Combination Chemotherapy in Treating Patients With Multiple Myeloma

Sponsor

NCIC Clinical Trials Group (Other)

Overall Status

Completed

CT.gov ID

NCT00002678

Collaborator

(none)

595

Enrollment

Locations

Arms

174.7

Actual Duration (Months)

16.1

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one drug may kill more tumor cells. It is not yet known which combination chemotherapy regimen is most effective in treating patients with multiple myeloma.

PURPOSE: Randomized phase III trial to compare the effectiveness of various combination chemotherapy regimens in treating patients with multiple myeloma.

Condition or Disease	Intervention/Treatment	Phase
Multiple Myeloma and Plasma Cell Neoplasm	Drug: dexamethasone Drug: melphalan Drug: prednisone	Phase 3

Detailed Description

OBJECTIVES:

Compare the overall survival of patients with previously untreated stage I-III multiple myelome treated with melphalan combined with dexamethasone or prednisone as induction therapy.
Compare the overall survival of patients with stable or responding disease after induction treated with dexamethasone vs observation alone as maintenance therapy.
Compare the time to progression, response rate, and quality of life of patients treated with these regimens.
Compare the toxic effects of these regimens in these patients.

OUTLINE: This is a randomized, multicenter study. Patients are stratified by center, stage (I or II vs III), creatinine (less than 2.0 mg/dL vs 2.0 mg/dL or greater), and intention to use prophylactic bisphosphonate (yes vs no).

Induction: Patients are randomized to 1 of 4 treatment arms.
Arms I and II: Patients receive induction comprising oral prednisone followed by oral melphalan on days 1-4.
Arms III and IV: Patients receive induction comprising oral melphalan and oral dexamethasone (DM) on days 1-4 of all courses and DM on days 15-18 of courses 1-3.

Induction for arms I-IV continues every 4 weeks for 12 courses in the absence of disease progression or unacceptable toxicity. Patients with stable or responding disease after induction proceed to maintenance therapy.

Maintenance:
Arms I and III: Patients undergo observation.
Arms II and IV: Patients receive oral DM on days 1-4. Maintenance therapy continues every 4 weeks for arms II and IV and every 3 months for arms I and III in the absence of disease progression or unacceptable toxicity. Patients on arms I-IV who develop disease progression proceed to reinduction.
Reinduction: Patients restart induction on the arm to which they were originally randomized. Reinduction continues every 4 weeks in the absence of stable response lasting 16 weeks, disease progression, or unacceptable toxicity. Patients who achieve a stable response lasting 16 weeks restart maintenance therapy. Patients who experience further disease progression during reinduction are taken off study.

Quality of life is assessed at baseline, on day 1 of courses 1-3 and then every 3 courses during induction, and then every 3 months during maintenance therapy.

Patients are followed every 6 months.

PROJECTED ACCRUAL: A maximum of 600 patients will be accrued for this study within 6 years.

Study Design

Study Type:

Interventional

Actual Enrollment :

595 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Comparative Study of Dexamethasone vs Prednisone (Both in Combination With Melphalan) as Induction Therapy in Untreated Symptomatic Myeloma With an Additional Assessment of Dexamethasone vs no Additional Treatment as Maintenance Therapy in Non-Progressing Patients

Actual Study Start Date :

Jun 2, 1995

Actual Primary Completion Date :

May 3, 2004

Actual Study Completion Date :

Dec 21, 2009

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Melphan plus prednisone melphalan plus prednisone qd x 4 28 day cycles x 12 cycles; No treatment after stable response.	Drug: melphalan 9 mg/m2 daily for 4 days given orally on an empty stomach every 4 weeks Drug: prednisone 100 mg daily for 4 days given orally on a full stomach with each cycle of melphalan
Active Comparator: Melphan, prednisone pluse dexamethasone melphalan plus prednisone qd x 4 28 day cycles x 12 cycles; dexamethasone qd x 4 q 28 days after non-progression	Drug: dexamethasone 40 mg daily for four days given orally and repeated every 28 days should commence on day 29 of the twelfth cycle of induction therapy.

Arm

Intervention/Treatment

Active Comparator: Melphan plus prednisone

melphalan plus prednisone qd x 4 28 day cycles x 12 cycles; No treatment after stable response.

Drug: melphalan

9 mg/m2 daily for 4 days given orally on an empty stomach every 4 weeks

Drug: prednisone

100 mg daily for 4 days given orally on a full stomach with each cycle of melphalan

Active Comparator: Melphan, prednisone pluse dexamethasone

melphalan plus prednisone qd x 4 28 day cycles x 12 cycles; dexamethasone qd x 4 q 28 days after non-progression

Drug: dexamethasone

40 mg daily for four days given orally and repeated every 28 days should commence on day 29 of the twelfth cycle of induction therapy.

Outcome Measures

Primary Outcome Measures

Overall survival [9 years]
To compare overall survival between: i) patients receiving melphalan-prednisone and those receiving melphalan-dexamethasone as induction therapy ii) patients maintained by dexamethasone and those on no additional treatment in the subgroup whose disease has not progressed at the time of the 12th induction cycle

Secondary Outcome Measures

Time to progression [9 years]
Response rates [9 years]
Toxicity [9 years]
Quality of Life [9 years]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 120 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

DISEASE CHARACTERISTICS:

Histologically proven previously untreated stage I-III multiple myeloma
Patients with stage I disease must be symptomatic
Must meet at least 1 of the following conditions:
Plasma cells in osteolytic lesion or soft tissue tumor biopsy
At least 10% plasmacytosis in bone marrow aspirate and/or biopsy
Less than 10% plasma cells in bone marrow but at least 1 bony lesion
Detectable serum M-component of IgG, IgA, IgD, or IgE
If only light chain disease (urine M-protein) present, urinary excretion of light chain (Bence Jones) protein must be at least 1.0 g/24 hours

