Published Ahead of Print on September 8, 2008 as 10.1200/JCO.2008.18.0109
The latest version is at http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2008.18.0109
VOLUME
26
NUMBER
29
OCTOBER
10
2008
J
CELEBRATING 25 YEARS OF JCO
OURNAL OF CLINICAL ONCOLOGY
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 labo-
with combination chemotherapy provided the best survival results
ratory and in the clinic.1,2 The development of the clonogenic
yet obtained by the Southwest Oncology Group and compared
human myeloma stem-cell assay allowed testing of fresh myeloma
favorably with all previously reported myeloma therapy trials,
bone marrow samples as well as a range of cell lines.3,4 Leukocyte
which had median survivals in the 30 to 32 month range. The initial
interferons were of particular interest at that time.5,6 These were
median survival projection of 48 months for patients randomly
heady times: interferons had been on the cover of Time magazine
assigned to VMCP plus levamisole was particularly promising. It
and were clearly the molecules to beat. However, although clinical
was intriguing that levamisole, an agent that influenced lympho-
trials confirmed antimyeloma activity, it was unclear whether the
cyte and macrophage function, could improve outcomes in my-
antitumor effect was mediated directly via antiproliferative action on
eloma treatment.
the myeloma cells or indirectly through cells in the microenviron-
Fast forward 25 years: surprisingly, the major elements of the
ment. Separate studies had shown that MRC-5 fibroblasts as well as
discussions and strategic planning are the same, and only the players
macrophages could serve as enhancing "mother" cells for myeloma
are different. Now, we have much better immunomodulatory ther-
colony growth.7 Cocultivation and self-renewal studies revealed a
apy in the form of thalidomide, lenalidomide, and bortezomib.11,12
complex interaction between self-renewing myeloma stem cells
These important new agents have a variety of properties ranging
and modulating microenvironmental accessory cells. Our results
from antimicrobial to antiangiogenic, immunomodulatory, and,
indicated synergy between interferons and cytotoxic agents, such
of course, proteasome inhibition, which has a multifaceted impact
as alkylating agents in the antimyeloma activity.4-6
on both cell function and cell-to-cell interactions. Although there
Subsequent clinical trials confirmed the therapeutic benefit in
has been great enthusiasm to attempt to emulate the success with
patients with myeloma using interferons within combinations as
imatinib as a targeted approach in chronic myelogenous leukemia,
front-line therapy as well as for maintenance.8,9 But over time, it also
the successful agents in myeloma are multifunctional, with a di-
became clear that the benefit was much less than we had hoped. On
verse impact on cell functions and pathways. This may indeed be
average, responses increased by approximately 15% and remissions
the secret of success.
and survival improved by 6 to 12 months at most. For the first time,
The level of success can be readily grasped by comparing the
there was more careful assessment and comparison of prolongation of
response rates and survival outcomes in the 1980s with 2008 as evi-
remission (progression-free survival) versus improvement in overall
denced in Table 1, which shows overall survivals then and now.10
survival (or not).
The change is substantial: 2008 survival of more than 96% at 1 year
With multiple studies, it seemed that interferons prolonged re-
versus 75% to 83% and 2008 survival still around 90% at 2 years
mission, but might or might not impact overall survival. Does this
versus 48% to 66% (Table 1). The benefit and comparisons are
sound familiar? These are the exact questions being addressed today
particularly interesting looking at the results with lenalidomide
with regard to thalidomide as part of the melphalan, prednisone,
plus low-dose (weekly) dexamethasone compared with the prior
and thalidomide combination or within the total therapy-2 ap-
results with interferon and levamisole.13 There is essentially a dou-
proach, with or without thalidomide.10 Interestingly, in our 1983
bling of survival at 2 years, with preliminary evidence that this
article using levamisole as an immunomodulating agent for main-
survival will be maintained for at least 3 to 4 years. The impact of
tenance, the same issue emerged.2 The alternating combination
the new agents was documented by the recent comparative survival
chemotherapy of vincristine, melphalan, cyclophosphamide, and
data from the Mayo Clinic experience, which showed the improved
prednisone (VMCP)/vincristine, cyclophosphamide, doxorubicin,
survival in the 2001 to 2006 timeframe.14
and prednisone or VMCP/vincristine, carmustine, doxorubicin,
The research capability was there 25 years ago. We just didn't
and prednisone versus melphalan and prednisone produced a sig-
have the drugs. We had the capacity to screen thousands of agents,
nificantly longer median survival of 40 months, as compared with
which we did. The self-renewal process was separately assessed to look
24 months for melphalan and prednisone (P
.01). With the
for agents capable of eliminating myeloma stem cells. Although we
addition of levamisole in the maintenance phase, there was a mar-
identified several promising agents, including bisantrene, these did
ginally enhanced improvement in survival (P
.06). These results
not prove clinically useful.15 Ultimately, the clinical observation of
Journal of Clinical Oncology, Vol 26, No 29 (October 10), 2008
© 2008 by American Society of Clinical Oncology
1
DOI: 10.1200/JCO.2008.18.0109; published online ahead of print at www.jco.org on September 8, 2008
Information downloaded from jco.ascopubs.org and provided by CEDARS SINAI MEDICAL CENTER MEDICAL LIBRARY
on September 9, 2008 from 207.214.247.93.
