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Understanding Second Primary Malignancies (SPMs) in Myeloma: Caution Required in Interpretation of New and Evolving Data

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EDIT 3/27/2013: Over the past few weeks I have received many comments 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 travelling 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 Hotline 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 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 longer term follow-up of the previously reported VISTA trial, which compares melphalan/prednisone (MP) with Velcade� plus melphalan/prednisone (VMP). In this study, 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 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.

1. http://www.nature.com/bmt/journal/vaop/ncurrent/full/bmt201310a.html

2. http://jco.ascopubs.org/content/31/4/448.abstract

7 Comments

Interesting!

My mother (73 YO at Diagnosis Dec 2010) underwent VMP treatment for a year (no ASCT due to ineligilbility). She only took the melphalan for about 4-5 months (discontinued it because it was almost impossible to find plus the Velcade was working great). She now has possible early stages of MDS (not enough mutated cells to say for 100% sure), just from the few months of melphalan use.

She's still in CR (last Velcade was Dec 2011) with no maintenance treatment, so hopefully both the MM and MDS will hold off for a good while longer!

Hubby was diagnosed with small cell lung cancer in 2012 after being on revlimid since 2004. Diag with mm in 2003.

I am puzzled by my latest labs.

Capsule Summary:
Smoldering IGD Lambda Multiple Myeloma diagnosed Dec 1995
Treated VAD then VBMCP in 1998
Never Transplanted
Recurrence treated with Revlimid + Steroid with good response
Platelets dropping, Bone Marrow showed no MM BUT now Monosomy 7 MDS
On Revlimid 10 mg 21/28
SPEP - no spike, but now light chains rising dramatically

What do you make of the persistent and now spiking light chains?

Hi Larry,

Dr. Durie is traveling over the next few weeks and apologizes that he won't be able to respond to your question for a little while. Until then, please contact the IMF Hotline at 800-452-CURE and they might be able to shed some light on your question!

Warmly,
Randi Lovett
Director of Annual Giving & Social Media
International Myeloma Foundation

I have been following updates on MM since my husband was diagnosed and continue to do so even after he died only two months after his diagnosis. I have yet to read an article on secondary complications, ie, amyloidosis unless I do an Internet search. Steve died at Mass General Hospital from gastrointestinal amyloid while going through round one of treatment for MM. Why has noone addressed this complication of MM?

Hi Joseph - My husband was just diagnosed (3 weeks ago) with MM, lambda light chain disease, stage III-a, with 90% marrow plasma cells and a Beta2 globulin value of 6.0. The odd thing is - he has had no symptoms. His GP found low RBC, WBC and platelets in a routine health check, leading to a visit to a hematologist, leading to a marrow biopsy, etc. He has no kidney damage, a clear bone survey, no bone pain, no fractures, no infections, mild anemia and mild fatigue, no hypercalcemia. He is almost 59 yrs old, with no other health issues (and no regular prescription drugs). A healthy, happy guy... So, the 90% and B2 6.0 sound awful and don't seem to add up with the lack of other symptoms. I was heartened to read your post about having had a similar diagnosis 20 years ago! Do you have any suggestions or information on similar cases? My husband has started Velcade + Decadron and will have ASCT in the next few months (hopefully). Thank you, Barbara (and husband Joe).

Hello. Several years before I was diagnosed with MM I worked with a weed killer in our back yard, and I wasn't very careful with protection. I also used Rymar stain on our house and decks. I've always wondered if there was a connection between such toxins and my MM. I've never been asked to fill out a questionnaire on toxins that I may have worked with, but I hope someday someone will do such research.

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