COMMENTARY

Multidrug resistance in myeloma: seeing the whole picture

DEBORAH RUND

Hematology Department, Hebrew University-Hadassah Medical School, Ein Kerem, Jerusalem, Israel

In this issue of Leukemia & Lymphoma, Drain et al.

[1] report a correlation between the genotype of a

polymorphic site, or SNP, in the MDR1 gene and

prognosis of patients with multiple myeloma (MM).

MDR1 encodes P-glycoprotein (P-gp), a drug efflux

pump. Patients who are homozygous for the T allele

at position 3435 had a worse prognosis than patients

either heterozygous or homozygous for C at that

position. This non-synonymous SNP has been

shown to affect gene activity apparently post-

transcriptionally, due to codon usage, as discussed

by the authors. Although the finding by Drain et al.

is very interesting, we are somewhat confused to

discover that two studies published in 2007, which

examined the same variables (genotype at position

3435 and prognosis of patients with MM), found

results that differ from those presented here. An

Italian study of 115 patients by Buda et al. [2] found

the opposite effect of that reported by Drain et al.:

patients with the TT and CT genotypes had longer

survival. These were patients treated with vincris-

tine, doxorubicin and dexamethasone (VAD) fol-

lowed by autologous transplantation. In addition, a

Dutch study by Schilthuizen et al. [3] of 209

patients found no effect of any of the genotypes

on prognosis, including in a subgroup of VAD-

treated patients.

What are we to understand from these three

contradictory studies? Aside from the obvious

justification that the studies used different treat-

ments, different study design and different study

populations, it has also been said that polymorphisms

exert small influences and that most studies are

underpowered [3]. It also can be said that single

SNPs are insufficient and that more comprehensive

haplotype analysis of MDR1 needs to be done to

determine genotypes associated with resistant dis-

ease. Recently, the Italian group quoted above

extended their study (of 110 patients) by examining

one additional MDR1 SNP (G to T at position 2677

in addition to that at 3435). The 2677 SNP is

synonymous, it encodes an amino acid change, thus

can alter gene activity. They found that MDR1

diplotypes influenced survival [4], again reporting

that TT at position 3435 was associated with longer

survival. This group examined only two polymorphic

sites. In fact, the MDR1 gene has at least 48

polymorphic sites and 64 haplotypes [5] making

complete genotyping a technical challenge.

Contemplating these varying results, I was re-

minded of the Indian parable of the six blind men

and the elephant, which they variously perceived as

resembling a wall, a rope, a tree trunk, a snake and so

on, depending on the part of the beast they touched.

Perhaps, the problem is that each of these studies

does not see the whole picture?

MDR1 polymorphisms may influence the activity

of the gene, but this data are only part of the

prerequisite knowledge for predicting whether they

will affect the prognosis of MM. Several factors

determine whether alterations P-gp expression will

influence the prognosis of MM (or in fact, any other

disease). First, we need to know if a particular

patient’s myeloma expresses elevated levels of P-gp.

Studies from over a decade ago found variable

results: between 0% and 41% of untreated patients

with MM expressed P-gp [6]. Second, we need to

know if various studies have found that P-gp over-

expression correlates with a poor prognosis in that

disease. This is of particular interest in studies in

Correspondence: Deborah Rund, Hematology Department, Hebrew University-Hadassah Medical School, Ein Kerem, Jerusalem, Israel 91120.

Tel: 972-2-6778712. Fax: 972-2-6423067. E-mail: rund@cc.huji.ac.il

Leukemia & Lymphoma, April 2009; 50(4): 521–522

ISSN 1042-8194 print/ISSN 1029-2403 online � 2009 Informa Healthcare USA, Inc.

DOI: 10.1080/10428190802699373

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which use drugs which are P-gp substrates. Thus far,

no clear-cut answer to this question exists in the

literature, and no benefit was found in randomised

trials which used P-gp inhibitors, either cyclosporine

A [7] or PSC833 [8] together with VAD for MM.

Third, we need to know whether the drugs used in

the supportive care of the patient with MM (such as

antibiotics) are extruded by P-gp. Fourth, it is

known that hematopoietic stem cells express P-gp at

high levels; to what degree is recovery of stem cells a

factor in patient survival after a particular treatment?