PATIENT CHARACTERISTICS:

Age:

18 and over

Performance status:

ECOG 0-4

Life expectancy:

Not specified

Hematopoietic:

Not specified

Hepatic:

Not specified

Renal:

Not specified

Other:

No other concurrent serious illness
Concurrent diabetes allowed, at the discretion of the treating physician, if changes in insulin requirements can be managed
No other prior or concurrent malignancy except curatively treated nonmelanomatous skin cancer or carcinoma in situ of the cervix

PRIOR CONCURRENT THERAPY:

Biologic therapy:

No concurrent immunizations
No concurrent filgrastim (G-CSF) or other growth factors as prophylaxis
Concurrent epoetin alfa for anemia allowed

Chemotherapy:

No prior chemotherapy

Endocrine therapy:

Prior dexamethasone or prednisone with radiotherapy for spinal cord compression allowed if cumulative dexamethasone dose no greater than 120 mg and cumulative prednisone dose no greater than 792 mg
Prior or concurrent corticosteroids for hypercalcemia allowed

Radiotherapy:

See Endocrine therapy
Prior focal radiotherapy allowed
Concurrent focal radiotherapy during induction allowed
Concurrent radiotherapy for palliation (e.g., painful osteolytic lesions or spinal cord compression) allowed

Surgery:

At least 2 years since prior surgery for radiologic or endoscopic diagnosis of gastric or duodenal ulcer

Other:

At least 2 years since prior medication for radiologic or endoscopic diagnosis of gastric or duodenal ulcer
Prior or concurrent bisphosphonates for hypercalcemia allowed

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	St. Mary's/Duluth Clinic Health System	Duluth	Minnesota	United States	55805
2	Tom Baker Cancer Center - Calgary	Calgary	Alberta	Canada	T2N 4N2
3	Cross Cancer Institute	Edmonton	Alberta	Canada	T6G 1Z2
4	British Columbia Cancer Agency - Centre for the Southern Interior	Kelowna	British Columbia	Canada	V1Y 5L3
5	British Columbia Cancer Agency	Vancouver	British Columbia	Canada	V5Z 4E6
6	Providence Health Care - Vancouver	Vancouver	British Columbia	Canada	V6Z 1Y6
7	British Columbia Cancer Agency - Vancouver Island Cancer Centre	Victoria	British Columbia	Canada	V8R 6V5
8	Moncton Hospital	Moncton	New Brunswick	Canada	E1C 6ZB
9	Doctor Leon Richard Oncology Centre	Moncton	New Brunswick	Canada	E1C 8X3
10	Saint John Regional Hospital	Saint John	New Brunswick	Canada	E2L 4L2
11	Newfoundland Cancer Treatment and Research Foundation	St. Johns	Newfoundland and Labrador	Canada	A1B 3V6
12	Nova Scotia Cancer Centre	Halifax	Nova Scotia	Canada	B3H 2Y9
13	William Osler Health Centre	Brampton	Ontario	Canada	L6W 2Z8
14	Cancer Care Ontario-Hamilton Regional Cancer Centre	Hamilton	Ontario	Canada	L8V 5C2
15	Kingston Regional Cancer Centre	Kingston	Ontario	Canada	K7L 5P9
16	Cancer Care Ontario-London Regional Cancer Centre	London	Ontario	Canada	N6A 4L6
17	Trillium Health Centre	Mississauga	Ontario	Canada	L5B 1B8
18	Credit Valley Hospital	Mississauga	Ontario	Canada	L5M 2N1
19	Southlake Regional Health Centre	Newmarket	Ontario	Canada	L3Y 2P9
20	Lakeridge Health Oshawa	Oshawa	Ontario	Canada	L1G 2B9
21	Algoma District Medical Group	Sault Sainte Marie	Ontario	Canada	P6B 1Y5
22	Hotel Dieu Health Sciences Hospital - Niagara	St. Catharines	Ontario	Canada	L2R 5K3
23	Northeastern Ontario Regional Cancer Centre, Sudbury	Sudbury	Ontario	Canada	P3E 5J1
24	Toronto East General Hospital	Toronto	Ontario	Canada	M4C 3E7
25	Toronto Sunnybrook Regional Cancer Centre	Toronto	Ontario	Canada	M4N 3M5
26	St. Michael's Hospital - Toronto	Toronto	Ontario	Canada	M5B 1W8
27	Toronto General Hospital	Toronto	Ontario	Canada	M5G 2C4
28	Princess Margaret Hospital	Toronto	Ontario	Canada	M5G 2M9
29	Humber River Regional Hospital	Weston	Ontario	Canada	M9N 1N8
30	Cancer Care Ontario - Windsor Regional Cancer Centre	Windsor	Ontario	Canada	N8W 2X3
31	Queen Elizabeth Hospital, PEI	Charlottetown	Prince Edward Island	Canada	C1A 8T5
32	CHUS-Hopital Fleurimont	Fleurimont	Quebec	Canada	J1H 5N4
33	Hopital Charles Lemoyne	Greenfield Park	Quebec	Canada	J4V 2H1
34	McGill University	Montreal	Quebec	Canada	H2W 1S6
35	Hopital de L'Enfant Jesus	Quebec City	Quebec	Canada	G1J 1Z4
36	Hopital du Saint-Sacrement, Quebec	Quebec City	Quebec	Canada	G1S 4L8
37	Allan Blair Cancer Centre	Regina	Saskatchewan	Canada	S4T 7T1