Second Primary Cancers in Myeloma: A Status ReportFebruary 2011
During the past few weeks members of the International Myeloma Working Group (IMWG)
have been considering and discussing results presented at ASH 2010 (See Table 1). Three large
randomized trials showed excellent prolongation of remissions with lenalidomide use, althoughsecond primary cancers (SPCs) were noted. A working subgroup of the IMWG met to review
the results, and the full IMWG (144 myeloma expert members) has been developing aconsensus statement to provide appropriate recommendations for the myeloma community.
The data that form the basis for discussions are summarized in Table 1 below.
Table 1IFM
Attal et al ASH 2010
CALGB
McCarthy et al ASH 20102010 ASH Presentations*
SPCs /Total% SPCs

Lenalidomide
Placebo

17**/299
3/292

5.5%**
1.0%

Lenalidomide
Placebo

15/231
6/229

6.5%
2.6%

MM015
Palumbo et al ASH 2010

MPR/MPRR***
11/355
3.1%
Placebo
2/154
1.3%* Cases of SPCs: numbers and percentages as of February 2011** These SPCs are: AML/MDS 5 (2 in placebo); Hodgkin’s disease 4 (0 in placebo); B-cell ALL 2 (0in placebo); colon cancer 2; prostate cancer 2; breast cancer 1; and esophageal cancer 1.
*** Includes Melphalan, Prednisone, Revlimid (MPR) with and without continued Revlimid(MPRR-R: Revlimid = lenalidomide)

It can be seen that there is an increase in the number of second cancers reported in two trials(IFM & CALGB: see Table 1) in which lenalidomide was administered as maintenance after highdose melphalan-based stem cell transplantation. In the third trial (MM015: see Table 1), anincrease in the number of second cancers was reported with the use of lenalidomide incombination with melphalan in the frontline setting.
The second primary cancers included solid tumor cancers such as breast, prostate, and coloncancer as well as hematologic cancers such as acute leukemias and lymphoma; there were also
some cases of myelodysplastic syndrome (MDS). The numbers and percentages listed aresimply the numbers of patients with SPCs in each study reported thus far. More sophisticated1analyses plus studies of risk factors are underway to assess occurrence of SPCs over time, thedifferent types of SPCs, as well as other details of the cases.
The IMWG has reached some interim conclusions and can provide preliminary
recommendations.
Known Occurrence of Second Primary Cancers
The occurrence of second primary cancers in myeloma patients has been recognized for several
decades. In an analysis by the National Cancer Institute’s (NCI) Surveillance, Epidemiology andEnd Results (SEER) Program from 1973-2000, approximately 5.1% of MM patients developed asecond primary cancer within twenty years. The overall number of second primary cancers in
the three ASH studies are thus consistent with the frequency expected in an older population(92% > 50yrs old). Of the leukemia cases, 80% were AML. The risk of developing AML and/or
MDS following the use of alkylating agents to treat MM has also been recognized for several
decades (Cuzick et al. 1987; Bergsagel et al. 1979). This risk typically increases with increasing
cumulative dose and/or duration of therapy of the alkylating agent. The risk is predominantlywith melphalan, and to a lesser degree, with cyclophosphamide (Cytoxan). The risk ofdeveloping second primary cancers following transplantation has also been recognized. In a
retrospective study of 800 patients who underwent high-dose therapy (HDT) and autologous
stem cell transplant (ASCT) from 1982-2000, the cumulative risk of developing a second primarycancer at 15 years was 11% (95% CI, 5-18%) (Forrest et al. 2003). Thus, depending upon thetime frame, second primary cancers in the range of 5-10% (1-2% per year of follow-up) are tobe expected, especially as the population ages and patients live longer, taking advantage ofmore and better therapies. According to SEER, the risk of second cancers is 1.4-2% per year offollow-up. The annual incidence rates of SPCs per 100 person-years for individuals over age 65
can also be calculated, and is 2.1/100 person-years. There are thus some comparators forongoing assessments.
Importance of the Recent Trial Results
 The important observations in the ASH 2010 randomized trials are the differences
between the placebo or control groups and those patients receiving lenalidomide.
 The main difference to note is that the lenalidomide-treated patients had remissions(Progression Free Survival [PFS]) on average twice as long (for example, 42 monthsvs. 21 months) as patients not receiving lenalidomide. This means that many morepatients are relapsing or progressing on the placebo, especially in the 2 nd, 3rd, andlater years of the trial. This is clearly evident in the IFM trial, the one with thelongest follow-up. At the present time, the follow-up is much shorter in the CALGBtrial.
2

