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Poor Outcome With Front-Line Autologous Transplantation in t(4;14) Multiple Myeloma: Low Complete Remission Rate and Short Duration of Remission

Institute of Hematology and Medical Oncology Seràgnoli, University of Bologna, Italy

Luciano Guardigni

Division of Medicine, Bufalini, Cesena, Italy

To the Editor:

In younger patients with newly diagnosed multiple myeloma (MM) high-dose therapy with autologous stem cell transplantation (ASCT) is considered the standard of care since it significantly prolonged the survival in comparison with conventional chemotherapy.¹ More recently, several studies provided demonstration that double ASCT was superior to a single transplantation,^2,3 particularly in patients who failed complete remission or good partial remission following the first transplantation. However, in other series double ASCT was of no clinical benefit for patients with monosomy or deletion of chromosome 13,⁴ emphasizing the relevance of detecting cytogenetic and molecular abnormalities as a means to reliably predict different outcomes of the disease. The t(11;14), for example, identifies a subset of low risk MM patients who are more likely to have prolonged duration of remission and event-free survival (EFS) following autologous transplantation.⁵ At the opposite end of the spectrum, several studies, one of whom has been recently published in this journal,⁶ included the t(4;14) in the list of the most adverse prognostic variables predicting for poor outcome with ASCT.^7-11 These results are consistent with those of an analysis we performed on a series of 63 previously untreated MM patients for whom bone marrow samples collected at diagnosis and stored for subsequent polymerase chain reaction (PCR) analyses were available. All patients were randomly assigned to receive either single or double ASCT as part of front-line therapy.³ The clinical study was approved by local ethical committee; informed consent was provided according to the declaration of Helsinki. Using a real time-nested PCR assay designed to detect the presence of IgH/MMSET fusion gene as a surrogate marker for t(4;14), we found that 17 patients (27%) carried this cytogenetic abnormality. Comparison between patients with and without IgH-MMSET hybrid transcripts showed that the two groups had similar characteristics at diagnosis, including M protein isotypes and serum beta2-microglobulin (beta2-m) levels. These results are consistent with those of a similar study,⁷ but differ from data of other studies showing a higher prevalence of IgA isotype and elevated beta2-m concentrations in patients with t(4;14).^8-10 In addition, a close relationship between t(4;14) and chromosome 13 abnormalities was generally reported,^7,8,11 and was found also in 73% of our patients. Using an intent-to-treat approach, we found that the probability to attain stringently defined complete remission following melphalan 200 mg/m² or melphalan 140 mg/m² and busulfan 12 mg/kg was only 12% for t(4;14)-positive patients, compared to 39% for t(4;14)-negative patients (P = .04). Notably, in a recent study¹⁰ resistance to alkylating agents after post-transplant relapse has been identified as a major factor contributing to the poor prognosis of t(4;14) patients treated with ASCT. With a median follow-up of 40 months from start of therapy, median EFS for our patients with and without IgH-MMSET hybrid transcripts was 23 and 32 months, respectively. The difference between the two groups was statistically significant (P = .01; Fig 1). Compared to patients without t(4;14), patients with this chromosomal abnormality also had a significantly shorter duration of remission (median, 30 months v 20 months; P = .01). In conclusion, the worsened outcome with ASCT observed in our patients with t(4;14) was related both to a higher degree of chemoresistance, that was not circumvented even by HDT, and to a disappointingly short duration of remission following ASCT. Newer and more effective treatment modalities should be explored in an attempt to improve on the dismal clinical outlook of MM patients carrying t(4;14).

View larger version (10K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Event-free survival for 17 patients with IgH/MMSET (median, 23 months) and 46 patients without IgH/MMSET (median, 32 months) hybrid transcripts (P = .01).

The authors indicated no potential conflicts of interest.

ACKNOWLEDGMENTS

Supported by Università di Bologna, Progetti di Ricerca ex-60% (M.C.), Ministero dell'Università e Ricerca Scientifica (MIUR), progetto FIRB, RBAU012E9A_001 (M.C.), and Fondazione Carisbo.

REFERENCES

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2. Attal M, Harousseau J-L, Facon T, et al: Single versus double autologous stem-cell transplantation for multiple myeloma. N Engl J Med 349:2495-2502, 2003[Abstract/Free Full Text]

3. Cavo M, Cellini C, Zamagni, et al: Superiority of double over single autologous stem cell transplantation as first-line therapy for multiple myeloma. Blood 104:155a, 2004 (abstr 536)

4. Desikan R, Barlogie B, Sawyer J, et al: Results of high-dose therapy for 1000 patients with multiple myeloma: Durable complete remissions and superior survival in the absence of chromosome 13 abnormalities. Blood 95:4008-4010, 2000[Abstract/Free Full Text]

5. Soverini S, Cavo M, Cellini C, et al: Cyclin D1 overexpression is a favorable prognostic variable for newly diagnosed multiple myeloma patients treated with high-dose chemotherapy and single or double autologous transplantation. Blood 102:1588-1594, 2003[Abstract/Free Full Text]

6. Jaksic W, Trudel S, Chang H, et al: Clinical outcomes in t(4; 14) multiple myeloma: A chemotherapy-sensitive disease characterized by rapid relapse and alkylating agent resistance. J Clin Oncol 23:7069-7073, 2005[Abstract/Free Full Text]

7. Keats JJ, Reiman T, Maxwell CA, et al: In multiple myeloma, t(4;14)(p16;q32) is an adverse prognostic factor irrespective of FGFR3 expression. Blood 101:1520-1529, 2003[Abstract/Free Full Text]

8. Moreau P, Facon T, Leleu X, et al: Recurrent 14q32 translocations determine the prognosis of multiple myeloma, especially in patients receiving intensive chemotherapy. Blood 100:1579-1583, 2002[Abstract/Free Full Text]

9. Avet-Loiseau H, Facon T, Grosbois B, et al: Oncogenesis of multiple myeloma: 14q32 and 13q chromosomal abnormalities are not randomly distributed, but correlate with natural history, immunological features, and clinical presentation. Blood 99:2185-2191, 2002[Abstract/Free Full Text]

10. Fonseca R, Blood E, Rue M, et al: Clinical and biologic implications of recurrent genomic aberrations in myeloma. Blood 101:4569-4575, 2003[Abstract/Free Full Text]

11. Gertz MA, Lacy MQ, Dispenzieri A, et al: Clinical implications of t(11; 14)(q13; q32), t(4; 14)(p16.3; q32), and –17p13 in myeloma patients treated with high-dose therapy. Blood 6:2837-2840, 2005

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