High-dose treatment and relevant prognostic factors

University of Arkansas experience with tandem transplants

Application of melphalan-based tandem autotransplants, with a curative intent, was first tested by the University of Arkansas group (Total Therapy 1 (TT1)) in 231 newly diagnosed or minimally pretreated patients; one and two courses of HDT were given to 84 and 71%, respectively.²¹ An increment in (stringently defined) CR rate, from 26% after one to 38% after two transplants on an intent-to-treat analysis, was seen (32 and 48% for patients who actually completed the intended treatment). The median EFS and OS were 30 and 68 months, respectively. Superior prognosis was seen in the absence of unfavorable karyotypes (chromosomes 13(13) and 11q abnormalities) and high -2 microglobulin (-2 m) levels. Time-dependent covariate analysis suggested that timely application of the second transplant (<6 months from the first one) did significantly extend both EFS and OS, independent of cytogenetics and -2 m levels.

Two additional cytogenetic parameters strongly associated with poor prognosis in MM are the presence of hypodiploidy and the so-called MM-MDS karyotype. It has recently been postulated that the poor prognosis of 13 is entirely due to its frequent association with hypodiploidy, which is the real poor prognostic factor.²² Analyzing our experience in 1475 MM patients intended to be treated with melphalan-based HDT and ASCT, we showed that both hypodiploidy and 13 (65% overlap rate with hypodiploidy) independently impart a poor prognosis in MM patients. The incorporation of pre-transplant--2 m >2.5 mg/l and albumin 35 g/l in the prognostic model did not appreciably alter the EFS and OS as predicted by the classification based only on cytogenetics.²³ The OS and EFS curves of the subgroup of 148 previously untreated TT1 patients based on the presence of 13 and/or hypodiploidy are depicted in Figure 1.

Figure 1.

OS (panel a) and EFS (panel b) of 148 previously untreated TT1 patients according to absence of cytogenetic abnormalities (no CA); abnormalities involving chromosome 13 deletion or hypodiploidy (CA 13, hypodiploidy); or other CA.

Full figure and legend (128K)

The presence of MDS-like cytogenetic abnormalities [del 5q, del 7q, add 8, del 20q, t (1;7)] in an otherwise typical for MM karyotype (MM-MDS) was recently found to impart a poor prognosis even after adjusting for any and all individual cytogenetic abnormalities.²⁴ Further investigation is needed in order to clarify the underlying biologic significance of this finding. The OS curve of over 2000 patients according to the detection of MM-MDS vs other karyotypes is depicted in Figure 2.

Figure 2.

MDS-like signature as part of MM karyotype abnormalities (MM-MDS) on survival among 2080 patients enrolled in melphalan-based tandem transplant trials.

Full figure and legend (89K)

The significance of elevated serum lactate dehydrogenase (LDH) levels in predicting poor prognosis has long been recognized in non-Hodgkin's lymphoma, but also in MM.²⁵ Elevated serum LDH at diagnosis has emerged as a significant prognostic factor in our analysis of 148 previously untreated TT1 patients who received at least one autotransplant. The combined use of 13-hypodiploidy/LDH levels identified subgroups with distinct prognosis. The median OS for patients with no 13-hypodiploidy/normal (<190 U/l) LDH was 8.2 years (vs 4.3 and 3.1 years for the groups with high LDH (irrespective of cytogenetic abnormalities) and with 13 and/or hypodiploidy/normal LDH, respectively) (Figure 3).

Figure 3.

OS (panel a) and EFS (panel b) based on CA13/hypodiploidy and serum LDH levels in 146 previously untreated TT1 patients.

Full figure and legend (153K)

With a median follow-up of 9 years, the prognostic implications of individual cytogenetic abnormalities in TT1 patients, were examined both at baseline and at follow-up bone marrow (BM) examination.²⁶ Superior prognosis was associated with the absence of any cytogenetic abnormalities at both diagnosis and relapse (10-year OS: 40%). On multivariate analysis, hypodiploidy/ 13 (present in 16% of patients at baseline) was the most important unfavorable cytogenetic parameter, independently associated with both short EFS and OS. Elevated LDH retained its independent unfavorable prognostic impact for OS.