Copyright
Copyright ©
2008
2008 by
by
the
American
American
Society
Society of
of
Clinical
Clinical
Oncology. AllOncology
rights reserved.
Brian G.M. Durie
Table 1. Early Outcomes: Then and Now
Then
Now
VMCP/VBAP
Melphalan, Prednisone,
Bortezomib, Melphalan,
Melphalan, Prednisone,
Lenalidomide and
Response Measure
MP, 1983
Combos, 1983
and Thalidomide
and Prednisone
and Lenalidomide
Low-Dose Dexamethasone
Response rate, %
ORR
32
49-58
76
71
81
71
VGPR
NA
NA
47
45
48
42
Early mortality
15
10
5
8
6
0.5
(
4 months), %
1-year overall survival, %
75
83
88
90
95
96
2-year overall survival, %
48
66
83
83
90
87
NOTE. "Then" indicates 19832; "Now" indicates 2008.10
Abbreviations: MP, melphalan and prednisone; VMCP, vincristine, melphalan, cyclophosphamide, and prednisone; VBAP, vincristine, carmustine, doxorubicin, and
prednisone; ORR, overall response rate; VGPR, very good partial response.
For MP and VMCP/VBAP, response is
75% regression (Southwest Oncology Group criterion of response); for others it is
partial response (
50% regression)
over
VGPR (
90% regression).
dramatic benefit with thalidomide opened the door to a new era of
AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
both laboratory and clinical research.16 Thalidomide, under inves-
Although all authors completed the disclosure declaration, the following
tigation as an antimycobacterial agent (including for the treatment
author(s) indicated a financial or other interest that is relevant to the subject
of leprosy), proved to be effective by blocking tumor necrosis
matter under consideration in this article. Certain relationships marked
with a "U" are those for which no compensation was received; those
factor- , angiogenesis, and a variety of other pathways now being
relationships marked with a "C" were compensated. For a detailed
diligently explored by researchers. Success with the first-generation
description of the disclosure categories, or for more information about
immune modulatory agent thalidomide spurred drug design re-
ASCO's conflict of interest policy, please refer to the Author Disclosure
finements to improve efficacy and reduce (in this case) neurotox-
Declaration and the Disclosures of Potential Conflicts of Interest section in
icity, resulting in the second-generation immune modulatory
Information for Contributors.
agent lenalidomide. Likewise, the success with bortezomib has led
Employment or Leadership Position: None Consultant or Advisory
to second- and third-generation drugs such as carfilzomib,17 with
Role: Brian G.M. Durie, Celgene (U), Millenium (U) Stock Ownership:
lesser neurotoxicity and perhaps greater efficacy, as well as other
None Honoraria: None Research Funding: None Expert Testimony:
oral proteasome inhibitors in development.
None Other Remuneration: None
However, the most important point is that success in the clinic
is what was required. There were multiple leads in the laboratory,
REFERENCES
which we have again today, but predicting clinical benefit is the
1. Salmon SE, Durie BGM, Young L, et al: Effects of cloned human leukocyte
hard part. This model of success is what needs to be heeded now.
interferons in the human tumor stem cell assay. J Clin Oncol 1:217-225, 1983
Response in patients is the hallmark that we must seek. Rapid
2. Salmon SE, Haut A, Bonnet JD, et al: Alternating combination chemother-
clinical screening must be the centerpiece of new drug discovery.
apy and levamisole improves survival in multiple myeloma: A Southwest Oncol-
The in vitro and in vivo animal studies possible now (as they were
ogy Group study. J Clin Oncol 1:453-461, 1983
3. Hamburger AW, Salmon SE: Primary bioassay of human tumor stem cells.
in the past) are reassuring, but ultimately they are not enough.
