 280 143 137

INELIGIBLE 21 12 9 ELIGIBLE 259 131 128 Analyzable, Pend. Elig. 4 2 2 RESPONSE ASSESSMENT Determinable 99 71 28 Not Determinable 13 10 3 Too Early 28 10 18 Not Applicable 119 40 79 TOXICITY ASSESSMENT Evaluable 109 109 0 Not Evaluable 13 12 1 Too Early 10 10 0 Not Applicable 127 0 127

Patient Characteristics Maintenance/Observation


Interferon

(n=131) Observation

(n=128) AGE Median

54 .0

55 .0

Minimum 29 32 Maximum 69 71 SEX Males

78

60%

71

55%

Females 53 40% 57 45% RACE White (Non-Hispanic)

104

79%

104

81%

Black (Non-Hispanic) 22 17% 21 16% Hispanic 2 2% 1 1% Asian 3 2% 1 1% Unknown 0 0% 1 1% TX Autol BMT

77

59%

73

57%

VBMCP 49 37% 50 39% VBMCP followed by Autol BMT 5 4% 5 4% RESPONSE 75-99%

104

79%

103

80%

CR 27 21% 25 20%


S9321/III

Treatment Summary Maintenance/Observation


Interferon NUMBER ON PROTOCOL TREATMENT 18


Number of Patients with a Given Type and Degree of Toxicity Maintenance/Observation Data as of July 15, 2002

Interferon Interferon (n=109) (n=109)

Grade

Grade

TOXICITY Unk 0 1 2 3 4 5 TOXICITY Unk 0 1 2 3 4 5 Cardiovascular 1 89 7 6 6 0 0 Lymphatics 0 108 1 0 0 0 0 Dermatologic 4 76 14 13 1 1 0 Metabolic 0 93 11 3 1 1 0 Ear 1 106 1 1 0 0 0 Miscellaneous 0 108 0 1 0 0 0 Endocrine 1 104 2 1 1 0 0 Musculoskeletal 1 103 3 2 0 0 0 Eye 1 104 2 1 1 0 0 Neurologic 2 53 20 24 8 2 0 Flu-like Symptoms 4 21 28 29 26 1 0 Pain 1 39 30 30 8 1 0 Gastrointestinal 3 42 24 28 12 0 0 Renal/Bladder 0 101 4 2 1 1 0 Hematologic 0 25 15 29 33 7 0 Secondary Malignancy 0 108 0 0 0 1 0 Hemorrhage 0 103 6 0 0 0 0 Sexual/Reproductive Function 0 105 2 2 0 0 0 Immunological 0 105 3 1 0 0 0 Infection 6 76 4 11 10 1 1 MAXIMUM GRADE Liver 0 93 12 3 1 0 0 ANY TOXICITY Lung 1 83 7 11 6 0 1 Number 0 2 4 28 60 14 1


S9628/II

S9628 Phase II Coordinating Group: SWOG

Phase II Study of Dexamethasone and Alpha-Interferon in AL Amyloidosis

Intergroup Participants: SWOG, CALGB

Study Coordinators: M Dhodapkar, R Larson (CALGB)




Objectives To evaluate the efficacy of dexamethasone and alpha interferon in terms of response in patients with primary systemic amyloidosis (AL amyloi-dosis).

To evaluate the overall and progression-free sur-vival.

To identify prognostic factors that may relate to response and overall survival in this group of pa-tients.

To evaluate the quantitative and qualitative tox-icities of this regimen in patients with AL amy-loidosis.

Patient Population Patients must have a histologic diagnosis of pri-mary systemic (AL) amyloidosis and evidence of tissue involvement other than carpal tunnel syn-drome. Patients must not have overt multiple myeloma.

Patients must not have received prior alpha inter-feron or be planning to receive dexamethasone for AL amyloidosis. Patients with prior Melpha-lan and prednisone therapy are eligible. Patients must not have received any cytotoxic therapy within four weeks of registration. Patients must have a performance status of 0-3 and no uncon-trolled diabetes, active peptic ulcer disease, New York Heart Association class IV congestive heart failure, or another medical condition precluding the use of high dose steroids.

To be eligible for the second registration, patients must have completed induction therapy without experiencing disease progression or unacceptable toxicity.

Stratification/Descriptive Factors At the time of induction registration, patients will be stratified by prior therapy: untreated vs previ-ously treated with Melphalan and prednisone, or iodo-doxorubicin.

Accrual Goals The accrual goal for this study is 50 patients in each of the prior treatment strata, for a total of 100 patients.

Summary Statement Eighty-eight patients have been registered to this study as of June 30, 2002, of whom seven are currently listed as ineligible (2 due to insufficient documentation that when submitted could make the patient eligible). One eligible patient received no protocol therapy and is not analyzable for any endpoint. Four patients had fatal toxicities from Dexamethasone induction: one died of cardiac failure and three died of as yet unknown but pos-sibly treatment-related causes. In addition, eleven other patients had Grade 4 induction toxicities.

