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Published on 23 March 2010

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Treatment of multiple myeloma

teaser

First line VMP for patients not eligible for high-dose therapy

Efstathios
Kastritis
MD
Meletios A
Dimopoulos
MD

Department of Clinical
Therapeutics
University of Athens
School of Medicine

Multiple myeloma (MM) is a disease of the elderly, although the improvement in outcome that has been documented over recent years was mainly found in younger patients. This is probably due to high-dose Melphalan (HDM) and autologous stem cell transplantation (ASCT), along with significant improvements in supportive care of MM patients. For patients not eligible for HDM with ASCT, the combination of oral Melphalan (MP) with steroids remained the standard of care because combinations of chemotherapeutic agents at standard doses showed no advantage over MP.[1] Thalidomide was introduced in the late 1990s for the treatment of patients
with relapsed/refractory disease[2] and subsequently
the combination of thalidomide with high-dose dexamethasone (with or without chemotherapy) as part of pre-transplant induction,[3,4] or in combination with the standard of care MP (MPT), was investigated.[5,7]

Five randomised clinical trials have been conducted, comparing different schedules and dosing of MPT to MP. MPT is associated with a significant improvement in response rates and progression-free survival in most trials; however, a survival advantage has been documented in two of these trials.[6,7] Bortezomib (BTZ) is the first in-class proteasome inhibitor that reversibly inhibits the chymotryptic-like activity of intracellular
proteasome. This agent proved to be active in relapsed MM patients and received an approval for the treatment of patients who have relapsed after at least one line of therapy.[8] BTZ has shown, in preclinical models, that it enhances synergistically the antimyeloma activity of chemotherapy and steroids.9 This was also confirmed in the clinical setting in randomised trials
in relapsed MM patients.[10] Thus, the combination of BTZ with MP was pursued as a treatment that could improve the outcome in MM patients who were not eligible for HDM with ASCT.

An initial phase I-II study of the combination in patients with newly diagnosed MM showed that the combination is feasible, with manageable toxicity, and that it induces high rates of complete responses, with a long progression-free survival.[11] As a result, a large phase III, multicentre, international trial was designed to assess and compare the efficacy of the VMP combination with that of the standard MP.[12]

In the VISTA (Velcade as Initial Standard Therapy in MM: Assessment with Melphalan and Prednisone) trial, myeloma patients of 65 years of age or older, were randomised to receive the combination of MP, with or without BTZ. This 1:1 randomisation was stratified according to the baseline levels of ß2-microglobulin, albumin and region (North America, Europe or other regions). The primary end point of this study was the
time to disease progression, while rates of complete response, the duration of response, the time to subsequent myeloma therapy and overall survival were pre-specified secondary end-points. Six hundred and eighty-two patients were randomised to receive nine 6-week cycles of VMP (N=344; BTZ 1.3mg/m2, d 1, 4, 8, 11, 22, 25, 29, 32, cycles 1-4; d 1, 8, 22, 29, cycles 5-9; melphalan 9mg/m2 d 1-4, prednisone 60mg/m2, d 1-4, all cycles) or MP (N=338) alone. Response was assessed using EBMT criteria with central laboratory M-protein analysis. After disease progression, patients were followed up for survival and subsequent therapy, including investigator-assessed best response to subsequent therapies.

Thirty per cent of patients were 75 years of age or older and 33% were ISS stage 3. The median time to progression, which was the primary end-point of the study, was 24 months in the VMP group and 16.6 months in the MP group (a reduction in the risk of progression by 52%;p<0.001). Importantly this improvement was independent of age, sex, race, baseline
ß2-microglobulin level, baseline albumin level, geographic
region, clinical stage (on the basis of the ISS) or creatinine clearance. The improvement in progression- free survival reflected the significant improvement in the response rates: 71% of patients in the VMP arm vs 35% in the MP arm achieved at least a partial response. Importantly, 35% of patients in the VMP arm achieved a complete response (vs 5% in the MP arm). These high rates of complete responses had never been achieved before in this population of transplant ineligible and elderly patients with any other frontline treatment. Furthermore, these responses were durable, being 19.9 months in the VMP arm vs 13.1 months in the MP arm (for all responders) and 24 months for those patients in the VMP arm who achieved a CR (vs 12.8 months in the MP arm). The
median time to the next antimyeloma treatment was longer in the VMP arm: 35% of patients treated with VMP required further antimyeloma treatment vs 57% in the MP arm in the following 2 years.