Possessing stem cells with high P-gp expression may

confer a survival advantage to the patient since his

recovery may be more rapid. Last, P-gp expression

may be a marker for other cellular effects which

accompany MDR1 expression. For example, activa-

tion of MDR1 expression by exposure to che-

motherapy was accompanied by increased activity of

the FOXO3a transcription factor, a member of

the forkhead family of proteins [9]. Increased

FOXO3a activity can have widespread influence,

including on genes other than MDR1. Another such

example is seen in the finding of overexpression of

anti-apoptotic proteins in patients with MM who

had chemotherapy-induced increased MDR1 ex-

pression [10]. The induction of MDR1 expression

caused activation of non-P-gp mediated resistance

mechanisms. Recent elegant studies have used the

technology of gene expression profiling to dissect

out changes in gene expression following exposure

to drugs used to treat MM [11], and found that

even short-term exposure causes profound altera-

tions in expression profiles following steroids or

thalidomide.

In summary, the search for factors, which predict

treatment response and survival in malignant disease,

including MM, is an ongoing process, which gets

more complex as technology advances. Seeing the

whole picture now requires large prospective studies,

which integrate clinical information with genetic and

molecular profiles. Such studies will be complex to

perform, but hopefully will reveal the whole picture

and show the elephant as it really is, transcending the

rudimentary, apparently contradictory information

we now have.

References

1. Drain S, Catherwood MA, Orr N, Galligan L, Rea IM,

Hodkinson C, et al. ABCB1 (MDR1) rs1045642 is associated

with increased overall survival in plasma cell myeloma. Leuk

Lymphoma 2009;50:566–570.

2. Buda G, Maggini V, Galimberti S, Martino A, Giuliani N,

Morabito F, et al. MDR1 polymorphism influences the out-

come of multiple myeloma patients. Br J Haematol 2007;

137:454–456.

3. Schilthuizen C, Broyl A, van der Holt B, de Knegt Y, Lokhorst

H, Sonneveld P. Influence of genetic polymorphisms in

CYP3A4, CYP3A5, GSTP1, GSTM1, GSTT1 and MDR1

genes on survival and therapy-related toxicity in multiple

myeloma. Haematologica 2007;92:277–278.

4. Maggini V, Buda G, Martino A, Presciuttini S, Galimberti S,

Orciuolo E, et al. MDR1 diplotypes as prognostic markers in

multiple myeloma. Pharmacogenet Genomics 2008;18:383–

389.

5. Kroetz DL, Pauli-Magnus C, Hodges LM, Huang CC,

Kawamoto M, Johns SJ, et al. Sequence diversity and haplotype

structure in the human ABCB1 (MDR1, multidrug resistance

transporter) gene. Pharmacogenetics 2003;13:481–494.

6. Nuessler V, Gieseler F, Gullis E, Pelka-Fleischer R, Stotzer O,

Zwierzina H, et al. Functional P-gp expression in multiple

myeloma patients at primary diagnosis and relapse or

progressive disease. Leukemia 1997;11(Suppl 5):S10–S14.

7. Sonneveld P, Suciu S, Weijermans P, Beksac M, Neuwirtova

R, Solbu G, et al. Cyclosporin A combined with vincristine,

doxorubicin and dexamethasone (VAD) compared with VAD

alone in patients with advanced refractory multiple myeloma:

an EORTC-HOVON randomized phase III study (06914). Br

J Haematol 2001;115:895–902.

8. Friedenberg WR, Rue M, Blood EA, Dalton WS, Shustik C,

Larson RA, et al. Phase III study of PSC-833 (valspodar) in

combination with vincristine, doxorubicin, and dexametha-

sone (valspodar/VAD) versus VAD alone in patients with

recurring or refractory multiple myeloma (E1A95): a trial of

the Eastern Cooperative Oncology Group. Cancer 2006;106:

830–838.

9. Hui RC, Francis RE, Guest SK, Costa JR, Gomes AR, Myatt

SS, et al. Doxorubicin activates FOXO3a to induce the

expression of multidrug resistance gene ABCB1 (MDR1) in

K562 leukemic cells. Mol Cancer Ther 2008;7:670–678.

10. Nakagawa Y, Abe S, Kurata M, Hasegawa M, Yamamoto K,

Inoue M, et al. IAP family protein expression correlates with

poor outcome of multiple myeloma patients in association

with chemotherapy-induced overexpression of multidrug

resistance genes. Am J Hematol 2006;81:824–831.

11. Burington B, Barlogie B, Zhan F, Crowley J, Shaughnessy JD

Jr. Tumor cell gene expression changes following short-term

in vivo exposure to single agent chemotherapeutics are related

to survival in multiple myeloma. Clin Cancer Res 2008;14:

4821–4829.

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