Forty-eight patients have been registered to the maintenance step, of whom none are currently listed as ineligible. One patient received an im-proper dosing schedule of dexamethosone, but is still evaluable for toxicity. Five patients have ex-perienced Grade 4 toxicities on the maintenance step.


S9628/II

Induction Therapy By 12 Month Intervals

0

10

20

Time of Registration

JAN 1997DEC 1997

16

JAN 1998DEC 1998

18

JAN 1999DEC 1999

12

JAN 2000DEC 2000

13

JAN 2001DEC 2001

17

JAN 2002DEC 2002

12

Total

Registration by Institution Induction Therapy

Registrations ending June 30, 2002

Institutions Total Reg Institutions

Total Reg

Cleveland Clinic OH 21 Carilion Medical Ctr/Temple University 1

Arkansas, U of 17 Central IL CCOP 1 CALGB 13 Columbus CCOP 1 Cincinnati MC, U of 3 Eisenhower Army MC/BAMC/WHMC 1 Montana CCOP 3 Henry Ford Hosp 1 Puget Sound 3 Kansas City CCOP 1 Scott & White/TX A&M 3 Keesler USAF Med Ctr/Mississippi, U of 1 Wichita CCOP 3 Meridia Hillcrest/Cleveland Clinic OH 1 Grand Rapids CCOP 2 Mississippi, U of 1 N Colorado Med Ctr/Colorado, U of 2 Our Lady of Lourdes/LSU-Shreveport 1 Scott & White CCOP 2 Upstate Carolina 1 St Luke's-Roosevelt/Columbia University 2 West Florida Med Ctr/Arkansas, U of 1 Arizona, U of 1 Total (26 Institutions) 88 Breslin Cancer Ctr/Henry Ford Hosp 1


S9628/II

Registration, Eligibility, and Evaluability Induction Therapy

Registrations ending June 30, 2002; Data as of July 15, 2002

Dexamethasone

Induction Dexamethasone

Induction NUMBER REGISTERED 88 RESPONSE ASSESSMENT 80

INELIGIBLE 7 Determinable 31 Insufficient Documentation 6 Not Determinable 15 Irreversible 4 Too Early 25 Reversible 2 Not Applicable 9 ELIG./ PEND. ELIG. 81 Analyzable, Pend. Elig. 8 TOXICITY ASSESSMENT Not Analyzable 1 Evaluable 72 Too Early 8

Patient Characteristics Induction Therapy


Dexamethasone Induction

(n=80) Dexamethasone Induction

(n=80)

AGE RACE Median 64 .5 White (Non-Hispanic) 68 85% Minimum 32 Black (Non-Hispanic) 8 10% Maximum 77 Hispanic 3 4% Native 1 1% SEX Males 60 75% PRIOR THERAPY Females 20 25% Yes 14 18% No 66 83%

Treatment Summary Induction Therapy


Dexamethasone

Induction NUMBER ON PROTOCOL TREATMENT 10



S9628/II

Number of Patients with a Given Type and Degree of Toxicity Induction Therapy


Dexamethasone Induction Dexamethasone Induction (n=72) (n=72)

Grade

Grade

TOXICITY Unk 0 1 2 3 4 5 TOXICITY Unk 0 1 2 3 4 5 ADR 0 69 0 0 0 0 3 Lung 2 51 4 11 3 1 0 Cardiovascular 2 33 6 15 10 5 1 Metabolic 1 58 8 2 3 0 0 Clotting 1 71 0 0 0 0 0 Miscellaneous 0 71 0 1 0 0 0 Dermatologic 0 66 4 1 0 1 0 Musculoskeletal 1 67 1 2 1 0 0 Endocrine 0 67 1 4 0 0 0 Neurologic 2 40 15 11 4 0 0 Eye 3 60 1 6 1 1 0 Pain 1 55 11 4 1 0 0 Flu-like Symptoms 1 38 18 11 4 0 0 Renal/Bladder 0 59 3 3 5 2 0 Gastrointestinal 2 42 11 8 7 2 0 Sexual/Reproductive Function 0 70 0 2 0 0 0 Hematologic 0 39 14 9 9 1 0 Hemorrhage 1 64 5 1 1 0 0 MAXIMUM GRADE Immunological 0 69 3 0 0 0 0 ANY TOXICITY Infection 1 63 0 3 4 1 0 Number 1 4 7 22 23 11 4 Liver 0 64 4 1 3 0 0

Registration, Eligibility, and Evaluability Maintenance


Dexamethasone+ Alpha

Interferon


Interferon NUMBER REGISTERED 48 TOXICITY ASSESSMENT 48

ELIG./ PEND. ELIG. 48 Evaluable 39 Analyzable, Pend. Elig. 4 Too Early 9 RESPONSE ASSESSMENT Determinable 10 Not Determinable 10 Too Early 16 Not Applicable 12

