EDIT 3/27/2013: Over the past few weeks I have received many comments on my two most recent blogs. I apologize for not responding to your comments and questions. Please know that they are very important to me. I am traveling to the International Myeloma Workshop in Kyoto, Japan, and will respond on my return. In the meantime, if you have a medical question, please contact the IMF InfoLine at 1-800-452-CURE (2873).

Two recent journal reports--one in NATURE the other in CLINICAL ONCOLOGY--draw attention to concerns about the occurrence of second primary malignancies (SPMs) in patients with myeloma. 

The first article reports the long-term follow-up of patients who received plerixafor (Mozobil) to mobilize stem cells prior to auto-stem cell transplant (ASCT) between 2006 and 2009. Of 43 patients who were able to proceed to ASCT, 4 developed MDS (myelodysplastic syndrome) and 1 developed AML (acute myelogenous leukemia). Actually, only one of these patients had myeloma: the others had a prior diagnosis of lymphoma. In addition, the single myeloma patient had received a prior ASCT before the second harvesting using plerixafor.  Thus, the subsequent onset of MDS/AML in this sole myeloma patient is definitely multifactorial in origin.

Let me explain.

First, it is known that there is an increased risk of MDS/AML in patients even before therapy when they have an MGUS/smoldering myeloma precursor state. Second, therapy-related MDS/AML is a well-recognized late complication with the use of high-dose melphalan (200 mg/m2) which this patient received. Third, patients who are difficult to harvest--in which plerixafor is used preferentially--are known to have reduced stem function and may have pre-existing latent MDS type cellular injury.

So to what extent did the use of plerixafor as a growth factor increase the likelihood of overt MDS/AML in this one myeloma patient?

Although the authors clearly raise this concern, they also write that further studies are required.  The key point in my mind is that this difficult-to-harvest subgroup of patients is intrinsically at a higher risk of developing MDS/AML. Thus, it is especially important to carefully assess for underlying MDS in such patients before proceeding to harvest. Until more information is available, it is probably reasonable to consider excluding such patients with documented underlying MDS (based upon cytogenetic/FISH) from further harvesting attempts. In this single reported myeloma case, the MDS/AML is more linked to the myeloma itself and prior myeloma therapy than the brief use of plerixafor for mobilization.

The second study provides an update with a longer-term follow-up of the previously reported VISTA trial, which compares melphalan/prednisone (MP) with Velcade plus melphalan/prednisone (VMP). In this study, the use of Velcade for up to approximately one year in the VMP arm did not lead to an increased occurrence of SPMs versus the MP arm of the study. The SPM rates of 4-6% are similar to previous studies evaluating the impact of melphalan. Thus, in this case, there is an increased SPM risk linked to the use of oral melphalan, but this is not enhanced with Velcade use. The open question is the use of melphalan versus Cytoxan (cyclophosphamide) as an alkylating agent. The recent excellent results with CyBorD (Cyotxan/bortezomib [Velcade]/dexamethasone [weekly]) provide an option to be considered

With all the novel approaches, as in life in general, "the devil is the details." So stay tuned as more information becomes available to assess the risks and options related to the development of SPMs. But for now, no drastic change in recommendations.



Image of Dr. Brian G.M. DurieDr. Brian G.M. Durie serves as Chairman of the International Myeloma Foundation and serves on its Scientific Advisory Board. Additionally, he is Chairman of the IMF's International Myeloma Working Group, a consortium of nearly 200 myeloma experts from around the world. Dr. Durie also leads the IMF’s Black Swan Research Initiative®.

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