Intensifying high-dose treatment-total therapy II

Intensification of TT1 is currently employed in total therapy II (TT2) trial (also randomizing patients to upfront thalidomide). Besides the addition of thalidomide, this protocol was designed to deliver more intensive treatment by intensifying remission induction treatment, adding consolidation chemotherapy during the first post-transplant year and providing pulse dexamethasone during the first year of interferon administration (second post-transplant year). Comparison of the outcome of the first 144 TT2 patients with at least 4 years of follow-up vs the 231 TT1 patients (median follow-up: 10 years) revealed significantly higher CR and near CR rates as well as superior EFS in the patients treated in the TT2 trial (Figure 4). The higher CR incidence was observed especially in the patients without baseline cytogenetic abnormalities. When patients achieving at least near CR were compared, 2-year estimates of near CR were superior in TT2 vs TT1 (true even for patients with hypodiploidy/13). CR duration (as surrogate marker for cure) was prolonged in TT2 vs TT1 and was adversely affected by the presence of cytogenetic abnormalities and elevated LDH levels (Figure 5). This evidence confirms that survival can be prolonged through treatment intensification and CR achievement. The relapse risk for TT1 and TT2 patients overall and according to cytogenetic abnormalities is depicted in Figure 6.

Figure 4.

Superior EFS (panel b) in 144 TT2 patients with at least 4-year follow-up vs 231 TT1 patients; no statistically significant difference is yet seen in OS (panel a0) (NR: not reached).

Full figure and legend (112K)

Figure 5.

Impact of cytogenetic abnormalities and serum LDH levels on CR duration on TT1 and TT2.

Full figure and legend (86K)

Figure 6.

Relapse risk for TT1 and TT2 patients overall (panel a) and based on the presence of cytogenetic abnormalities (panel b).

Full figure and legend (108K)

Tandem transplants-randomized trials

The concept of tandem transplants has been tested in a randomized fashion by several European groups. The IFM 94 trial tested one (melphalan/total body irradiation (TBI)) vs two (melphalan followed by melphalan/TBI) transplants; with a median follow-up of 6 years, the median EFS and OS were superior in the double vs the single transplant arm (30 and 58 months vs 25 and 48 months, respectively; P=0.03 and 0.01, respectively).¹⁹ The EFS and OS curves separated only after 3 years of follow-up. Younger age, low serum LDH and -2 m levels and tandem transplants were associated with longer OS on multivariable analysis. Patients who achieved less than near CR after the first transplant appeared to have the biggest benefit from two transplants. The importance of achieving post-transplant CR was also supported by a recent phase II trial conducted by the Spanish GELTAMO group.²⁷

The French study (MAG 95) tested one (melphalan/etoposide/cyclophosphamide/TBI) transplant vs two (melphalan followed by melphalan/etoposide/cyclophosphamide/TBI) transplants; with a median follow-up of 53 months, there was no difference in CR rate, EFS and OS.²⁸ The Italian study (BOLOGNA 96) tested one (melphalan) transplant vs two (melphalan followed by melphalan/busulfan) transplants; no difference in CR rates was seen.²⁹ A statistically significant superior EFS for the two transplants arm has already been detected. With a median follow-up of 38 months, no difference in OS was yet observed. The Dutch–Belgian HOVON study (fully reported) compared intermediate-dose melphalan (70 mg/m² 2) without stem-cell support with the same regimen followed by one transplant (TBI, cyclophosphamide); with a median follow-up of 33 months, higher CR rate and longer time to progression were detected in the transplant arm. However, OS was not different (50 vs 47 months) in the two arms.³⁰ All studies have a rather limited follow-up. It is worth remembering that in the IFM 94 trial the separation in the EFS and OS curves only occurred after 3 years of follow-up (with the interim analysis revealing no difference between the arms). Furthermore, it is now known that TBI-based regimens are inferior to melphalan alone.^31,32 Finally, salvage transplants offered at relapse may well obscure the OS benefit of tandem transplants. A summary of these trials comparing one vs two courses of high-dose chemotherapy with autologous stem cell support is shown in Table 1.

Table 1 - Summary of single vs tandem transplant trials in MM.

Full table

New agents

Thalidomide

The introduction of thalidomide in the clinical arena was prompted by the observation that increased neovascularization does occur in BM biopsies from myeloma patients and is prognostically relevant.³³ Thalidomide was, at the time (1998), the only drug available with major antiangiogenic activity. It is now known that thalidomide exerts a plethora of effects targeting the interaction between malignant plasma cells and BM microenvironment as well as various aspects of the immune system.³⁴ Despite lack of correlation between response rate and microvessel density in the BM biopsies, our landmark study reported an overall response rate (50% reduction in monoclonal component) of 32% – with a median time to response of 1 month – in a group of 84 relapsing patients following at least one course of HDT.⁸ The median response duration was approximately 15 months. In an update of 169 MM patients, absence of cytogenetic abnormalities, low -2 m levels and low plasma cell labeling index (PCLI) as well as higher cumulative thalidomide dose were associated with superior survival.³⁵ These results have been reproduced by several investigators. Advanced age, high LDH levels and impaired renal function predicted for poor EFS and OS in a phase II multicenter trial,³⁶ while higher cumulative thalidomide dose during the first 3 months of treatment was associated with improved survival.^37,38

