Stem cell transplantation for multiple myeloma: current and future status

Abstract

High-dose melphalan with autologous stem cell support has been an integral part of myeloma therapy for more than 25 years either as salvage therapy or as consolidation of an initial remission. Although multiple phase III trials have demonstrated that this therapy results in higher response rates and longer remission duration than conventional chemotherapy the use of thalidomide, lenalidomide and bortezomib as induction therapy have limited the clinical relevance of these trials. In this manuscript, we will summarize the results of ongoing and recently published clinical trials and describe how they have impacted current transplant recommendations, and their relevance to the treatment of myeloma patients in developing countries.

Keywords:

• Stem cell transplantation
• Myeloma

Introduction and Historical Perspective

It has now been more than 25 years since McElwain and Powles demonstrated the clinical relevance of melphalan dose and disease response in patients with relapsed and refractory multiple myeloma.1,2 Barlogie et al.3^–5 demonstrated that the toxicity of high-dose melphalan could be decreased by autologous bone marrow transplantation. The high response rates seen in patients with relapsed or refractory disease led to the exploration of high-dose therapy with autologous marrow transplantation as consolidation of an initial response. Table 1 summarizes the largest Phase III trials comparing high-dose chemotherapy to conventional therapy that were performed from 1996 to 2006. Of note, all these trials included a standard induction regimen with steroids and alkylators or an anthracycline.6^–11 These results although of historical importance for North America (were more than 75% of patients receive induction with lenalidomide or bortezomib), remain relevant today for areas of the world were bortezomib, thalidomide or lenalidomide are not available.12

Table 1. Phase III trials comparing high-dose therapy to conventional chemotherapy as frontline therapy for multiple myeloma

Reference	N	Induction chemo used	%CR (HDT vs chemo)	%EFS @ x years (HDT vs chemo)	%OS @ x years (HDT vs chemo)	Comments
6	200	VMCP/BVAP	22 vs 5	28 vs 10 @ 5 years	52 vs 12 @ 5 years	Only nine patients received salvage SCT in the chemo group
7	179	VAMP for HDT	18 vs 5	Median EFS 50 m vs 13 m	5 year	Late SCT planned for chemo group
		VMCP for chemo			55 vs 55*
8	401	VMCP for HDT	44 vs 8	5 year	5 year	SCT not offered as salvage
		BCAM for chemo		50 vs 45*	27 vs 10*
9	186	VBMCP/VBAD	30 vs 11	5 year	5 year	Included only patients responding to induction. No SCT rescue for chemo group
				50 vs 50*	30 vs 30*
10	190	CHOP/VAMP for HDT	34 vs 19	3 years	5 years	No SCT rescue patients between 55 and 65 years of age
		VMCP for chemo		28 vs 22 (P = 0·07)	36 vs 36
11	516	VAD for HDT	11 vs 11	7 years	7 years	Half of chemo patients received salvage SCT.
		VBMCP for chemo		17 vs 14	39 vs 38

Note: N: number; CR: complete remission; EFS: event free survival; HDT: high-dose therapy; OS: overall survival; V: vincristine; M: melphalan; C: cyclophosphamide; P: prednisone; B: carmustine, A: adriamycin; SCT: stem cell transplantation.

Optimal Induction Treatment Prior to Stem Cell Transplantation (SCT)

Response prior to transplant has been shown to improve transplant outcomes, but the optimal type and duration of induction therapy has not been well defined.13 Macro et al.14 reported the results of a randomized trial comparing induction with thalidomide and dexamethasone versus vincristine, adriamycin and dexamethasone. In this trial despite a higher pre-SCT response to thalidomide-dexamethasone (VGPR rate of 34·7 vs 12·6% for VAD) post-transplant both groups had similar VGPR rates of 42 and 44%. In contrast to this study, three randomized trials have demonstrated that a bortezomib based induction results in improved outcomes post-autologous SCT.15^–17 The results of these trials are summarized in Table 2.

Table 2. Bortezomib based induction therapy results of phase III randomized trials

Reference	N	Treatments	%CR/nCR after all therapy	%PFS @ x years	%OS @ x years	Significance
15	474	BTD vs TD	58 vs 41	68 vs 56 @ 3 years	86 vs 84 @ 3 years	P<0·05 for response and PFS
16	482	BD vs VAD	40 vs 23	Median 36 m vs 29·7 m	81 vs 77 @ 3 years	P<0·05 for response and PFS
17		PAD vs TAD	50 vs 38	48 vs 42 @ 3 years	78 vs 71 @ 3 years	P<0·05 for PFS and OS

Note: N: number; CR: complete remission; nCR: near complete remission; PFS: progression free survival; OS: overall survival; B: bortezomib; T: thalidomide; D: dexamethasone; V: vincristine; A: adriamycin; P: bortezomib; m: months.

Lenalidomide based induction is being more frequently used in the United States for transplant eligible patients.12 Lenalidomide in combination with dexamethasone has been shown to be an effective induction therapy for myeloma with the advantage of being administered orally and well tolerated.18 A recent retrospective analysis of patients treated on E4A03 who underwent an autologous SCT after 4 cycles of lenalidomide/dexamethasone therapy had an overall survival (OS) at 3-years of 94% and a progression free survival (PFS) of 64% leading to the inclusion of lenalidomide based induction as an acceptable choice of induction therapy for transplant eligible patients.19,20 However, due to its cost and availability, lenalidomide based inductions may not be the induction treatment of choice in most developing world countries despite the fact that induction therapy with lenalidomide, bortezomib, and dexamethasone is associated with very high rates of VGPR’s or better (67%).21,22 In summary, for transplant eligible patients in developing countries a bortezomib based induction would probably be the most cost effective induction strategy prior to SCT.