In the initial report of the study,[12] despite the short follow-up of 16.3 months, there was a significant improvement in the overall survival (p=0.008) although the median had not been reached for both arms. Furthermore, half (50%) of the patients who progressed after MP, received BTZ. In an updated analysis,[13] after a median follow-up of 36.7 months, there was a 35% reduction of the risk of death with VMP vs MP (p=0.0008) with a median overall survival in the VMP arm not yet reached (more than 50% were still alive) vs 43.1 months for patients who were initially treated with MP. Thus, the 3-year survival rates were 68.5% vs 54% for VMP and MP, respectively. This survival benefit was also found among elderly patients (aged>75 years, with 3-year survival rates of 74.1% vs 55.5% for MP). In this updated analysis, 52% of patients who
received VMP and 69% of patients who received MP, had received subsequent therapy. The median time to subsequent therapy was 28.1 months for VMP and 19.2 months for MP (HR 0.527, p<0.0001) for a median treatment-free interval of 17.6 vs 8.4 months for VMP and MP, respectively (HR 0.543, p<0.0001).

VMP treatment also significantly improved outcome for patients with high-risk features or in patients suffering myeloma complications, such as renal impairment. Renal impairment is a frequent presenting complication of MM affecting 20-40% at initial diagnosis. The management of these patients is challenging and restoration of adequate renal function is a key target for the improvement of their outcome and quality of life.
Previous studies have shown that BTZ is effective in patients with MM with various degrees of renal impairment, including dialysis dependence, and that its pharmacokinetics is not affected by renal impairment.[14-16]

However, MP is less effective in patients with renal impairment and is associated with more toxicity, so that MP dose reductions may be required for patients with renal impairment who receive MP. In the VISTA study, patients had serum creatinine ≤2mg/dL, according to the inclusion criteria of the study, however, approximately one- third of the patients on each arm presented with impaired renal function, defined as a creatinine clearance of 50ml/min or less. Most had moderate impairment, but 6% in the VMP arm and 4% in the MP arm had severe renal impairment (<30ml/min). Overall response rates, complete responses, time to next treatment and time to progression were significantly improved in the VMP-treated patients with renal impairment compared with MP-treated patients. The rates of renal function improvement was higher with VMP, with 44% of patients with baseline GFR lower than 50ml/min improving to higher than 60ml/min on treatment, compared with 34% of patients on the MP arm. Furthermore, time to renal impairment reversal was significantly shorter with VMP versus MP.[17]

Although the trial did not mandate cytogenetic studies and there was no centralisation of cytogenetics studies, 26 patients in the VMP group had high-risk cytogenetics, defined as the presence of a t(4;14),t(14;16) translocation or a 17p deletion, and 142 patients had standard cytogenetic profiles. The response rates, progression-free and overall survival were similar for standard vs high-risk patients.[12]

Most patients, who initially received VMP, subsequently were treated with thalidomide (46%) or lenalidomide (32%), however 24% were re-treated with BTZ-based therapy. The response rates to subsequent treatment were significant, being 41% for thalidomidebased, 59% for lenalidomide-based and 47% for BTZbased treatments. In the MP arm, 59% responded to subsequent BTZ-based treatment, 53% to thalidomidebased and 52% to lenalidomide-based treatment. Thus, upfront VMP does not induce more resistant relapses, and several patients can be re-treated with BTZ-based regimens with a high probability of response. Indeed, the survival from start of subsequent therapy following VMP was 30.2 months and for MP was 21.9 months.

These results show that the strategy of using VMP at the upfront setting is probably more beneficial, in terms of progression-free survival, treatment-free survival and overall survival, than saving BTZ- and other novel-agent-based treatment until relapse, as salvage options after conventional upfront treatment. Nevertheless, the optimal sequence of novel treatments has not been assessed in a randomised trial.

