Combination Chemotherapy in Treating Patients With Multiple Myeloma

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

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.

Study Overview

• Status: Completed
• Conditions: Multiple Myeloma and Plasma Cell Neoplasm
• Intervention / Treatment: Drug: melphalan; Drug: prednisone; Drug: dexamethasone

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 Type: Interventional
• Enrollment (Actual): 595
• Phase: Phase 3

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 120 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival	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	9 years

Secondary Outcome Measures

Outcome Measure	Time Frame
Time to progression	9 years
Response rates	9 years
Toxicity	9 years
Quality of Life	9 years

Collaborators and Investigators

• Sponsor: NCIC Clinical Trials Group
• Investigators: Study Chair: Chaim Shustik, MD, Royal Victoria Hospital - Montreal

Publications and helpful links

General Publications

• Shustik C, Belch A, Robinson S, Rubin SH, Dolan SP, Kovacs MJ, Grewal KS, Walde D, Barr R, Wilson J, Gill K, Vickars L, Rudinskas L, Sicheri DA, Wilson K, Djurfeldt M, Shepherd LE, Ding K, Meyer RM. A randomised comparison of melphalan with prednisone or dexamethasone as induction therapy and dexamethasone or observation as maintenance therapy in multiple myeloma: NCIC CTG MY.7. Br J Haematol. 2007 Jan;136(2):203-11. doi: 10.1111/j.1365-2141.2006.06405.x.
• Shustik C, Belch A, Robinson S, et al.: Dexamethasone (dex) maintenance versus observation (obs) in patients with previously untreated multiple myeloma: a National Cancer Institute of Canada Clinical Trials Group study: MY.7. [Abstract] J Clin Oncol 22 (Suppl 14): A-6510, 560s, 2004.
• Shustik C, Belch A, Meyer R, et al.: Melphalan-dexamethasone is not superior to melphalan-prednisone as induction therapy in multiple myeloma. [Abstract] Proceedings of the American Society of Clinical Oncology 20: A-1191, 2001.

Study record dates

Study Major Dates

• Study Start (Actual): June 2, 1995
• Primary Completion (Actual): May 3, 2004
• Study Completion (Actual): December 21, 2009

Study Registration Dates

• First Submitted: November 1, 1999
• First Submitted That Met QC Criteria: January 26, 2003
• First Posted (Estimate): January 27, 2003

Study Record Updates

• Last Update Posted (Actual): April 2, 2020
• Last Update Submitted That Met QC Criteria: March 31, 2020
• Last Verified: March 1, 2020

More Information

Terms related to this study

• Keywords: stage II multiple myeloma; stage III multiple myeloma; stage I multiple myeloma
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Immunoproliferative Disorders; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Multiple Myeloma; Neoplasms, Plasma Cell; Plasmacytoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Dexamethasone; Prednisone; Melphalan
• Other Study ID Numbers: MY7; CAN-NCIC-MY7 (Other Identifier: PDQ); NCI-V95-0713 (Other Identifier: NCI); CDR0000064328 (Other Identifier: PDQ)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No