Patient Characteristics Maintenance


Dexamethasone+Alpha Interferon

(n=48)

Dexamethasone+Alpha Interferon

(n=48)

AGE RACE Median 63 .0 White (Non-Hispanic) 43 90% Minimum 32 Black (Non-Hispanic) 4 8% Maximum 78 Hispanic 1 2% SEX Males 37 77% Females 11 23%


S9628/II

Treatment Summary Maintenance



Interferon NUMBER ON PROTOCOL TREATMENT 15


Number of Patients with a Given Type and Degree of Toxicity Maintenance


Dexamethasone+ Alpha Interferon Dexamethasone+

Alpha Interferon (n=39) (n=39)

Grade

Grade

TOXICITY Unk 0 1 2 3 4 5 TOXICITY Unk 0 1 2 3 4 5 Cardiovascular 3 23 6 4 2 1 0 Lung 1 26 1 9 2 0 0 Dermatologic 1 25 11 2 0 0 0 Metabolic 0 28 8 1 2 0 0 Endocrine 0 37 0 2 0 0 0 Musculoskeletal 0 33 3 2 1 0 0 Eye 1 29 3 5 1 0 0 Neurologic 1 20 11 2 5 0 0 Flu-like Symptoms 2 13 13 7 4 0 0 Pain 1 24 3 8 3 0 0 Gastrointestinal 1 18 8 6 5 1 0 Renal/Bladder 0 27 2 3 7 0 0 Hematologic 0 20 6 5 6 2 0 Sexual/Reproductive Function 0 38 1 0 0 0 0 Hemorrhage 1 35 1 2 0 0 0 Immunological 0 38 1 0 0 0 0 MAXIMUM GRADE Infection 1 31 2 1 4 0 0 ANY TOXICITY Liver 0 33 3 0 2 1 0 Number 0 3 6 7 18 5 0


S0115/II

S0115 Phase II

A Phase II Trial Evaluating Modified High Dose Melphalan (100 mg/m2) and Autologous Peripheral Blood Stem Cell Supported Transplantation

(SCT) for High Risk Patients with Multiple Myeloma and/or Light Chain Amyloidosis (AL Amyloidosis) (A BMT Study)

Study Coordinators: V Sanchorawala, J Cruz



Objectives To evaluate overall survival in patients with ei-ther high risk (age > 65 years or on dialysis sec-ondary to renal failure) multiple myeloma or high risk AL amyloidosis treated with modified high-dose intravenous melphalan (modified HDM) (100 mg/m2) x 2 cycles with autologous stem cell transplantation.

To evaluate hematologic responses in multiple myeloma and AL amyloidosis after 2 courses of modified HDM.

To evaluate the quantitative and qualitative tox-icities associated with this regimen.

To evaluate the prognostic importance of immu-nological and cytogenetic markers in this patient population.

Patient Population Patients must have been diagnosed with stage II or III multiple myeloma or biopsy proven amy-loidosis in association with a clonal plasma cell disorder within one year prior to registration. All patients must be greater than 65 years of age or have insufficient renal function defined as creatinine greater than 2 mg/dL, in spite of hydra-tion, resolution of hypercalcemia, and induction chemotherapy if treated previously. Patients with

multiple myeloma must have quantifiable M-components of IgG, IgA, IgD, IgE and/or urinary kappa or lambda light chain [Bence Jones pro-tein] excretion must be present. Patients must not have IgM peaks.

Patients must not have received more than one prior treatment for multiple myeloma or AL amy-loidosis including VAD, dexamethasone alone, cyclophosphamide or up to three months of tha-lidomide (patients on thalidomide for more than three months are ineligible). Patients must not have received prior transplant or treatment with melphalan/prednisone.

Patients must have a Zubrod performance status of 0-2. MM patients may have performance status of 3-4 based solely on bone pain and AL patients may have performance status of 3 relating to pe-ripheral neuropathy. Patients must have adequate hematologic, cardiac, pulmonary and hepatic function.

Stratification/Descriptive Factors Patients are stratified by disease type: high risk multiple myeloma vs. amyloidosis

Accrual Goals Ninety-nine eligible patients will be accrued to this study.


S0120/BIOLOGIC

S0120 Biologic

A Prospective Observational Biologic Study of Asymptomatic Patients with Monoclonal Gammopathy and Plasmaproliferative Disorders

Study Coordinators: M Dhodapkar, J Shaughnessy, B Barlogie, S Wolman

Statisticians: J Crowley, J McCoy



Objectives To establish a serum, cell and tissue bank of pro-spectively collected samples from patients with asymptomatic plasmaproliferative diseases in a national cooperative group setting.