Proteasome inhibitorsthalidomide

Proteasome inhibitors represent another novel approach of targeting MM cells and their microenvironment. In a phase II trial of 202 heavily pretreated (64% of them had failed HDT and 83% thalidomide) patients, bortezomib induced a response rate of 35% (including some CRs) with an acceptable toxicity profile.⁹ On multivariate analysis, response rates were lower in patients with abnormal BM cytogenetic analysis (but not deletion of chromosome 13) and 50% BM infiltration by plasma cells.³⁹ At our institution, the combination of bortezomib/thalidomidedexamethasone has yielded a response rate (>50% reduction in monoclonal component) of 57% when tried in 56 heavily pretreated patients.⁴⁰ No aggravation (although the follow-up is limited) of pre-existing thalidomide-induced neurotoxicity by bortezomib or any synergistic toxicity between the two agents were detected. EFS and OS were superior in patients presenting without cytogenetic abnormalities at relapse. The EFS and OS curves updated (by 02/04) for the first 70 patients in the study, according to the presence of cytogenetic abnormalities, are shown in Figure 7.

Figure 7.

OS (panel a) and EFS (panel b) of 70 patients treated with bortezomib+ thalidomide based on the presence of cytogenetic abnormalities.

Full figure and legend (108K)

Revimid

The drug, a small-molecule thalidomide derivative, lacks the sedative and neurotoxic side effects of the parent compound. Revimid was administered at escalating doses (5, 10, 25 and 50 mg/day) to 27 MM patients with refractory/relapsing disease, mostly after HDT and thalidomide. The maximum tolerated dose was considered to be 25 mg/day, with significant myelosuppression seen at the higher dose level of 50 mg/day. Seven (26%) patients had at least 50% reduction in monoclonal component.⁴¹ We confirmed these results in a group of 52 heavily pretreated patients by using the same cumulative dose of revimid administered in two different schedules (25 mg 20 doses and 50 mg 10 doses every 28 days).⁴² We observed higher response rates with the more prolonged 25 mg dose schedule (Figure 8). Greater than grade II, thrombocytopenia was linked to lower pretreatment platelet counts as a reflection of limited hematopoietic reserve.

Figure 8.

Revimid for advanced/refractory myeloma: response kinetics according to dosing schedule.

Full figure and legend (98K)

Low-risk patients

The mere prolongation of EFS and OS as an effect of a therapeutic modality (as has been convincingly shown in several trials of HDT and ASCT) is, by no means, equivalent to cure. Instead, a plateau has to be shown in the survival curves. In a recent update of the TT1 protocol, we focused on 146 (of 231 enrolled) patients who received tandem autotransplants 12 months apart (131 had their transplants <6 months apart) and survived 2 months after the second transplant.⁴³ With a median follow-up of 9.3 years after enrollment, 31 (21%) patients remain in either complete or stable partial remission, requiring no additional intervention than the maintenance treatment outlined in the protocol. A total of 31 additional patients are alive on different treatments for relapsing disease. In seven of these 31 patients, the interval between relapse and date of analysis is already longer than the interval between the first transplant and relapse. When prognostic factors were analyzed in the subgroup of relapsed patients, only the detection of cytogenetic abnormalities and -2 m> 4 mg/l (both at relapse) retained their significance for postrelapse survival. The EFS and OS curves of over 2000 patients, with prolonged follow-up, according to cytogenetic abnormalities are depicted in Figure 9; a plateau consistent with cure is apparent in patients without cytogenetic abnormalities.

Figure 9.

OS (panel a) and EFS (panel b) of 2080 patients based on the presence of baseline cytogenetic abnormalities; plateau in the survival curves is consistent with cure.