Role of Autologous SCT

Prior to the advent of IMIDs and proteosome inhibitors the CR rate after induction therapy was less than 10% thus the rationale to proceeding to high-dose therapy with autologous stem cell support was to increase the depth of response and the number of patients who achieve a CR.23 This rationale was supported by multiple retrospective analysis confirming CR as an important surrogate endpoint for survival and long term disease control.12,23 To increase dose intensity Barlogie et al. showed the feasibility of tandem autologous PBSC transplants using melphalan 200 mg/m² for the first transplant and melphalan 200 mg/m² or melphalan and TBI for the second transplant. Of 123 patients 76% completed a second autologous transplantation. Tandem transplantation was associated with a 40% CR rate and a median EFS of 49 months.24 Two subsequent randomized trials have been completed and published. Attal et al. reported on 399 patients less than 60 years of age randomized to either single or tandem autologous SCT. Tandem transplant significantly improved seven-year EFS and overall survival. Cavo et al. reported on 321 patients, randomly assigned to receive either single or tandem courses of high-dose therapy with stem cell support. Patients in the tandem arm had a significantly increased probability of attaining at least a near complete response (nCR; 33 vs 47%), and prolonged EFS (EFS; median, 23 vs 35 months, however, no survival benefit was observed. Neither of these studies included induction therapies with either an IMID or a proteosome inhibitor and therefore as with the initial randomized trials of single transplant versus chemotherapy are not as relevant today as when they were originally published.25,26

Post-transplant Therapies

Thalidomide is an immune-modulatory drug that is relatively inexpensive and has been studied in several randomized trials as post-transplant maintenance therapy. Two of these studies have shown an OS benefit for patients receiving thalidomide. Notwithstanding, the side effect profile has made it difficult for patients and physicians to adopt.27^–30 Lenalidomide with its better side effect profile was a logical candidate drug to study as post-transplant maintenance therapy. Two randomized trials have been performed and recently reported using lenalidomide. The IFM 2005 reported on 614 patients randomized to receive either lenalidomide or placebo post-transplant after 2 cycles of lenalidomide intensification. With a median follow-up of 34 months the median PFS was 42 months for the lenalidomide arm vs 24 months for the placebo arm (P<10–8).31 At the time of last report no significant difference in overall survival was reported but a significant increased risk of secondary malignancies was seen in the lenalidomide arm (primarily hematologic malignancies). The CALGB 100104 was also updated at the International Myeloma Workshop meeting in Paris. As with the IFM 2005 study there was a significant improvement in time to progression (TTP) for patients receiving lenalidomide maintenance (median 43·6 vs 21·5 months for placebo). With a median follow-up of 18 months, there were significant less deaths in the lenalidomide arm versus placebo (21 vs 37, P<0·019) despite the crossover design. Post-hoc analysis suggest that the benefit of lenalidomide maintenance is seen regardless of response to SCT and type of induction therapy.32

Bortezomib maintenance has also been demonstrated to reduce the risk of relapse post-SCT. Sonneveld et al. reported on the outcomes of 626 patients randomized to receive bortezomib during induction in combination with doxorubicin and dexamethasone followed by post-transplant bortezomib every other week for 2 years or thalidomide during induction and post-transplant. Bortezomib therapy was associated with a higher response rate (60% VGPR or greater vs 40% for thalidomide), on multivariate analysis bortezomib therapy was also associated with improvements in PFS and OS.17

In summary, both IMIDs and bortezomib have been shown to enhance disease control when given as post-transplant therapy in patients with multiple myeloma. The increased risk of secondary malignancies seen after lenalidomide requires further study and careful discussion and risk assessment before this can be considered standard of care. Although the data to date suggest that most patients may benefit from institution of post-transplant therapies particularly if they still have evidence of residual disease, the optimal agent, timing and duration of post-transplant therapy remains to be defined. In developing countries, long-term lenalidomide maintenance will be difficult to support due to cost issues, thalidomide is much more accessible but requires careful monitoring particularly in younger patients of child bearing potential. Thus, design, planning and implementing clinical trials addressing these specific issues in the developing world will be essential.

The ‘standard of care’ for Transplant Eligible Patients in Developing Countries

With the primary objective of achieving the longest possible remission with the ‘least burden of therapy’ most experts would recommend that all transplant eligible patients be offered participation in a prospective clinical trial. Although high-dose therapy and autologous SCT is now one of the most cost-effective treatments for myeloma. The number of transplants being performed for myeloma in developing countries is woefully small (albeit increasing). Lack of infrastructure, and trained personnel are just one reason. However, with most countries now having one or more well developed stem cell transplant units in tertiary centers access to these centers is an important barrier to overcome. In the developing world, optimal induction therapy will probably include a bortezomib based or a thalidomide based combination. In patients with high risk disease induction therapy with bortezomib, an IMID (lenalidomide or thalidomide) and dexamethasone should be considered the treatment of choice if patients have no specific contraindication to these agents. The optimal duration of induction therapy has not been established but most experts recommend between 4 and 6 cycles of induction before proceeding to stem cell collection and consolidation with high-dose therapy.33 Post-transplant maintenance therapy with thalidomide should be attempted as long as patients can be monitored effectively.

Each country should be encouraged to develop clinical trials that address issues specific to their patient population.