Science 197:461-463, 1977
The challenge today is to identify new useful agents with
4. Durie BGM, Young LA, Simon SE: Human myeloma in vitro colony growth:
greater efficacy or lesser toxicities in the setting of already high
Interrelationships between drug sensitivity, cell kinetics, and patient survival
response rates. Can longer remissions and overall survival be pre-
duration. Blood 61:929-934, 1983
5. Durie BGM, Levy HB, Voakes J, et al: Poly (I,C)-LC as an interferon inducer
dicted or do we just have to wait and see? But, this is a great new
in refractory multiple myeloma. J Biol Response Mod 4:518-524, 1985
problem. It is exciting to have several new active drugs and the
6. Durie BGM, Clouse L, Braich T, et al: Alpha-2b-interferon/cyclophospha-
opportunity to search for predictors and the best answers. As the
mide combination studies: In vitro and phase 1 clinical results. Semin Oncol
role of high-dose chemotherapy with stem-cell transplantation is
3:84-88, 1986 (suppl)
coming under renewed scrutiny, it is important to personalize
7. Salmon SE (ed): Cloning of Human Tumor Stem Cells. New York, NY, Liss,
1980
treatment approaches based on age,18 genetic features,19 and other
8. Myeloma Trialists' Collaborative Group: Interferon as therapy for multiple
risk factors. For some patient groups, novel combinations alone
myeloma: An individual patient data overview of 24 randomized trials and 4012
may work well; for others, transplantation and other options may
patients. Br J Haematol 113:1020-1034, 2001
be indicated. But modulating the disease in the best possible fash-
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,
ion remains the central paradigm now as in 1983.
2000
10. Rajkumar SV, Hayman SR: Controversies surrounding the initial treatment
Editors' Note
of multiple myeloma. Am Soc Clin Oncol Ed Book 369-374, 2008
When the article by Salmon et al was originally published in 1983,
11. Ghobrial J, Ghobrial IM, Mitsiades C, et al: Novel therapeutic avenues in
myeloma: Changing the treatment paradigm. Oncology 21:785-792, 2007
it contained an error. The title should have read, "Alternating Combi-
12. Richardson PG, Hideshima T, Mitsiades C, et al: The emerging role of novel
nation Chemotherapy Improves Survival in Multiple Myeloma: A
therapies for the treatment of relapsed myeloma. J Natl Compr Canc Netw
Southwest Oncology Group Study."
5:149-162, 2007
2
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JOURNAL OF CLINICAL ONCOLOGY
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on September 9, 2008 from 207.214.247.93.
Copyright © 2008 by the American Society of Clinical Oncology. All rights reserved.
Editorial
13. Rajkumar SV, Jacobus S, Callander N, et al: Randomized trial of lenalido-
16. Singhal S, Mehta J, Deskian R, et al: Antitumor activity of thalidomide in
mide plus high-dose dexamethasone versus lenalidomide plus low-dose dexa-
refractory multiple myeloma. N Engl J Med 341:1565-1571, 1999
methasone in newly diagnosed myeloma (E4A03), a trial coordinated by the
17. Demo SD, Kirk CJ, Aujay M, et al: Antitumor activity of PR-171, a
Eastern Cooperative Oncology Group: Analysis of response, survival, and out-
novel irreversible inhibitor of the proteasome. Cancer Res 67:6383-6391,
come with primary therapy and with stem cell transplantation. J Clin Oncol
2007
26:455s, 2008 (suppl; abstr 8505)
18. Ludwig H, Durie BGM, Bolejack V, et al: Myeloma in patients younger than
14. Kumar SK, Rajkumar SV, Dispenzieri A, et al: Improved survival in multiple
age 50 years presents with more favorable features and shows better survival:
myeloma and the impact of novel therapies. Blood 111:2516-2520, 2008
An analysis of 10,549 patients from the International Myeloma Working Group.
15. Durie BGM, Crowley J, Coltman C, et al: Phase II evaluation of bisantrene
Blood 111:4039-4047, 2008
in refractory multiple myeloma, a Southwest Oncology Group study. Invest New
19. Stewart AK: A risk-adapted approach to myeloma therapy. Am Soc Clin
Drugs 9:329-331, 1991
Oncol Ed Book 380-384, 2008
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Information downloaded from jco.ascopubs.org and provided by CEDARS SINAI MEDICAL CENTER MEDICAL LIBRARY
on September 9, 2008 from 207.214.247.93.
Copyright © 2008 by the American Society of Clinical Oncology. All rights reserved.