Full figure and legend (123K)

These data suggest that cure is possible in a subset of MM patients. These patients either have achieved (and maintain) CR or continue to have partial remission with small (stable) levels of monoclonal protein and minimal marrow plasmacytosis (likely regression to an MGUS phase). For all practical purposes, they can be compared to patients with good-risk diffuse large-cell lymphoma who are cured from their disease achieving either complete radiologic remission or remaining with stable, residual, non-viable lymphadenopathy (complete remission unconfirmed). Another subgroup of MM patients can enjoy long survival interrupted, however, by relapses. As long as there is no detection of cytogenetic abnormalities, application of various therapeutic modalities (thalidomide, further cytotoxic chemotherapy including HDT, bortezomib, etc) will very likely reinduce long-lasting remissions. These patients can be compared to patients with follicular lymphoma, the prototypic hematologic malignancy characterized by remissions and relapses, in which recently introduced treatments (radioconjugated monoclonal antibodies)⁴⁴ may change the natural history of the disease by inducing longer remissions than the ones achieved with previous lines of treatment. Unfortunately, as in follicular lymphoma, patients with this form of 'chronic remitting and relapsing myeloma' are obviously at risk for 'transformation'; the acquisition of new cytogenetic abnormalities will lead to the development of genetic resistance (which, in contrast to epigenetic resistance cannot be overcome by HDT) by the malignant clone, which will now be characterized by complete independence of the bone marrow stroma, higher proliferative potential and frequent extramedullary manifestations. This is exactly the group of patients in whom, at least on theoretical grounds, a survival benefit may be anticipated through achieving higher CR rate (incorporation of thalidomide as in TT2 trial or other agents) and decreasing the chances of 'transformation' to a more biologically aggressive disease variant.

High-risk patients

For high-risk patients (comprising approximately 30% of the total), that is, patients with any chromosome 13 abnormalities, hypodiploidy (overlapping with chromosome 13 abnormalities in 65% of patients) and the so-called MM-MDS karyotype, and/or elevated baseline LDH levels, even the timely application of tandem transplants is not a curative approach. They can be compared to poor-risk diffuse large-cell lymphoma patients. The less pronounced benefit in such patients may be due to the malignant clone's inherent genetic resistance with resultant less cytoreduction beyond the clinical CR detection threshold. Sensitive methods to monitor minimal residual disease levels will clarify this issue. Faster regrowth kinetics between the chemotherapy courses may also contribute to the poor prognosis in this patient group; the observed pattern of early relapse even during the remission induction treatment phase supports this notion. Alternatively, epigenetic factors derived from an activated BM microenvironment may feed the growth of myeloma cells and induce drug resistance. Our ongoing research focuses on addressing these issues both at laboratory and clinical levels. Currently allogeneic transplant is a potentially curative approach in this high-risk group.

Allogeneic transplant

Allogeneic transplantation with its well-established immunologically mediated graft-versus-myeloma⁴⁵ effect is an attractive option in, otherwise suitable for the procedure, high-risk patients. The conventional, fully myeloablative, allotransplant is applicable in a small minority of affected patients and has been associated with considerable (30–50%) TRM and other toxicities.^46,47 The recent advent of the so-called 'mini-transplants' (nonmyeloablative transplants) with their decreased immediate post-transplant toxicity has allowed the more 'liberal' use of the procedure by expanding the pool of the potential recipients.

The Seattle group, in an effort to decrease TRM, separated the immunotherapeutic effect of the allogeneic transplant from the toxicity of the HDT; the cytoreduction induced by autotransplant (with low TRM) was combined with the curative potential of a subsequent 'mini-transplant'.⁴⁸ A total of 54 previously treated MM patients (median age: 52 years, 52% refractory/relapsed disease) received melphalan 200 mg/m² and ASCT followed (in 52 patients) 40–229 days later (median: 62), by TBI (200 cGy), immune suppression with mycophenolate mofetil (for 1 month) and cyclosporine (for at least 2 months) and unmanipulated peripheral blood stem cells from HLA-matched siblings. All (52) engrafted post-allotransplant; the 100-day TRM was 0%. With a median follow-up of about 18 months after the allograft, the OS is 78%. In total, 12 patients have died (11 after allograft, mainly due to progressive disease and GvHD-related complications). Acute graft-versus-host disease (GvHD) developed in 38% of the patients (mostly grade II), while 46% required treatment for chronic GvHD. The overall response rate was 83% (CR of 57%). Longer follow-up will be needed before the curative potential of this promising approach can be fully appreciated.

Recently, others have reported similar results with the application of dose-reduced conditioning regimen (melphalan, fludarabine, antithymocyte globulin) and allogeneic transplant from either a related or unrelated donor following an autologous transplant (Mel 200 mg/m²).⁴⁹ The median interval between the two transplants was 4 months. Strictly defined CR rate was 73% after allografting. Of 17 patients with advanced myeloma, 13 are alive (12 progression-free) with a median follow-up of 13 months after the allogeneic transplant. A summary of these trials consisting of autologous followed by 'by design' allogeneic transplant is shown in Table 2.