To assess the feasibility of accruing patients with this disease.

To evaluate if patterns of gene expression or cy-togenetics exist that allow molecular delineation of "MGUS subtypes".

To characterize the cellular and humoral immune response to known tumor antigens in these pa-tients and cryopreserve sera / T cells for future evaluation.

To identify, in a preliminary fashion, biological correlates that may relate to progression to symp-tomatic disease.

Patient Population Patients must have a plasmaproliferative disease including MGUS, asymptomatic myeloma and solitary plasmacytoma that does not require ther-apy.

Patients must not have received prior treatment for their disease with the exception of bisphos-phonates.

Patients must have a Zubrod performance status of 0-2.


Summary Statement As of June 30, 2002 no patients have been regis-tered to this study.


S0204/II

S0204 Phase II

A Phase II Trial of Thalidomide/Dexamethasone Induction Followed by Tandem Melphalan Transplant and Prednisone/Thalidomide Maintenance

in Newly Diagnosed Multiple Myeloma Patients (A BMT Study)

Study Coordinators: M Hussein, J Shaughnessy, P Lin, A Mohamed, J Batanian




Objectives To assess efficacy and toxicity of thalido-mide/dexamethasone as a pre-transplant induction regimen.

To obtain preliminary data relative to the safety, and efficacy of combining prednisone and tha-lidomide for maintenance.

To determine the relationship of chromosome 13 abnormalities by conventional cytogenetics and FISH analysis to therapeutic responses in recently diagnosed myeloma patients and to examine the predictive value of specific subsets of chromo-some aberrations in relation to event-free and overall survival after intensive treatment.

To evaluate the immune reconstitution and recov-ery post-transplant for both first and second transplants.

Patient Population Patients must have newly diagnosed active multi-ple myeloma requiring treatment (Durie-Salmon

Stage of I or higher). Patients with IgM peaks are ineligible unless there is either > 30% bone mar-row plasmacytosis or > 3 lytic lesions on skeletal survey.

Patients must not have received more than one cycle of prior chemotherapy. Patients must not have received prior radiotherapy to greater than half of the pelvis.

Patients must have adequate renal, pulmonary and cardiac function. Patients must be between 18 and 66 years of age at registration and have a Zubrod performance status of 0-2. Patients with poor performance status (3-4) based solely on bone pain will be eligible.


Summary Statement As of June 30, 2002 no patients have been regis-tered to this study.


S0231/II

S0231 Phase II

A Natural History, Observational Study of Patients with Asymptomatic Myeloma, Followed by a Phase II Study of Treatment with Zoledronate,

Thalidomide, and Dexamethasone at the Time of Progression to Symptomatic Myeloma

Study Coordinator: P Mehta



Objectives To enroll in an observational study and follow progress of patients with asymptomatic multiple myeloma.

Upon progression or presentation de novo with high risk features, to re-register patients to an ex-ploratory phase II prevention trial to prevent fur-ther progression to symptomatic multiple mye-loma and/or to re-establish an earlier stage of dis-ease (i.e. MGUS).

To investigate a combination of zoledronate, low dose thalidomide and dexamethasone for the pur-pose of further stopping progression of disease and causing regression of disease.

To evaluate baseline features with special empha-sis on genomics to examine at the genomic level

the subset of patients with early disease progres-sion versus those who continue with indolent dis-ease.

To examine toxicities of the chemoprevention regimen in these patients.

Patient Population Patients must have a diagnosis of monoclonal gammopathy and must be asymptomatic. Patients with small lytic bone lesions are eligible.

Patients must have a Zubrod performance status of 0-2 and adequate renal and hepatic function.

Accrual Goals One-hundred fifty eligible patients will be ac-crued to this study.


S0232/III

S0232 Phase III

Phase III Trial Comparing Dexamethasone to Dexamethasone + ImiD in Patients with Newly Diagnosed Multiple Myeloma

Study Coordinators: J Zonder, B Barlogie



Objectives To compare the progression-free survival in newly diagnosed multiple myeloma patients treated with either Dexamethasone followed by ImiD at progression, or the combination of Dex-amethasone and ImiD.

To evaluate the associated toxicities and possible long-term side effects of these regimens in pa-tients with newly diagnosed multiple myeloma.

Patient Population Patients must be newly diagnosed with multiple myeloma with quantifiable M-protein.

Patients must not have had any prior therapy for multiple myeloma. Localized radiation is allowed provided it was not given to the sole site of evaluable disease. Patients must not be eligible or willing to receive any concurrent transplant ther-apy for multiple myeloma.

Patients must have adequate marrow function and a Zubrod performance status of 0-2

Accrual Goals Five hundred eligible patients will be accrued to this study.

myeloma committee agenda 2002/myeloma.pdfs0115 high risk, auto transplant dr. cruz s0231...

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