Supplement No. 3
Tailoring Initial Treatment for Newly Diagnosed, Transplantation-Eligible Multiple Myeloma
By Edward A. Stadtmauer, MD1 |
March 8, 2010
1Abramson Cancer Center University of Pennsylvania Perelman Center for Advanced Medicine Philadelphia, Pennsylvania
Achieving CR rates ≥ 30% and ORRs up to 100% is a remarkable advance in the treatment of myeloma. It is important to examine, though, whether deeper remission translates into improved long-term outcomes after ASCT.
Vogl et al retrospectively compared the outcomes of 28 patients who received thal/dex induction and 41 patients who received VAD or doxorubicin(Drug information on doxorubicin)/vincristine/dexamethasone (DVD). Despite similar response rates during induction, thal/dex was associated with significantly better PFS after transplantation compared with anthracycline-based induction (hazard ratio = 0.18; 95% confidence interval = 0.04–0.80; P = .011). Overall survival was comparable in the two groups. The results were similar when the investigators considered only the 28 patients who had not received any consolidation or maintenance therapy after transplantation.
For bortezomib(Drug information on bortezomib)-based regimens, data are available from some of the prospective phase III trials described above. In IFM 2005/01, the better response after induction treatment with Vel/dex translated into significantly better response after first ASCT, with CR/nCR rates of 35% vs 23% (P = .006). However, there was no significant difference between treatment arms in OS or PFS at 18 months. In the HOVON-65/GMMG-HD4 trial posttransplant response rates were similar to those observed pretransplant, and as with response to induction, the efficacy of BDD was superior to that of VAD. Specifically, 80% of patients on BDD achieved at least VGPR after transplantation, compared with 50% of those on VAD (P = .002), and the ORR after transplantation was 83% vs 59% (P = .002). In the GIMEMA study, the superiority of VTD to thal/dex as induction therapy translated into significantly higher CR/nCR and VGPR rates after first ASCT, second ASCT, and consolidation therapy. Even more importantly, 2-year PFS was significantly better in the VTD-treated group (90% vs 80%, P = .009). Overall 2-year survival did not differ significantly between the groups. The median follow-up was rather short (15 months ) and longer-term survival data will be of great interest.
The ECOG E4A03 trial of Rd was designed to evaluate only induction therapy, not the long-term efficacy of that combination. Intriguingly, though, a subgroup analysis suggests that ASCT for myeloma is still pertinent in the era of novel agents. The researchers compared 85 patients who underwent ASCT after four cycles of Rd with 142 patients who continued on the regimen. The 2-year OS was 94% for those who underwent ASCT vs 70% for those who did not.
Results from studies now underway will yield important information about whether the choice of induction therapy has a bearing on post-ASCT outcomes. Likewise, the role of ASCT for eligible patients in the era of newer agents is a question to be examined in future randomized, clinical trials.
Guidance for Using Multiple Myeloma Induction Therapies Prior to Transplantation
Table 3 [11,13-16,18,23,27-41] presents information from the myeloma literature that can help clinicians use various induction therapies. It is important to keep in mind that patients with severe renal insufficiency, history of thromboembolism, history of neuropathy, and other relevant comorbidities have generally been excluded from myeloma clinical trials. In addition, relatively few head-to-head trials of newer regimens have been conducted. Longer experience with the newer agents will be necessary before comprehensive evidence-based recommendations are available.
Very recently, an expert panel of the International Myeloma Working Group (IMWG) was convened to review the impact of thalidomide(Drug information on thalidomide)-based, bortezomib-based, and lenalidomide-based regimens on stem cell mobilization and collection. The panel found contradictory data on the impact of thalidomide in this respect, but it concluded that the effect, if any, appears to be relatively small, has limited impact on the ability to proceed with ASCT, and has no effect on the engraftment potential of the collected cells. Phase III trials of bortezomib-based regimens, even those that include lenalidomide or thalidomide, have generally not shown an adverse effect on the ability to collect stem cells. The exception is that in the IFM 2005/01 trial, there was a trend toward lower CD34+ cell numbers in patients receiving Vel/dex than in those receiving VAD. Even so, stem cell collection was adequate in 97% and 99% of the groups, respectively.
Two retrospective analyses have documented that prior treatment with lenalidomide is a risk factor for lower stem cell yields and increased mobilization failure rates when granulocyte colony-stimulating factor (G-CSF) is used alone for stem cell mobilization.[43,44] Patient age and duration of lenalidomide therapy were associated factors. There is no evidence that lenalidomide affects the quality of the stem cells collected. The use of cyclophosphamide(Drug information on cyclophosphamide) in addition to G-CSF lowers back to baseline the incidence of collection failure among lenalidomide-treated patients, independent of the duration of lenalidomide therapy.[45,46] The IMWG panel advises early stem cell mobilization, preferably within the first four cycles of initial therapy, for any patient who may undergo ASCT, whether immediately or later in the disease course.
It is possible that as experience grows with thalidomide, bortezomib, lenalidomide, and agents that are now investigational, the role of ASCT in myeloma treatment will become less routine. For the foreseeable future, however, consideration of ASCT as part of first-line myeloma therapy is appropriate for eligible patients. Numerous induction regimens now meet the goals of achieving CR and allowing subsequent stem cell collection, with acceptable toxicity. Newer combinations, especially those containing bortezomib and/or lenalidomide, are associated with depth and quality of response likely to result in better survival in these patients.
Whether one or two of the regimens are superior to all others remains to be determined, but bortezomib-based and/or lenalidomide-based regimens now have adequate level 1 evidence and consensus to be recommended for induction therapy for the transplantation-eligible patient with myeloma. Ongoing studies should provide further guidance for choosing among these regimens based on cytogenetic abnormalities, renal disease, and other prognostic indicators. Additional research is needed to evaluate the optimal use of newer regimens and incorporation of new biologic prognostic factors in the front-line setting.
Acknowledgements: The author thanks medical writer Faith Reidenbach for assistance with drafting the manuscript.
Address all correspondence to: Edward A. Stadtmauer, md Abramson Cancer Center University of Pennsylvania Perelman Center for Advanced Medicine 3400 Civic Center Blvd, Second Floor Philadelphia, PA 19104 e-mail: Edward.Stadtmauer@uphs.upenn.edu
Multiple Myeloma Therapy Supplement
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