Since this study was conducted in elderly patients, ie, patients that may be also compromised because of comorbidities associated with their advanced age, the toxicity and tolerability of the treatment are important factors. However, the median number of treatment cycles administered was eight (46 weeks) in the VMP group and seven (39 weeks) in the MP group, reflecting both the tolerability and activity of VMP. Furthermore,
early death rates during treatment or treatment-related deaths were comparable (5% vs 4%, and 1% vs 2% for VMP and MP respectively). BTZ is not a significantly myelotoxic drug, and thus, haematologic toxicity was similar in the two groups. Gastrointestinal symptoms were more frequent in the BTZ group, as was herpes zoster (13% vs 4%). However, the incidence of herpes zoster was reduced to 3% in patients in the BTZ group who were receiving antiviral prophylaxis, indicating that acyclovir prophylaxis is effective and should be mandated for all elderly patients treated with BTZ.

BTZ is a neurotoxic agent and, as expected, peripheral sensory neuropathy was reported frequently in the VMP group: 44% of patients developed neuropathy, including 13% who developed grade 3 and one patient who developed grade 4 neuropathy. In most patients peripheral-neuropathy improves over time, even during treatment, after dose reduction and modification.

Nevertheless, in several patients neuropathy persisted or did not improve significantly, indicating that patients treated with BTZ should be frequently and thoroughly assessed for symptoms of peripheral neuropathy and immediate dose reductions and modifications should be employed. Forthcoming data 18-20 show that once-weekly BTZ or lower doses in elderly patients may significantly reduce the rates of peripheral neuropathy without compromising responses. It is also important to note that the safety profile of VMP appeared only somewhat affected by renal impairment, similar to the MP arm. This data suggests an effect independent of the addition of BTZ, possibly associated with the increase in haematologic toxicities with MP in patients with moderate-to-severe renal impairment.

Conclusion
In conclusion, the upfront combination of BTZ with MP induces unprecedented rates of complete haematologic responses and improves both progression-free and overall survival of patients who are not eligible for stem cell transplantation. The benefit of VMP is evident across all high-risk categories and the very elderly patients. The safety of BTZ in patients with renal impairment and the favourable effect on renal function suggest that BTZ should be the preferred upfront treatment for those who present with moderate-to-severe renal impairment. The upfront use of BTZ does not compromise salvage options, as patients who relapse after VMP can still achieve high response rates with other novel agents, such as IMiDs, but also can benefit from re-treatment with BTZ.

Forthcoming data from other studies show that a modified schedule of BTZ, given once-weekly, may significantly reduce toxicity, especially peripheral neuropathy, without compromising responses. This schedule should be considered for patients of more advanced age or those with pre-existing myeloma-related neuropathy.

References
1. Myeloma Trialists’ Collaborative Group. J Clin Oncol 1998;16:3832-42.
2. Singhal S et al. New Eng J Med 1999;341:1565-71.
3. Rajkumar SV et al. J Clin Oncol 2006;24:431-36.
4. Rajkumar SV et al. J Clin Oncol 2008;26:2171-77.
5. Palumbo A et al. Lancet 2006;367:825-31.
6. Facon T et al. Lancet 2007;370:1209-18.
7. Hulin C et al. J Clin Oncol 2009;27:3664-70.
8. Richardson PG et al. New Eng J Med 2005;352:2487-98.
9. Mitsiades N et al. Blood 2003;101:2377-80.
10. Orlowski RZ et al. J Clin Oncol 2007;25:389-901.
11. Mateos MV et al. Blood 2006;108:2165-72.
12. San Miguel JF et al. New Eng J Med 2008;359:906-17.
13. Mateos M-V et al. Poster presentation at 51st Annual Meeting and Exposition of the American Society of Hematology, December 5-8, 2009, New Orleans, Louisiana, USA.
14. Chanan-Khan AA et al. Blood 2007;109:2604-6.
15. Roussou M et al. Leuk Lymphoma 2008;49:890-95.
16. Dimopoulos MA et al. Clin Lymphoma Myeloma 2009;9:302-6.
17. Dimopoulos MA et al. J Clin Oncol 2009;36:6086-93.
18. Mateos M-V et al. Program and abstracts of the 51st
Annual Meeting and Exposition of the American Society
of Hematology, December 5-8, 2009, New Orleans, Louisiana, USA. (abstract 3)
19. Palumbo A et al. Blood (ASH Annual Meeting Abstracts) 2008;112:652.
20. Palumbo A, Bringhen S et al. Program and abstracts of the 51st ASH Annual Meeting and Exposition 2008:112 (abstract 652).



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