Since ASH 2010 the IFM team has carefully reviewed the study results. In theirstudy, all the lenalidomide-treated patients had received at least 2 years oflenalidomide treatment as of December 2010. Because substantial benefit had
already accrued (that is remission lasting approximately twice as long) and since it isunknown if further lenalidomide will increase the risk of second primary cancers, theIFM decided to stop the trial for safety reasons. Thus, 70 patients in remission after
2 years or more of lenalidomide treatment have been taken off treatment. Since
this is the first trial in which this situation has occurred, the strategy to stop thelenalidomide in this particular trial has been understood and acknowledged.
Follow-up in the CALGB trial is one year shorter. CALGB/NCI, after reviewing all theissues, recently announced that the study will continue with additional monitoring inboth arms of the trial.
Other ongoing trials are also continuing with appropriately enhanced monitoring.
During the time frame that patients in the placebo group are relapsing, patients inthe treatment group are remaining in remission; but ultimately (thus far) 3.1-6.5%
are developing a second primary cancer. The numbers involved are illustrated inTable 2, which lists both the percent in remission (PFS%) and the SPC data.

Table 2 Comparison of Relapse-Free and Cancer-Free Survival With and Without
Lenalidomide (Placebo)
Still In Remission
SPCs(PFS%)IFM
At 4 yrs from diagnosis
Lenalidomide
60%
5.5%
Placebo
33%
1.0%
MM015
At 2 yrs from diagnosis
MPR-R
54.11%2%
MPR + placebo
24.18%
5%MP
18.84%
1%These are some of the data that form the basis for “risk-benefit” discussions. Otherelements in this discussion include: What are the details of the reported cancers?
 Are the cancers occurring in a particular type of patient?
 Are these the same types of patients (related to risk factors such as age,chromosome changes, or melphalan therapy) reported to develop second
primary cancers in the past, or are different kinds of patients at risk?
 Are chromosome abnormalities such as microsatellite instability and p53
mutations important as in other types of therapy-related leukemia (tAML)?
 What is the expected outcome for patients developing a second primarycancer had they not received lenalidomide?
3 Do the SPCs only occur in the setting of certain other types of treatment?
 Is the length of the lenalidomide treatment a critical factor?
 Is the dose and/or schedule (for example, continuous vs. 21/28 days) ofthe lenalidomide a critical factor?
 Is the exact timing of lenalidomide treatment (related to conventional or
high-dose melphalan, for example) an important factor?

Current Recommendations Regarding Second Primary Cancers in Myeloma
Relapsed/Refractory Myeloma
 No increased incidence of SPCs has been reported with use of lenalidomide inrelapsed/refractory myeloma.
 No changes are recommended to currently accepted lenalidomide treatment
approaches in this setting.
Newly Diagnosed Myeloma
Based upon currently available data, the IMWG does not recommend changes to currently
accepted lenalidomide treatment approaches in the frontline setting either as pre-treatment
induction or primary therapy.
Post-Transplant Therapy
 There is no consensus recommendation at this time with regard to ongoing treatment
with lenalidomide in this setting.
 Enhanced monitoring of patients for SPCs in all clinical trials is strongly recommended.
 If post-transplant therapy with lenalidomide is used, the IMWG recommends that thepotential risk of second cancer be discussed with each patient. This treatment decision
requires physician/patient discussions to evaluate the benefits of disease control versus
potential risks of continued therapy.
 In the clinical trial setting, it is a priority to ensure consistent and thorough datacollection, monitoring, and reporting of second primary cancers.
 It is recommended that information about the potential risk of second cancers be
included in the informed consent for all clinical trials.

In collaboration with the NIH/NCI, the IMWG has initiated a concerted
effort to further characterize the cases of second cancer that havebeen reported to define underlying mechanisms and identify risk
factors, including molecular features and DNA SNPs. In addition, the4

IMWG will closely monitor further developments and provide updates
as appropriate. Any feedback or comments from patients, physicians,
caregivers, or any other interested parties will be appreciated.

BACKGROUND REFERENCES
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