Originally published as JCO Early Release 10.1200/JCO.2008.18.0109 on September 8 2008

This Article Full Text (PDF) From JCO 1983 Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Google Scholar Articles by Durie, B. G.M. PubMed PubMed Citation Articles by Durie, B. G.M.

Myeloma Therapy: 25 Years Forward—Immune Modulation Then and Now

Brian G.M. Durie

Cedars-Sinai Outpatient Cancer Center at the Samuel Oschin Comprehensive Cancer Institute, Hematology/Oncology; and Aptium Oncology, Los Angeles, CA

In 1983, immune modulation was being studied in the laboratory and in the clinic.^1,2 The development of the clonogenic human myeloma stem-cell assay allowed testing of fresh myeloma bone marrow samples as well as a range of cell lines.^3,4 Leukocyte interferons were of particular interest at that time.^5,6 These were heady times: interferons had been on the cover of Time magazine and were clearly the molecules to beat. However, although clinical trials confirmed antimyeloma activity, it was unclear whether the antitumor effect was mediated directly via antiproliferative action on the myeloma cells or indirectly through cells in the microenvironment. Separate studies had shown that MRC-5 fibroblasts as well as macrophages could serve as enhancing "mother" cells for myeloma colony growth.⁷ Cocultivation and self-renewal studies revealed a complex interaction between self-renewing myeloma stem cells and modulating microenvironmental accessory cells. Our results indicated synergy between interferons and cytotoxic agents, such as alkylating agents in the antimyeloma activity.^4-6

Subsequent clinical trials confirmed the therapeutic benefit in patients with myeloma using interferons within combinations as front-line therapy as well as for maintenance.^8,9 But over time, it also became clear that the benefit was much less than we had hoped. On average, responses increased by approximately 15% and remissions and survival improved by 6 to 12 months at most. For the first time, there was more careful assessment and comparison of prolongation of remission (progression-free survival) versus improvement in overall survival (or not).

With multiple studies, it seemed that interferons prolonged remission, but might or might not impact overall survival. Does this sound familiar? These are the exact questions being addressed today with regard to thalidomide as part of the melphalan, prednisone, and thalidomide combination or within the total therapy-2 approach, with or without thalidomide.¹⁰ Interestingly, in our 1983 article using levamisole as an immunomodulating agent for maintenance, the same issue emerged.² The alternating combination chemotherapy of vincristine, melphalan, cyclophosphamide, and prednisone (VMCP)/vincristine, cyclophosphamide, doxorubicin, and prednisone or VMCP/vincristine, carmustine, doxorubicin, and prednisone versus melphalan and prednisone produced a significantly longer median survival of 40 months, as compared with 24 months for melphalan and prednisone (P = .01). With the addition of levamisole in the maintenance phase, there was a marginally enhanced improvement in survival (P = .06). These results with combination chemotherapy provided the best survival results yet obtained by the Southwest Oncology Group and compared favorably with all previously reported myeloma therapy trials, which had median survivals in the 30 to 32 month range. The initial median survival projection of 48 months for patients randomly assigned to VMCP plus levamisole was particularly promising. It was intriguing that levamisole, an agent that influenced lymphocyte and macrophage function, could improve outcomes in myeloma treatment.

Fast forward 25 years: surprisingly, the major elements of the discussions and strategic planning are the same, and only the players are different. Now, we have much better immunomodulatory therapy in the form of thalidomide, lenalidomide, and bortezomib.^11,12 These important new agents have a variety of properties ranging from antimicrobial to antiangiogenic, immunomodulatory, and, of course, proteasome inhibition, which has a multifaceted impact on both cell function and cell-to-cell interactions. Although there has been great enthusiasm to attempt to emulate the success with imatinib as a targeted approach in chronic myelogenous leukemia, the successful agents in myeloma are multifunctional, with a diverse impact on cell functions and pathways. This may indeed be the secret of success.

The level of success can be readily grasped by comparing the response rates and survival outcomes in the 1980s with 2008 as evidenced in Table 1, which shows overall survivals then and now.¹⁰ The change is substantial: 2008 survival of more than 96% at 1 year versus 75% to 83% and 2008 survival still around 90% at 2 years versus 48% to 66% (Table 1). The benefit and comparisons are particularly interesting looking at the results with lenalidomide plus low-dose (weekly) dexamethasone compared with the prior results with interferon and levamisole.¹³ There is essentially a doubling of survival at 2 years, with preliminary evidence that this survival will be maintained for at least 3 to 4 years. The impact of the new agents was documented by the recent comparative survival data from the Mayo Clinic experience, which showed the improved survival in the 2001 to 2006 timeframe.¹⁴

However, the most important point is that success in the clinic is what was required. There were multiple leads in the laboratory, which we have again today, but predicting clinical benefit is the hard part. This model of success is what needs to be heeded now. Response in patients is the hallmark that we must seek. Rapid clinical screening must be the centerpiece of new drug discovery. The in vitro and in vivo animal studies possible now (as they were in the past) are reassuring, but ultimately they are not enough.