Table 2 - Autologous followed by allogeneic transplant trials in MM.

Full table

The preliminary results of two IFM protocols (IFM9903 and IFM 9904) have been recently presented in an abstract form.⁵⁰ Patients with high-risk features (serum -2 m >3 mg/l and chromosome 13 deletion by FISH) received a brief remission induction treatment (VADX4) followed either by two courses of ASCT (Mel 200 mg/m², Mel 220 mg/m²anti-IL6 monoclonal antibody) (IFM 9904) or one course of ASCT (Mel 200 mg/m²) followed by 'mini-transplant' (fludarabine, antithymocyte globulin and low-dose busulfan) from an available HLA-matched sibling (IFM 9903). 'Mini-transplant' was actually given to 29/45 (64%) and two courses of ASCT were actually given to 73/105 (69%) of the patients enrolled. With a limited follow-up, the median EFS is 21 months in the 9903 and 25 months in the 9904 trial (P=0.08); the 3-year survival from diagnosis is 52% and 54% respectively (P=0.37).

In a similar fashion, we performed allogeneic 'mini-transplants', from HLA-matched siblings (mainly) or unrelated donors, in 31 high-risk patients (median age: 56 years) using melphalan 100 mg/m² and cyclosporine for GvHD prophylaxis.⁵¹ We reported superior outcome when the 'mini-transplant' was performed at chemosensitive relapse and after 1 vs >1 prior ASCT. Indeed, chemosensitive disease and adequate performance status were the only significant factors for EFS and OS in our recent analysis of 45 such patients.⁵² We currently recommend (nonmyeloablative) allotransplant (preferably from HLA-matched sibling) after one ASCT, only in high-risk patients based on baseline cytogenetic evaluation and elevated LDH levels.

Based on the encouraging preliminary data reported by the Seattle group, a trial launched by Bone Marrow Transplant-Clinical Trials Network (BMT-CTN) will compare tandem autotransplants (with or without post-transplant maintenance) vs one autologous followed by allogeneic, nonmyeloablative transplant in patients with an available HLA-matched sibling. Although the trial will likely provide information regarding the benefit of post-transplant maintenance, no consideration has been given to the disease risk stratification. The TRM of 'mini-transplants' performed in a multicenter setting is not expected to be <20% and there is considerable morbidity due to GvHD; although the risk may be well justified in patients with high-risk cytogenetic abnormalities, such a risk is unacceptable in low-risk patients.

Conclusions – future directions

We propose that application of a comprehensive treatment approach, based on tandem autotransplants, in newly diagnosed myeloma patients will cure a substantial minority (approximately 10–15%) of them. This subgroup, characterized by low -2 m and LDH levels and the absence of adverse cytogenetic abnormalities, comprises patients with true CR and patients with persistently detectable, stable monoclonal protein. An additional 20–25% of patients (with the same favorable baseline features) will enjoy a long survival, interrupted, however, by responsive relapses. These patients remain at risk for 'transformation' to aggressive myeloma. Our early experience with the intensified chemotherapy, as delivered in TT2 trial, at least suggests that true, stringently defined, CR is critical in increasing the cure rate in this patient subgroup. The benefit of any post-transplant manipulations, although widely used in our institution, remains to be proven for these groups of patients.

The remaining patients, characterized by adverse cytogenetic abnormalities and high LDH levels, will derive a less meaningful survival benefit from HDT and ASCT as currently employed. Upfront use of novel agents (bortezomib, revimid) targeting not only the malignant cells but the stromal elements (which by paracrine action 'feed' the growth and survival of tumor) as well, in combination with intensive HDT may increase the proportion of patients achieving cure or long-term disease control in this high-risk group. Currently, allogeneic transplant appears to be a potentially curative approach for these patients; further understanding of the GvHD and the graft-versus-myeloma effect mechanisms will likely render the procedure more effective.

The optimal integration of new drugs in clinical practice will be achieved at a much faster pace (and definitely in a more rational way) by using the gene expression profiling (GEP) technology.⁵³ This approach is expected to allow in the near future more 'clever' selection of novel agents in treating individual patients, better understanding of a specific drugs' mechanism of action and development of agents specific for (so far) unrecognized targets. Responding to these challenges should be viewed as an exciting opportunity (by clinicians and basic researchers alike) towards increasing the proportion of patients being cured from a disease for which palliation was considered a reasonable achievement even up to 10 years ago.

References

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Acknowledgements

This work was supported in part by CA55819 from the National Cancer Institute, Bethesda, MD, USA.