Introduction
Multiple myeloma (MM) has a low possibility of cure. However, important therapeutic improvements have been made. Scheduled autologous hematopoietic stem cell transplantation (auto-HSCT) after initial cytoreduction has resulted in a complete remission/near-complete remission (CR/nCR) rate of about 20% [
1], which translates into a benefit in overall survival (OS). Recently, the advent of targeted therapy such as bortezomib results in important advances in the treatment of MM. Bortezomib, a proteasome inhibitor that inhibits nuclear factor kappa B [
2], leads to a CR/nCR rate of 10% in heavily treated, refractory, and relapsing patients with MM [
3,
4]. Moreover, upfront use of bortezomib in combination with chemotherapy has resulted in a CR rate about of 20% (17–43%) even in the absence of auto-HSCT [
5,
6]. This is an important aspect in the management of MM as MM is a disease of the elderly, with the majority of the patients ineligible for auto-HSCT that leads to a high CR rate [
1]. Furthermore, bortezomib is non-myelotoxic and hence may be used in combination with conventional chemotherapy. Indeed, synergism of tumor cytotoxicity has been demonstrated when chemotherapy is combined with bortezomib, thus restoring chemosensitivity to previously chemoresistant tumor cells [
7,
8]. Based on these encouraging data, the upfront use of bortezomib in combination with conventional chemotherapy has been tested in younger patients before HSCT and in elderly patients who are not HSCT candidates. Expectedly, the upfront use of combined bortezomib and chemotherapy has resulted in a CR rate of about 20–30% in elderly patients [
9] and a more encouraging CR rate of about 50% in younger patients when followed by auto-HSCT [
10,
11]. The improved CR rates have translated into superior progression-free survival and OS [
12].
Both bortezomib and HSCT have emerged as important components in the management of MM, although their roles and timing relative to each other have not been determined. Bortezomib is an expensive medication with significant side effects. To optimally position bortezomib and HSCT, we reasoned that patients reaching a satisfactory response with conventional treatment might not need additional cytoreduction with bortezomib pre-HSCT. However, for patients with suboptimal response to conventional treatment, additional cytoreduction with bortezomib pre-HSCT might improve the outcome. Therefore, a staged approach was adopted in which newly diagnosed myeloma patients who achieved a ≥75% reduction in paraprotein level after standard vincristine, adriamycin, and dexamethasone (VAD) would proceed to auto-HSCT, whereas those with a <75% paraprotein reduction would receive bortezomib, thalidomide, and dexamethasone (VTD) for additional cytoreduction prior to auto-HSCT.
Discussion
In this study, the response to standard VAD was used to dichotomized patients to a chemosensitive group (≥75% paraprotein reduction after VAD) who proceeded directly to auto-HSCT and a relative chemoresistant group (<75% paraprotein reduction) who received additional cytoreduction with VTD before auto-HSCT. We surmised that this staged approach might maximize the reduction of neoplastic cells prior to HSC mobilization and restrict the use of the expensive bortezomib to chemoresistant patients.
There are several interesting observations. We achieved a cumulative CR rate of >50% after auto-HSCT. Recent studies showed that first-line use of bortezomib-based regimens gave CR rate of up to 30% even without HSCT [
9]. Furthermore, total therapy using bortezomib-containing regimens for initial cytoreduction prior to auto-HSCT resulted in a CR rate of about 50% (43% to 56%) [
10‐
12]. Therefore, the results in this study provide an alternative method of achieving an appreciable CR rate with a reduced use of bortezomib. In less affluent countries or health care systems, our approach offers a means of alleviating the financial burden of bortezomib without compromising the overall treatment results of patients with MM.
Despite the relatively high CR rate after auto-HSCT in our cohort, it is noteworthy that the CR rate only changed from 4% to 8% when VTD was used in patients not responding optimally to VAD. These results contrasted that of the regimen (PAD, bortezomib, doxorubicin, dexamethasone) in untreated MM patients where the CR rate was around 25% after PAD alone [
10,
11]. While these results could not be directly compared as different regimens were used on dissimilar patient populations, this disparity might be partially explained by the fact that only relatively chemoresistant patients received VTD in our study.
On the other hand, using VAD upfront resulted in very frequent (48%) sensory neuropathy prior to VTD. Moreover, eight had new onset or increased severity of neuropathy after VTD. Therefore, it would have been more preferable to use AD instead of VAD to avoid excessive neuropathy without compromising the chemotherapy response prior to VTD.
On follow-up, a significant number of patients developed a new paraprotein distinct from the one at diagnosis. Indeed, development of isotypic change and oligoclonal bands has been reported in about 10% of MM patients undergoing HSCT [
18]. The long-term outcome of these new clones remains to be determined. If these new clones represented expansion of minor subclones consequent to effective elimination of major clones, this phenomenon of oligoclonal reconstitution might become more common as more effective treatment becomes available. Alternatively, appearance of the new clone might represent clonal evolution from the original clone. Case 5 who developed two Gκ bands evolving from one Gκ at diagnosis might be explained by this mechanism. Whatever the pathogenesis, oligoclonal reconstitution affects the management of patients. Firstly, the diagnosis of CR may be difficult. In our case, we define CR as the absence of the original clone, and hence, the emergence of another clone does not alter the diagnosis of CR. Secondly, the long-term outcome of these new clones in our patients is yet to be defined, which might be transient [
18].
Two of our patients developed central nervous system (CNS) myeloma at progression in addition to cutaneous deposition and plasma cell leukemia. This is a rare complication [
19,
20], and the factors predisposing to CNS dissemination remain to be elucidated. However, it would have been ideal if clonal analysis of the CSF plasma cells had been performed.
Finally, deep vein thrombosis (DVT) did not occur in any of our patients despite the omission of prophylaxis. In Western patients, when thalidomide was combined with dexamethasone or chemotherapy, the risk of DVT might be increased to 10–27% [
21]. Our observation concurred with another study showing a low incidence of DVT in a cohort of 85 Chinese MM patients receiving thalidomide [
22]. Moreover, the incidence of DVT in Chinese has been shown to be much less frequent than Caucasian patients to the extent that prophylaxis is not a standard practice even in patients undergoing orthopedic surgery [
23,
24]. This disparity might at least be partially explained by the absence of factor V Leiden and prothrombin 20210 mutations, both hereditary thrombophilic tendencies prevalent in Caucasians, in the Chinese population [
25,
26]. Therefore, we believe that Chinese patients do not require prophylactic aspirin while receiving thalidomide.
In conclusion, our VAD-VTD/auto-HSCT algorithm resulted in a high response rate and promising survivals. This staged approach has significant financial implications in the treatment of MM.
Acknowledgement
We thank Drs Joyce Chan, Bonnie Khoo, Herman Liu, Thomas Lau from Pamela Youde Nethersole East Hospital; Drs Dominic Yeung, M.F. Law, Candia Chan and L.G. Wong from Tuen Mun Hospital; Drs K.K. Lee, Joycelyn Sim, Vivien Mak and Sandy Ho from Princess Margaret Hospital, for their patient referral and management. We also thank Mr Edwin Leong for funding support of bortezomib.