The challenge today is to identify new useful agents with greater efficacy or lesser toxicities in the setting of already high response rates. Can longer remissions and overall survival be predicted or do we just have to wait and see? But, this is a great new problem. It is exciting to have several new active drugs and the opportunity to search for predictors and the best answers. As the role of high-dose chemotherapy with stem-cell transplantation is coming under renewed scrutiny, it is important to personalize treatment approaches based on age,¹⁸ genetic features,¹⁹ and other risk factors. For some patient groups, novel combinations alone may work well; for others, transplantation and other options may be indicated. But modulating the disease in the best possible fashion remains the central paradigm now as in 1983.

Editors’ Note

When the article by Salmon et al was originally published in 1983, it contained an error. The title should have read, "Alternating Combination Chemotherapy Improves Survival in Multiple Myeloma: A Southwest Oncology Group Study."

AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: None Consultant or Advisory Role: Brian G.M. Durie, Celgene (U), Millenium (U) Stock Ownership: None Honoraria: None Research Funding: None Expert Testimony: None Other Remuneration: None

NOTES

published online ahead of print at www.jco.org on September 8, 2008

REFERENCES

1. Salmon SE, Durie BGM, Young L, et al: Effects of cloned human leukocyte interferons in the human tumor stem cell assay. J Clin Oncol 1:217-225, 1983[Abstract]

2. Salmon SE, Haut A, Bonnet JD, et al: Alternating combination chemotherapy and levamisole improves survival in multiple myeloma: A Southwest Oncology Group study. J Clin Oncol 1:453-461, 1983[Abstract]

3. Hamburger AW, Salmon SE: Primary bioassay of human tumor stem cells. Science 197:461-463, 1977[Abstract/Free Full Text]

4. Durie BGM, Young LA, Simon SE: Human myeloma in vitro colony growth: Interrelationships between drug sensitivity, cell kinetics, and patient survival duration. Blood 61:929-934, 1983[Abstract/Free Full Text]

5. Durie BGM, Levy HB, Voakes J, et al: Poly (I,C)-LC as an interferon inducer in refractory multiple myeloma. J Biol Response Mod 4:518-524, 1985[Medline]

6. Durie BGM, Clouse L, Braich T, et al: Alpha-2b-interferon/cyclophosphamide combination studies: In vitro and phase 1 clinical results. Semin Oncol 3:84-88, 1986 (suppl)

7. Salmon SE (ed): Cloning of Human Tumor Stem Cells. New York, NY, Liss, 1980

8. Myeloma Trialists’ Collaborative Group: Interferon as therapy for multiple myeloma: An individual patient data overview of 24 randomized trials and 4012 patients. Br J Haematol 113:1020-1034, 2001[CrossRef][Medline]

9. Fritz E, Ludwig H: Interferon-alpha treatment in multiple myeloma: Meta-analysis of 30 randomised trials among 3948 patients. Ann Oncol 11:1427-1436, 2000[Abstract/Free Full Text]

10. Rajkumar SV, Hayman SR: Controversies surrounding the initial treatment of multiple myeloma. Am Soc Clin Oncol Ed Book 369-374, 2008

11. Ghobrial J, Ghobrial IM, Mitsiades C, et al: Novel therapeutic avenues in myeloma: Changing the treatment paradigm. Oncology 21:785-792, 2007[Medline]

12. Richardson PG, Hideshima T, Mitsiades C, et al: The emerging role of novel therapies for the treatment of relapsed myeloma. J Natl Compr Canc Netw 5:149-162, 2007[Medline]

13. Rajkumar SV, Jacobus S, Callander N, et al: Randomized trial of lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone in newly diagnosed myeloma (E4A03), a trial coordinated by the Eastern Cooperative Oncology Group: Analysis of response, survival, and outcome with primary therapy and with stem cell transplantation. J Clin Oncol 26:455s, 2008 (suppl; abstr 8505)[CrossRef]

14. Kumar SK, Rajkumar SV, Dispenzieri A, et al: Improved survival in multiple myeloma and the impact of novel therapies. Blood 111:2516-2520, 2008

15. Durie BGM, Crowley J, Coltman C, et al: Phase II evaluation of bisantrene in refractory multiple myeloma, a Southwest Oncology Group study. Invest New Drugs 9:329-331, 1991[Medline]

16. Singhal S, Mehta J, Deskian R, et al: Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med 341:1565-1571, 1999[Abstract/Free Full Text]

17. Demo SD, Kirk CJ, Aujay M, et al: Antitumor activity of PR-171, a novel irreversible inhibitor of the proteasome. Cancer Res 67:6383-6391, 2007[Abstract/Free Full Text]

18. Ludwig H, Durie BGM, Bolejack V, et al: Myeloma in patients younger than age 50 years presents with more favorable features and shows better survival: An analysis of 10,549 patients from the International Myeloma Working Group. Blood 111:4039-4047, 2008

19. Stewart AK: A risk-adapted approach to myeloma therapy. Am Soc Clin Oncol Ed Book 380-384, 2008

This Article Full Text (PDF) From JCO 1983 Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Google Scholar Articles by Durie, B. G.M. PubMed PubMed Citation Articles by Durie, B. G.M.